Abstract
Non-pituitary growth hormone (npGH) expression is well established in extrapituitary tissues, but an understanding of the physiological role of npGH remains rather limited. Pro-tumorigenic npGH impacting the tumor microenvironment has been reviewed. We focus here on autocrine/paracrine npGH effects in non-tumorous tissues and discuss its mechanisms of action in the normal tissue microenvironment. We address the tissue-specific effects of npGH in regulating stem, endothelial, immune, and epithelial cells and highlight the related role of npGH-associated changes in tissue aging.
Introduction
Pituitary growth hormone (GH) secretion is highly regulated physiologically and declines with age (Hartman et al. 1993, Ho & Hoffman 1993). The contribution of non-pituitary GH (npGH) to the circulation is considered to be negligible (Harvey & Hull 1997) but is expressed in multiple tissues (Devesa et al. 2016a, Harvey et al. 2000a, Hattori 2009, Harvey et al. 2015) and may exhibit autocrine/paracrine actions that affect the tissue microenvironment. Many effects of pituitary GH are mediated by insulin-like growth factor 1 (IGF1), and the GH/IGF1 axis plays an important role in skeletal growth and lipid and carbohydrate metabolism (Isaksson et al. 1988, Moller & Jorgensen 2009). The membrane GH receptor (GHR) dimer signals through JAK2/STAT (Waters et al. 2006), as well as through Src/ERK (Ling et al. 2003, Rowlinson et al. 2008). GHR is also translocated to the nuclei of proliferating cells, for example in hepatocytes during tissue regeneration (Conway-Campbell et al. 2007) and in several cancers where nuclear GHR enhances proliferation (Brooks et al. 2008). During pregnancy, pituitary GH (GH-N) is suppressed while placental GH (GH-V) is induced. As GH mRNA and protein are also expressed in extrapituitary tissues (for reviews see (Kyle et al. 1981, Harvey & Hull 1997, Harvey et al. 2000a, Perez-Ibave et al. 2014, Chesnokova & Melmed 2019)), ubiquitous GHR expression facilitates autocrine or paracrine npGH acting on tissue physiology in situ.
GH exerts multiple actions favoring cell survival (Sanders et al. 2010) and tissue development (Nguyen et al. 1996, Sanders & Harvey 2004, Baudet et al. 2009). Extrapituitary GH mRNA transcripts are identical to those expressed in the anterior pituitary and share similar endonuclease restriction sites. Indeed, the GH cDNA nucleotide sequence in human mammary cells (Raccurt et al. 2002) and in human and rat lymphocytes is homologous with pituitary GH cDNA (Lin et al. 1993, Rohn & Weigent 1995, Liu et al. 1997), as is GH cDNA isolated from chicken immune (Render et al. 1995a) and neural (Render et al. 1995b) tissues. Although extrapituitary GH is produced in the brain, liver, kidney, bone cartilage, heart, colon, and retina ((Sundler et al. 1979, Daude et al. 2016) and reviewed in (Harvey et al. 2000b, Perez-Ibave et al. 2014)), understanding physiological npGH actions remains largely unexplored.
The question arises as to how npGH is regulated in peripheral tissue. While pituitary GH transcription is regulated by the Pit1 transcription factor, extrapituitary GH may be Pit1-independent and regulated by other transcription factors (Harvey et al. 2000b), such as, for example FOXF1, as shown for hGH-V (Lomenick et al. 2006). Pit1 is not ubiquitously expressed, and even when present, it may be unrelated to GH gene expression (Harvey et al. 2000b). For example, npGH is expressed in the bone marrow of Pit1-deficient Snell dwarf mice (Kooijman et al. 1997a, Harvey et al. 2000b), and placental hGH-V is expressed in Pit1-deficient patients unable to express pituitary GH (Melen et al. 1997). We found that colon cell npGH expression does not require Pit1 (unpublished data) and showed that GH can be transcriptionally induced by p53 in both pituitary and non-pituitary cells (Chesnokova et al. 2013).
npGH may act by inducing IGF1 or may elicit direct IGF1-independent effects in peripheral tissues. While the liver is the main production source of circulating IGF1, this protein can also be produced locally. Thus, GH is expressed in human cartilage (Kyle et al. 1981), and its growth-promoting effects in bone may be mediated by stimulating local IGF1 production (Schlechter et al. 1986). Both GH and IGF1 are synthesized in CNS during development but exhibit distinct overlapping roles in CNS function. Thus, despite stimulation of cellular PI3 kinase (PI3K) activity by each hormone, IGF1-stimulated (but not GH-stimulated) PI3K is predominantly associated with insulin receptor substrate (IRS1), while GH stimulation (but not IGF1 stimulation) of PI3K activity is maintained in IRS1-null cells. Further, while IRS1 is required for GH-stimulated STAT5-mediated transcription, IGF1 stimulates neither phosphorylation nor transactivation through STAT5 (Lobie et al. 2000). npGH is produced in the liver of hypophysectomized rats subjected to partial hepatectomy and directly induces hepatocyte growth factor (Ekberg et al. 1992, Devesa et al. 2016b). We showed that GH induced in colon cells in response to DNA damage and p53 upregulation suppresses DNA damage repair independent of IGF1 (Chesnokova et al. 2019a). Thus, whether acting through IGF1, or directly, npGH effects appear to be tissue- and cell-type specific.
npGH in the non-tumorous tissue microenvironment
The tissue microenvironment is composed of tissue-specific epithelial cell types and tissue-resident cell types including immune, mesenchymal, endothelial, and stem cells. These cells maintain tissue homeostasis, which may also be disrupted with a propensity for age-related or neoplastic changes. Knowledge of the microenvironment complexity and adaptability in response to external or internal insults is limited, especially for non-tumorous tissue. npGH is expressed in all cell types comprising the tissue microenvironment (Kyle et al. 1981, Harvey & Hull 1997, Harvey et al. 2000a, Hattori 2009, Perez-Ibave et al. 2014), and autocrine/paracrine npGH effects are likely tissue-specific.
npGH effects on stem/progenitor cells
npGH expression in fetal and adult brain enables a favorable milieu for developing neurons (Laron & Galatzer 1985, Donahue et al. 2002, Harvey et al. 2003, Sun et al. 2005a ). GH is expressed in brain regions where neurogenesis occurs, including the hippocampal dentate gyrus. npGH emanating from mature neurons and glia provides a favorable microenvironment for neuronal stem cell proliferation, differentiation, migration, and survival (Sun et al. 2005a, Donahue et al. 2006, Pathipati et al. 2011) while blocking GHR impedes neuronal precursor survival (Devesa et al. 2011). GH effects on proliferation could be mediated by IGF1, as IGF1 administration also induced the proliferation of rat neural progenitors (Aberg et al. 2000). GH-induced neuroprotection mediated by PI3K and MAPK, exerting pro-survival functions by inhibiting pro-apoptotic caspases 3 and 9, as well as GSK3β (Herrington & Carter-Su 2001). Abundant rat hippocampal GH is induced by 17β-estradiol (Donahue et al. 2006) and also by injury (Parent 2003) and npGH was suggested to promote neuron generation (Parent 2003, Blackmore et al. 2009). Homozygous Ames Prop1 knockout mice deficient in pituitary GH, prolactin, and thyrotrophin paradoxically exhibit increased hippocampal GH with increased numbers of hippocampal neurons (Sun et al. 2005b).
Mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) constitute a reserve to replace damaged and aged cells (Caplan 2005, da Silva Meirelles et al. 2006) and may differentiate into chondrocytes, myocytes, osteoblasts, and adipocytes (Pittenger et al. 2019). Activated npGH can affect MSC proliferation by triggering GHR internalization and nuclear translocation via STAT5 phosphorylation and initiation of cyclinD1 and cyclinD1/CDK4 to phosphorylate Rb and release E2F1, which, in turn, promotes MSC proliferation (Zheng et al. 2022). npGH can also suppress differentiation toward adipocytes in MSCs derived from human trabecular bone (Bolamperti et al. 2019).
In transgenic GH-overexpressing mice (bGH-Tg), expression of adipogenic C/EBPα and adiponectin as well as lipogenic lipoprotein lipase and acetyl-CoA carboxylase are reduced, whereas osteogenic factors are increased. Adipose tissues derived from these GH-overexpressing animals exhibit less lipid accumulation and lower levels of adipogenesis-related genes than do both wildtype and GHR knockout (GHRKO) mice (Olarescu et al. 2015). Wnt signaling plays a key role in MSC commitment by favoring osteogenesis at the expense of adipogenesis (Ross et al. 2000, Prestwich & Macdougald 2007). As transcription of AXIN2, a target of Wnt/β-catenin signaling, is increased in bGH-Tg mice, GH could modulate MSC fate toward osteogenesis (Olarescu et al. 2015). npGH may also synergize with BMP9, an osteogenesis activator, which directly stimulates GH transcription, suggesting an autocrine/paracrine activity for npGH. In an ectopic bone formation model, BMP9 and GH co-stimulation of MSCs induces more bone formation than does BMP9 alone, an effect inhibited by silencing GH or by JAK/STAT signaling pathway inhibitors (Huang et al. 2012).
Growth and regeneration of intestinal mucosa are dependent on crypt intestinal stem cells (ISCs), which produce transit-amplifying cells that migrate and differentiate into Paneth cells, absorptive enterocytes, goblet cells, and enteroendocrine lineages (Barker 2014). Lgr5, Bmi (Sangiorgi & Capecchi 2008), Msi1 (Potten et al. 2003), and EphB3 (Holmberg et al. 2006) are ISC stemness markers. GH induces Lgr5 in murine three-dimensional intestinal organoids, and in vivo GH increased Lgr5, Msi1, and EphB3 and increased crypt Ki67, a marker of proliferation (Chen et al. 2018). As npGH is markedly induced in colonocytes and in intestinal stroma cells in response to DNA damage (Chesnokova et al. 2021), it is plausible that local GH accelerates intestinal crypt stem cell proliferation, differentiation, and turnover. These npGH properties may protect intestinal mucosa during inflammation.
C2C12 myoblasts express npGH and GHR (Ogilvie et al. 2000, Sadowski et al. 2001), and autocrine GH/IGF1, but not exogenous GH, inhibits apoptosis, increases DNA synthesis, and retards myotube differentiation by suppressing AKT, required for myogenic conversion (Jiang et al. 1999), as well as α actin (Shimokawa et al. 1998) and troponin T (Meriane et al. 2000), both molecular markers for myogenic differentiation, (Segard et al. 2003).
