Tumour-Derived Human Growth Hormone As a Therapeutic Target in Oncology

doi:10.1016/j.tem.2017.05.003

Trends in Endocrinology & Metabolism

Volume 28, Issue 8, August 2017, Pages 587-596

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Trends

The evidence indicates that GH exerts not only endocrine effects but also autocrine/paracrine effects through local tumour expression.

Expression of GH by tumour cells is associated with reduced survival and local metastasis in patients with breast, endometrial, and liver cancer.

Autocrine GH enhances multiple aspects of cancer progression and promotes a cancer stem cell-like phenotype.

Antagonism of GH signal transduction reduces tumour growth and sensitises to radiotherapy in preclinical studies.

Therapeutic use of GH antagonism in cancer need not be restricted to GH-positive tumours because GH-negative cancer cells may be more sensitive to systemic GH stimulation.

The growth hormone (GH) and insulin-like growth factor-1 (IGF1) axis is the key regulator of longitudinal growth, promoting postnatal bone and muscle growth. The available data suggest that GH expression by tumour cells is associated with the aetiology and progression of various cancers such as endometrial, breast, liver, prostate, and colon cancer. Accordingly there has been increased interest in targeting GH-mediated signal transduction in a therapeutic setting. Because GH has endocrine, autocrine, and paracrine actions, therapeutic strategies will need to take into account systemic and local functions. Activation of related hormone receptors and crosstalk with other signalling pathways are also key considerations.

Introduction

GH is a classical pituitary hormone, with endocrine functions and additional autocrine and paracrine actions. GH is secreted from the anterior pituitary in a pulsatile fashion, while a variant placental GH is secreted tonically from the placenta during pregnancy. In addition to essential and well-described roles in growth and metabolism, the GH and IGF1 axis has wide-reaching functions in numerous physiological systems, for example by promoting lipolysis, neurogenesis, folliculogenesis, and increasing muscle mass by promoting myoblast fusion 1, 2.

Increasing evidence in animals and humans also supports a role for GH in the aetiology and progression of cancer. The evidence points not only to the involvement of systemic GH but also to autocrine/paracrine effects through local tumour expression. The purpose of this review is to highlight recent advances and challenges in the field with specific reference to these autocrine and paracrine functions. Owing to space considerations we have focused on the recent literature, and reviews have been cited instead of original works in many instances. We refer readers to reviews for further background reading regarding the actions of GH and IGF1 in cancer 1, 3, 4, 5, 6, 7, 8, 9.

Section snippets

Epidemiology and Cancer Risk Factors

The somatotrophic (GH and IGF1) axis is the key regulator of longitudinal growth, and promotes postnatal bone and muscle growth. Interestingly, a clear and consistent association between adult height and cancer risk has been observed across numerous cancer sites in both large cohort and ecological studies 10, 11, 12, 13. The association is stronger for particular cancer sites, such as melanoma, colon, and breast cancer, while for others the relative risk is small. In a recent meta-analysis of

Clinical Correlations

A small number of studies have found that elevated circulating GH correlates with an increased risk of breast, gastric, colon, or lung cancer 4, 30, 31, 32, 33. Owing to the pulsatile nature of pituitary GH secretion, studies investigating serum GH concentrations in cancer can be problematic. One source of elevated serum GH may in fact arise from GH secretion from tumour cells – studies of canine mammary tumours have demonstrated a strong link between high serum and intratumoural GH and IGF1

Autocrine, Paracrine, and Systemic Functions in Cancer

GH acts in an endocrine and autocrine/paracrine fashion, impacting on both cancer cells and the tumour microenvironment, and contributes to multiple aspects of cancer progression (Figure 1). In addition to secretion from tumour cells, GH is also secreted from cells in the microenvironment such as endothelial cells [54]. Functional effects of tumour-expressed GH include oncogenic transformation, cell proliferation, cell survival, epithelial to mesenchymal transition, cell migration, and invasion

Targeting Different Facets of GH Secretion – Therapeutic Considerations

With an increasing number of studies implicating GH signalling in cancer, there has been a great deal of interest in antagonising this axis for therapeutic purposes. In an oncology setting, antagonism of GH signalling would be expected to have the added benefit of suppressing IGF1-mediated effects on cancer progression.

