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  • 99mTC-Sestamibi Breast Imaging: Current Status, New ideas and Future Perspectives
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-23
    Nicoletta Urbano; Manuel Scimeca; Virginia Tancredi; Elena Bonanno; Orazio Schillaci

    Here we proposed the most recent innovations in the use of Breast Specific Gamma Imaging with 99mTc-sestamibi for the management of breast cancer patients. To this end, we reported the recent discoveries concerning: a) the implementation of both instrumental devices and software, b) the biological mechanisms involved in the 99mTc-sestamibi uptake in breast cancer cells, c) the evaluation of Breast Specific Gamma Imaging with 99mTc-sestamibi as predictive markers of metastatic diseases. In this last case, we also reported preliminary data about the capability of Breast Specific Gamma Imaging with 99mTc-sestamibi to identify breast cancer lesions with high propensity to form bone metastatic lesions due to the presence of Breast Osteoblast-Like Cells.

    更新日期:2020-01-23
  • Tumor hypermetabolism confers resistance to immunotherapy
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-23
    Arthur Liu; Michael A. Curran

    Advances in our understanding of tumor immune biology and development of cancer immunotherapies have led to improved outcomes for patients that suffer from aggressive cancers such as metastatic melanoma. Despite these advances, a significant proportion of patients still fail to benefit, and as a result, attention has shifted to understanding how cancer cells escape immune destruction. Of particular interest is the metabolic landscape of the tumor microenvironment, as recent studies have demonstrated how both competition for essential nutrients and depletion of specific amino acids can promote T cell dysfunction. Here, we will discuss the major energetic pathways engaged by both T cells and cancer cells, metabolic substrates present in the tumor microenvironment, and emerging therapeutic strategies that seek to improve T cell metabolic fitness and bolster the antitumor immune response.

    更新日期:2020-01-23
  • Emergence in protein derived nanomedicine as anticancer therapeutics: More than a tour de force
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-18
    Zhenchang Wang; Kangkang Zhi; Zhongyang Ding; Yi Sun; Shuang Li; Manyuan Li; Kefeng Pu; Jun Zou

    Cancer has thwarted as a major health problem affecting the global population. With an alarming increase in the patient population suffering from diverse varieties of cancers, the global demographic data predicts sharp escalation in the number of cancer patients. This can be expected to reach 420 million cases by 2025. Among the diverse types of cancers, the most frequently diagnosed cancers are the breast, colorectal, prostate and lung cancer. From years, conventional treatment approaches like surgery, chemotherapy and radiation therapy have been practiced. In the past few years, increasing research on molecular level diagnosis and treatment of cancers have significantly changed the realm of cancer treatment. Lately, uses of advanced chemotherapy and immunotherapy like treatments have gained significant progress in the cancer therapy, but these approaches have several limitations on their safety and toxicity. This has generated lot of momentum for the evolution of new drug delivery approaches for the effective delivery of anticancer therapeutics, which may improve the pharmacokinetic and pharmacodynamic effect of the drugs along with significant reduction in the side effects. In this regard, the protein-based nano-medicines have gained wider attention in the management of cancer. Proteins are organic macromolecules essential, for life and have quite well explored in developing the nano-carriers. Furthermore, it provides passive or active tumour cell targeted delivery, by using protein based nanovesicles or virus like structures, antibody drug conjugates, viral particles, etc. Moreover, by utilizing various formulation strategies, both the animal and plant derived proteins can be converted to produce self-assembled virus like nano-metric structures with high efficiency in targeting the metastatic cancer cells. Therefore, the present review extensively discusses the applications of protein-based nano-medicine with special emphasis on intracellular delivery/drug targeting ability for anticancer drugs.

    更新日期:2020-01-21
  • Nanoparticles guided drug delivery and imaging in gastric cancer
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-16
    Ganji Purnachandra Nagaraju; Gowru Srivani; Begum Dariya; Gayathri Chalikonda; Batoul Farran; Santosh Kumar Behera; Afroz Alam; Mohammad Amjad Kamal

    Gastric cancer represents a deadly malignancy worldwide, yet current therapeutic regimens remain ineffective. Nanoparticle (NP) -based solutions could allow the design of novel therapeutic methods to eliminate this fatal disease. NPs typically carry out a significant role in multifunctional, multimodal imaging, and drug delivery carriers. In the recent decade, they have emerged as candidate approaches for the design of novel treatment strategies. Tumor nanotherapeutics characteristically possess various distinct advantages compared to conventional anti-cancer medications, which suffer from nonspecific bio-distribution, low solubility, and poor bioavailability. In this review, we will discuss the application of NPs in diagnosis and controlled drug delivery in gastric cancer (GC). We will focus on various NPs-based strategies employed against GC.

    更新日期:2020-01-17
  • Overcoming immunotherapeutic resistance by targeting the cancer inflammation cycle
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-15
    Max M. Wattenberg; Gregory L. Beatty

    Inflammation is a hallmark of cancer and supports tumor growth, proliferation, and metastasis, but also inhibits T cell immunosurveillance and the efficacy of immunotherapy. The biology of cancer inflammation is defined by a cycle of distinct immunological steps that begins during disease conception with the release of inflammatory soluble factors. These factors communicate with host organs to trigger bone marrow mobilization of myeloid cells, trafficking of myeloid cells to the tumor, and differentiation of myeloid cells within the tumor bed. Tumor-infiltrating myeloid cells then orchestrate an immunosuppressive microenvironment and assist in sustaining a vicious cycle of inflammation that co-evolves with tumor cells. This Cancer-Inflammation Cycle acts as a rheostat or “inflammostat” that impinges upon T cell immunosurveillance and prevents the development of productive anti-tumor immunity. Here, we define the major nodes of the Cancer-Inflammation Cycle and describe their impact on T cell immunosurveillance in cancer. Additionally, we discuss emerging pre-clinical and clinical data suggesting that intervening upon the Cancer-Inflammation Cycle will be a necessary step for broadening the potential of immunotherapy in cancer.

    更新日期:2020-01-15
  • SR-BI as a target of natural products and its significance in cancer
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-11
    Dongdong Wang; Jiansheng Huang; Ting Gui; Yaxin Yang; Tingting Feng; Nikolay T. Tzvetkov; Tao Xu; Zhibo Gai; Ying Zhou; Jingjie Zhang; Atanas G. Atanasov

    Scavenger receptor class B type I (SR-BI) protein is an integral membrane glycoprotein. SR-BI is emerging as a multifunctional protein, which regulates autophagy, efferocytosis, cell survival and inflammation. It is well known that SR-BI plays a critical role in lipoprotein metabolism by mediating cholesteryl esters selective uptake and the bi-directional flux of free cholesterol. Recently, SR-BI has also been identified as a potential marker for cancer diagnosis, prognosis, or even a treatment target. Natural products are a promising source for the discovery of new drug leads. Multiple natural products were identified to regulate SR-BI protein expression. There are still a number of challenges in modulating SR-BI expression in cancer and in using natural products for modulation of such protein expression. In this review, our purpose is to discuss the relationship between SR-BI protein and cancer, and the molecular mechanisms regulating SR-BI expression, as well as to provide an overview of natural products that regulate SR-BI expression.

    更新日期:2020-01-13
  • Integrating tumor hypoxic stress in novel and more adaptable strategies for cancer immunotherapy
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-09
    Raefa Abou Khouzam; Hassan Venkatesh Goutham; Rania Faouzi Zaarour; Ali N Chamseddine; Amirtharaj Francis; Stéphanie Buart; Stéphane Terry; Salem Chouaib

    Immunotherapy is poised to become an increasingly utilized therapy in the treatment of cancer. However, several abnormalities in the tumor microenvironment (TME) that can thwart the efficacy of immunotherapies have been established. Microenvironmental hypoxia is a determining factor in shaping aggressiveness, metastatic potential and treatment resistance of solid tumors. The characterization of this phenomenon could prove beneficial for determining a patient’s treatment path and for the introduction of novel targetable factors that can enhance therapeutic outcome. Indeed, the ablation of hypoxia has the potential to sensitize tumors to immunotherapy by metabolically remodeling their microenvironment. In this review, we discuss the intrinsic contributions of hypoxia to cellular plasticity, heterogeneity, stemness and genetic instability in the context of immune escape. In addition, we will shed light on how managing hypoxia can ameliorate response to immunotherapy and how integrating hypoxia gene signatures could play a role in this pursuit.