Breast epithelium cells that express stem/progenitor cell markers express GHR. npGH secreted locally by normal human mammary epithelial cells upon progesterone stimulation increases stem- and early progenitor-cell proliferation. Expanded GHR-positive cell population occurs in ductal carcinoma in situ lesions (Lombardi et al. 2014).
Overall, available evidence suggests that npGH induces stem cell/progenitor proliferation with tissue-specific effects on cell differentiation.
npGH and the vascular system
GH contributes to diabetic retinopathy, the most frequent cause of adult blindness, characterized by increased vascular permeability and often by the growth of new retinal and vitreous blood vessels (Antonetti et al. 2012). npGH is synthesized and secreted in retinal ganglion cells (RGCs) and stimulates endothelial cell proliferation (Rymaszewski et al. 1991, Struman et al. 1999, Sanders et al. 2009). Within RGCs, GH has also been shown to promote cell survival by acting as an antiapoptotic factor by inducing STAT5 phosphorylation and increased BCL2 production. In a post-mortem study of humans with eye disease, most of the RGC positive for GH were negative for apoptotic markers, while RGC negative for GH were all positive for TUNEL labeling (Sanders et al. 2009). GHRs are detected in blood vessels and in endothelial cells (Clapp et al. 2009). In the microvascular endothelial-like cell line HMEC-1, autocrine/paracrine npGH promotes capillary-like tube formation as a consequence of VEGF-A expression. Blocking HMEC-1-derived npGH reduced cell survival, proliferation, migration/invasion, and tube formation (Brunet-Dunand et al. 2009). npGH may induce retinal blood vessels via IGF1, which is also expressed in retinal cells and is altered in response to hyperglycemia and hypoxia. Vitreous IGF1 is increased with diabetic retinopathy and may induce proliferation by stimulating Akt (Zheng & Quirion 2006, Xu et al. 2012), NFκB/AP1 (Chetty et al. 2006), and HIF1α/PI3K to induce VEGF (Akagi et al. 1998, Fukuda et al. 2002). Trials of GHR antagonists and antisense oligonucleotides, somatostatin receptor ligands, and IGF1R neutralizing antibodies aim to impair retinal neovascularization (Wilkinson-Berka et al. 2006) and a microenvironment favoring vascularization and aberrant cell growth.
npGH and the immune system
Immune-cell microenvironment components express GHR and npGH (Weigent et al. 1988). npGH is expressed in leukocytes and bone marrow-derived granulocytes (Hattori 2009), and npGH is secreted from human peripheral blood mononuclear cells (Hattori et al. 1990, Varma et al. 1993, Melen et al. 1997), neutrophils (Kooijman et al.1997b, Hattori et al. 1999), and T- and B-lymphocytes (Kao et al. 1992). As immune cells also produce GH-releasing hormone (Varma et al. 1993) and somatostatin (Lygren et al. 1984), npGH production and secretion from peripheral blood cells may be regulated (Hattori et al. 1994, Poppi et al. 2002). Unlike in the anterior pituitary, immune cells do not store GH in secretory granules and instead immediately release the hormone upon production. Moreover, secreted npGH enhances further lymphocyte npGH secretion (Hattori et al. 1993). Potential mechanisms of immune cell-derived npGH secretion affecting the microenvironment include phosphorylation of JAK/STAT3 and p125FAK, thus enforcing neutrophil adhesion to tissue inflammation sites (Ryu et al. 2000). Additionally, npGH, acting through PI3K/MAPK, acts as a monocyte hemoattractant to repair tissue damage (Kahler et al. 2001). Autocrine/paracrine GH induces the release of IFN-γ (Ivashkiv & Donlin 2014) from mononuclear cells (Malarkey et al. 2002). Furthermore, intrathymic GH injection modulates T-cell migration (Dardenne et al. 2009). npGH secreted from T-lymphocytes, even without stimulation, may participate in intrathymic T-cell differentiation and thymocyte migration (Savino & Dardenne 2010). Indeed, GH increases T-cell proliferation 2.5-fold in rat splenic cells (Postel-Vinay et al. 1997) and GH treatment reversed thymic atrophy in HIV-1 infected adults (Napolitano et al. 2008). T-cell lymphoma npGH overexpression reduced expression of pro-apoptotic BAD as well as caspases 3, 8, and 9, while anti-apoptotic BCL2 was induced. Inhibition of endogenous GH in lymphoma cells enhanced lymphoma apoptosis (Arnold & Weigent 2004).
GH modulates inflammatory responses (Huang et al. 2020), although reports are inconsistent. Acromegaly patients have increased proinflammatory cytokines including TNFα, IL1β, and IL6 (Longobardi et al. 1998, Arikan et al. 2009, Huang et al. 2022), with similar changes in healthy volunteers injected with GH (Andreassen et al. 2012), although the inflammatory marker CRP is decreased (Verhelst et al. 2013). Similarly, GH-transgenic animal models exhibit increased levels of circulating proinflammatory cytokines (Friedbichler et al. 2012). Inconsistent with proinflammatory GH effects, however, patients with adult GH deficiency exhibit increased inflammatory cytokines and CRP, and GH replacement yields anti-inflammatory effects (Huang et al. 2020). Further complicating the interpretation of these observations, older pituitary-deficient Snell dwarf mice and GHRKO mice have reduced tissue inflammation (Li et al. 2020, Young et al. 2020). GH treatment of aging animals reduces hepatic, pancreatic, and thymic inflammatory markers and reduced NFκB activation occurs in aging WT animals (Kireev et al. 2010, Cuesta et al. 2011, de Mello-Coelho et al. 2017).
npGH action in the colon microenvironment is more consistent in its anti-inflammatory role. npGH expression is markedly induced in colon plasma cells from patients with inflammatory bowel disease (IBD) (Chesnokova et al. 2016). In experimental models of colitis (Soendergaard et al. 2017), GH/STAT5 signaling promotes mucosal wound healing and improves barrier function during inflammation (Han et al. 2009, Gilbert et al. 2012), likely by inducing proliferation and suppressing apoptosis. GH, by inhibiting NFκB transcription factor, also suppresses TNFα (Han et al. 2007), thus interrupting proinflammatory cytokine effects on colon mucosa, an effect likely underlying anti-inflammatory GH actions in IBD patients (Slonim et al. 2000). We found GH signaling deficiency also results in severe colon inflammation and morbidity of GHRKO mice with acute colitis induced by dextran sodium sulfate (DSS) (unpublished data). Discordant pituitary and npGH action may be explained by direct GH effects vs those mediated through IGF1, insulin, glucose, or free fatty acids, which are normally induced with GH increase (Huang et al. 2022). Thus, high IGF1, but not GH, may activate cytokine production (Wolters et al. 2019). It is plausible that the effects of GH/IGF1 on inflammation differ from direct GH effects when IGF1 is not expressed or not locally regulated by GH.
npGH is expressed in macrophages (Hattori 2009, Huang et al. 2020), and autocrine/paracrine npGH in tissue microenvironment may modulate the macrophage gene signature (Lawrence & Natoli 2011, Soler Palacios et al. 2020). GH enriches anti-inflammatory gene expression, while proinflammatory genes are suppressed in monocyte-derived human macrophages and in macrophages from bGH-Tg mice with acute DSS-induced colitis. Yet multiple in vitro studies show both pro- and anti-inflammatory action of GH treatment in macrophages (Huang et al. 2022). An attractive hypothesis (Huang et al. 2022) postulates that in quiescent macrophages, GH and IGF1 polarize cells toward a proinflammatory phenotype. They promote anti-infection function through activation of STAT5 and MAPK/ERK, which regulate the production of TNFα and IL1β, whereas JAK/JNK triggers production the of TNFα, IFNγ, and IL-12, mediating proinflammatory macrophage responses to GH (Tripathi & Sodhi 2009). Thereafter, GH and IGF1 autocrine/paracrine action may limit pro-inflammatory responses through PI3K-mediated downregulation of activin A and upregulation of MAFB, supporting anti-inflammatory macrophages (Soler Palacios et al. 2020). In macrophage-specific GHRKO mice, increased NFκB activity and proinflammatory marker expression with an increased ratio of pro-/anti-inflammatory macrophages in adipose tissue occurred under high-fat diet (Lu et al. 2013). This effect could be mediated by decreased autocrine IGF1 macrophage production, as deletion of the IGF1 receptor led to reduced anti-inflammatory-related gene expression (Spadaro et al. 2017, Huang et al. 2022). Thus, paracrine npGH may attenuate macrophage microenvironment anti-inflammatory responses.
npGH in epithelial cells and stroma: implications for aging and the preneoplastic environment
Although aging-associated physiological and pathological changes leading to tissue fragility and neoplasia have been well studied (Martincorena et al. 2015), little is known about the early microenvironmental steps underlying these changes. Cancer may arise from a ‘cancerized condition’ (Curtius et al. 2018), with cancerization of the microenvironmental field mostly referring to the development of pro-tumorigenic genetic mutations (Slaughter et al. 1953, Braakhuis et al. 2003, Rubin 2011, Curtius et al. 2018). It is, however, now apparent that the progression of preneoplastic and neoplastic cells depends on surrounding microenvironmental changes (Marongiu et al. 2016); driver mutations alone may not be sufficient to induce aging or tumorigenesis, as they, too, require a permissive microenvironment of cellular promoting factors (Balmain 2020). Thus, based on more recent advances, we propose a broader understanding of field cancerization that encompasses both cells with an age-associated phenotype potentiating benign tissue growth that may progress to malignancy, as well as stromal processes enabling these early changes. Such phenotypic changes could include increased proliferation, decreased apoptosis, increased unrepaired DNA damage accumulation, chromosomal instability, and immune landscape changes. While the GH role in the cancer microenvironment and in cancer therapy resistance has been observed (Chhabra et al. 2011, Brittain et al. 2017, Perry et al. 2017, Basu & Kopchick 2019, Boguszewski & Boguszewski 2019, Chesnokova & Melmed 2019, Kopchick et al. 2022), it could be equally important to understand npGH action as contributing to an aging tissue milieu that may support the development of benign or malignant tumors.