The GHR is a challenging therapeutic target because it has no intrinsic kinase activity and relies on the recruitment of non-receptor tyrosine kinases for activity. A detailed

Concluding Remarks and Future Perspectives

Recent clinical studies have gone a long way towards supporting target validation, and provide a framework for expanding clinical correlation into larger cohorts. However, despite substantial evidence supporting a causal role for the GH/IGF1 axis in cancer, the potential utility of GH antagonism in cancer therapy is still unclear and further preclinical studies are warranted. Therapeutic use of GH antagonism in cancer need not be restricted to GH-positive tumours, given that GH-negative cancer

Disclaimer Statement

PEL is an inventor on patent application US2010-0203060A1. TZ and PEL have consulted for Perseis Therapeutics Ltd. TZ and PEL consult for and have equity interest in Wuhan Long Ke Ltd. TZ and PEL are inventors on Chinese patent 20130446539.5.

References (100)

V.N. Anisimov et al.
The key role of growth hormone–insulin–IGF-1 signaling in aging and cancer
Crit. Rev. Oncol. Hematol.
(2013)
S. Harvey
Autocrine/paracrine roles of extrapituitary growth hormone and prolactin in health and disease: an overview
Gen. Comp. Endocrinol.
(2015)
A.G. Renehan
Height and cancer: consistent links, but mechanisms unclear
Lancet Oncol.
(2011)
N. Stefan
Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications
Lancet Diabetes Endocrinol.
(2016)
R. Tripaldi
Human height genes and cancer
Biochim. Biophys. Acta
(2013)
J.K. Perry
The oncogenic potential of growth hormone
Growth Horm. IGF Res.
(2006)
A.G. Renehan et al.
Acromegaly, growth hormone and cancer risk
Best Pract. Res. Clin. Endocrinol. Metab.
(2008)
J.J. Kopchick
Lessons learned from studies with the growth hormone receptor
Growth Horm. IGF Res.
(2016)
B. Marek
Acromegaly and the risk of cancer
Pathophysiology
(2001)
F.L. Queiroga
Serum and intratumoural GH and IGF-I concentrations: prognostic factors in the outcome of canine mammary cancer
Res. Vet. Sci.
(2010)

R.W. Lea

Growth hormone and cancer: GH production and action in glioma?

Gen. Comp. Endocrinol.

(2015)

E.G. Sustarsic

Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

Biochem. Biophys. Res. Commun.

(2013)

Y.J. Chen

Autocrine human growth hormone stimulates the tumor initiating capacity and metastasis of estrogen receptor-negative mammary carcinoma cells

Cancer Lett.

(2015)

K.J. Wernli

Body size, IGF and growth hormone polymorphisms, and colorectal adenomas and hyperplastic polyps

Growth Horm. Igf. Res.

(2010)

K.K. Kaulsay

Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone

Exp. Cell Res.

(1999)

N.E. Banziger-Tobler

Growth hormone promotes lymphangiogenesis

Am. J. Pathol.

(2008)

A. Evans

Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model

Cancer Lett.

(2016)

A. Zekri

Autocrine human growth hormone increases sensitivity of mammary carcinoma cell to arsenic trioxide-induced apoptosis

Mol. Cell. Endocrinol.

(2013)

W. Zhang

Autocrine/paracrine human growth hormone-stimulated microRNA 96-182-183 cluster promotes epithelial–mesenchymal transition and invasion in breast cancer

J. Biol. Chem.

(2015)

X.Q. Xu

Gene expression profiling to identify oncogenic determinants of autocrine human growth hormone in human mammary carcinoma

J. Biol. Chem.

(2005)

C. Carter-Su

Growth hormone signaling pathways

Growth Horm. IGF Res.

(2016)

T. Zhu

Signal transduction via the growth hormone receptor

Cell. Signal.

(2001)

S. Lombardi

Growth hormone is secreted by normal breast epithelium upon progesterone stimulation and increases proliferation of stem/progenitor cells

Stem Cell Rep.

(2014)

J.J. Kopchick

Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications

Mol. Cell. Endocrinol.

(2014)

P.U. Freda

Long-term treatment with pegvisomant as monotherapy in patients with acromegaly: experience from ACROSTUDY

Endocr. Pract.

