Cancer Letters

Cancer Letters

Volume 477, 1 May 2020, Pages 76-87
Cancer Letters

Mini-review
The metabolic landscape of urological cancers: New therapeutic perspectives

https://doi.org/10.1016/j.canlet.2020.02.034Get rights and content

Highlights

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    Metabolic alterations are critical for cancer development and progression.

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    In urological tumors, metabolic genes upregulation is associated with poor prognosis.

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    Metabolic inhibitors have arisen as novel target therapies.

Abstract

Deregulation of cell metabolism is an established cancer hallmark that contributes to tumor initiation and progression, as well as tumor heterogeneity. In solid tumors, alterations in different metabolic pathways, including glycolysis, pentose phosphate pathway, glutaminolysis and fatty acid metabolism, support the high proliferative rates and macromolecule biosynthesis of cancer cells. Despite advances in therapy, urothelial tumors still exhibit high recurrence and mortality rates, especially in advanced stages of disease. These tumors harbor gene mutations and expression patterns which play an important role in metabolic reprogramming. Taking into account the unique metabolic features underlying carcinogenesis in these cancers, new and promising therapeutic targets based on metabolic alterations must be considered. Furthermore, the combination of metabolic inhibitors with conventional targeted therapies may improve effectiveness of treatments. This review will summarize the metabolic alterations present in urological tumors and the results with metabolic inhibitors currently available.

Introduction

Malignant solid tumors are often heterogeneous, with highly disorganized structures composed by several types of cells in the tumor microenvironment (TME) [1]. Accordingly, solid tumors exhibit diverse metabolic features due several intrinsic factors and also signals imposed by the microenvironment [2]. Importantly, tumor metabolic heterogeneity and flexibility among tumors and within distinct regions of the same tumor, support the presence of a metabolic symbiosis and complementarity between tumor cells and the TME [3]. This metabolic symbiosis has high clinical relevance, since it can help to explain the mechanisms behind the tumor therapeutic vulnerabilities, including treatment failures, and may predict clinical outcomes.

Section snippets

Cancer metabolism

Deregulation of energetic metabolism constitutes a well-established cancer hallmark [4]. The high proliferative rates of cancer cells impose a high demand of energy and macromolecule precursor synthesis to sustain tumor growth and progression [5]. This requirement is ensured by the presence of tumor metabolic reprogramming, a feature present in several tumors.

Prostate cancer

Prostate cancer (PCa) is the most commonly diagnosed cancer among men and the second leading cause of cancer-related death in developed countries [26]. PCa screening relies on prostate-specific antigen (PSA), a widely used prostate cancer marker, in combination to digital rectal examination (DRE) and transrectal ultrasound biopsy [27]. Despite all studies, the molecular pathogenesis of these tumors is not yet fully known. However, fusion chromosomal rearrangements with specific prostate

Conclusions

Considering the unique metabolic features and metabolism-related enzyme deregulation present in urological cancers, new and promising metabolic therapeutic targets should be explored, especially in the treatment of advanced and metastatic disease, where they are most needed. Also, the combination of metabolic inhibitors with conventional standard therapies may improve effectiveness of patients’ treatment.

Until now, in PCa and RCC, metabolic inhibitors demonstrate promising results in

Funding

This work was supported by the Research Center, Portuguese Oncology Institute of Porto (CI-IPOP): PI 112-CI-IPOP 92-2018-MCTKidCan. VM-G received a fellowship from POCI-01-0145-FEDER-29043: Development of novel prognostic and predictive epigenetic biomarkers for malignant testicular germ cell tumors and AL from UID/DTP/00776/POCI-01-0145-FEDER-006868.

Author contributions

AL and VM-G conceptualized the review and drafted the manuscript. AL and VM-G collected and analyzed the information and elaborated the figures. RH, FB and CJ revised the manuscript. All authors read and approved the final manuscript.

CRediT authorship contribution statement

Vera Miranda-Gonçalves: Conceptualization, Writing - original draft. Ana Lameirinhas: Conceptualization, Writing - original draft. Rui Henrique: Writing - original draft. Fátima Baltazar: Writing - review & editing. Carmen Jerónimo: Writing - review & editing.

Declaration of competing interest

None.

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