    更新日期:2020-01-09
  • Translational Genomics of Malignant Rhabdoid Tumours: Current Impact and Future Possibilities
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-07
    Martina A Finetti; Yura Grabovska; Simon Bailey; Daniel Williamson

    Malignant Rhabdoid Tumours (MRT) are the quintessential example of an epigenetic cancer. Mutation of a single gene, SMARCB1 or more rarely SMARCA4, is capable of causing one of the most aggressive and lethal cancers of early childhood and infancy. SMARCB1 encodes a core subunit of the SWI/SNF complex and its mutation evokes genome-wide downstream effects which may be counteracted therapeutically. Here we review and discuss the use of translational genomics in the study of MRT biology and the ways in which this has impacted clinical practice or may do so in the future. First, the diagnosis and definition of MRT and the transition from a histopathological to a molecular definition. Second, epigenetic and transcriptomic subgroups within MRT, their defining features and potential prognostic or therapeutic significance. Third, functional genomic studies of MRT by mouse modelling and forced re-expression of SMARCB1 in MRT cells. Fourth, studies of underlying epigenetic mechanisms (e.g. EZH2, HDACs) or deregulated kinases (e.g. PDGFR, FGFR1) and the potential therapeutic opportunities these provide. Finally, we discuss likely future directions and proffer opinion on how future translational genomics should be integrated into future biological/clinical studies to select and evaluate the best anti-MRT therapeutic agents.

    更新日期:2020-01-07
  • Machine and Deep Learning Approaches for Cancer Drug Repurposing
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-03
    Naiem T. Issa; Vasileios Stathias; Stephan Schürer; Sivanesan Dakshanamurthy

    Knowledge of the underpinnings of cancer initiation, progression and metastasis has increased exponentially in recent years. Advanced “omics” coupled with machine learning and artificial intelligence (deep learning) methods have helped elucidate targets and pathways critical to those processes that may be amenable to pharmacologic modulation. However, the current anti-cancer therapeutic armamentarium continues to lag behind. As the cost of developing a new drug remains prohibitively expensive, repurposing of existing approved and investigational drugs is sought after given known safety profiles and reduction in the cost barrier. Notably, successes in oncologic drug repurposing have been infrequent. Computational in-silico strategies have been developed to aid in modeling biological processes to find new disease-relevant targets and discovering novel drug-target and drug-phenotype associations. Machine and deep learning methods have especially enabled leaps in those successes. This review will discuss these methods as they pertain to cancer biology as well as immunomodulation for drug repurposing opportunities in oncologic diseases.

    更新日期:2020-01-04
  • Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-03
    Kelly Olino; Tristen Park; Ntia Ahuja

    Advances in immunotherapy, most notably antibodies targeting the inhibitory immune receptors cytotoxic T-lymphocyte associated protein 4 (CTLA-4/CD152), programmed death protein 1 (PD-1/CD279) and programmed death-ligand 1 (PD-L1/B7H1/CD274) have become effective standard therapies in advanced malignancies including melanoma,1–4 merkel cell carcinoma5, urological cancers6–8, non-small cell lung cancer9–11, mis-match repair (MMR) deficient tumors12, and Hodgkin lymphoma with response rates ranging from 25-60% in the first and second line settings13,14. FDA approval has also been given for treatment for hepatocellular carcinoma, gastric cancer, triple negative breast cancer, cervical and head and neck cancers with response rates closer to 15%15. Additionally, some clinical efficacy has been observed in ovarian cancer, mesothelioma, prostate cancer, diffuse large B cell lymphoma, follicular lymphoma, and both cutaneous and peripheral T-cell lymphoma. However, despite these successes, most patients will initially fail to respond to treatment and almost half of initial responders will develop secondary resistance to immunotherapy and progress. Moreover, many prevalent solid organ tumors remain resistant to immunotherapy including colorectal, pancreatic and hepatobiliary cancers. Therefore, new therapies are needed to increase both initial and durable response rates and to develop new mechanistic insights into pathways of immune resistance so that immunotherapy may become more widely available as a therapeutic option in common malignancies.

    更新日期:2020-01-04
  • Roles of microbiota in response to cancer immunotherapy
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-03
    Kentaro Inamura

    Immunotherapy, which shows great promise for treating patients with metastatic malignancies, has dramatically changed the therapeutic landscape of cancer, particularly subsequent to the discovery of immune checkpoint inhibitors. However, the responses to immunotherapy are heterogeneous and often transient. More problematic is that a high proportion of patients with cancer are resistant to such therapy. Much effort has been expended to identify reliable biomarkers that accurately predict clinical responses to immunotherapy. Unfortunately, such tools are lacking, and our knowledge of the mechanisms underlying its efficacy and safety is insufficient. The microbiota is increasingly recognized for its influence on human health and disease. Microbes create a pro- or an anti-inflammatory environment through complex interactions with host cells and cytokines. Emerging evidence indicates that microbes alter the efficacy and toxicity of immunotherapy by modulating the host’s local and systemic immune responses. It is therefore critically important to exploit the microbiota to develop biomarkers as well as to identify therapeutic targets that can be applied to cancer immunotherapy. This review provides insights into the challenges that must be addressed to achieve these goals.

    更新日期:2020-01-04
  • The functions and regulations of Smurfs in cancers
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-30
    Lin Fu; Chun-Ping Cui; Xueli Zhang; Lingqiang Zhang

    Smad ubiquitination regulatory factor 1 (Smurf1) and Smurf2 are HECT-type E3 ubiquitin ligases, and both Smurfs were initially identified to regulate Smad protein stability in the TGF-β/BMP signaling pathway. In recent years, Smurfs have exhibited E3 ligase-dependent and -independent activities in various kinds of cells. Smurfs act as either potent tumor promoters or tumor suppressors in different tumors by regulating biological processes, including metastasis, apoptosis, cell cycle, senescence and genomic stability. The regulation of Smurfs activity and expression has therefore emerged as a hot spot in tumor biology research. Further, the Smurf1- or Smurf2-deficient mice provide more in vivo clues for the functional study of Smurfs in tumorigenesis and development. In this review, we summarize these milestone findings and, in turn, reveal new avenues for the prevention and treatment of cancer by regulating Smurfs.

    更新日期:2019-12-30
  • Antibody–drug conjugates for lung cancer in the era of personalized oncology
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-30
    Biagio Ricciuti; Giuseppe Lamberti; Elisa Andrini; Carlo Genova; Andrea De Giglio; Vanessa Bianconi; Amirhossein Sahebkar; Rita Chiari; Matteo Pirro

    With 9.6 million deaths in 2018, cancer represents one of the most common causes of death, both in men and women. Despite recent advances in the understanding of molecular mechanisms involved in cancer development and progression, treatment options are still limited. Limitations of traditional chemotherapy include the lack of selectivity and the unfavorable safety profile. The efficacy of targeted therapies (e.g., tyrosine kinase inhibitors) is also limited by their cytostatic action, which inhibits tumor cell proliferation without inducing tumor cell death, and by the risk of acquired resistance. Antibody-drug conjugates (ADCs), a newly developed class of engineered anticancer drugs, consist of recombinant monoclonal antibodies against tumor-specific antigens that are covalently bound to cytotoxic agents. They have been designed to overcome the limitations of traditional chemotherapy and targeted therapies by combining the target selectivity of monoclonal antibodies with the high potency of cytotoxic drugs. Currently, ADCs that have received regulatory approval include brentuximab vedotin for CD30-positive Hodgkin lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2-positive breast cancer. However, over 80 novel ADCs are actively being investigated in preclinical studies and early-phase clinical trials. In this review, we will provide a comprehensive overview of the biological rational, efficacy and safety of ADCs as therapeutic agents against non-small cell lung cancer and small cell lung cancer.

    更新日期:2019-12-30
  • Somatic copy number aberrations in metastatic patients: The promise of liquid biopsies
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-28
    Shawn Baldacchino; Godfrey Grech

    Cancer metastasis is the leading cause of cancer-related mortality. The metastatic process involves measurable cellular changes that confer migratory potential, proliferative advantage and the ability to colonise a distinct microenvironment. Accumulation of aberrations and clonal evolution add complexity to patient management and the assessment of the therapeutic sensitivity profile of malignancies. Liquid biopsy presents a repeatable and minimally invasive assessment tool to detect early metastasis, characterise tumour phenotype and detect minimal residual disease. The promise of liquid biopsies is to inform patient management and therapeutic decisions in a timely manner. Clinical translation requires robust methodologies with high sensitivity and tumour specificity. This can be achieved through technological advances but also through novel biologically informed approaches that harness existing knowledge on tumorigenesis. Here we present a review of copy number variations as potential biomarkers for early detection of metastatic potential and outline a biomarker validation process in the context of liquid biopsies.