(2015)

X. Li

Synergy in ERK activation by cytokine receptors and tyrosine kinase growth factor receptors

Cell. Signal.

(2011)

Y. Huang

Growth hormone-induced phosphorylation of epidermal growth factor (EGF) receptor in 3T3-F442A cells: modulation of EGF-induced trafficking and signaling

J. Biol. Chem.

(2003)

A.J. Brooks et al.

The growth hormone receptor: mechanism of activation and clinical implications

Nat. Rev. Endocrinol.

(2010)

J. Devesa

Multiple effects of trowth hormone in the body: is it really the hormone for growth?

Clin. Med. Insights Endocrinol. Diabetes

(2016)

E.J. Gallagher et al.

Minireview: IGF, insulin, and cancer

Endocrinology

(2011)

J.K. Perry

Growth hormone and cancer: an update on progress

Curr. Opin. Endocrinol. Diabetes Obes.

(2013)

J.K. Perry

The contribution of growth hormone to mammary neoplasia

J. Mammary Gland Biol. Neoplasia

(2008)

M. Pollak

The insulin and insulin-like growth factor receptor family in neoplasia: an update

Nat. Rev. Cancer

(2012)

Y. Chhabra

Role of the growth hormone–IGF-1 axis in cancer

Expert Rev. Endocrinol. Metab.

(2011)

Y. Jiang

An international ecological study of adult height in relation to cancer incidence for 24 anatomical sites

Cancer Causes Control

(2015)

D. Albanes

Adult stature and risk of cancer

Cancer Res.

(1988)

B. Zhang

Height and breast cancer risk: evidence from prospective studies and mendelian randomization

J. Natl. Cancer Inst.

(2015)

N.K. Khankari

Association between adult height and risk of colorectal, lung, and prostate cancer: results from meta-analyses of prospective studies and mendelian randomization analyses

PLoS Med.

(2016)

A.P. Thrift

Mendelian randomization study of height and risk of colorectal cancer

Int. J. Epidemiol.

(2015)

H. Lango Allen

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Nature

(2010)

I. Menashe

Pathway analysis of breast cancer genome-wide association study highlights three pathways and one canonical signaling cascade

Cancer Res.

(2010)

R. Dineen

Acromegaly

QJM

(2016)

C.L. Boguszewski et al.

Management of endocrine disease: acromegaly and cancer: an old debate revisited

Eur. J. Endocrinol.

(2016)

A. Tirosh et al.

Complications of acromegaly: thyroid and colon

Pituitary

(2017)

K. Wolinski

Risk of malignant neoplasms in acromegaly: a case–control study

J. Endocrinol. Invest.

(2017)

S. Loeper et al.

Acromegaly: re-thinking the cancer risk

Rev. Endocr. Metab. Disord.

(2008)

J. Guevara-Aguirre

Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans

Sci. Transl. Med.

(2011)

R. Steuerman

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Eur. J. Endocrinol.

(2011)

J.T. Emerman

Elevated growth hormone levels in sera from breast cancer patients

Horm. Metab. Res.

(1985)

G. Mazzoccoli

Decreased serum levels of insulin-like growth factor (IGF)-I in patients with lung cancer: temporal relationship with growth hormone (GH) levels

Anticancer Res.

(1999)

Cited by (41)

