Growth hormone in the tumor microenvironment

Tumor development is a multistep process whereby local mechanisms enable somatic mutations during preneoplastic stages. Once a tumor develops, it becomes a complex organ composed of multiple cell types. Interactions between malignant and non-transformed cells and tissues create a tumor microenvironment (TME) comprising epithelial cancer cells, cancer stem cells, non-tumorous cells, stromal cells, immune-inflammatory cells, blood and lymphatic vascular network, and extracellular matrix. We review reports and present a hypothesis that postulates the involvement of growth hormone (GH) in field cancerization. We discuss GH contribution to TME, promoting epithelial-to-mesenchymal transition, accumulation of unrepaired DNA damage, tumor vascularity, and resistance to therapy. Arch Endocrinol Metab. 2019;63(6):568-75.

[1]  J. Kopchick,et al.  The effects of growth hormone on therapy resistance in cancer , 2019, Cancer drug resistance.

[2]  S. Melmed,et al.  Growth Hormone Induces Colon DNA Damage Independent of IGF-1. , 2019, Endocrinology.

[3]  A. Bartke,et al.  Growth Hormone Deficiency: Health and Longevity. , 2018, Endocrine reviews.

[4]  S. Melmed,et al.  Excess growth hormone suppresses DNA damage repair in epithelial cells. , 2019, JCI insight.

[5]  R. Raychowdhury,et al.  Extranuclear DNA accumulates in aged cells and contributes to senescence and inflammation , 2019, Aging cell.

[6]  G. David,et al.  Pro- and anti-tumorigenic functions of the senescence-associated secretory phenotype , 2019, Expert opinion on therapeutic targets.

[7]  C. Boguszewski,et al.  Growth Hormone's Links to Cancer. , 2018, Endocrine reviews.

[8]  Susan A. Cole,et al.  Field , 2018, The Body Wars.

[9]  H. Sørensen,et al.  Cancer Incidence in Patients With Acromegaly: A Cohort Study and Meta-Analysis of the Literature , 2018, The Journal of clinical endocrinology and metabolism.

[10]  Wei Sha,et al.  Inhibition of experimental small‐cell and non‐small‐cell lung cancers by novel antagonists of growth hormone‐releasing hormone , 2018, International journal of cancer.

[11]  J. Kopchick,et al.  MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects? , 2018, European journal of endocrinology.

[12]  D. Bernard,et al.  Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence , 2018, Cell Death & Disease.

[13]  T. Graham,et al.  An evolutionary perspective on field cancerization , 2017, Nature Reviews Cancer.

[14]  T. Zhu,et al.  Autocrine hGH stimulates oncogenicity, epithelial-mesenchymal transition and cancer stem cell-like behavior in human colorectal carcinoma , 2017, Oncotarget.

[15]  J. Kopchick,et al.  Growth Hormone and the Epithelial-to-Mesenchymal Transition , 2017, The Journal of clinical endocrinology and metabolism.

[16]  T. Zhu,et al.  Tumour-Derived Human Growth Hormone As a Therapeutic Target in Oncology , 2017, Trends in Endocrinology & Metabolism.

[17]  E. Sahai,et al.  Tumor Microenvironment and Differential Responses to Therapy. , 2017, Cold Spring Harbor perspectives in medicine.

[18]  T. Zhu,et al.  Autocrine Human Growth Hormone Promotes Invasive and Cancer Stem Cell-Like Behavior of Hepatocellular Carcinoma Cells by STAT3 Dependent Inhibition of CLAUDIN-1 Expression , 2017, International journal of molecular sciences.

[19]  Shiyong Wu,et al.  Growth Hormone Receptor Knockdown Sensitizes Human Melanoma Cells to Chemotherapy by Attenuating Expression of ABC Drug Efflux Pumps , 2017, Hormones and Cancer.

[20]  Wei Xiong,et al.  Role of tumor microenvironment in tumorigenesis , 2017, Journal of Cancer.

[21]  Shiyong Wu,et al.  Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways , 2017, Oncotarget.

[22]  J. Jackson,et al.  SASP: Tumor Suppressor or Promoter? Yes! , 2016, Trends in cancer.

[23]  Giovanni Simone,et al.  Angiogenesis and Antiangiogenesis in Triple-Negative Breast cancer1 , 2016, Translational oncology.

[24]  E. Vilain,et al.  WNT4 mediates the autocrine effects of growth hormone in mammary carcinoma cells. , 2016, Endocrine-related cancer.

[25]  S. Melmed,et al.  Growth hormone is permissive for neoplastic colon growth , 2016, Proceedings of the National Academy of Sciences.

[26]  Yuchen Jiang,et al.  Role of the tumor microenvironment in tumor progression and the clinical applications (Review). , 2016, Oncology reports.