Although GH is an important determinant of aging, its role remains enigmatic (Corpas et al. 1993, Bartke 2008, 2021, Anisimov & Bartke 2013, Aguiar-Oliveira & Bartke 2019, Colon et al. 2019). The GH/IGF1 system plays a key role during the lifespan, and pituitary GH secretion declines with age (Ho & Hoffman 1993), concomitant with age-related decreased protein synthesis, bone mass, and changes in body composition, all of which are classically attributed to GH decline. However, decreased GH/IGF1 signaling also has been shown to extend lifespan and reduce age-associated pathologies in experimental models (Anisimov & Bartke 2013, Basu et al. 2018, Bartke 2021, Qian et al. 2022), as well as increase insulin sensitivity and cancer prevention in human subjects (Aguiar-Oliveira & Bartke 2019). In contrast to decreased circulating GH, npGH expression remains abundant with aging in both non-tumorous human epithelial cells and in stromal fibroblasts but is low in colon samples derived from young individuals (Chesnokova et al. 2021). These intracellular changes could be explained by increased npGH in response to age-associated DNA damage accumulation (Chesnokova et al. 2021). DNA damage is associated with upregulation of p53, which induces npGH transcription (Chesnokova et al. 2013). Thus, it is likely that aging colon GH induction is p53-dependent. Indeed, npGH is induced in both epithelial and stromal cells after DNA-damaging radio- and chemotherapy and is also secreted from DNA-damaged normal human colon cells and intestinal organoids (Chesnokova et al. 2019a, 2021).
Aging is associated with senescent cell accumulation due to telomere shortening followed by DNA damage induction. Radiation, oxidative stress, and activated oncogenes induce DNA damage and trigger senescence when DNA is not repaired, and unrepaired DNA damage, in turn, is linked to chromosomal instability and malignant transformation (Schumacher et al. 2008, O'Driscoll 2012). Senescence is a protective mechanism for arresting the uncontrolled proliferation of potentially tumorigenic cells and also results in the depletion of viable cells (Sharpless & Sherr 2015, McHugh & Gil 2018, Gorgoulis et al. 2019, Di Micco et al. 2021). DNA damage and senescence are both hallmarks of aging (Lopez-Otin et al. 2023), and we found that npGH is induced and secreted from DNA-damaged senescent cells (Chesnokova et al. 2013). This may explain increased npGH expression in aging colon tissue concomitant with DNA damage accrual (Chesnokova et al. 2021), potentially resulting in chromosomal instability, as demonstrated for GH-secreting pituitary tumors (Ben-Shlomo et al. 2020).
Although acutely protective, stably senescent cells contribute to a pro-neoplastic environment by a senescence-associated secretory phenotype (SASP) comprising metalloproteases, IGF-binding proteins, cytokines, chemokines, and growth factors (Kuilman & Peeper 2009, Coppe et al. 2010). While SASP may be beneficial in activating immune responses to eliminate senescent cells (Krizhanovsky et al. 2008), it also may have pathological effects. Thus, SASP may induce senescence through paracrine action on neighboring cells, altering tissue homeostasis (Hoare & Narita 2013). Furthermore, SASP factors may alter the microenvironment by promoting low-grade inflammation, enhancing the proliferation of neighboring cells and facilitating the conversion of premalignant to malignant cells (Lee & Schmitt 2019). We found that npGH induced in senescent cells is a SASP component acting in an autocrine/paracrine manner (Chesnokova & Melmed 2022). npGH, induced and secreted in non-tumorous colon cells either as a result of acute DNA damage or as a result of senescence, may suppress p53 in neighboring cells (Chesnokova et al. 2019b), triggering senescence evasion with proliferation of post-senescent cells.
A complex network of DNA repair mechanisms minimizes damage and maintains cellular homeostasis. However, these mechanisms become less efficient with age (Feng et al. 2007, Gutierrez-Martinez et al. 2018, Vijg & Dong 2020, Stead & Bjedov 2021) and accumulation of genomic damage enhances susceptibility to cancer and other age-related diseases. Ineffective DNA repair accelerates tissue aging and underlies several progeroid syndromes that may also predispose to cancers. Thus, genomic instability is proposed to be a ‘meta-hallmark’ of both aging and cancer (Lopez-Otin et al. 2023).
npGH constrains the DNA damage pathway by inhibiting phosphorylation of DNA repair proteins including ATM, Chk2, and H2AX in neighboring cells, which, in turn, reduces DNA repair by both homologous and non-homologous end-joining, promoting DNA damage accumulation (Chesnokova et al. 2019b, 2021) and creating a pro-neoplastic environment in aging tissue. These observations may, to some extent, resolve the uncertainty surrounding the role of GH in aging. In addition to low IGF1, improved insulin sensitivity, and increased mitochondrial biogenesis (for review see (Bartke et al. 2016, Basu et al. 2018)), animal models with GH deficiency lacking not only circulating GH but also local GH signaling exhibit enhanced tissue DNA repair efficiency (Chesnokova & Melmed 2020) and may be resistant to age-associated microenvironment changes leading to neoplastic growth. Thus, GHRKO mice exhibit remarkably low cancer incidence (Zhou et al. 1997, Junnila et al. 2013, Basu et al. 2018) similar to Laron syndrome patients harboring inactivating GHR mutations (Guevara-Aguirre et al. 2011, Laron 2015, Bartke et al. 2016), while in acromegaly, unrepaired lymphocyte DNA damage (Bayram et al. 2014), high rates of colon polyps, enhanced soft tissue growth, and probably colon adenocarcinomas (Melmed 2009) occur, and bGH-Tg mice also develop tumors at an early age (Kopchick et al. 2014). These results provide potential mechanisms for observed decreased cancer development, as we observed that fibroblasts derived from Laron patients exhibit increased p53 expression and decreased proliferation (Chesnokova et al. 2016), while 24-month-old GHRKO mice also exhibit induced colon p53 associated with reduced unrepaired DNA damage (Chesnokova et al. 2021). When DNA damage persists, the cell may become senescent. In fact, GH-deficient and -resistant mice exhibited a lower senescent adipocyte burden. Conversely, concordant with deficient DNA damage repair caused by GH, GH-overexpressing and GH-treated mice accumulated more senescent adipose cells similar to observations in chronologically aged mice (Stout et al. 2014, 2015).
The ultimate effects of npGH may also depend on intermediate interacting factors. Thus, in addition to the antiapoptotic and pro-proliferative effects of npGH via p53 suppression as well as attenuation of DNA damage repair, the colon microenvironment could be primed by suppressing tumor suppressors APC and PTEN in non-tumorous human colon cells and 3D intestinal organoids (Chesnokova et al. 2016). APC is regulated by CDX2 (Olsen et al. 2013), and GH, by inducing ERK phosphorylation (Hodge et al. 1998, Ji et al. 2002), in turn, suppresses CDX2, resulting in decreased APC (Chesnokova et al. 2016). Low APC expression leads to β-catenin nuclear accumulation and increased Wnt signaling with the activation of pro-proliferative genes (Clevers & Nusse 2012). In human non-tumorous colon cells, GH induced β-catenin nuclear translocation, with subsequent activation of β-catenin–mediated transcriptional activity (Chesnokova et al. 2016). As PTEN blocks mTOR signaling (Carracedo & Pandolfi 2008), restraining cell proliferation, p53, APC, and PTEN suppression may underlie the pro-growth potentials of GH. By suppressing both p53 and PTEN, GH also abrogated apoptosis, thereby favoring cell survival (Zoncu et al. 2011).
Stromal reprogramming may also determine the age-associated microenvironment, and aberrant stroma and immune cell population composition occurs in pre-malignant disease (Curtius et al. 2018). npGH is expressed in colon epithelial and stromal cells (Chesnokova et al. 2016, 2021), and we found that co-culture of normal human colon fibroblasts secreting GH results in suppressed p53/p21 and increased proliferation of neighboring human normal colon epithelial cells growing on a Colon Intestine-Chip microfluidic device. Paracrine npGH also leads to epithelial cell DNA damage (Chesnokova et al. 2016, 2021).
Thus, npGH emanating from senescent epithelial cells, or from stromal cells as observed in the IBD colon (Chesnokova 2016), may have similar detrimental effects on the tissue microenvironment, promoting genomic instability and ultimately neoplasia.
Microenvironmental npGH may also trigger malignant transformation of preneoplastic or existing benign lesions. Sustained activation of both S6 kinase and AKT could trigger the progression of benign to rapidly growing malignant lesions (Stemmer et al. 2009), and we showed increased phosphorylation of S6 kinase in GH-treated cells followed by increased proliferation (Chesnokova et al. 2016). BMP family members expressed by stromal cells are important for cancer development risk (Tomlinson et al. 2011), and stromal GH induces BMP2/4 in human dental fibroblasts (Li et al. 1998). Similar to the effects of npGH on neuronal precursors, it also increases stem and early progenitor cell proliferation in normal breast epithelium (Lombardi et al. 2014).
npGH also enables the progression of normal mammary human tissue to benign lesion to premetastatic stage (fibroadenoma) to metastatic cancer (Raccurt et al. 2002). GH was detected in epithelial cells and also in cells of the reactive stroma, including myofibroblastic and myoepithelial cells, inflammatory lymphocytes, and endothelial cells in areas of neovascularization, and in both the epithelial and stromal compartments, expression was always stronger compared with that in adjacent normal tissue. hGH was also more abundant in proliferative disorders of the mammary gland compared with extracts derived from the normal mammary gland, suggesting a role for autocrine hGH in neoplastic mammary progression. npGH, acting through STAT5, induced DNA-damage inducible transcript 3 (CHOP), which enhances GH protection against apoptosis in a p38 MAPK-dependent manner (Mertani et al. 2001), and also induced anti-apoptotic p53-regulated placental PTGH-β (Graichen et al. 2002), suppressing apoptosis and inducing mammary cancer cell progression. Autocrine GH also increases telomerase activity in mammary carcinoma by upregulating αCP1 and αCP2, which stabilize TERT mRNA (Emerald et al. 2007), likely ensuring enhanced tumor cell proliferation. Moreover, autocrine GH induces trefoil factors that promote cell survival, motility, anchorage-independent growth, and cell transformation (Perry et al. 2008). Fibroblast-derived npGH triggered the transformation of an already cancerized lineage, as we showed increased migration and anchorage-independent growth of human colon adenocarcinoma HCT116 cells co-cultured with normal colon fibroblasts expressing npGH, likely by inducing early-stage EMT transcription factors Snai1 and Twist2 (Chesnokova et al. 2016) and permitting a permissive microenvironment toward a mesenchymal phenotype. By contrast, disrupted GH signaling attenuates progression from initiated prostate cells to intraepithelial neoplasia in T-antigen transgenic mice (Wang et al. 2005). Thus, induced npGH contributes to a microenvironment favoring age-associated tissue changes that may potentially support neoplastic development.