    更新日期:2019-12-29
  • Nanotechnology, in silico and endocrine-based strategy for delivering paclitaxel and miRNA: Prospects for the therapeutic management of breast cancer
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-28
    Mohammad Azam Ansari; Muthu Thiruvengadam; Zeba Farooqui; Govindaswamy Rajakumar; Qazi Mohammad Sajid Jamal; Mohammad A. Alzohairy; Ahmad Almatroudi; Mohammad N. Alomary; Ill-Min Chung; Ebtesam Abdullah Al-Suhaimi
    更新日期:2019-12-29
  • The tumor organismal environment: role in tumor development and cancer immunotherapy
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-28
    Lothar C. Dieterich; Andreas Bikfalvi

    Tumor immunotherapy has resulted in dramatic effects in some cancer types, including curing of previously untreatable patients. However, the response rates are typically very heterogenous, with some patients showing dramatic responses whereas others do not or only barely respond. Consequently, there has been an ever-increasing research effort to better understand the factors that govern immunotherapy responsiveness and efficiency in order to identify predictive biomarkers and novel therapeutic targets. Clearly, traits of the tumor cells as well as aspects of the tumor microenvironment (TME) play an important role in this regard. However, a growing tumor not only interacts with cells in its immediate vicinity, but also reciprocally communicates with the entire host organism (and its microbiota). Thus, systemic influences on tumor growth and progression are likely to be similarly important as the microenvironment. In this review, we focus on various aspects of the “tumor organismal environment” (TOE), namely the lymphatic, the hematopoietic, the microbial, the neurogenic and the metabolic environment, and discuss their impact on tumor growth and immunotherapy.

    更新日期:2019-12-29
  • Roles of autophagy in breast cancer treatment: target, bystander or benefactor
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-27
    Liliya Tyutyunyk-Massey; David A. Gewirtz

    Despite the availability of largely effective treatments for breast cancer, such as the combination of aromatase inhibitors or anti-estrogens with cdk4/6 inhibitors for estrogen receptor positive/Her 2 negative breast cancer, breast cancer remains a significant cause of morbidity and mortality. This is due, in large part, to a very limited understanding of the mechanisms underlying the failure of conventional therapies and disease recurrence after tumor dormancy. One cellular process that is activated in response to the majority of breast cancer treatments is autophagy. Proven to be an indispensable cellular function, autophagy is largely accepted as a pro-survival mechanism in tumor cells and has consequently generated significant interest in cancer research and treatment strategies. Autophagy plays multiple and often disparate roles during different stages of tumorigenesis and in response to anti-tumor treatments; in fact, autophagy is induced by almost all conventional treatments of breast cancer and is considered a target for pharmacologic blockade in the clinic. Consequently, it is important to further our understanding of this process and its role in breast cancer.

    更新日期:2019-12-27
  • Tumor intrinsic and extrinsic immune functions of CD155
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-26
    Jake. S. O’Donnell; Jason Madore; Xian-Yang Li; Mark J. Smyth

    CD155 (PVR/necl5/Tage4), a member of the nectin-like family of adhesion molecules, is highly upregulated on tumor cells across multiple cancer types and has been associated with worse patient outcomes. In addition to well described cell-intrinsic roles promoting tumor progression and metastasis, CD155 has now been implicated in immune regulation. The role of CD155 as a potent immune ligand with diverse cell-extrinsic functions is now being defined. CD155 signaling to immune cells is mediated through interactions with the co-stimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96, which are differentially regulated at the cell surface on T cells and NK cells. The integration of signals from CD155 cognate receptors modifies the activity of tumor-infiltrating lymphocytes in a context-dependent manner, making CD155 an attractive target for immune-oncology. Preclinical studies suggest that targeting this axis can improve immune-mediated tumor control, particularly when combined with existing anti-PD-1 checkpoint therapies. In this review, we discuss the roles of CD155 on host and tumor cells in controlling tumor progression and discuss the possibility of targeting CD155 for cancer therapy.

    更新日期:2019-12-27
  • Repurposing old drugs as new inhibitors of the ubiquitin-proteasome pathway for cancer treatment
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-26
    Huanjie Yang; Xin Chen; Kai Li; Hassan Cheaito; Qianqian Yang; Guojun Wu; Jinbao Liu; Q. Ping Dou

    The ubiquitin-proteasome system (UPS) plays a central role in the degradation of cellular proteins. Targeting protein degradation has been validated as an effective strategy for cancer therapy since 2003. Several components of the UPS have been validated as potential anticancer targets, including 20S proteasomes, 19S proteasome-associated deubiquitinases (DUBs) and ubiquitin ligases (E3s). 20S proteasome inhibitors (such as bortezomib/BTZ and carfilzomib/CFZ) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM) and some other liquid tumors. Although survival of MM patients has been improved by the introduction of BTZ-based therapies, these clinical 20S proteasome inhibitors have several limitations, including emergence of resistance in MM patients, neuro-toxicities, and little efficacy in solid tumors. One of strategies to improve the current status of cancer treatment is to repurpose old drugs with UPS-inhibitory properties as new anticancer agents. Old drug reposition represents an attractive drug discovery approach compared to the traditional de novo drug discovery process which is time-consuming and costly. In this review, we summarize status of repurposed inhibitors of various UPS components, including 20S proteasomes, 19S-associated DUBs, and ubiquitin ligase E3s. The original and new mechanisms of action, molecular targets, and potential anticancer activities of these repurposed UPS inhibitors are reviewed, and their new uses including combinational therapies for cancer treatment are discussed.

    更新日期:2019-12-27
  • Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-26
    Thomas Efferth; Franz Oesch

    Drug repurposing (or repositioning) is an emerging concept to use old drugs for new treatment indications. Phytochemicals isolated from medicinal plants have been largely neglected in this context, although their pharmacological activities have been well investigated in the past, and they may have considerable potentials for repositioning. A grand number of plant alkaloids inhibit syngeneic or xenograft tumor growth in vivo. Molecular modes of action in cancer cells include induction of cell cycle arrest, intrinsic and extrinsic apoptosis, autophagy, inhibition of angiogenesis and glycolysis, stress and anti-inflammatory responses, regulation of immune functions, cellular differentiation, and inhibition of invasion and metastasis. Numerous underlying signaling processes are affected by plant alkaloids. Furthermore, plant alkaloids suppress carcinogenesis, indicating chemopreventive properties. Some plant alkaloids reveal toxicities such as hepato-, nephro- or genotoxicity, which disqualifies them for repositioning purposes. Others even protect from hepatotoxicity or cardiotoxicity of xenobiotics and established anticancer drugs. The present survey of the published literature clearly demonstrates that plant alkaloids have the potential for repositioning in cancer therapy. Exploitation of the chemical diversity of natural alkaloids may enrich the candidate pool of compounds for cancer chemotherapy and –prevention. Their further preclinical and clinical development should follow the same stringent rules as for any other synthetic drug as well. Prospective randomized, placebo-controlled clinical phase I and II trials should be initiated to unravel the full potential of plant alkaloids for drug repositioning.

    更新日期:2019-12-27
  • PD-L1 status in breast cancer: Current view and perspectives
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-26
    Semir Vranic; Farhan S. Cyprian; Zoran Gatalica; Juan Palazzo

    Breast cancer was traditionally not considered a particularly immunogenic tumor. However, recent developments have shown that some aggressive triple-negative breast cancers are immunogenic, exhibit a resistance to chemotherapy and have a poor prognosis. These cancers have been shown to express molecules identified as targets for immunotherapy. Despite the advances, the challenges are many, and include identifying the patients that may benefit from immunotherapy. The best methods to analyze these samples and to evaluate immunogenicity are also major challenges. Therefore, the most accurate and reliable assessment of immune cells as potential targets is one of the most important aims in the current research in breast immunotherapy. In the present review, we briefly discuss the mechanisms of the regulation of checkpoint inhibitors (PD-1/PD-L1) in breast cancer and explore the predictive aspects in the PD-L1 testing.

    更新日期:2019-12-27
  • Phyotochemical candidates repurposing for cancer therapy and their molecular mechanisms
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-26
    Ji Hoon Jung; Jisung Hwang; Ju-Ha Kim; Deok Yong Shim; Eunji Im; Ji Eon Park; Woon Yi Park; Bum-Sang Shim; Bonglee Kim; Sung-Hoon Kim

    Though limited success through chemotherapy, radiotherapy and surgery has been obtained for efficient cancer therapy for modern decades, cancers are still considered high burden to human health worldwide to date. Recently repurposing drugs are attractive with lower cost and shorter time compared to classical drug discovery, just as Metformin from Galega officinalis, originally approved for treating Type 2 diabetes by FDA, is globally valued at millions of US dollars for cancer therapy. As most previous reviews focused on FDA approved drugs and synthetic agents, current review discussed the anticancer potential of phytochemicals originally approved for treatment of cardiovascular diseases, diabetes, infectious diarrhea, depression and malaria with their molecular mechanisms and efficacies and suggested future research perspectives.