Acromegaly: pathogenesis, diagnosis, and management
2022, The Lancet Diabetes and Endocrinology
Growth hormone-secreting pituitary adenomas that cause acromegaly arise as monoclonal expansions of differentiated somatotroph cells and are usually sporadic. They are almost invariably benign, yet they can be locally invasive and show progressive growth despite treatment. Persistent excess of both growth hormone and its target hormone insulin-like growth factor 1 (IGF-1) results in a wide array of cardiovascular, respiratory, metabolic, musculoskeletal, neurological, and neoplastic comorbidities that might not be reversible with disease control. Normalisation of IGF-1 and growth hormone are the primary therapeutic aims; additional treatment goals include tumour shrinkage, relieving symptoms, managing complications, reducing excess morbidity, and improving quality of life. A multimodal approach with surgery, medical therapy, and (more rarely) radiation therapy is required to achieve these goals. In this Review, we examine the epidemiology, pathogenesis, diagnosis, complications, and treatment of acromegaly, with an emphasis on the importance of tailoring management strategies to each patient to optimise outcomes.
Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage
2021, Cell Reports
Citation Excerpt :
These results suggest that local npGH induced with aging in human tissue alters the tissue microenvironment by suppressing tumor suppressor proteins and enhancing epithelial proliferation and DNA damage. The results are consistent with observations that exogenous GH treatment increases proliferative capacity, colony formation, and metastases in DJ-1 KO mice (Chien et al., 2016), and with evidence that GH induction in human tumor cells is associated with the progression of several cancers (Perry et al., 2017); these comport with our results showing fewer colony formations and smaller colony size with GH suppression. DNA damage repair pathways protect against chromosomal instability that drives cellular transformation (Negrini et al., 2010).
Microenvironmental factors modulating age-related DNA damage are unclear. Non-pituitary growth hormone (npGH) is induced in human colon, non-transformed human colon cells, and fibroblasts, and in 3-dimensional intestinal organoids with age-associated DNA damage. Autocrine/paracrine npGH suppresses p53 and attenuates DNA damage response (DDR) by inducing TRIM29 and reducing ATM phosphorylation, leading to reduced DNA repair and DNA damage accumulation. Organoids cultured up to 4 months exhibit aging markers, p16, and SA-β-galactosidase and decreased telomere length, as well as DNA damage accumulation, with increased npGH, suppressed p53, and attenuated DDR. Suppressing GH in aged organoids increases p53 and decreases DNA damage. WT mice exhibit age-dependent colon DNA damage accumulation, while in aged mice devoid of colon GH signaling, DNA damage remains low, with elevated p53. As age-associated npGH induction enables a pro-proliferative microenvironment, abrogating npGH signaling could be targeted as anti-aging therapy by impeding DNA damage and age-related pathologies.
Morphological and molecular effects of overexpressed GH on mice mammary gland
2021, Molecular and Cellular Endocrinology
Citation Excerpt :
Normal mammary epithelial cells express the growth hormone gene, which is also expressed in the mammary stroma in proliferative disorders of the mammary gland (Subramani et al. 2017). Moreover, autocrine GH action has been associated with tumor development (Perry et al. 2017). Due to ectopic expression of the bGH transgene, transgenic mice overexpress the hormone in the mammary tissue.
Growth Hormone (GH) plays crucial roles in mammary gland development and growth, and its upregulation has been associated with breast cancer promotion and/or progression. To ascertain how high GH levels could promote mammary tissue oncogenic transformation, morphological characteristics and the expression of receptors involved in mammary growth, development and cancer, and of mitogenic mediators were analyzed in the mammary gland of virgin adult transgenic mice that overexpress GH.
Whole mounting and histologic analysis evidenced that transgenic mice exhibit increased epithelial ductal elongation and enlarged ducts along with deficient branching and reduced number of alveolar structures compared to wild type mice. The number of differentiated alveolar structures was diminished in transgenic mice while the amount of terminal end buds (TEBs) did not differ between both groups of mice. GH, insulin-like growth factor 1 (IGF1) and GH receptor mRNA levels were augmented in GH-overexpressing mice breast tissue, as well as IGF1 receptor protein content. However, GH receptor protein levels were decreased in transgenic mice. Fundamental receptors for breast growth and development like progesterone receptor and epidermal growth factor receptor were also increased in mammary tissue from transgenic animals. In turn, the levels of the proliferation marker Ki67, cFOS and Cyclin D1 were increased in GH-overexpressing mice, while cJUN expression was decreased and cMYC did not vary.
In conclusion, prolonged exposure to high GH levels induces morphological and molecular alterations in the mammary gland that affects its normal development. While these effects would not be tumorigenic per se, they might predispose to oncogenic transformation.
The tumour microenvironment of pituitary neuroendocrine tumours
2020, Frontiers in Neuroendocrinology
Citation Excerpt :