Conclusions
Our understanding of GH action has changed with time. More than simply a pituitary growth factor acting mostly by inducing IGF1, we now recognize GH as a multifunctional hormone involved in complex tissue- and cell-specific actions shaping the tissue microenvironment. From an evolutionary point of view, the fact that the GH gene evolved from a common GH-PRL gene by multiple duplications and conversion may allow other actions reflecting changes in GH functions in addition to its basic growth-promoting effects (Wallis 1997, Devesa & Devesa 2023).
Several in vivo examples underscore the significance of npGH effects. Thus, in homozygous Prop1 knockout (Ames) mice, hippocampal GH compensates for the absence of pituitary GH activating neurogenesis (Sun et al. 2005b). npGH is expressed in bone marrow of Pit1-deficient Snell mice lacking pituitary GH, promoting hematopoiesis (Kooijman et al. 1997a, Harvey et al. 2000b). In a patient with Pit1 deficiency, placental GH-V is expressed (Melen et al. 1997) contributing to fetal health during pregnancy. In all these cases, npGH appeared to serve as a backup for pituitary GH failure. However, in other instances, npGH manifests its own specific role in the tissue microenvironment.
GH appears to act by antagonistic pleiotropy, supporting growth and development at an early age, while facilitating the aging phenotype later in life as it is secreted from senescent cells, suppressing p53 and DNA repair and triggering genomic instability, all hallmarks of aging. Thus, the ‘somatopause’ described with declining circulating GH appears to be protective as it restrains adverse GH actions. However, local intracellular npGH, induced with age by environmental insults, ionizing radiation, chemotherapy, or oncogenes may reverse this protection, enabling a tissue microenvironment primed for age-associated pre-neoplastic changes.
npGH acts on stem/progenitor cells, affecting processes of cell differentiation and tissue repair, induces vascularization, and interacts with local immune cells. The conflicting results of npGH effects in the immune system may depend on the in vivo microenvironment, which is difficult to reproduce in vitro (Huang et al. 2022).
Unresolved issues and controversies precluding a better understanding of npGH actions in the aging microenvironment include effects on fibrosis (recently reviewed for circulating GH in (Kopchick et al. 2022)). Little is known about which pathways – other than DNA damage – are involved in npGH induction in normal, non-tumorous tissues. It is not clear what mechanisms underlie the tissue-specificity of npGH effects. For example, npGH triggers the proliferation and differentiation of neuronal stem cells, not creating tumors, but enhancing cognition in Ames mice (Sun et al. 2005a). At the same time, increased proliferation of mammary stem cells by npGH may be associated with creating pre-neoplastic and neoplastic lesions (Mertani et al. 2001, Raccurt et al. 2002). In some tissues, the action of exogenous GH differs from npGH action, as demonstrated in C2C12 stem cells (Segard et al. 2003), suggesting that this phenomenon may also be applicable for paracrine vs autocrine npGH effects. In this regard, it is important to note that post-translation modification of npGH protein could also be tissue specific. Post-translationally modified forms of hGH include N-acylated, deamidated, and O-glycosylated forms of monomeric GH, as well as non-covalent and disulfide-linked oligomers up to pentameric GH (Baumann 1991). For example, in immune cells, higher molecular weight (48–10035 kDa) oligomer GH isoforms appear in response to oxidative stress, with specific nuclear 65 and 48 kDa detected (Weigent 2011). Thus, oligomeric isoforms may exert biological activity distinct from monomeric pituitary 22 kDa. Furthermore, npGH actions in each tissue and cell type may depend on its ability to induce local IGF1, which may have independent tissue microenvironment actions. Although, in contrast to GH, blocking IGF1/IGF1R increased DNA damage repair, these experiments were performed mostly in tumorous cell lines (Chesnokova & Melmed 2020). In non-tumorous colon cells, blocking colon IGF1R did not disrupt the suppressive effects of GH on DNA damage (Chesnokova et al. 2019a).
Notwithstanding the apparent inconsistencies, elucidating available information on npGH action in the normal and diseased microenvironment has enhanced knowledge and added new perspectives to our understanding of mechanisms underlying normal tissue homeostasis and aging processes engendered by GHR signaling.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work was supported by the National Institutes of Health (grant number AG070211 and DK113998), Pfizer, Inc. (grant number 61421295), and the Doris Factor Molecular Endocrinology Laboratory at Cedars-Sinai.
References
Aberg MA, Aberg ND, Hedbacker H, Oscarsson J & & Eriksson PS 2000 Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. Journal of Neuroscience 20 2896–2903. (https://doi.org/10.1523/JNEUROSCI.20-08-02896.2000)
Aguiar-Oliveira MH & & Bartke A 2019 Growth hormone deficiency: health and longevity. Endocrine Reviews 40 575–601. (https://doi.org/10.1210/er.2018-00216)
Akagi Y, Liu W, Zebrowski B, Xie K & & Ellis LM 1998 Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. Cancer Research 58 4008–4014.
Andreassen M, Frystyk J, Faber J & & Kristensen LØ 2012 GH activity and markers of inflammation: a crossover study in healthy volunteers treated with GH and a GH receptor antagonist. European Journal of Endocrinology 166 811–819. (https://doi.org/10.1530/EJE-11-1009)
Anisimov VN & & Bartke A 2013 The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer. Critical Reviews in Oncology/Hematology 87 201–223. (https://doi.org/10.1016/j.critrevonc.2013.01.005)
Antonetti DA, Klein R & & Gardner TW 2012 Diabetic retinopathy. New England Journal of Medicine 366 1227–1239. (https://doi.org/10.1056/NEJMra1005073)
Arikan S, Bahceci M, Tuzcu A & & Gokalp D 2009 Serum tumour necrosis factor-alpha and interleukin-8 levels in acromegalic patients: acromegaly may be associated with moderate inflammation. Clinical Endocrinology 70 498–499. (https://doi.org/10.1111/j.1365-2265.2008.03362.x)
Arnold RE & & Weigent DA 2004 The inhibition of apoptosis in EL4 lymphoma cells overexpressing growth hormone. Neuroimmunomodulation 11 149–159. (https://doi.org/10.1159/000076764)
Balmain A 2020 The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk. Nature Genetics 52 1139–1143. (https://doi.org/10.1038/s41588-020-00727-5)
Barker N 2014 Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nature Reviews. Molecular Cell Biology 15 19–33. (https://doi.org/10.1038/nrm3721)
Bartke A 2008 Growth hormone and aging: a challenging controversy. Clinical Interventions in Aging 3 659–665. (https://doi.org/10.2147/cia.s3697)
Bartke A 2021 Growth hormone and aging. Reviews in Endocrine and Metabolic Disorders 22 71–80. (https://doi.org/10.1007/s11154-020-09593-2)
Bartke A, List EO & & Kopchick JJ 2016 The somatotropic axis and aging: benefits of endocrine defects. Growth Hormone and IGF Research 27 41–45. (https://doi.org/10.1016/j.ghir.2016.02.002)
Basu R & & Kopchick JJ 2019 The effects of growth hormone on therapy resistance in cancer. Cancer Drug Resistance 2 827–846. (https://doi.org/10.20517/cdr.2019.27)
Basu R, Qian Y & & Kopchick JJ 2018 Mechanisms in endocrinology: lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects? European Journal of Endocrinology 178 R155–R181. (https://doi.org/10.1530/EJE-18-0018)
Baudet ML, Rattray D, Martin BT & & Harvey S 2009 Growth hormone promotes axon growth in the developing nervous system. Endocrinology 150 2758–2766. (https://doi.org/10.1210/en.2008-1242)
Baumann G 1991 Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins. Endocrine Reviews 12 424–449. (https://doi.org/10.1210/edrv-12-4-424)
Bayram F, Bitgen N, Donmez-Altuntas H, Cakir I, Hamurcu Z, Sahin F, Simsek Y & & Baskol G 2014 Increased genome instability and oxidative DNA damage and their association with IGF-1 levels in patients with active acromegaly. Growth Hormone and IGF Research 24 29–34. (https://doi.org/10.1016/j.ghir.2013.12.002)
Ben-Shlomo A, Deng N, Ding E, Yamamoto M, Mamelak A, Chesnokova V, Labadzhyan A & & Melmed S 2020 DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas. Journal of Clinical Investigation 130 5738–5755. (https://doi.org/10.1172/JCI138540)
Blackmore DG, Golmohammadi MG, Large B, Waters MJ & & Rietze RL 2009 Exercise increases neural stem cell number in a growth hormone-dependent manner, augmenting the regenerative response in aged mice. Stem Cells 27 2044–2052. (https://doi.org/10.1002/stem.120)
Boguszewski CL & & Boguszewski MCDS 2019 Growth hormone's links to cancer. Endocrine Reviews 40 558–574. (https://doi.org/10.1210/er.2018-00166)
Bolamperti S, Guidobono F, Rubinacci A & & Villa I 2019 The role of growth hormone in mesenchymal stem cell commitment. International Journal of Molecular Sciences 20 5264. (https://doi.org/10.3390/ijms20215264)
Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR & & Brakenhoff RH 2003 A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Research 63 1727–1730.