    更新日期:2019-12-27
  • Nano-immunotherapy: Overcoming tumour immune evasion
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-25
    Maria L Guevara; Francesca Persano; Stefano Persano

    Immunotherapy is emerging as a groundbreaking cancer treatment, offering the unprecedented opportunity to effectively treat and in several cases, even cure previously untreatable malignancies. Anti-tumour immunotherapies designed to amplify T cell responses against defined tumour antigens have long been considered effective approaches for cancer treatment. Despite a clear rationale behind such immunotherapies, extensive past efforts were unsuccessful in mediating clinically relevant anti-tumour activity in humans. This is mainly because tumours adopt specific mechanisms to circumvent the host´s immunity. Emerging data suggest that the full potential of cancer immunotherapy will be only achieved by combining immunotherapies designed to generate or amplify anti-tumour T cell responses with strategies able to impair key tumour immune-evasion mechanisms. However, many approaches aimed to re-shape the tumour immune microenvironment (TIME) are commonly associated with severe systemic toxicity, require frequent administration, and only show modest efficacy in clinical settings. The use of nanodelivery systems is revealing as a valid means to overcome these limitations by improving the targeting efficiency, minimising systemic exposure of immunomodulatory agents, and enabling the development of novel combinatorial immunotherapies. In this review, we examine the emerging field of therapeutic modulation of TIME by the use of nanoparticle-based immunomodulators and potential future directions for TIME-targeting nanotherapies.

    更新日期:2019-12-26
  • Understanding genetic determinants of resistance to immune checkpoint blockers
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-24
    Sandrine Aspeslagh; Roman M. Chabanon; Stéphane Champiat; Sophie Postel-Vinay

    The advent of immune checkpoint blockers (ICB) has revolutionized patient outcome in many tumor types. However, only a minority of patients truly benefits from these therapies and displays a durable and robust anti-tumor response that translates into improved outcome. Thorough mechanistic preclinical studies and comprehensive investigations performed in tumor biopsies of patients treated with ICB have unveiled multiple resistance mechanisms involving both tumor-intrinsic and tumor-extrinsic characteristics. Here, we comprehensively review all known tumor-intrinsic genetic and epigenetic resistance mechanisms to ICB, provide an evaluation of their current level of evidence and propose rationale therapeutic strategies to circumvent them.

    更新日期:2019-12-25
  • The balance between breast cancer and the immune system: challenges for prognosis and clinical benefit from immunotherapies
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-24
    Constantin N. Baxevanis; Sotirios P. Fortis; Sonia A. Perez

    Cancer evolution is a complex process influenced by genetic factors and extracellular stimuli that trigger signaling pathways to coordinate the continuous and dynamic interaction between tumor cells and the elements of the immune system. For over 20 years now, the immune mechanisms controlling cancer progression have been the focus of intensive research. It is well established that the immune system conveys protective antitumor immunity by destroying immunogenic tumor variants, but also facilitates tumor progression by shaping tumor immunogenicity in a process called “immunoediting”. It is also clear that immune-guided tumor editing is associated with tumor evasion from immune surveillance and therefore reinforcing the endogenous antitumor immunity is a desired goal in the context of cancer therapies. The tumor microenvironment (TME) is a complex network which consists of various cell types and factors having important roles regarding tumor development and progression. Tumor infiltrating lymphocytes (TILs) and other tumor infiltrating immune cells (TIICs) are key to our understanding of tumor immune surveillance based on tumor immunogenicity, whereby the densities and location of TILs and TIICs in the tumor regions, as well as their functional programs (comprising the “immunoscore”) have a prominent role for prognosis and prediction for several cancers. The presence of tertiary lymphoid structures (TLS) in the TME or in peritumoral areas has an influence on the locally produced antitumor immune response, and therefore also has a significant prognostic impact. The cross-talk between elements of the immune system with tumor cells in the TME is greatly influenced by hypoxia, the gut and/or the local microbiota, and several metabolic elements, which, in a dynamic interplay, have a crucial role for tumor cell heterogeneity and reprogramming of immune cells along their activation and differentiation pathways. Taking into consideration the recent clinical success with the application immunotherapies for the treatment of several cancer types, increasing endeavors have been made to gain better insights into the mechanisms underlying phenotypic and metabolic profiles in the context of tumor progression and immunotherapy. In this review we will address (i) the role of TILs, TIICs and TLS in breast cancer (BCa); (ii) the different metabolic-based pathways used by immune and breast cancer cells; and (iii) implications for immunotherapy-based strategies in BCa.

    更新日期:2019-12-25
  • Oncogenic signaling pathways associated with immune evasion and the resistance to immune checkpoint inhibitors in cancer
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-23
    Yoshie Kobayashi; Seung-Oe Lim; Hirohito Yamaguchi

    Immune checkpoint inhibitors (ICIs) are novel class of anti-cancer drugs that exhibit significant therapeutic effects even in patients with advanced stage cancer. However, the efficacy of ICIs is limited due to resistance. Therefore, appropriate biomarkers to select patients who are likely to respond to these drugs as well as combination therapy to overcome the resistance are urgently necessary. Cancer is caused by various genetic alterations that lead to abnormalities in oncogenic signaling pathways. The aberrant oncogenic signaling pathways serve as not only prognostic and predictive biomarkers, but also targets for molecularly targeted therapy. Growing evidence shows that the aberrant oncogenic signaling pathways in cancer cells facilitate the resistance to ICIs by modulating the regulation of immune checkpoint and cancer immune surveillance. Indeed, it has been demonstrated that some molecular targeted therapies significantly improve the efficacy of ICIs in preclinical and clinical studies. In this review, we highlighted several oncogenic signaling pathways including receptor tyrosine kinases (RTKs), RAS-RAF-MAPK, PI3K-AKT-mTOR, JAK-STAT, Hippo, and Wnt pathways, and summarized the recent findings of the mechanisms underlying the regulation of cancer immunity and the ICI resistance induced by these aberrant oncogenic signaling pathways in cancer cells. Moreover, we discussed potential combination therapies with ICIs and molecularly targeted drugs to overcome the resistance and increase the efficacy of ICIs.

    更新日期:2019-12-23
  • Combining epigenetic and immune therapy to overcome cancer resistance
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-23
    Stephanie Gomez; Tomasz Tabernacki; Julie Kobyra; Paige Roberts; Katherine B. Chiappinelli

    Cancer undergoes “immune editing” to evade destruction by cells of the host immune system including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Current adoptive cellular immune therapies include CAR T cells and dendritic cell vaccines, strategies that have yet to show success for a wide range of tumors. Cancer resistance to immune therapy is driven by extrinsic factors and tumor cell intrinsic factors that contribute to immune evasion. These extrinsic factors include immunosuppressive cell populations such as regulatory T cells (Tregs), tumor-associated macrophages (TAMS), and myeloid-derived suppressor cells (MDSCs). These cells produce and secrete immunosuppressive factors and express inhibitory ligands that interact with receptors on T cells including PD-1 and CTLA-4. Immune checkpoint blockade (ICB) therapies such as anti-PD-1 and anti-CTLA-4 have shown success by increasing immune activation to eradicate cancer, though both primary and acquired resistance remain a problem. Tumor cell intrinsic factors driving primary and acquired resistance to these immune therapies include genetic and epigenetic mechanisms. Epigenetic therapies for cancer including DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), and histone methyltransferase inhibitors (HMTi) can stimulate anti-tumor immunity in both tumor cells and host immune cells. Here we discuss in detail tumor mechanisms of immune evasion and how common epigenetic therapies for cancer may be used to reverse immune evasion. Lastly, we summarize current clinical trials combining epigenetic therapies with immune therapies to reverse cancer immune resistance mechanisms.

    更新日期:2019-12-23
  • The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-23
    Sara K. Daniel; Y. Dave Seo; Venu G. Pillarisetty

    Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13 K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.

    更新日期:2019-12-23
  • Drug Repurposing for Cancer Therapy, Easier Said Than Done
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-23
    Aurora Gonzalez-Fierro; Alfonso Dueñas-González

    Drug repurposing for cancer therapy is currently a hot topic of research. Theoretically, in contrast to the known hurdles of developing new molecular entities, the approach of repurposing has several advantages. Mostly, it is said that it is faster, safer, easier, and cheaper. In the real world, however, there are only three repurposed drugs so far, that are listed in widely recognized cancer guidelines, but a large number of them are being studied. Among the many barriers to repurposing cancer drugs, economical-driven are the most important that difficult the clinical development of them. In this review, we provide an overview of the current status of drug repurposing for cancer therapy and the barriers that need to be overcome to realize the benefit of this approach. It means to have repositioned drugs for cancer therapy accepted as standard therapy for cancer indications at low cost.