[27]  Björn Schumacher,et al.  p53 in the DNA-Damage-Repair Process. , 2016, Cold Spring Harbor perspectives in medicine.

[28]  M. Zhang,et al.  Human growth hormone and human prolactin function as autocrine/paracrine promoters of progression of hepatocellular carcinoma , 2016, Oncotarget.

[29]  A. Lam,et al.  Immune Cell Infiltrates in Pituitary Adenomas: More Macrophages in Larger Adenomas and More T Cells in Growth Hormone Adenomas , 2015, Endocrine Pathology.

[30]  A. Khanna DNA damage in cancer therapeutics: a boon or a curse? , 2015, Cancer research.

[31]  M. Zhang,et al.  Autocrine/Paracrine Human Growth Hormone-stimulated MicroRNA 96-182-183 Cluster Promotes Epithelial-Mesenchymal Transition and Invasion in Breast Cancer* , 2015, The Journal of Biological Chemistry.

[32]  Laurent Beaugerie,et al.  Cancers complicating inflammatory bowel disease. , 2015, The New England journal of medicine.

[33]  R. Subramani,et al.  Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma , 2014, Experimental & Molecular Medicine.

[34]  O. O. Gul,et al.  Investigation of genotoxicity in acromegaly from peripheral blood lymphocyte cultures using a micronucleus assay. , 2014, The Journal of clinical endocrinology and metabolism.

[35]  V. Tillmann,et al.  Translational Neuroendocrinology: Control of Human Growth , 2014, Journal of neuroendocrinology.

[36]  D. Chia Minireview: mechanisms of growth hormone-mediated gene regulation. , 2014, Molecular endocrinology.

[37]  B. Rini,et al.  Angiogenesis and the tumor microenvironment: vascular endothelial growth factor and beyond. , 2014, Seminars in oncology.

[38]  G. Baskol,et al.  Increased genome instability and oxidative DNA damage and their association with IGF-1 levels in patients with active acromegaly. , 2014, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[39]  P. Adams,et al.  Senescence at a glance , 2013, Journal of Cell Science.

[40]  S. Melmed,et al.  Growth hormone is a cellular senescence target in pituitary and nonpituitary cells , 2013, Proceedings of the National Academy of Sciences.

[41]  J. Kopchick,et al.  The GH/IGF-1 axis in ageing and longevity , 2013, Nature Reviews Endocrinology.

[42]  C. Carter-Su,et al.  Phosphorylation of the adaptor protein SH2B1&bgr; regulates its ability to enhance growth hormone-dependent macrophage motility , 2013, Journal of Cell Science.

[43]  A. Bartke,et al.  Hepatocellular alterations and dysregulation of oncogenic pathways in the liver of transgenic mice overexpressing growth hormone , 2013, Cell cycle.

[44]  A. Noel,et al.  Targeting the tumor microenvironment for cancer therapy. , 2013, Clinical chemistry.

[45]  Nicola J. Curtin,et al.  DNA repair dysregulation from cancer driver to therapeutic target , 2012, Nature Reviews Cancer.

[46]  T. Hagemann,et al.  The tumor microenvironment at a glance , 2012, Journal of Cell Science.

[47]  T. Zhu,et al.  Autocrine human GH promotes radioresistance in mammary and endometrial carcinoma cells. , 2012, Endocrine-related cancer.

[48]  T. Graham,et al.  Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis. , 2012, Gastroenterology.

[49]  D. Sabatini,et al.  mTOR Signaling in Growth Control and Disease , 2012, Cell.

[50]  D. Molè,et al.  Growth hormone receptor blockade inhibits growth hormone-induced chemoresistance by restoring cytotoxic-induced apoptosis in breast cancer cells independently of estrogen receptor expression. , 2012, The Journal of clinical endocrinology and metabolism.

[51]  M. Waters,et al.  Growth hormone and cell growth. , 2012, Endocrine development.

[52]  Helen H. W. Chen,et al.  Autocrine human growth hormone reduces mammary and endometrial carcinoma cell sensitivity to mitomycin C. , 2011, Oncology reports.

[53]  D. Lyden,et al.  The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. , 2011, Seminars in cancer biology.

[54]  J. Carlson Faculty of 1000 evaluation for Fields and field cancerization: the preneoplastic origins of cancer: asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture. , 2011 .

[55]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[56]  M. Bronner,et al.  Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation. , 2011, Cancer research.

[57]  J. Campisi,et al.  Four faces of cellular senescence , 2011, The Journal of cell biology.

[58]  C. Gialeli,et al.  Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting , 2011, The FEBS journal.

[59]  M. Waters,et al.  The growth hormone receptor: mechanism of activation and clinical implications , 2010, Nature Reviews Endocrinology.

[60]  Z. Werb,et al.  Tumors as organs: complex tissues that interface with the entire organism. , 2010, Developmental cell.