Brittain AL, Basu R, Qian Y & & Kopchick JJ 2017 Growth hormone and the epithelial-to-mesenchymal transition. Journal of Clinical Endocrinology and Metabolism 102 3662–3673. (https://doi.org/10.1210/jc.2017-01000)
Brooks AJ, Wooh JW, Tunny KA & & Waters MJ 2008 Growth hormone receptor; mechanism of action. International Journal of Biochemistry and Cell Biology 40 1984–1989. (https://doi.org/10.1016/j.biocel.2007.07.008)
Brunet-Dunand SE, Vouyovitch C, Araneda S, Pandey V, Vidal LJ, Print C, Mertani HC, Lobie PE & & Perry JK 2009 Autocrine human growth hormone promotes tumor angiogenesis in mammary carcinoma. Endocrinology 150 1341–1352. (https://doi.org/10.1210/en.2008-0608)
Caplan AI 2005 Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Engineering 11 1198–1211. (https://doi.org/10.1089/ten.2005.11.1198)
Carracedo A & & Pandolfi PP 2008 The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 27 5527–5541. (https://doi.org/10.1038/onc.2008.247)
Chen Y, Tseng SH, Yao CL, Li C & & Tsai YH 2018 Distinct effects of growth hormone and glutamine on activation of intestinal stem cells. JPEN. Journal of Parenteral and Enteral Nutrition 42 642–651. (https://doi.org/10.1177/0148607117709435)
Chesnokova V & & Melmed S 2019 Growth hormone in the tumor microenvironment. Archives of Endocrinology and Metabolism 63 568–575. (https://doi.org/10.20945/2359-3997000000186)
Chesnokova V & & Melmed S 2020 Peptide hormone regulation of DNA damage responses. Endocrine Reviews 41 bnaa009. (https://doi.org/10.1210/endrev/bnaa009)
Chesnokova V & & Melmed S 2022 GH and senescence: a new understanding of adult GH action. Journal of the Endocrine Society 6 bvab177. (https://doi.org/10.1210/jendso/bvab177)
Chesnokova V, Zhou C, Ben-Shlomo A, Zonis S, Tani Y, Ren SG & & Melmed S 2013 Growth hormone is a cellular senescence target in pituitary and nonpituitary cells. PNAS 110 E3331–E3339. (https://doi.org/10.1073/pnas.1310589110)
Chesnokova V, Zonis S, Apostolou A, Estrada HQ, Knott S, Wawrowsky K, Michelsen K, Ben-Shlomo A, Barrett R, Gorbunova V, et al.2021 Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage. Cell Reports 37 110068. (https://doi.org/10.1016/j.celrep.2021.110068)
Chesnokova V, Zonis S, Barrett R, Kameda H, Wawrowsky K, Ben-Shlomo A, Yamamoto M, Gleeson J, Bresee C, Gorbunova V, et al.2019b Excess growth hormone suppresses DNA damage repair in epithelial cells. JCI Insight 4 e125762. (https://doi.org/10.1172/jci.insight.125762)
Chesnokova V, Zonis S, Barrett RJ, Gleeson JP & & Melmed S 2019a Growth hormone induces colon DNA damage independent of IGF-1. Endocrinology 160 1439–1447. (https://doi.org/10.1210/en.2019-00132)
Chesnokova V, Zonis S, Zhou C, Recouvreux MV, Ben-Shlomo A, Araki T, Barrett R, Workman M, Wawrowsky K, Ljubimov VA, et al.2016 Growth hormone is permissive for neoplastic colon growth. PNAS 113 E3250–E3259. (https://doi.org/10.1073/pnas.1600561113)
Chetty A, Cao GJ & & Nielsen HC 2006 Insulin-like growth factor-I signaling mechanisms, type I collagen and alpha smooth muscle actin in human fetal lung fibroblasts. Pediatric Research 60 389–394. (https://doi.org/10.1203/01.pdr.0000238257.15502.f4)
Chhabra Y, Waters MJ & & Brooks AJ 2011 Role of the growth hormone-IGF-1 axis in cancer. Expert Review of Endocrinology and Metabolism 6 71–84. (https://doi.org/10.1586/eem.10.73)
Clapp C, Thebault S, Jeziorski MC & & Martinez De La Escalera G 2009 Peptide hormone regulation of angiogenesis. Physiological Reviews 89 1177–1215. (https://doi.org/10.1152/physrev.00024.2009)
Clevers H & & Nusse R 2012 Wnt/beta-catenin signaling and disease. Cell 149 1192–1205. (https://doi.org/10.1016/j.cell.2012.05.012)
Colon G, Saccon T, Schneider A, Cavalcante MB, Huffman DM, Berryman D, List E, Ikeno Y, Musi N, Bartke A, et al.2019 The enigmatic role of growth hormone in age-related diseases, cognition, and longevity. GeroScience 41 759–774. (https://doi.org/10.1007/s11357-019-00096-w)
Conway-Campbell BL, Wooh JW, Brooks AJ, Gordon D, Brown RJ, Lichanska AM, Chin HS, Barton CL, Boyle GM, Parsons PG, et al.2007 Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis. PNAS 104 13331–13336. (https://doi.org/10.1073/pnas.0600181104)
Coppe JP, Desprez PY, Krtolica A & & Campisi J 2010 The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathology 5 99–118. (https://doi.org/10.1146/annurev-pathol-121808-102144)
Corpas E, Harman SM & & Blackman MR 1993 Human growth hormone and human aging. Endocrine Reviews 14 20–39. (https://doi.org/10.1210/edrv-14-1-20)
Cuesta S, Kireev R, Garcia C, Forman K, Vara E & & Tresguerres JA 2011 Effect of growth hormone treatment on pancreatic inflammation, oxidative stress, and apoptosis related to aging in SAMP8 mice. Rejuvenation Research 14 501–512. (https://doi.org/10.1089/rej.2011.1166)
Curtius K, Wright NA & & Graham TA 2018 An evolutionary perspective on field cancerization. Nature Reviews. Cancer 18 19–32. (https://doi.org/10.1038/nrc.2017.102)
da Silva Meirelles L, Chagastelles PC & & Nardi NB 2006 Mesenchymal stem cells reside in virtually all post-natal organs and tissues. Journal of Cell Science 119 2204–2213. (https://doi.org/10.1242/jcs.02932)
Dardenne M, Smaniotto S, de Mello-Coelho V, Villa-Verde DM & & Savino W 2009 Growth hormone modulates migration of developing T cells. Annals of the New York Academy of Sciences 1153 1–5. (https://doi.org/10.1111/j.1749-6632.2008.03977.x)
Daude N, Lee I, Kim TK, Janus C, Glaves JP, Gapeshina H, Yang J, Sykes BD, Carlson GA, Hood LE, et al.2016 A common phenotype polymorphism in mammalian brains defined by concomitant production of prolactin and growth hormone. PLoS One 11 e0149410. (https://doi.org/10.1371/journal.pone.0149410)
de Mello-Coelho V, Cutler RG, Bunbury A, Tammara A, Mattson MP & & Taub DD 2017 Age-associated alterations in the levels of cytotoxic lipid molecular species and oxidative stress in the murine thymus are reduced by growth hormone treatment. Mechanisms of Ageing and Development 167 46–55. (https://doi.org/10.1016/j.mad.2017.08.015)
Devesa J, Almenglo C & & Devesa P 2016a Multiple effects of growth hormone in the body: is it really the hormone for growth? Clinical Medicine Insights. Endocrinology and Diabetes 9 47–71. (https://doi.org/10.4137/CMED.S38201)
Devesa J & & Devesa P 2023 Growth hormone gene family and its evolution. In Growth Hormone - New Insights. Bernardo-Filho M, da Cunha de Sá-Caputo D, de Oliveira Maranhão TM, & Taiar R, Eds. Rijeka: IntechOpen.
Devesa J, Lema H, Zas E, Munin B, Taboada P & & Devesa P 2016b Learning and memory recoveries in a young girl treated with growth hormone and neurorehabilitation. Journal of Clinical Medicine 5 14. (https://doi.org/10.3390/jcm5020014)
Devesa P, Reimunde P, Gallego R, Devesa J & & Arce VM 2011 Growth hormone (GH) treatment may cooperate with locally-produced GH in increasing the proliferative response of hippocampal progenitors to kainate-induced injury. Brain Injury 25 503–510. (https://doi.org/10.3109/02699052.2011.559611)
Di Micco R, Krizhanovsky V, Baker D & & d'Adda di Fagagna F 2021 Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature Reviews. Molecular Cell Biology 22 75–95. (https://doi.org/10.1038/s41580-020-00314-w)
Donahue CP, Jensen RV, Ochiishi T, Eisenstein I, Zhao M, Shors T & & Kosik KS 2002 Transcriptional profiling reveals regulated genes in the hippocampus during memory formation. Hippocampus 12 821–833. (https://doi.org/10.1002/hipo.10058)
Donahue CP, Kosik KS & & Shors TJ 2006 Growth hormone is produced within the hippocampus where it responds to age, sex, and stress. PNAS 103 6031–6036. (https://doi.org/10.1073/pnas.0507776103)
Ekberg S, Luther M, Nakamura T & & Jansson JO 1992 Growth hormone promotes early initiation of hepatocyte growth factor gene expression in the liver of hypophysectomized rats after partial hepatectomy. Journal of Endocrinology 135 59–67. (https://doi.org/10.1677/joe.0.1350059)
Emerald BS, Chen Y, Zhu T, Zhu Z, Lee KO, Gluckman PD & & Lobie PE 2007 AlphaCP1 mediates stabilization of hTERT mRNA by autocrine human growth hormone. Journal of Biological Chemistry 282 680–690. (https://doi.org/10.1074/jbc.M600224200)
Feng Z, Hu W, Teresky AK, Hernando E, Cordon-Cardo C & & Levine AJ 2007 Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations. PNAS 104 16633–16638. (https://doi.org/10.1073/pnas.0708043104)
Friedbichler K, Themanns M, Mueller KM, Schlederer M, Kornfeld JW, Terracciano LM, Kozlov AV, Haindl S, Kenner L, Kolbe T, et al.2012 Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer. Hepatology 55 941–952. (https://doi.org/10.1002/hep.24765)
Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM & & Semenza GL 2002 Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. Journal of Biological Chemistry 277 38205–38211. (https://doi.org/10.1074/jbc.M203781200)
Gilbert S, Zhang R, Denson L, Moriggl R, Steinbrecher K, Shroyer N, Lin J & & Han X 2012 Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation. EMBO Molecular Medicine 4 109–124. (https://doi.org/10.1002/emmm.201100192)
Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, Campisi J, Collado M, Evangelou K, Ferbeyre G, et al.2019 Cellular senescence: defining a path forward. Cell 179 813–827. (https://doi.org/10.1016/j.cell.2019.10.005)
Graichen R, Liu D, Sun Y, Lee KO & & Lobie PE 2002 Autocrine human growth hormone inhibits placental transforming growth factor-beta gene transcription to prevent apoptosis and allow cell cycle progression of human mammary carcinoma cells. Journal of Biological Chemistry 277 26662–26672. (https://doi.org/10.1074/jbc.M109931200)
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, et al.2011 Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Science Translational Medicine 3 70ra13. (https://doi.org/10.1126/scitranslmed.3001845)