    更新日期:2019-12-23
  • Repurposing amino-bisphosphonates by liposome formulation for a new role in cancer treatment
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-23
    Ninh M. La-Beck; Xinli Liu; Hilary Shmeeda; Claire Shudde; Alberto A. Gabizon

    Amino-bisphosphonates (N-BPs) have been commercially available for over four decades and are used for the treatment of osteoporosis, Paget’s disease, hypercalcemia of malignancy, and bone metastases derived from various cancer types. Zoledronate and alendronate, two of the most potent N-BPs, have demonstrated direct tumoricidal activity on tumor cells and immune modulatory effects on myeloid cells and T cells in vitro and in animal models of cancer. However, the rapid renal clearance and sequestration in mineral bone of these drugs in free form severely limit their systemic exposure and applications in cancer patients. Reformulation of N-BPs by encapsulation in liposomal nanoparticles addresses these pharmacokinetic barriers, and liposomal zoledronate and alendronate formulations have been found to increase the anticancer efficacy of cytotoxic chemotherapies and adoptive T cell immunotherapies in murine cancer models. Herein, we review the differences in pharmacology between N-BPs versus non-N-BPs (e.g., clodronate), free versus liposomal N-BP formulations, and targeted versus non-targeted liposomal N-BPs, and the clinical and preclinical evidence supporting a role for liposomal N-BPs in the treatment cancer. We propose that pegylated liposomal alendronate (PLA) has the most potential for clinical translation based on favorable therapeutic index, ability to passively target and accumulate in tumors, proven biocompatibility of the liposome carrier, and preclinical anticancer efficacy.

    更新日期:2019-12-23
  • Glyco-Nanoparticles: New drug delivery systems in cancer therapy
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-20
    Haroon Khan; Hamid Reza Mirzaei; Atefeh Amiri; Esra Kupeli Akkol; Syed Muhammad Ashhad Haleemi; Hamed Mirzaei

    Cancer is known as one of the most common diseases that are associated with high mobility and mortality in the world. Despite several efforts, current cancer treatment modalities often are highly toxic and lack efficacy and specificity. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems which are highly selective for tumors and allow a slow release of active anticancer agents. Different Nanoparticles (NPs) such as the silicon-based nano-materials, polymers, liposomes and metal NPs have been designed to deliver anti-cancer drugs to tumor sites. Among different drug delivery systems, carbohydrate-functionalized nanomaterials, specially based on their multi-valent binding capacities and desirable bio-compatibility, have attracted considerable attention as an excellent candidate for controlled release of therapeutic agents. In addition, these carbohydrate functionalized nano-carriers are more compatible with construction of the intracellular delivery platforms like the carbohydrate-modified metal NPs, quantum dots, and magnetic nano-materials. In this review, we discuss recent research in the field of multifunctional glycol-nanoparticles (GNPs) intended for cancer drug delivery applications.

    更新日期:2019-12-20
  • NANOMEDICINE IN TREATMENT OF BREAST CANCER – A CHALLENGE TO CONVENTIONAL THERAPY
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-20
    Muhammad Afzal; Ameed uzzafar; Khalid Saad Alharbi; Nabil K Alruwaili; Fahad A. Al-Abassi; Abdulrahman Al Labeed Al-Malki; Imran Kazmi; Vikas Kumar; Mohammad Amjad Kamal; Muhammad Shahid Nadeem; Muhammad Aslam; Firoz Anwar

    Amongst the various types of cancer, breast cancer is a highly heterogeneous disease and known as the leading cause of death among women globally. The extensive interdisciplinary investigation in nanotechnology and cancer biomedical research has been evolved over the years for its effective treatment. However, the advent of chemotherapeutic resistance in breast cancer is one of the major confront researchers are facing in achieving successful chemotherapy. Research in the area of cancer nanotechnology over the years have now been revolutionized through the development of smart polymers, lipids, inorganic materials and eventually their surface-engineering with targeting ligands. Moreover, nanotechnology further extended and brings in the notice the new theranostic approach which combining the therapy and imaging simultaneously. Currently, research is being envisaged in the area of novel nano-pharmaceutical design viz. liposome, nanotubes, polymer lipid hybrid system, which focuses to make the chemotherapy curative and long-lasting. In this review, we aimed to discuss the recent advancement of different surface-engineered/targeted nanomedicines that improved the drug efficacy in breast cancer.

    更新日期:2019-12-20
  • Overcoming Malignant Cell-Based Mechanisms of Resistance to Immune Checkpoint Blockade Antibodies
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-19
    Reham Ajina; David J. Zahavi; Yong-Wei Zhang; Louis M. Weiner

    Traditional cancer treatment approaches have focused on surgery, radiation therapy, and cytotoxic chemotherapy. However, with rare exceptions, metastatic cancers were considered to be incurable by traditional therapy. Over the past 20 years a fourth modality – immunotherapy – has emerged as a potentially curative approach for patients with advanced metastatic cancer. However, in many patients cancer “finds a way” to evade the anti-tumor effects of immunotherapy. Immunotherapy resistance mechanisms can be employed by both cancer cells and the non-cancer elements of tumor microenvironment. This review focuses on the resistance mechanisms that are specifically mediated by cancer cells. In order to extend the impact of immunotherapy to more patients and across all cancer types, and to inhibit the development of acquired resistance, the underlying biology driving immune escape needs to be better understood. Elucidating mechanisms of immune escape may shed light on new therapeutic targets, and lead to successful combination therapeutic strategies.

    更新日期:2019-12-19
  • Calcium transport and signalling in breast cancer: functional and prognostic significance
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-19
    Shane O’Grady; Maria P. Morgan

    Comprised of a complex network of numerous intertwining pathways, the Ca2+ signalling nexus is an essential mediator of many normal cellular activities. Like many other such functions, the normal physiological activity of Ca2+ signalling is frequently co-opted and reshaped in cases of breast cancer, creating a potent oncogenic drive within the affected cell population. Such modifications can occur within pathways mediating either Ca2+ import (e.g. TRP channels, ORAI-STIM1) or Ca2+ export (e.g. PMCA), indicating that both increases and decreases within cellular Ca2+ levels have the potential to increase the malignant potential of a cell. Increased understanding of these pathways may offer clinical benefit in terms of both prognosis and treatment; patient survival has been linked to expression levels of certain Ca2+ transport proteins, whilst selective targeting of these factors with novel anti-cancer agents has demonstrated a variety of anti-tumour effects in in vitro studies. In addition, the activity of several Ca2+ signalling pathways has been shown to influence chemotherapy response, suggesting that a synergistic approach coupling traditional chemotherapy with Ca2+ targeting agents may also improve patient outcome. As such, targeted modulation of these pathways represents a novel approach in precision medicine and breast cancer therapy.

    更新日期:2019-12-19
  • Prospective of Nanoscale Metal Organic Frameworks [NMOFs] For Cancer Therapy
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-19
    Mohammed Razeeth Shait Mohammed; Varish Ahmad; Abrar Ahmad; Shams Tabrez; Hani Choudhry; Mazin A. Zamzami; Muhammed A. Bakhrebah; Aftab Ahmad; Samina Wasi; Hasan Mukhtar; Mohammad Imran Khan

    Nano metal organic frameworks (NMOFs) belong to the group of nanoporous materials. Over the decades, the conducted researches explored the area for the potential applications of NMOFs in areas like biomedical, chemical engineering and materials science. Recently, NMOFs have been explored for their potential use in cancer diagnosis and therapeutics. The excellent physico-chemical features of NMOFs also make them a potential candiadate to facilitate drug design, delivery and storage against cancer cells. In this review, we have explored the characterstic features, synthesis methods, NMOFs based drug delivery, diagnosis and imaging in various cancer types. In addition to this, we have also pondered on the stability and toxicological concerns of NMOFs. Despite, a significant research has been done for the potential use of NMOFs in cancer diagonostic and therapeutics, more information regarding the stability, in-vivo clearance, toxicology, and pharmacokinetics is still needed to ehnace the use of NMOFs in cancer diagonostic and therapeutics.

    更新日期:2019-12-19
  • Mechanisms of resistance to CAR T cell therapies
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-19
    Nathan Singh; Elena Orlando; Jun Xu; Jie Xu; Zev Binder; McKensie A. Collins; Donald M. O’Rourke; J. Joseph Melenhorst

    Chimeric antigen receptor (CAR)-engineered T cells have demonstrated remarkable success in the treatment of B cell malignancies. FDA approval of these therapies represents a watershed moment in the development of therapies for cancer. Despite the successes of the last decade, many patients will unfortunately not experience durable responses to CAR therapy. Emerging research has shed light on the biology responsible for these failures, and further highlighted the hurdles to broader success. Here, we review the recent research identifying how interactions between cancer cells and engineered immune cells result in resistance to CAR therapies.