[61]  J. Campisi,et al.  The senescence-associated secretory phenotype: the dark side of tumor suppression. , 2010, Annual review of pathology.

[62]  S. Melmed Acromegaly pathogenesis and treatment. , 2009, The Journal of clinical investigation.

[63]  D. Molè,et al.  Growth hormone excess promotes breast cancer chemoresistance. , 2009, The Journal of clinical endocrinology and metabolism.

[64]  G. Nelson,et al.  DNA damage response and cellular senescence in tissues of aging mice , 2009, Aging cell.

[65]  J. Campisi,et al.  Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion , 2009, Nature Cell Biology.

[66]  R. Weinberg,et al.  Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits , 2009, Nature Reviews Cancer.

[67]  C. Print,et al.  Autocrine human growth hormone promotes tumor angiogenesis in mammary carcinoma. , 2009, Endocrinology.

[68]  Adrian V. Lee,et al.  Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions. , 2009, Endocrine reviews.

[69]  Donald J. Johann,et al.  Cancer and the tumor microenvironment: a review of an essential relationship , 2009, Cancer Chemotherapy and Pharmacology.

[70]  F. D. D. Fagagna Living on a break: cellular senescence as a DNA-damage response , 2008, Nature Reviews Cancer.

[71]  R. Hakem,et al.  DNA‐damage repair; the good, the bad, and the ugly , 2008, The EMBO journal.

[72]  K. M. Mohankumar,et al.  The Contribution of Growth Hormone to Mammary Neoplasia , 2008, Journal of Mammary Gland Biology and Neoplasia.

[73]  P. Singal,et al.  Growth hormone in vascular pathology: neovascularization and expression of receptors is associated with cellular proliferation. , 2007, Anticancer research.

[74]  M. Waters,et al.  Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis , 2007, Proceedings of the National Academy of Sciences.

[75]  C. Carter-Su,et al.  Recent advances in growth hormone signaling , 2007, Reviews in Endocrine and Metabolic Disorders.

[76]  J. Iñiguez-Lluhí,et al.  Multiple mechanisms of growth hormone-regulated gene transcription. , 2007, Molecular genetics and metabolism.

[77]  R. Kanaar,et al.  DNA double-strand break repair: all's well that ends well. , 2006, Annual review of genetics.

[78]  M. Lavin,et al.  Involvement of novel autophosphorylation sites in ATM activation , 2006, The EMBO journal.

[79]  K. Kovitz,et al.  The expression of the pituitary growth hormone-releasing hormone receptor and its splice variants in normal and neoplastic human tissues. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[80]  P. Gluckman,et al.  Gene Expression Profiling to Identify Oncogenic Determinants of Autocrine Human Growth Hormone in Human Mammary Carcinoma* , 2005, Journal of Biological Chemistry.

[81]  Stephen P. Jackson,et al.  Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage , 2005, Nature.

[82]  C. Kenyon The Plasticity of Aging: Insights from Long-Lived Mutants , 2005, Cell.

[83]  R. Wanke,et al.  Accelerated growth and visceral lesions in transgenic mice expressing foreign genes of the growth hormone family: an overview , 1991, Pediatric Nephrology.

[84]  Yoshio Miki,et al.  Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage , 2004, Cancer science.

[85]  P. Gluckman,et al.  Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[86]  J. Barrett,et al.  Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks , 2004, Nature Cell Biology.

[87]  C. R. Leemans,et al.  A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. , 2003, Cancer research.

[88]  M. Waters,et al.  Growth hormone and colorectal carcinoma: localization of receptors. , 2000, In vivo.

[89]  G. Morel,et al.  Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone. , 1999, Experimental cell research.

[90]  L. Ellis,et al.  Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. , 1998, Cancer research.

[91]  M. Waters,et al.  Cellular expression of growth hormone and prolactin receptors in human breast disorders , 1998, International journal of cancer.

[92]  D. Donner,et al.  Induction of Vascular Endothelial Growth Factor by Insulin-like Growth Factor 1 in Colorectal Carcinoma* , 1996, The Journal of Biological Chemistry.

[93]  C. Wiedermann,et al.  Stimulation of monocyte chemotaxis by human growth hormone and its deactivation by somatostatin. , 1993, Blood.

[94]  O. Isaksson,et al.  Induction of mammary adenocarcinomas in metallothionein promoter‐human growth hormone transgenic mice , 1991, International journal of cancer.

[95]  M. Brandon,et al.  The expression of a metallothionein-ovine growth hormone fusion gene in transgenic mice does not impair fertility but results in pathological lesions in the liver. , 1989, Endocrinology.

[96]  D. Slaughter,et al.  “Field cancerization” in oral stratified squamous epithelium. Clinical implications of multicentric origin , 1953, Cancer.