Gutierrez-Martinez P, Hogdal L, Nagai M, Kruta M, Singh R, Sarosiek K, Nussenzweig A, Beerman I, Letai A & & Rossi DJ 2018 Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nature Cell Biology 20 413–421. (https://doi.org/10.1038/s41556-018-0054-y)
Han X, Benight N, Osuntokun B, Loesch K, Frank SJ & & Denson LA 2007 Tumour necrosis factor alpha blockade induces an anti-inflammatory growth hormone signalling pathway in experimental colitis. Gut 56 73–81. (https://doi.org/10.1136/gut.2006.094490)
Han X, Ren X, Jurickova I, Groschwitz K, Pasternak BA, Xu H, Wilson TA, Hogan SP & & Denson LA 2009 Regulation of intestinal barrier function by signal transducer and activator of transcription 5b. Gut 58 49–58. (https://doi.org/10.1136/gut.2007.145094)
Hartman ML, Iranmanesh A, Thorner MO & & Veldhuis JD 1993 Evaluation of pulsatile patterns of growth hormone release in humans: a brief review. American Journal of Human Biology 5 603–614. (https://doi.org/10.1002/ajhb.1310050603)
Harvey S, Azumaya Y & & Hull KL 2000b Pituitary and extrapituitary growth hormone: Pit-1 dependence? Canadian Journal of Physiology and Pharmacology 78 1013–1028. (https://doi.org/10.1139/y00-095)
Harvey S & & Hull KL 1997 Growth hormone. A paracrine growth factor? Endocrine 7 267–279. (https://doi.org/10.1007/BF02801319)
Harvey S, Johnson CD & & Sanders EJ 2000a Extra-pituitary growth hormone in peripheral tissues of early chick embryos. Journal of Endocrinology 166 489–502. (https://doi.org/10.1677/joe.0.1660489)
Harvey S, Kakebeeke M, Murphy AE & & Sanders EJ 2003 Growth hormone in the nervous system: autocrine or paracrine roles in retinal function? Canadian Journal of Physiology and Pharmacology 81 371–384. (https://doi.org/10.1139/y03-034)
Harvey S, Martinez-Moreno CG, Luna M & & Aramburo C 2015 Autocrine/paracrine roles of extrapituitary growth hormone and prolactin in health and disease: an overview. General and Comparative Endocrinology 220 103–111. (https://doi.org/10.1016/j.ygcen.2014.11.004)
Hattori N 2009 Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system. Growth Hormone and IGF Research 19 187–197. (https://doi.org/10.1016/j.ghir.2008.12.001)
Hattori N, Ikekubo K, Ishihara T, Moridera K, Hino M & & Kurahachi H 1994 Spontaneous growth hormone (GH) secretion by unstimulated human lymphocytes and the effects of GH-releasing hormone and somatostatin. Journal of Clinical Endocrinology and Metabolism 79 1678–1680. (https://doi.org/10.1210/jcem.79.6.7989474)
Hattori N, Kitagawa K & & Inagaki C 1999 Human lymphocytes express hGH-N gene transcripts of 22kDa, 20kDa and minor forms of GH, but not hGH-V gene. European Journal of Endocrinology 141 413–418. (https://doi.org/10.1530/eje.0.1410413)
Hattori N, Shimatsu A, Sugita M, Kumagai S & & Imura H 1990 Immunoreactive growth hormone (GH) secretion by human lymphocytes: augmented release by exogenous GH. Biochemical and Biophysical Research Communications 168 396–401. (https://doi.org/10.1016/0006-291x(9092334-v)
Hattori N, Shimomura K, Ishihara T, Moridera K, Hino M, Ikekubo K & & Kurahachi H 1993 Growth hormone (GH) secretion from human lymphocytes is up-regulated by GH, but not affected by insulin-like growth factor-I. Journal of Clinical Endocrinology and Metabolism 76 937–939. (https://doi.org/10.1210/jcem.76.4.8473409)
Herrington J & & Carter-Su C 2001 Signaling pathways activated by the growth hormone receptor. Trends in Endocrinology and Metabolism 12 252–257. (https://doi.org/10.1016/s1043-2760(0100423-4)
Ho KK & & Hoffman DM 1993 Aging and growth hormone. Hormone Research 40 80–86. (https://doi.org/10.1159/000183771)
Hoare M & & Narita M 2013 Transmitting senescence to the cell neighbourhood. Nature Cell Biology 15 887–889. (https://doi.org/10.1038/ncb2811)
Hodge C, Liao J, Stofega M, Guan K, Carter-Su C & & Schwartz J 1998 Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. Journal of Biological Chemistry 273 31327–31336. (https://doi.org/10.1074/jbc.273.47.31327)
Holmberg J, Genander M, Halford MM, Anneren C, Sondell M, Chumley MJ, Silvany RE, Henkemeyer M & & Frisen J 2006 EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125 1151–1163. (https://doi.org/10.1016/j.cell.2006.04.030)
Huang E, Zhu G, Jiang W, Yang K, Gao Y, Luo Q, Gao JL, Kim SH, Liu X, Li M, et al.2012 Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/IGF1 pathway in murine multilineage cells. Journal of Bone and Mineral Research 27 1566–1575. (https://doi.org/10.1002/jbmr.1622)
Huang Z, Huang L, Waters MJ & & Chen C 2020 Insulin and growth hormone balance: implications for obesity. Trends in Endocrinology and Metabolism 31 642–654. (https://doi.org/10.1016/j.tem.2020.04.005)
Huang Z, Xiao L, Xiao Y & & Chen C 2022 The modulatory role of growth hormone in inflammation and macrophage activation. Endocrinology 163 bqac088. (https://doi.org/10.1210/endocr/bqac088)
Isaksson OG, Lindahl A, Nilsson A & & Isgaard J 1988 Action of growth hormone: current views. Acta Paediatrica Scandinavica. Supplement 343 12–18. (https://doi.org/10.1111/j.1651-2227.1988.tb10794.x)
Ivashkiv LB & & Donlin LT 2014 Regulation of type I interferon responses. Nature Reviews. Immunology 14 36–49. (https://doi.org/10.1038/nri3581)
Ji S, Frank SJ & & Messina JL 2002 Growth hormone-induced differential desensitization of STAT5, ERK, and Akt phosphorylation. Journal of Biological Chemistry 277 28384–28393. (https://doi.org/10.1074/jbc.m111723200)
Jiang BH, Aoki M, Zheng JZ, Li J & & Vogt PK 1999 Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B. PNAS 96 2077–2081. (https://doi.org/10.1073/pnas.96.5.2077)
Junnila RK, List EO, Berryman DE, Murrey JW & & Kopchick JJ 2013 The GH/IGF-1 axis in ageing and longevity. Nature Reviews. Endocrinology 9 366–376. (https://doi.org/10.1038/nrendo.2013.67)
Kahler CM, Pischel AB, Haller T, Meierhofer C, Djanani A, Kaufmann G & & Wiedermann CJ 2001 Signal transduction pathways in directed migration of human monocytes induced by human growth hormone in vitro. International Immunopharmacology 1 1351–1361. (https://doi.org/10.1016/s1567-5769(0100067-4)
Kao TL, Harbour DV & & Meyer WJ 3rd 1992 Immunoreactive growth hormone production by cultured lymphocytes. Annals of the New York Academy of Sciences 650 179–181. (https://doi.org/10.1111/j.1749-6632.1992.tb49117.x)
Kireev RA, Tresguerres AC, Garcia C, Borras C, Ariznavarreta C, Vara E, Vina J & & Tresguerres JA 2010 Hormonal regulation of pro-inflammatory and lipid peroxidation processes in liver of old ovariectomized female rats. Biogerontology 11 229–243. (https://doi.org/10.1007/s10522-009-9242-2)
Kooijman R, Berus D, Malur A, Delhase M & & Hooghe-Peters EL 1997b Human neutrophils express GH-N gene transcripts and the pituitary transcription factor Pit-1b. Endocrinology 138 4481–4484. (https://doi.org/10.1210/endo.138.10.5568)
Kooijman R, Malur A, Van Buul-Offers SC & & Hooghe-Peters EL 1997a Growth hormone expression in murine bone marrow cells is independent of the pituitary transcription factor Pit-1. Endocrinology 138 3949–3955. (https://doi.org/10.1210/endo.138.9.5414)
Kopchick JJ, Basu R, Berryman DE, Jorgensen JOL, Johannsson G & & Puri V 2022 Covert actions of growth hormone: fibrosis, cardiovascular diseases and cancer. Nature Reviews. Endocrinology 18 558–573. (https://doi.org/10.1038/s41574-022-00702-6)
Kopchick JJ, List EO, Kelder B, Gosney ES & & Berryman DE 2014 Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications. Molecular and Cellular Endocrinology 386 34–45. (https://doi.org/10.1016/j.mce.2013.09.004)
Krizhanovsky V, Xue W, Zender L, Yon M, Hernando E & & Lowe SW 2008 Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology. Cold Spring Harbor Symposia on Quantitative Biology 73 513–522. (https://doi.org/10.1101/sqb.2008.73.048)
Kuilman T & & Peeper DS 2009 Senescence-messaging secretome: SMS-ing cellular stress. Nature Reviews. Cancer 9 81–94. (https://doi.org/10.1038/nrc2560)
Kyle CV, Evans MC & & Odell WD 1981 Growth hormone-like material in normal human tissues. Journal of Clinical Endocrinology and Metabolism 53 1138–1144. (https://doi.org/10.1210/jcem-53-6-1138)
Laron Z 2015 Lessons from 50 years of study of Laron syndrome. Endocrine Practice 21 1395–1402. (https://doi.org/10.4158/EP15939.RA)
Laron Z & & Galatzer A 1985 Growth hormone, somatomedin and prolactin--relationship to brain function. Brain and Development 7 559–567. (https://doi.org/10.1016/s0387-7604(8580001-2)
Lawrence T & & Natoli G 2011 Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nature Reviews. Immunology 11 750–761. (https://doi.org/10.1038/nri3088)
Lee S & & Schmitt CA 2019 The dynamic nature of senescence in cancer. Nature Cell Biology 21 94–101. (https://doi.org/10.1038/s41556-018-0249-2)
Li H, Bartold PM, Zhang CZ, Clarkson RW, Young WG & & Waters MJ 1998 Growth hormone and insulin-like growth factor I induce bone morphogenetic proteins 2 and 4: a mediator role in bone and tooth formation? Endocrinology 139 3855–3862. (https://doi.org/10.1210/endo.139.9.6211)
Li X, Frazier JA, Spahiu E, McPherson M & & Miller RA 2020 Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice. Aging (Albany NY) 12 8766–8789. (https://doi.org/10.18632/aging.103380)
Lin SC, Lin CR, Gukovsky I, Lusis AJ, Sawchenko PE & & Rosenfeld MG 1993 Molecular basis of the little mouse phenotype and implications for cell type-specific growth. Nature 364 208–213. (https://doi.org/10.1038/364208a0)
Ling L, Zhu T & & Lobie PE 2003 Src-CrkII-C3G-dependent activation of Rap1 switches growth hormone-stimulated p44/42 MAP kinase and JNK/SAPK activities. Journal of Biological Chemistry 278 27301–27311. (https://doi.org/10.1074/jbc.M302516200)
Liu J, Zheng D, Deng J, Xiao S, Liu S & & Shi Y 1997 Immunoreactive growth hormone in human peripheral T lymphocytes: encoding sequence of cDNA identical to that of the pituitary human growth hormone. Chinese Medical Journal 110 362–365.