    更新日期:2019-12-19
  • Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: A novel therapeutic strategy
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-19
    Devesh Tewari; Pooja Patni; Anusha Bishayee; Archana N. Sah; Anupam Bishayee

    The phosphatidylinositol 3-kinase (PI3K)-Akt and the mammalian target of rapamycin (mTOR) represent two vital intracellular signaling pathways, which are associated with various aspects of cellular functions. These functions play vital roles in quiescence, survival, and growth in normal physiological circumstances as well as in various pathological disorders, including cancer. These two pathways are so intimately connected to each other that in some instances these are considered as one unique pathway crucial for cell cycle regulation. The purpose of this review is to emphasize the role of PI3K-Akt-mTOR signaling pathway in different cancer conditions and the importance of natural products targeting the PI3K-Akt-mTOR signaling pathway. This review also aims to draw the attention of scientists and researchers to the assorted beneficial effects of the numerous classes of natural products for the development of new and safe drugs for possible cancer therapy. We also summarize and critically analyze various preclinical and clinical studies on bioactive compounds and constituents, which are derived from natural products, to target the PI3K-Akt-mTOR signaling pathway for cancer prevention and intervention.

    更新日期:2019-12-19
  • The genomics of undifferentiated sarcoma of soft tissue: progress, challenges and opportunities
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-19
    Christopher D. Steele; Nischalan Pillay

    Undifferentiated sarcoma of soft tissue (USTS) are aggressive sarcomas that remain a diagnosis of exclusion and show extreme genomic complexity. Many advances in diagnostic criteria have resulted in several revisions in the definition of this rare cancer type. Recent sequencing efforts have illuminated the nature of the genome complexity and have revealed extensive copy number heterogeneity and multiple evolutionary patterns of development. This review places these recent advances into their historical and translational context and covers the changes in nomenclature, molecular classification, and the promise of personalised medicine.

    更新日期:2019-12-19
  • Regulation of autophagy by canonical and non-canonical ER stress responses
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-12-12
    Monika Bhardwaj; Nektaria Maria Leli; Constantinos Koumenis; Ravi K. Amaravadi

    Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic reticulum (ER) stress, which can be counterbalanced by triggering the unfolded protein response (UPR) which is considered the canonical ER stress response. The UPR is characterized by three major proteins that lead to specific changes in transcriptional and translational programs in stressed cells. Activation of the UPR can induce apoptosis, but also can induce cytoprotective programs such as autophagy. There is increasing appreciation for the role that UPR-induced autophagy plays in supporting tumorigenesis and cancer therapy resistance. More recently several new pathways that connect cell stresses, components of the UPR and autophagy have been reported, which together can be viewed as non-canonical ER stress responses. Here we review recent findings on the molecular mechanisms by which canonical and non-canonical ER stress responses can activate cytoprotective autophagy and contribute to tumor growth and therapy resistance. Autophagy has been identified as a druggable pathway, however the components of autophagy (ATG genes) have proven difficult to drug. It may be the case that targeting the UPR or non-canonical ER stress programs can more effectively block cytoprotective autophagy to enhance cancer therapy. A deeper understanding of these pathways could provide new therapeutic targets in cancer.

    更新日期:2019-12-13
  • Receptor tyrosine kinases in PI3K signaling: The therapeutic targets in cancer
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-03-31
    Wei Jiang, Meiju Ji

    The phosphoinositide 3-kinase (PI3K) pathway, one of the most commonly activated signaling pathways in human cancers, plays a crucial role in the regulation of cell proliferation, differentiation, and survival. This pathway is usually activated by receptor tyrosine kinases (RTKs), whose constitutive and aberrant activation is via gain-of-function mutations, chromosomal rearrangement, gene amplification and autocrine. Blockage of PI3K pathway by targeted therapy on RTKs with tyrosine kinases inhibitors (TKIs) and monoclonal antibodies (mAbs) has achieved great progress in past decades; however, there still remain big challenges during their clinical application. In this review, we provide an overview about the most frequently encountered alterations in RTKs and focus on current therapeutic agents developed to counteract their aberrant functions, accompanied with discussions of two major challenges to the RTKs-targeted therapy in cancer – resistance and toxicity.

    更新日期:2019-12-05
  • RAS mutations in human cancers: Roles in precision medicine
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-06-27
    Avaniyapuram Kannan Murugan, Michele Grieco, Nobuo Tsuchida

    Ras proteins play a crucial role as a central component of the cellular networks controlling a variety of signaling pathways that regulate growth, proliferation, survival, differentiation, adhesion, cytoskeletal rearrangements and motility of a cell. Almost, 4 decades passed since Ras research was started and ras genes were originally discovered as retroviral oncogenes. Later on, mutations of the human RAS genes were linked to tumorigenesis. Genetic analyses found that RAS is one of the most deregulated oncogenes in human cancers. In this review, we summarize the pioneering works which allowed the discovery of RAS oncogenes, the finding of frequent mutations of RAS in various human cancers, the role of these mutations in tumorigenesis and mutation-activated signaling networks. We further describe the importance of RAS mutations in personalized or precision medicine particularly in molecular targeted therapy, as well as their use as diagnostic and prognostic markers as therapeutic determinants in human cancers.

    更新日期:2019-12-05
  • PIK3CA in cancer: The past 30 years
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-02-10
    Rand Arafeh, Yardena Samuels

    Almost thirty years ago, PI3K was discovered as a lipid kinase associated with certain oncoproteins. The first decade of research on PI3K saw the identification, purification and cloning of PI3Kα. The second decade of research was noted for the identification of some of PI3K’s activators and effectors. This was accompanied by the discovery that PI3K acts as a retroviral oncogene. The third decade was known for the establishment of the direct involvement of PI3K in cancer, demonstrated by the identification of cancer-specific mutations. Efforts to target PI3K were on the rise from that moment on, accompanied by the first clinical trials for PI3K inhibitor therapies. In the fourth decade of research, PI3K-based cancer drugs will continue to emerge, as will new knowledge regarding other uncovered functions of this protein and pathway.

    更新日期:2019-12-05
  • Phosphoinositide phosphatases in cancer cell dynamics—Beyond PI3K and PTEN
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-03-25
    Takeshi Ijuin

    Phosphoinositides are a group of lipids that regulate intracellular signaling and subcellular biological events. The signaling by phosphatidylinositol-3,4,5-trisphosphate and Akt mediates the action of growth factors that are essential for cell proliferation, gene transcription, cell migration, and polarity. The hyperactivation of this signaling has been identified in different cancer cells; and, it has been implicated in oncogenic transformation and cancer cell malignancy. Recent studies have argued the role of phosphoinositides in cancer cell dynamics, including actin cytoskeletal rearrangement at the plasma membrane and the organization of intracellular compartments. The focus of this review is to summarize the impact of the activities of phosphoinositide phosphatases on intracellular signaling related to cancer cell dynamics and to discuss how the abnormalities in the activities of the enzymes alter the levels of phosphoinositides in cancer cells.

    更新日期:2019-12-05
  • Mechanisms of PTEN loss in cancer: It’s all about diversity
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-02-07
    Virginia Álvarez-Garcia, Yasmine Tawil, Helen M. Wise, Nicholas R. Leslie

    PTEN is a phosphatase which metabolises PIP3, the lipid product of PI 3-Kinase, directly opposing the activation of the oncogenic PI3K/AKT/mTOR signalling network. Accordingly, loss of function of the PTEN tumour suppressor is one of the most common events observed in many types of cancer. Although the mechanisms by which PTEN function is disrupted are diverse, the most frequently observed events are deletion of a single gene copy of PTEN and gene silencing, usually observed in tumours with little or no PTEN protein detectable by immunohistochemistry. Accordingly, with the exceptions of glioblastoma and endometrial cancer, mutations of the PTEN coding sequence are uncommon (<10%) in most types of cancer. Here we review the data relating to PTEN loss in seven common tumour types and discuss mechanisms of PTEN regulation, some of which appear to contribute to reduced PTEN protein levels in cancers.

