Abstract
The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and thyroid neoplasms. However, recent studies found increased risks in gastric, breast, and urinary tract cancer also. Concordantly, clinical situations where GH and insulin-like growth facto-I deficits exist are indeed associated with diminished malignancy incidence. In line with these observations, gain-of-function mutations of various enzymes belonging to the GH and IGF-I signaling pathways have been associated with increased carcinogenesis; similarly, loss-of-function mutations of other enzymes that usually work as tumor repressors are also associated with augmented cancer risk. In a study performed in Ecuador, it was demonstrated that subjects in the Ecuadorian cohort with Laron syndrome (ELS), who have a mutant GH receptor and greatly diminished GH and IGF-I signaling, display diminished incidence of cancer. Along with absent action of GH and IGF-I, ELS individuals also have low serum insulin levels and decreased insulin resistance. Furthermore, hyperglycemia and hyperinsulinemia are indispensable for fast cell mitosis, including that of those cells present in the benign and malignant neoplasms. Notably, and despite their obesity, subjects with the ELS display normoglycemia and hypo-insulinemia, along with diminished incidence of malignancies. We believe that the dual low-IGF-I/low insulin serum levels are responsible for the cancer protection, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic as well as pathologic events.
Overview of GH-related malignancies
Cancer in subjects with circulating GH excess
Gigantism and acromegaly are clinical examples of circulating growth hormone (GH) excess in humans. These clinical situations appear when GH hypersecretion occurs before or after epiphyseal growth plate closure, respectively (Hannah-Shmouni et al. 2016). High GH levels have been linked to increased neoplasia and cancer risks (Mustacchi & Shimkin 1957, Chhabra et al. 2011, Perry et al. 2013), and subjects with acromegaly have increased incidence of colon and thyroid cancer (Loeper & Ezzat 2008, Chhabra et al. 2011). While some polymorphisms in genes belonging to the GH/insulin-like growth factor (IGF-I) pathway have been associated with susceptibility to breast cancer (Wagner et al. 2007, 2020), no direct links between acromegalic subjects and breast cancer were observed up until 2016 (Boguszewski & Ayuk 2016). Moreover, Petrossians et al. (2017) conducted a study in ten countries including 3173 subjects and found that only 64 developed malignancies; hence, these authors concluded that cancer incidence was comparable to that of the general population. Due to this and similar evidence, it was then thought that the detection of cancer in patients with acromegaly should follow the same protocols as those applicable to the general population, except for colonoscopy and thyroid evaluation (Melmed et al. 2018). These conclusions are contradicted in recent studies; hence, a more comprehensive discussion where evidence shows that acromegaly associates with other cancers is presented below.
Cancer in subjects with circulating GH deficit
GH via IGF-I, the main mediator of its actions, is the main influence in human growth (Gallagher & LeRoith 2011), and GH deficiency (GHD) has been associated with diminished incidence of malignancies (Samani et al. 2007, Perry et al. 2017, Boguszewski & Boguszewski 2019). Accordingly, subjects with congenital IGF-I deficiency (IGFD) were compared to their relatives to search for associations between low IGF-1 and cancer incidence. The authors found that these individuals, which included subjects with GHD, have no malignancies whereas their relatives displayed a 9–24% cancer incidence (Shevah & Laron 2007). Protection against cancer was not absolute, but malignancy incidence in IGFD individuals appeared diminished when compared to the non-IGFD relatives (Aguiar-Oliveira et al. 2010, 2017, Steuerman et al. 2011, Marinho et al. 2018).
Cancer protective pathways in Laron syndrome
There are various reports on the negative association of Laron syndrome (LS) and cancer, and, in general, these studies show that cancer incidence is diminished in subjects with a non-functional GH receptor (GHR). Besides anecdotal observations, Shevah & Laron (2007) were the first to publish this valuable information (Laron et al. 2017, Werner et al. 2019). They studied a group of 169 subjects and their relatives and found no evidence of malignancy when compared to their relatives (Shevah & Laron 2007). A larger global study included 538 subjects with congenital IGFD and 752 family members. About 230 subjects had LS, 116 had isolated GHD, 3 had GHRH-H (growth hormone releasing hormone receptor) defects, and 4 had multiple pituitary hormone deficiency (MPHD). Among others, this study found that LS individuals, with an age range of 1–75 years, had no malignancies, as opposed to a 22.1% cancer incidence in their relatives (Steuerman et al. 2011).