Lobie PE, Zhu T, Graichen R & & Goh EL 2000 Growth hormone, insulin-like growth factor I and the CNS: localization, function and mechanism of action. Growth Hormone and IGF Research 10(Supplement B) S51–S56. (https://doi.org/10.1016/s1096-6374(0080010-6)
Lombardi S, Honeth G, Ginestier C, Shinomiya I, Marlow R, Buchupalli B, Gazinska P, Brown J, Catchpole S, Liu S, et al.2014 Growth hormone is secreted by normal breast epithelium upon progesterone stimulation and increases proliferation of stem/progenitor cells. Stem Cell Reports 2 780–793. (https://doi.org/10.1016/j.stemcr.2014.05.005)
Lomenick JP, Hubert MA & & Handwerger S 2006 Transcription factor FOXF1 regulates growth hormone variant gene expression. American Journal of Physiology. Endocrinology and Metabolism 291 E947–E951. (https://doi.org/10.1152/ajpendo.00128.2006)
Longobardi S, Di Somma C, Di Rella F, Angelillo N, Ferone D, Colao A, Merola B & & Lombardi G 1998 Bone mineral density and circulating cytokines in patients with acromegaly. Journal of Endocrinological Investigation 21 688–693. (https://doi.org/10.1007/BF03350799)
Lopez-Otin C, Pietrocola F, Roiz-Valle D, Galluzzi L & & Kroemer G 2023 Meta-hallmarks of aging and cancer. Cell Metabolism 35 12–35. (https://doi.org/10.1016/j.cmet.2022.11.001)
Lu C, Kumar PA, Sun J, Aggarwal A, Fan Y, Sperling MA, Lumeng CN & & Menon RK 2013 Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity. Journal of Biological Chemistry 288 15725–15735. (https://doi.org/10.1074/jbc.M113.460212)
Lygren I, Revhaug A, Burhol PG, Giercksky KE & & Jenssen TG 1984 Vasoactive intestinal polypeptide and somatostatin in leucocytes. Scandinavian Journal of Clinical and Laboratory Investigation 44 347–351. (https://doi.org/10.3109/00365518409083818)
Malarkey WB, Wang J, Cheney C, Glaser R & & Nagaraja H 2002 Human lymphocyte growth hormone stimulates interferon gamma production and is inhibited by cortisol and norepinephrine. Journal of Neuroimmunology 123 180–187. (https://doi.org/10.1016/s0165-5728(0100489-1)
Marongiu F, Serra MP, Doratiotto S, Sini M, Fanti M, Cadoni E, Serra M & & Laconi E 2016 Aging promotes neoplastic disease through effects on the tissue microenvironment. Aging (Albany NY) 8 3390–3399. (https://doi.org/10.18632/aging.101128)
Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DC, Fullam A, Alexandrov LB, Tubio JM, et al.2015 Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348 880–886. (https://doi.org/10.1126/science.aaa6806)
McHugh D & & Gil J 2018 Senescence and aging: causes, consequences, and therapeutic avenues. Journal of Cell Biology 217 65–77. (https://doi.org/10.1083/jcb.201708092)
Melen L, Hennen G, Dullaart RP, Heinen E & & Igout A 1997 Both pituitary and placental growth hormone transcripts are expressed in human peripheral blood mononuclear cells (PBMC). Clinical and Experimental Immunology 110 336–340. (https://doi.org/10.1111/j.1365-2249.1997.tb08337.x)
Melmed S 2009 Acromegaly pathogenesis and treatment. Journal of Clinical Investigation 119 3189–3202. (https://doi.org/10.1172/JCI39375)
Meriane M, Roux P, Primig M, Fort P & & Gauthier-Rouviere C 2000 Critical activities of Rac1 and Cdc42Hs in skeletal myogenesis: antagonistic effects of JNK and p38 pathways. Molecular Biology of the Cell 11 2513–2528. (https://doi.org/10.1091/mbc.11.8.2513)
Mertani HC, Zhu T, Goh EL, Lee KO, Morel G & & Lobie PE 2001 Autocrine human growth hormone (hGH) regulation of human mammary carcinoma cell gene expression. Identification of CHOP as a mediator of hGH-stimulated human mammary carcinoma cell survival. Journal of Biological Chemistry 276 21464–21475. (https://doi.org/10.1074/jbc.M100437200)
Moller N & & Jorgensen JO 2009 Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocrine Reviews 30 152–177. (https://doi.org/10.1210/er.2008-0027)
Napolitano LA, Schmidt D, Gotway MB, Ameli N, Filbert EL, Ng MM, Clor JL, Epling L, Sinclair E, Baum PD, et al.2008 Growth hormone enhances thymic function in HIV-1-infected adults. Journal of Clinical Investigation 118 1085–1098. (https://doi.org/10.1172/JCI32830)
Nguyen AP, Chandorkar A & & Gupta C 1996 The role of growth hormone in fetal mouse reproductive tract differentiation. Endocrinology 137 3659–3666. (https://doi.org/10.1210/endo.137.9.8756530)
O'Driscoll M 2012 Diseases associated with defective responses to DNA damage. Cold Spring Harbor Perspectives in Biology 4 a012773. (https://doi.org/10.1101/cshperspect.a012773)
Ogilvie M, Yu X, Nicolas-Metral V, Pulido SM, Liu C, Ruegg UT & & Noguchi CT 2000 Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. Journal of Biological Chemistry 275 39754–39761. (https://doi.org/10.1074/jbc.M004999200)
Olarescu NC, Berryman DE, Householder LA, Lubbers ER, List EO, Benencia F, Kopchick JJ & & Bollerslev J 2015 GH action influences adipogenesis of mouse adipose tissue-derived mesenchymal stem cells. Journal of Endocrinology 226 13–23. (https://doi.org/10.1530/JOE-15-0012)
Olsen AK, Coskun M, Bzorek M, Kristensen MH, Danielsen ET, Jorgensen S, Olsen J, Engel U, Holck S & & Troelsen JT 2013 Regulation of APC and AXIN2 expression by intestinal tumor suppressor CDX2 in colon cancer cells. Carcinogenesis 34 1361–1369. (https://doi.org/10.1093/carcin/bgt037)
Parent JM 2003 Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry 9 261–272. (https://doi.org/10.1177/1073858403252680)
Pathipati P, Gorba T, Scheepens A, Goffin V, Sun Y & & Fraser M 2011 Growth hormone and prolactin regulate human neural stem cell regenerative activity. Neuroscience 190 409–427. (https://doi.org/10.1016/j.neuroscience.2011.05.029)
Perez-Ibave DC, Rodriguez-Sanchez IP, Mde G-R & & Barrera-Saldaña HA 2014 Extrapituitary growth hormone synthesis in humans. Growth Hormone and IGF Research 24 47–53. (https://doi.org/10.1016/j.ghir.2014.01.005)
Perry JK, Kannan N, Grandison PM, Mitchell MD & & Lobie PE 2008 Are trefoil factors oncogenic? Trends in Endocrinology and Metabolism 19 74–81. (https://doi.org/10.1016/j.tem.2007.10.003)
Perry JK, Wu ZS, Mertani HC, Zhu T & & Lobie PE 2017 Tumour-derived human growth hormone as a therapeutic target in oncology. Trends in Endocrinology and Metabolism 28 587–596. (https://doi.org/10.1016/j.tem.2017.05.003)
Pittenger MF, Discher DE, Peault BM, Phinney DG, Hare JM & & Caplan AI 2019 Mesenchymal stem cell perspective: cell biology to clinical progress. npj Regenerative Medicine 4 22. (https://doi.org/10.1038/s41536-019-0083-6)
Poppi L, Dixit VD, Baratta M, Giustina A, Tamanini C & & Parvizi N 2002 Growth hormone secretagogue (GHS) analogue, hexarelin stimulates GH from peripheral lymphocytes. Experimental and Clinical Endocrinology and Diabetes 110 343–347. (https://doi.org/10.1055/s-2002-34991)
Postel-Vinay MC, de Mello Coelho V, Gagnerault MC & & Dardenne M 1997 Growth hormone stimulates the proliferation of activated mouse T lymphocytes. Endocrinology 138 1816–1820. (https://doi.org/10.1210/endo.138.5.5108)
Potten CS, Booth C, Tudor GL, Booth D, Brady G, Hurley P, Ashton G, Clarke R, Sakakibara S & & Okano H 2003 Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation; Research in Biological Diversity 71 28–41. (https://doi.org/10.1046/j.1432-0436.2003.700603.x)
Prestwich TC & & Macdougald OA 2007 Wnt/beta-catenin signaling in adipogenesis and metabolism. Current Opinion in Cell Biology 19 612–617. (https://doi.org/10.1016/j.ceb.2007.09.014)
Qian Y, Berryman DE, Basu R, List EO, Okada S, Young JA, Jensen EA, Bell SRC, Kulkarni P, Duran-Ortiz S, et al.2022 Mice with gene alterations in the GH and IGF family. Pituitary 25 1–51. (https://doi.org/10.1007/s11102-021-01191-y)
Raccurt M, Lobie PE, Moudilou E, Garcia-Caballero T, Frappart L, Morel G & & Mertani HC 2002 High stromal and epithelial human gh gene expression is associated with proliferative disorders of the mammary gland. Journal of Endocrinology 175 307–318. (https://doi.org/10.1677/joe.0.1750307)
Render CL, Hull KL & & Harvey S 1995a Expression of the growth hormone gene in immune tissues. Endocrine 3 729–735. (https://doi.org/10.1007/BF03000205)
Render CL, Hull KL & & Harvey S 1995b Neural expression of the pituitary GH gene. Journal of Endocrinology 147 413–422. (https://doi.org/10.1677/joe.0.1470413)
Rohn WM & & Weigent DA 1995 Cloning and nucleotide sequencing of rat lymphocyte growth hormone cDNA. Neuroimmunomodulation 2 108–114. (https://doi.org/10.1159/000096879)
Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL & & MacDougald OA 2000 Inhibition of adipogenesis by Wnt signaling. Science 289 950–953. (https://doi.org/10.1126/science.289.5481.950)
Rowlinson SW, Yoshizato H, Barclay JL, Brooks AJ, Behncken SN, Kerr LM, Millard K, Palethorpe K, Nielsen K, Clyde-Smith J, et al.2008 An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. Nature Cell Biology 10 740–747. (https://doi.org/10.1038/ncb1737)
Rubin H 2011 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. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 33 224–231. (https://doi.org/10.1002/bies.201000067)
Rymaszewski Z, Cohen RM & & Chomczynski P 1991 Human growth hormone stimulates proliferation of human retinal microvascular endothelial cells in vitro. PNAS 88 617–621. (https://doi.org/10.1073/pnas.88.2.617)
Ryu H, Lee JH, Kim KS, Jeong SM, Kim PH & & Chung HT 2000 Regulation of neutrophil adhesion by pituitary growth hormone accompanies tyrosine phosphorylation of Jak2, p125FAK, and paxillin. Journal of Immunology 165 2116–2123. (https://doi.org/10.4049/jimmunol.165.4.2116)
Sadowski CL, Wheeler TT, Wang LH & & Sadowski HB 2001 GH regulation of IGF-I and suppressor of cytokine signaling gene expression in C2C12 skeletal muscle cells. Endocrinology 142 3890–3900. (https://doi.org/10.1210/endo.142.9.8365)
Sanders EJ & & Harvey S 2004 Growth hormone as an early embryonic growth and differentiation factor. Anatomy and Embryology (Berl) 209 1–9. (https://doi.org/10.1007/s00429-004-0422-1)
Sanders EJ, Lin WY, Parker E & & Harvey S 2010 Growth hormone expression and neuroprotective activity in a quail neural retina cell line. General and Comparative Endocrinology 165 111–119. (https://doi.org/10.1016/j.ygcen.2009.06.013)
Sanders EJ, Parker E & & Harvey S 2009 Endogenous growth hormone in human retinal ganglion cells correlates with cell survival. Molecular Vision 15 920–926.