    更新日期:2019-12-05
  • Akt in cancer: Mediator and more
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-06-04
    Sundaramoorthy Revathidevi, Arasambattu Kannan Munirajan

    Akt is a serine/threonine kinase and it participates in the key role of the PI3K signaling pathway. The Akt can be activated by a wide range of growth signals and the biochemical mechanisms leading to Akt activation are well defined. Once activated, Akt modulates the function of many downstream proteins involved in cellular survival, proliferation, migration, metabolism, and angiogenesis. The Akt is a central node of many signaling pathways and it is frequently deregulated in many types of human cancers. In this review, we provide an overview of Akt function and its role in the hallmarks of human cancer. We also discussed various mechanisms of Akt dysregulation in cancers, including epigenetic modifications like methylation, post-transcriptional non-coding RNAs-mediated regulation, and the overexpression and mutation.

    更新日期:2019-12-05
  • Emerging role of PI3K/AKT in tumor-related epigenetic regulation
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-04-02
    Qi Yang, Wei Jiang, Peng Hou

    Epigenetic alterations, along with genetic alterations, have long been regarded as the most important mechanism participating in carcinogenesis. DNA methylation, histone modifications, and RNA-mediated regulation are involved in many cellular processes that are essential to cancer initiation and progression. A plethora of chromatin-associated proteins and modifying proteins take control of these processes and they are under the modulation of signaling pathways. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway (PI3K/AKT) is in manage of multiple biological processes and is frequently aberrantly activated in human cancers. Increasing evidence has demonstrated that critical epigenetic modifiers are directly or indirectly modulated by PI3K/AKT signaling, and participate in oncogenicity of PI3K cascade in cancers. In this review, we revisit the mechanism of the PI3K/AKT signaling pathway modulating epigenetic reprogramming in cancer and attempt to establish the connection between PI3K/AKT cascade and the epigenome.

    更新日期:2019-12-05
  • PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-07-16
    Ali S. Alzahrani

    Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is one of the major cellular signaling pathways that plays an important role in basic intracellular functions. The PI3K/Akt/mTOR pathway regulates cell proliferation, growth, cell size, metabolism, and motility. Component genes of this pathway have been extensively studied and found to be commonly activated in human cancer. Inhibition of this pathway has been shown to lead to regression of human tumors and has been studied in preclinical setup and evaluated in many clinical trials at various levels. Some inhibitors of this pathway are approved by the Food and Drug Administration after their potency and safety have been shown in clinical trials. This review discusses the recent trends in exploiting the PI3K/Akt/mTOR pathway towards the molecular targeted therapy using small molecule inhibitors in human cancer.

    更新日期:2019-12-05
  • Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-05-22
    Meran Keshawa Ediriweera, Kamani Hemamala Tennekoon, Sameera Ranganath Samarakoon

    Ovarian cancer (OC) is a lethal gynecological cancer. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the regulation of cell survival, growth, and proliferation. Irregularities in the major components of the PI3K/AKT/mTOR signaling pathway are common in human cancers. Despite the availability of strong pre-clinical and clinical data of PI3K/AKT/mTOR pathway inhibitors in OC, there is no FDA approved inhibitor available for the treatment of OC. Here, we outline the importance of PI3K/AKT/mTOR signaling pathway in OC tumorigenesis, proliferation and progression, and pre-clinical and clinical experience with several PI3K/AKT/mTOR pathway inhibitors in OC.

    更新日期:2019-12-05
  • The “-OMICS” facet of melanoma: Heterogeneity of genomic, proteomic and metabolomic biomarkers
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-07-08
    Douglas Donnelly, Phyu P. Aung, George Jour

    In the recent decade, cutting edge molecular and proteomic analysis platforms revolutionized biomarkers discovery in cancers. Melanoma is the prototype with over 51,100 biomarkers discovered and investigated thus far. These biomarkers include tissue based tumor cell and tumor microenvironment biomarkers and circulating biomarkers including tumor DNA (cf-DNA), mir-RNA, proteins and metabolites. These biomarkers provide invaluable information for diagnosis, prognosis and play an important role in prediction of treatment response. In this review, we summarize the most recent discoveries in each of these biomarker categories. We will discuss the challenges in their implementation and standardization and conclude with some perspectives in melanoma biomarker research.

    更新日期:2019-12-05
  • Role of angiogenesis in melanoma progression: Update on key angiogenic mechanisms and other associated components
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-06-27
    Woo Cheal Cho, George Jour, Phyu P. Aung

    Angiogenesis, the formation of new blood vessels from existing blood vessels, is a complex and highly regulated process that plays a role in a wide variety of physiological and pathological processes. In malignancy, angiogenesis is essential for neoplastic cells to acquire the nutrients and oxygen critical for their continued proliferation. Angiogenesis requires a sequence of well-coordinated events mediated by a number of tightly regulated interactions between pro-angiogenic factors and their corresponding receptors expressed on various vascular components (e.g., endothelial cells and pericytes) and stromal components forming the extracellular matrix. In this review, we discuss the functional roles of key growth factors and cytokines known to promote angiogenesis in cutaneous melanoma and key factors implicated in the extracellular matrix remodeling that acts synergistically with angiogenesis to promote tumor progression in melanoma, incorporating some of the most up-to-date basic science knowledge from recently published in vivo and in vitro experimental studies.

    更新日期:2019-12-05
  • Metabolic flexibility in melanoma: A potential therapeutic target
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-07-27
    Maria Rosaria Ruocco, Angelica Avagliano, Giuseppina Granato, Elena Vigliar, Stefania Masone, Stefania Montagnani, Alessandro Arcucci

    Cutaneous melanoma (CM) represents one of the most metastasizing and drug resistant solid tumors. CM is characterized by a remarkable metabolic plasticity and an important connection between oncogenic activation and energetic metabolism. In fact, melanoma cells can use both cytosolic and mitochondrial compartments to produce adenosine triphosphate (ATP) during cancer progression. However, the CM energetic demand mainly depends on glycolysis, whose upregulation is strictly linked to constitutive activation of BRAF/MAPK pathway affected by BRAFV600E kinase mutant. Furthermore, the impressive metabolic plasticity of melanoma allows the development of resistance mechanisms to BRAF/MEK inhibitors (BRAFi/MEKi) and the adaptation to microenvironmental changes. The metabolic interaction between melanoma cells and tumor microenvironment affects the immune response and CM growth. In this review article, we describe the regulation of melanoma metabolic alterations and the metabolic interactions between cancer cells and microenvironment that influence melanoma progression and immune response. Finally, we summarize the hallmarks of melanoma therapies and we report BRAF/MEK pathway targeted therapy and mechanisms of metabolic resistance.

    更新日期:2019-12-05
  • MicroRNA heterogeneity in melanoma progression
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-06-01
    Anita Thyagarajan, Kenneth Y. Tsai, Ravi P. Sahu

    The altered expression of miRNAs has been linked with neocarcinogenesis or the development of human malignancies including melanoma. Of significance, multiple clinical studies have documented that distinct sets of microRNAs (miRNAs) could be utilized as prognostic biomarkers for cancer development or predict the outcomes of treatment responses. To that end, an in-depth validation of such differentially expressed miRNAs is necessary in diverse settings of cancer patients in order to devise novel approaches to control tumor growth and/or enhance the efficacy of clinically-relevant therapeutic options. Moreover, considering the heterogeneity and sophisticated regulation of miRNAs, the precise delineation of their cellular targets could also be explored to design personalized medicine. Given the significance of miRNAs in regulating several key cellular processes of tumor cells including cell cycle progression and apoptosis, we review the findings of such miRNAs implicated in melanoma tumorigenesis. Understanding the novel mechanistic insights of such miRNAs will be useful for developing diagnostic or prognostic biomarkers or devising future therapeutic intervention for malignant melanoma.

    更新日期:2019-12-05
  • Cellular and molecular biology of cancer stem cells in melanoma: Possible therapeutic implications
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-06-29
    Monica Marzagalli, Michela Raimondi, Fabrizio Fontana, Marina Montagnani Marelli, Roberta M. Moretti, Patrizia Limonta

    Malignant melanoma is a tumor characterized by a very high level of heterogeneity, responsible for its malignant behavior and ability to escape from standard therapies. In this review we highlight the molecular and biological features of the subpopulation of cancer stem cells (CSCs), well known to be characterized by self-renewal properties, deeply involved in triggering the processes of tumor generation, metastasis, progression and drug resistance. From the molecular point of view, melanoma CSCs are identified and characterized by the expression of stemness markers, such as surface markers, ATP-binding cassette (ABC) transporters, embryonic stem cells and intracellular markers. These cells are endowed with different functional features. In particular, they play pivotal roles in the processes of tumor dissemination, epithelial-to-mesenchymal transition (EMT) and angiogenesis, mediated by specific intracellular signaling pathways; moreover, they are characterized by a unique metabolic reprogramming. As reported for other types of tumors, the CSCs subpopulation in melanoma is also characterized by a low immunogenic profile as well as by the ability to escape the immune system, through the expression of a negative modulation of T cell functions and the secretion of immunosuppressive factors. These biological features allow melanoma CSCs to escape standard treatments, thus being deeply involved in tumor relapse. Targeting the CSCs subpopulation is now considered an attractive treatment strategy; in particular, combination treatments, based on both CSCs-targeting and standard drugs, will likely increase the therapeutic options for melanoma patients. The characterization of CSCs in liquid biopsies from single patients will pave the way towards precision medicine.