GH has been suggested to influence and shape the TME in different cancers, and potentially also for PitNETs (Brittain et al., 2017; Chesnokova and Melmed, 2019; Colon-Echevarria et al., 2019). GH may create a pro-tumourigenic environment in normal epithelial cells, inhibiting tumour suppressor proteins and promoting neoplastic transformation through a number of autocrine/paracrine tumour-promoting actions in normal or cancer cells (reviewed in detail in (Boguszewski and Boguszewski, 2019; Brooks and Waters, 2010; Perry et al., 2017)). Recent studies have suggested that GH can induce EMT either indirectly via IGF-1 or directly through the activation of several signalling pathways (JAK-STAT, MAPK or AKT pathways), with subsequent influences on the transcription of EMT-related genes, in both non-cancerous or cancerous epithelial cells, as shown in breast and colorectal cancer, melanoma, endometrial carcinoma and pancreatic ductal adenocarcinoma (reviewed in detail in (Brittain et al., 2017)).
The tumour microenvironment (TME) includes a variety of non-neoplastic cells and non-cellular elements such as cytokines, growth factors and enzymes surrounding tumour cells. The TME emerged as a key modulator of tumour initiation, progression and invasion, with extensive data available in many cancers, but little is known in pituitary tumours. However, the understanding of the TME of pituitary tumours has advanced thanks to active research in this field over the last decade. Different immune and stromal cell subpopulations, and several cytokines, growth factors and matrix remodelling enzymes, have been characterised in pituitary tumours. Studying the TME in pituitary tumours may lead to a better understanding of tumourigenic mechanisms, identification of biomarkers useful to predict aggressive disease, and development of novel therapies. This review summarises the current knowledge on the different TME cellular/non-cellular elements in pituitary tumours and provides an overview of their role in tumourigenesis, biological behaviour and clinical outcomes.
Long-Acting Human Growth Hormone Receptor Antagonists Produced in E. coli and Conjugated with Polyethylene Glycol
2020, Bioconjugate Chemistry
Growth hormone (GH) is a peptide hormone that mediates actions through binding to a cell surface GH receptor (GHR). The GHR antagonist, B2036, combines an amino acid substitution at 120 that confers GHR antagonist activity, with eight additional amino acid substitutions. Conjugation to polyethylene glycol (PEG) increases the serum half-life of these proteins due to reduced renal clearance. Recombinant forms of GH and its antagonists are mainly produced in prokaryotic expression systems, such as E. coli. However, efficient production in E. coli is problematic, as these proteins form aggregates as inclusion bodies resulting in poor solubility. In the present study, we demonstrate that N-terminal fusion to a thioredoxin (Trx) fusion partner improves soluble expression of codon-optimized B2036 in E. coli when expressed at 18 °C. Expression, purification and PEGylation protocols were established for three GHR antagonists: B2036, B20, and G120Rv. Following purification, these antagonists inhibited the proliferation of Ba/F3-GHR cells in a concentration-dependent manner. PEGylation with amine-reactive 5 kDa methoxy PEG succinimidyl propionate yielded a heterogeneous mixture of conjugates containing four to seven PEG moieties. PEGylation significantly reduced in vitro bioactivity of the conjugates. However, substitution of lysine to arginine at amino acid residue 120 in B2036 improved the in vitro activity of the PEGylated protein when compared to unmodified PEGylated B2036. Pharmacokinetic analysis demonstrated that the circulating half-life of PEGylated B20 was 15.2 h in mice. Taken together, we describe an effective strategy to produce biologically active PEGylated human GHR antagonists.
Off-label use and misuse of testosterone, growth hormone, thyroid hormone, and adrenal supplements: Risks and costs of a growing problem
2020, Endocrine Practice
Over the past few decades, there has been an unprecedented rise in off-label use and misuse of testosterone, growth hormone, thyroid hormone, and adrenal supplements. Testosterone therapy is often promoted to men for the treatment of low energy, lower libido, erectile dysfunction, and other symptoms. Growth hormone is used in attempts to improve athletic performance in athletes and to attenuate aging in older adults. Thyroid hormone and/or thyroid supplements or boosters are taken to treat fatigue, obesity, depression, cognitive impairment, impaired physical performance, and infertility. Adrenal supplements are used to treat common nonspecific symptoms due to “adrenal fatigue,” an entity that has not been recognized as a legitimate medical diagnosis. Several factors have contributed to the surge in off-label use and misuse of these hormones and supplements: direct-to-consumer advertising, websites claiming to provide legitimate medical information, and for-profit facilities promoting therapies for men's health and anti-aging. The off-label use and misuse of hormones and supplements in individuals without an established endocrine diagnosis carries known and unknown risks. For example, the risks of growth hormone abuse in athletes and older adults are unknown due to a paucity of studies and because those who abuse this hormone often take supraphysiologic doses in sporadic intervals. In addition to the health risks, off-label use of these hormones and supplements generates billions of dollars of unnecessary costs to patients and to the overall health-care system. It is important that patients honestly disclose to their providers off-label hormone use, as it may affect their health and treatment plan. General medical practitioners and adult endocrinologists should be able to begin a discussion with their patients regarding the unfavorable balance between the risks and benefits associated with off-label use of testosterone, growth hormone, thyroid hormone, and adrenal supplements.
Abbreviations: DHEA = dehydroepiandrosterone; FDA = U.S. Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LT3 = L-triiodothyronine; LT4 = levothyroxine; T3 = total triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone

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Trends in Endocrinology & Metabolism

ReviewTumour-Derived Human Growth Hormone As a Therapeutic Target in Oncology

Trends

Introduction

Section snippets

Epidemiology and Cancer Risk Factors

Clinical Correlations

Autocrine, Paracrine, and Systemic Functions in Cancer

Targeting Different Facets of GH Secretion – Therapeutic Considerations

Concluding Remarks and Future Perspectives

Disclaimer Statement

Crit. Rev. Oncol. Hematol.

Gen. Comp. Endocrinol.

Lancet Oncol.

Lancet Diabetes Endocrinol.

Biochim. Biophys. Acta

Growth Horm. IGF Res.

Best Pract. Res. Clin. Endocrinol. Metab.

Growth Horm. IGF Res.

Pathophysiology

Res. Vet. Sci.

Gen. Comp. Endocrinol.

Biochem. Biophys. Res. Commun.

Cancer Lett.

Growth Horm. Igf. Res.

Exp. Cell Res.

Am. J. Pathol.

Cancer Lett.

Mol. Cell. Endocrinol.

J. Biol. Chem.

J. Biol. Chem.

Growth Horm. IGF Res.

Cell. Signal.

Stem Cell Rep.

Mol. Cell. Endocrinol.

Endocr. Pract.

Cell. Signal.

J. Biol. Chem.

The growth hormone receptor: mechanism of activation and clinical implications

Nat. Rev. Endocrinol.

Multiple effects of trowth hormone in the body: is it really the hormone for growth?

Clin. Med. Insights Endocrinol. Diabetes

Minireview: IGF, insulin, and cancer

Endocrinology

Growth hormone and cancer: an update on progress

Curr. Opin. Endocrinol. Diabetes Obes.

The contribution of growth hormone to mammary neoplasia

J. Mammary Gland Biol. Neoplasia

The insulin and insulin-like growth factor receptor family in neoplasia: an update

Nat. Rev. Cancer

Role of the growth hormone–IGF-1 axis in cancer

Expert Rev. Endocrinol. Metab.

An international ecological study of adult height in relation to cancer incidence for 24 anatomical sites

Cancer Causes Control

Adult stature and risk of cancer

Cancer Res.

Height and breast cancer risk: evidence from prospective studies and mendelian randomization

J. Natl. Cancer Inst.

Association between adult height and risk of colorectal, lung, and prostate cancer: results from meta-analyses of prospective studies and mendelian randomization analyses

PLoS Med.

Mendelian randomization study of height and risk of colorectal cancer

Int. J. Epidemiol.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Nature

Pathway analysis of breast cancer genome-wide association study highlights three pathways and one canonical signaling cascade

Cancer Res.

Acromegaly

QJM

Management of endocrine disease: acromegaly and cancer: an old debate revisited

Eur. J. Endocrinol.

Complications of acromegaly: thyroid and colon

Pituitary

Risk of malignant neoplasms in acromegaly: a case–control study

J. Endocrinol. Invest.

Acromegaly: re-thinking the cancer risk

Rev. Endocr. Metab. Disord.

Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans

Sci. Transl. Med.

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Eur. J. Endocrinol.

Review
Tumour-Derived Human Growth Hormone As a Therapeutic Target in Oncology