Sangiorgi E & & Capecchi MR 2008 Bmi1 is expressed in vivo in intestinal stem cells. Nature Genetics 40 915–920. (https://doi.org/10.1038/ng.165)
Savino W & & Dardenne M 2010 Pleiotropic modulation of thymic functions by growth hormone: from physiology to therapy. Current Opinion in Pharmacology 10 434–442. (https://doi.org/10.1016/j.coph.2010.04.002)
Schlechter NL, Russell SM, Spencer EM & & Nicoll CS 1986 Evidence suggesting that the direct growth-promoting effect of growth hormone on cartilage in vivo is mediated by local production of somatomedin. PNAS 83 7932–7934. (https://doi.org/10.1073/pnas.83.20.7932)
Schumacher B, Garinis GA & & Hoeijmakers JH 2008 Age to survive: DNA damage and aging. Trends in Genetics 24 77–85. (https://doi.org/10.1016/j.tig.2007.11.004)
Segard HB, Moulin S, Boumard S, Augier de Cremiers C, Kelly PA & & Finidori J 2003 Autocrine growth hormone production prevents apoptosis and inhibits differentiation in C2C12 myoblasts. Cellular Signalling 15 615–623. (https://doi.org/10.1016/s0898-6568(0300005-6)
Sharpless NE & & Sherr CJ 2015 Forging a signature of in vivo senescence. Nature Reviews. Cancer 15 397–408. (https://doi.org/10.1038/nrc3960)
Shimokawa T, Kato M, Ezaki O & & Hashimoto S 1998 Transcriptional regulation of muscle-specific genes during myoblast differentiation. Biochemical and Biophysical Research Communications 246 287–292. (https://doi.org/10.1006/bbrc.1998.8600)
Slaughter DP, Southwick HW & & Smejkal W 1953 Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6 963–968. (https://doi.org/10.1002/1097-0142(195309)6:5<963::aid-cncr2820060515>3.0.co;2-q)
Slonim AE, Bulone L, Damore MB, Goldberg T, Wingertzahn MA & & McKinley MJ 2000 A preliminary study of growth hormone therapy for Crohn's disease. New England Journal of Medicine 342 1633–1637. (https://doi.org/10.1056/NEJM200006013422203)
Soendergaard C, Young JA & & Kopchick JJ 2017 Growth hormone resistance-special focus on inflammatory bowel disease. International Journal of Molecular Sciences 18 1019. (https://doi.org/10.3390/ijms18051019)
Soler Palacios B, Nieto C, Fajardo P, Gonzalez de la Aleja A, Andres N, Dominguez-Soto Á, Lucas P, Cuenda A, Rodriguez-Frade JM, Martinez C, et al.2020 Growth hormone reprograms macrophages toward an anti-inflammatory and reparative profile in an MAFB-dependent manner. Journal of Immunology 205 776–788. (https://doi.org/10.4049/jimmunol.1901330)
Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV & & Dixit VD 2017 IGF1 shapes macrophage activation in response to immunometabolic challenge. Cell Reports 19 225–234. (https://doi.org/10.1016/j.celrep.2017.03.046)
Stead ER & & Bjedov I 2021 Balancing DNA repair to prevent ageing and cancer. Experimental Cell Research 405 112679. (https://doi.org/10.1016/j.yexcr.2021.112679)
Stemmer K, Ellinger-Ziegelbauer H, Ahr HJ & & Dietrich DR 2009 Molecular characterization of preneoplastic lesions provides insight on the development of renal tumors. American Journal of Pathology 175 1686–1698. (https://doi.org/10.2353/ajpath.2009.081071)
Stout MB, Tchkonia T & & Kirkland JL 2015 Growth hormone in adipose dysfunction and senescence. Oncotarget 6 10667–10668. (https://doi.org/10.18632/oncotarget.3997)
Stout MB, Tchkonia T, Pirtskhalava T, Palmer AK, List EO, Berryman DE, Lubbers ER, Escande C, Spong A, Masternak MM, et al.2014 Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY) 6 575–586. (https://doi.org/10.18632/aging.100681)
Struman I, Bentzien F, Lee H, Mainfroid V, D'Angelo G, Goffin V, Weiner RI & & Martial JA 1999 Opposing actions of intact and N-terminal fragments of the human prolactin/growth hormone family members on angiogenesis: an efficient mechanism for the regulation of angiogenesis. PNAS 96 1246–1251. (https://doi.org/10.1073/pnas.96.4.1246)
Sun LY, Al-Regaiey K, Masternak MM, Wang J & & Bartke A 2005a Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiology of Aging 26 929–937. (https://doi.org/10.1016/j.neurobiolaging.2004.07.010)
Sun LY, Evans MS, Hsieh J, Panici J & & Bartke A 2005b Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology 146 1138–1144. (https://doi.org/10.1210/en.2004-1115)
Sundler F, Alumets J & & Hakanson R 1979 Growth hormone-like immunoreactivity in gastrin cells and gastrinomas. Histochemistry 59 343–346. (https://doi.org/10.1007/BF00689616)
Tomlinson IP, Carvajal-Carmona LG, Dobbins SE, Tenesa A, Jones AM, Howarth K, Palles C, Broderick P, Jaeger EE, Farrington S, et al.2011 Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLOS Genetics 7 e1002105. (https://doi.org/10.1371/journal.pgen.1002105)
Tripathi A & & Sodhi A 2009 Growth hormone-induced production of cytokines in murine peritoneal macrophages in vitro: role of JAK/STAT, PI3K, PKC and MAP kinases. Immunobiology 214 430–440. (https://doi.org/10.1016/j.imbio.2008.11.013)
Varma S, Sabharwal P, Sheridan JF & & Malarkey WB 1993 Growth hormone secretion by human peripheral blood mononuclear cells detected by an enzyme-linked immunoplaque assay. Journal of Clinical Endocrinology and Metabolism 76 49–53. (https://doi.org/10.1210/jcem.76.1.8421102)
Verhelst J, Velkeniers B, Maiter D, Haentjens P, T'Sjoen G, Rietzschel E, Corvilain B, Abrams P, Nobels F, Abs R, et al.2013 Active acromegaly is associated with decreased hs-CRP and NT-proBNP serum levels: insights from the Belgian registry of acromegaly. European Journal of Endocrinology 168 177–184. (https://doi.org/10.1530/EJE-12-0753)
Vijg J & & Dong X 2020 Pathogenic mechanisms of somatic mutation and genome mosaicism in aging. Cell 182 12–23. (https://doi.org/10.1016/j.cell.2020.06.024)
Wallis M 1997 Function switching as a basis for bursts of rapid change during the evolution of pituitary growth hormone. Journal of Molecular Evolution 44 348–350. (https://doi.org/10.1007/pl00013142)
Wang Z, Prins GS, Coschigano KT, Kopchick JJ, Green JE, Ray VH, Hedayat S, Christov KT, Unterman TG & & Swanson SM 2005 Disruption of growth hormone signaling retards early stages of prostate carcinogenesis in the C3(1)/T antigen mouse. Endocrinology 146 5188–5196. (https://doi.org/10.1210/en.2005-0607)
Waters MJ, Hoang HN, Fairlie DP, Pelekanos RA & & Brown RJ 2006 New insights into growth hormone action. Journal of Molecular Endocrinology 36 1–7. (https://doi.org/10.1677/jme.1.01933)
Weigent DA 2011 High molecular weight isoforms of growth hormone in cells of the immune system. Cellular Immunology 271 44–52. (https://doi.org/10.1016/j.cellimm.2011.06.001)
Weigent DA, Baxter JB, Wear WE, Smith LR, Bost KL & & Blalock JE 1988 Production of immunoreactive growth hormone by mononuclear leukocytes. FASEB Journal 2 2812–2818. (https://doi.org/10.1096/fasebj.2.12.3044906)
Wilkinson-Berka JL, Wraight C & & Werther G 2006 The role of growth hormone, insulin-like growth factor and somatostatin in diabetic retinopathy. Current Medicinal Chemistry 13