    更新日期:2019-12-05
  • Transmembrane (TMEM) protein family members: Poorly characterized even if essential for the metastatic process
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-08-24
    Sébastien Marx, Thomas Dal Maso, Jia-Wei Chen, Marina Bury, Johan Wouters, Carine Michiels, Benjamin Le Calvé

    The majority of cancer-associated deaths are related to secondary tumor formation. This multistep process involves the migration of cancer cells to anatomically distant organs. Metastasis formation relies on cancer cell dissemination and survival in the circulatory system, as well as adaptation to the new tissue notably through genetic and/or epigenetic alterations. A large number of proteins are clearly identified to play a role in the metastatic process but the structures and modes of action of these proteins are essentially unknown or poorly described. In this review, we detail the involvement of members of the transmembrane (TMEM) protein family in the formation of metastases or in the mechanisms leading to cancer cell dissemination such as migration and extra-cellular matrix remodelling. While the phenotype associated with TMEM over or down-expression is clear, the mechanisms by which these proteins allow cancer cell spreading remain, for most of them, unclear. In parallel, the 3D structures of these proteins are presented. Moreover, we proposed that TMEM proteins could be used as prognostic markers in different types of cancers and could represent potential targets for cancer treatment. A better understanding of this heterogeneous family of poorly characterized proteins thus opens perspectives for better cancer patient care.

    更新日期:2019-12-05
  • Unraveling the molecular mechanisms and the potential chemopreventive/therapeutic properties of natural compounds in melanoma
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-06-22
    Fabrizio Fontana, Michela Raimondi, Alessandro Di Domizio, Roberta M. Moretti, Marina Montagnani Marelli, Patrizia Limonta

    Melanoma is the most fatal form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, targeted therapy and immunotherapy. However, these treatment strategies are associated with development of drug resistance and severe side effects. In recent years, natural compounds have also been extensively studied for their anti-melanoma effects, including tumor growth inhibition, apoptosis induction, angiogenesis and metastasis suppression and cancer stem cell elimination. Moreover, a considerable number of studies reported the synergistic activity of phytochemicals and standard anti-melanoma agents, as well as the enhanced effectiveness of their synthetic derivatives and novel formulations. However, clinical data confirming these promising effects in patients are still scanty. This review emphasizes the anti-tumor mechanisms and potential application of the most studied natural products for melanoma prevention and treatment.

    更新日期:2019-12-05
  • Targeting integrins for cancer management using nanotherapeutic approaches: Recent advances and challenges
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-08-24
    Khurshid Ahmad, Eun Ju Lee, Sibhghatulla Shaikh, Anuj Kumar, Kummara Madhusudana Rao, So-Yong Park, Jun O Jin, Sung Soo Han, Inho Choi

    Integrins are the main cell surface receptors and execute multifaceted functions such as the bidirectional transmission of signals (i.e., inside-out and outside-in) and provide communication between cells and their microenvironments. Integrins are the key regulators of critical biological functions and contribute significantly to the promotion of cancer at almost every stage of disease progression from initial tumor formation to metastasis. Integrin expressions are frequently altered in different cancers, and consequently, several therapeutic strategies targeting integrins have been developed. Furthermore, nanotechnology-based approaches have been devised to overcome the intrinsic limitations of conventional therapies for cancer management, and have been shown to more precise, safer, and highly effective therapeutic tools. Although nanotechnology-based approaches have achieved substantial success for the management of cancer, certain obstacles remain such as inadequate knowledge of nano–bio interactions and the challenges associated with the three stages of clinical trials. This review highlights the different roles of integrins and of integrin-dependent signaling in various cancers and describes the applications of nanotherapeutics targeting integrins. In addition, we discuss RGD-based approaches and challenges posed to cancer management.

    更新日期:2019-12-05
  • Aberrations in DNA repair pathways in cancer and therapeutic significances
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-03-25
    Akira Motegi, Mitsuko Masutani, Ken-ichi Yoshioka, Tadayoshi Bessho

    Cancer cells show various types of mutations and aberrant expression in genes involved in DNA repair responses. These alterations induce genome instability and promote carcinogenesis steps and cancer progression processes. These defects in DNA repair have also been considered as suitable targets for cancer therapies. A most effective target so far clinically demonstrated is “homologous recombination repair defect”, such as BRCA1/2 mutations, shown to cause synthetic lethality with inhibitors of poly(ADP-ribose) polymerase (PARP), which in turn is involved in DNA repair as well as multiple physiological processes. Different approaches targeting genomic instability, including immune therapy targeting mismatch-repair deficiency, have also recently been demonstrated to be promising strategies. In these DNA repair targeting-strategies, common issues could be how to optimize treatment and suppress/conquer the development of drug resistance. In this article, we review the extending framework of DNA repair response pathways and the potential impact of exploiting those defects on cancer treatments, including chemotherapy, radiation therapy and immune therapy.

    更新日期:2019-11-18
  • Interplay between epigenetic abnormalities and deregulated expression of microRNAs in cancer
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-02-08
    Ammad Ahmad Farooqi, Enrique Fuentes-Mattei, Sundas Fayyaz, Priyank Raj, Matthew Goblirsch, Palmiro Poltronieri, George A. Calin

    Epigenetic abnormalities and aberrant expression of non-coding RNAs are two emerging features of cancer cells, both of which are responsible for deregulated gene expression. In this review, we describe the interplay between the two. Specific themes include epigenetic silencing of tumor suppressor miRNAs, epigenetic activation of oncogenic miRNAs, epigenetic aberrations caused by miRNAs, and naturally occurring compounds which modulate miRNA expression through epigenetic mechanisms.

    更新日期:2019-11-18
  • MicroRNA regulation of TRAIL mediated signaling in different cancers: Control of micro steering wheels during the journey from bench-top to the bedside
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-02-01
    Sundas Fayyaz, Zeeshan Javed, Rukset Attar, Ammad Ahmad Farooqi, Ilhan Yaylim, Aamir Ahmad

    Large-scale sequencing methodologies have helped us identify numerous genomic alterations and we have started to scratch the surface of many new targets for treatment of cancer and the associated predictive biomarkers. TRAIL (TNF-related apoptosis-inducing ligand) is a highly appreciated anti-cancer molecule because of its ability to selectively target cancer cells. However, confluence of information suggests that cancer cells develop resistance against TRAIL-based therapeutics. It is being realized that overexpression of anti-apoptotic proteins and inactivation of pro-apoptotic proteins significantly impairs TRAIL triggered apoptosis, particularly in clinical settings. Re-balancing of pro-and anti-apoptotic proteins and upregulation of death receptors with functionally active extrinsic and intrinsic apoptotic pathways are necessary to sensitize cancer cells to TRAIL based therapeutics. microRNAs (miRNAs) are involved in regulation of myriad of molecular processes and characterized into oncogenic and tumor suppressor miRNAs. Accumulating data has identified miRNAs which positively or negatively regulate TRAIL mediated signaling in cancer cells, helping us understand different steps at which TRAIL-mediated apoptotic signaling can be targeted. Here, we assess the status of our understanding of the mechanisms related to miRNA regulation of TRAIL mediated signaling, as well as the existing gaps therein, and discuss the challenges and opportunities that will help us get closer to personalized medicine.

    更新日期:2019-11-18
  • Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2019-01-08
    Ammad Ahmad Farooqi, Marc de la Roche, Mustafa B.A. Djamgoz, Zahid H. Siddik

    Colorectal cancer is a multifaceted disease which is therapeutically challenging. Based on insights gleaned from almost a quarter century of research, it is obvious that deregulation of spatio-temporally controlled signaling pathways play instrumental role in development and progression of colorectal cancer. High-throughput technologies have helped to develop a sharper and broader understanding of the wide ranging signal transduction cascades which also contribute to development of drug resistance, loss of apoptosis and, ultimately, of metastasis. In this review, we have set the spotlight on role of JAK/STAT, TGF/SMAD, Notch, WNT/β-Catenin, SHH/GLI and p53 pathways in the development and progression of colorectal cancer. We have also highlighted recent reports on TRAIL-mediated pathways and molecularly distinct voltage-gated sodium channels in colorectal cancer.

    更新日期:2019-11-18
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