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

Chhabra, Yash; Waters, Michael J.; Brooks, Andrew J.

doi:10.1586/eem.10.73

Cited by 76 publications

(83 citation statements)

References 138 publications

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“…In GH treated patients with childhood-or adult-onset GHD, no association of GH treatment and development of primary cancer was found, based on available data (112,113). Several excellent reviews have discussed the topic in recent years (24,114,115,116,117,118). A recent genome wide association study (GWAS) had reported the GH induced intracellular signaling network to be the third highest pathway associated with enhanced susceptibility to breast cancer (119).…”

Section: Cancermentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Basu

Qian

Kopchick

2018

European Journal of Endocrinology

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Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 40-50 years. Work on the GH receptor (R) knock-out (GHRKO) mice and results of studies on GH resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition, and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.

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Section: Cancermentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Basu

Qian

Kopchick

2018

European Journal of Endocrinology

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“…In many preclinical cancer models, tumor growth can be stimulated by IGF-I or IGF-II, and tumors grow substantially slower in mice carrying a mutation that reduces IGF ligand levels (4). Moreover, a separate line of indirect evidence for the relevance of IGF signaling for neoplasia comes from the observation that there is considerable interindividual variation in circulating IGF-I levels, and that risk and prognosis of certain cancers are related to circulating IGF-I concentration (2,14,15). Finally, IGF signaling may also play a role as a resistance mechanism, which limits the effectiveness of cytotoxic or targeted anticancer agents, including rapalogs (16)(17)(18)(19)(20)(21).…”

Section: Igf-i Signals By Binding To the Igf-i Receptor (Igf-ir) Or Tmentioning

confidence: 99%

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Friedbichler

Hofmann

Kroez

et al. 2014

Molecular Cancer Therapeutics

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Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity to human IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycininduced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies. Mol Cancer Ther; 13(2); 399-409. Ó2013 AACR.

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“…As mentioned earlier, several tissues express GH locally and it has been suggested that autocrine GH can serve as a cytokine, promoting cell cycle progression and preventing apoptosis (Chhabra et al, 2011). Autocrine GH has been implicated in oncogenic transformation and metastasis in several different types of malignancies (Perry et al, 2006;Waters & Barclay, 2007).…”

Section: Autocrine Mode Of Gh Signallingmentioning

confidence: 97%

“…Certain embryonic cell types (notably in the brain) produce GH before ontogenic differentiation of pituitary somatotrophs (Lobie et al, 1993;. In addition, many tumour cells have been reported to express GH and GHR (Perry et al, 2006;Chhabra et al, 2011). The GH-V is produced in a continuous manner by the placenta, gradually replacing the pituitary GH-N in pregnancy, so that GH-N becomes undetectable in the maternal circulation (Lacroix et al, 2002).…”

Section: )mentioning

confidence: 99%

“…A search of the Oncomine database reveals underexpression of GH1 and no listing for GH2 transcripts in invasive ductal breast carcinoma against normal tissue, in contrast to the prolactin transcript, which is highly expressed. Many human prostate cancers overexpress GH1 or GH2 and GHR transcripts as evidenced in the Oncomine database (Chhabra et al, 2011). Furthermore, an immunohistochemical study of 20 prostate cancers and 17 controls reported a four-fold increase in human GH expression in prostatic carcinoma where it is believed to act locally as almost all of them express GHR .…”

Section: Autocrine Mode Of Gh Signallingmentioning

confidence: 99%

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The growth hormone receptor mediated oncogenesis

Chhabra¹

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Growth hormone (GH) is a major regulator of postnatal growth, cellular proliferation and differentiation, as well as of metabolism. All actions of GH are mediated via its cognate Growth Hormone Receptor (GHR). It is now clear that the role of GH extends well beyond the conventional notions of longitudinal growth and childhood development. A substantial body of evidence supports a role for the GH/IGF-1 axis in cancer incidence and progression in animals and humans and because of widespread clinical application of GH, there has been considerable interest in the mechanism of activation of its receptor. It was originally thought that GH initiated its actions by sequentially binding two GHR monomers, resulting in receptor dimerisation and initiation of intracellular signalling cascades, including Jak/STAT and MAPK pathways. However, recent evidence by our group and others has indicated that the GHR is constitutively dimerised, and that dimerisation alone is not sufficient for GHR activation.To this end the main objective of this thesis was to evaluate the role of GH-mediated signalling via its GHR in mediating oncogenesis. We have taken a multi-disciplinary approach by first determining how the GHR is activated via its transmembrane domain (TMD) and the nature of its interaction with Src family of tyrosine kinase (Lyn). We have determined the basis of the contrasting actions of autocrine GH from independent publications and sought to evaluate the effect of various constitutively active GHR constructs in cancer promotion in vitro and in vivo by establishing a tissue-specific delivery system (TVA system) for introducing multiple genes in a spatial and temporally controlled manner. We have provided the molecular basis of increased cancer susceptibility of the first reported GHR variant from two independent epidemiological studies. Finally, we have evaluated cancer resistance and anti-aging pathways in various GHR knockin and knockout mice models.In order to determine the role of GHR transmembrane domain (TMD) and upper juxtamembrane domain (JMD) in signalling, cysteine-scanning mutagenesis was employed with truncated and full length receptors in a thiol-free background. Using these GHR constructs and sequentially substituting residues along the GHR JMD and TMD with cysteine we observed a ligandindependent spontaneous dimerisation pattern of upper JMD and TMD residues with evidence for a 'tilt and twist' movement for this region of GHR during activation. By using Cu-o-phenanthroline we were able to show that GHR activation could occur following disulfide bond formation at the upper TMD boundary resulting in constitutive activation. Finally we were able to conclude that GHR activation requires the JMD residues to come in close proximity which results in separation of iii the lower TMD residues and activation. Another outcome of this study was the generation of the first full-length constitutively active receptor.GHR has been shown to activate numerous pathways and one such pathway involves Src Family Kinase (SFK),...

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

Cited by 76 publications

References 138 publications

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

The growth hormone receptor mediated oncogenesis

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