The absence of cancer in LS individuals (Shevah & Laron 2007, Steuerman et al. 2011) prompted the search for genetic modifications on elements of the GH/IGF-I pathway that could explain the protection against malignancy (Werner et al. 2019). These efforts included the investigation of details of intracellular signaling routes that could explain the observed cancer absence (Brooks & Waters 2010, Lapkina-Gendler et al. 2016, Dehkhoda et al. 2018, Werner et al. 2020). In addition, novel cancer-protective pathways were identified by genome-wide profiling in four LS subjects (Lapkina-Gendler et al. 2016), and a more general identification of signaling pathways associated with shielding against cancer in LS was suggested by Brooks and Waters (2010) and Dehkhoda et al. (2018). Overall, it appears that research in LS provides an ideal and pragmatic human model to obtain insights into carcinogenesis (Guevara-Aguirre et al. 2011, Junnila et al. 2013).
Cancer protective pathways in the Ecuadorian LS cohort
The Ecuadorian LS cohort (ELS) represents one-third of the World’s population with this condition (Guevara-Aguirre et al. 1993) and, due to its inherent specific qualities, appears as the most suited population to make inferences about carcinogenesis. Indeed, the ELS is the most homogenous genetic LS group in the world since all subjects have GH receptor deficiency (GHRD) due, in most of them, to a splice-site mutation occurring at the 180 codon of exon 6 of the GHR (ss180/ss180 (ss180)). This abnormality renders the GHR, a pivotal element in the GH/IGF-I signaling pathway, as an unstable receptor that binds GH poorly and is easily degradable (Guevara-Aguirre et al. 1993, Rosenfeld et al. 1994).
Moreover, and corresponding to its autosomal recessive inheritance pattern, genotyping of the ELS relatives showed either a heterozygous (WT/ss180) or normal (WT/WT) result (Berg et al. 1992). All tested parents and non-effected children of ELS subjects are, as expected, obligate heterozygotes (WT/ss180) (Berg et al. 1992). In addition to high biologic similarity, this highly concentrated, inbred, genetically homogeneous group of ELS subjects and their families live in small, isolated cities and villages in southern Ecuador (Guevara-Aguirre et al. 1993), and the three groups, affected, heterozygotes, and non-carrier relatives, share similar contextual circumstances, including the same environmental, nutritional, hygienic, and public health variables. Because the same research team observed them for more than three decades, the published data were obtained with similar investigator’s sources of error.
We published our first report on morbidity and mortality in 2011 (Guevara-Aguirre et al. 2011) and, up until that date, we did not observe any cancer cases in ELS subjects, while their age- and sex-matched relatives had a ~17% malignancy-associated mortality (Guevara-Aguirre et al. 2011). These findings suggested that the GH-induced intracellular signaling impairment, due to the non-functional GHR, was responsible for our observations. Indeed, this GHR abnormality is associated with extremely low levels of insulin and IGF-I, two important growth and mitogenic factors. Nonetheless, in 2013, we found one woman in this cohort who had ovarian cancer and later died (Guevara-Aguirre et al. 2007, 2015, 2021). One additional cancer case is under study and, if confirmed, will be included in a follow-up report.
Of note, there has been a major change in southern Ecuador in the last 15 years. Roads connecting this area with the rest of our country have noticeably improved, bringing along vast and obvious advantages; however, this evident social progress is accompanied by dramatic changes in nutrition and the habits of the population. Indeed, these communities left their traditional food and lifestyle and now consume a typical ‘Westernized diet.’ We believe that this nutritional transition will have effects in both cancer and T2D incidence in ELS subjects as well as in their families.
Epidemiology of GH excess and cancer
Acromegaly and cancer
Below, we present a summary of cohort studies and metaanalysis to assess the relationship between acromegaly, the most typical GH excess condition, and cancer. This issue is the subject of an old debate and still a controversial matter.
Ucan et al. (2021) evaluated cancer risk in a cohort of 280 acromegalic patients (male: 120, female: 160, mean age 50.93 ± 12.07 years). Nineteen patients had malignancies (6.8%) and 9 of them (47%) had thyroid cancer, which was also the most common tumor. Other cancers found were of the colon in three patients, breast in two, skin in one, renal cell in one, malignant meningioma in one, and lung in one. One patient had both thyroid and breast cancer. Standardized incidence ratios (SIRs) of all cancers were 0.8 (95% CI 0.5–1.1) and 1.0 (95% CI 0.8–1.3) in men and women, respectively.
In a metaanalysis, Dal et al. (2018) found that a pooled SIR for overall cancer in patients with acromegaly was 1.5 (95% CI, 1.2–1.8), with considerable heterogeneity (I 2 = 84%). If stratified by cancer type, elevated risks were found for colorectal (pooled SIR = 2.6; 95% CI, 1.7–4.0), thyroid (pooled SIR = 9.2; 95% CI, 4.2–19.9), stomach (pooled SIR = 2.0; 95% CI, 1.4–2.9), breast (pooled SIR = 1.6; 95% CI, 1.1–2.3), and urinary tract (pooled SIR = 1.5; 95% CI, 1.0–2.3). SIRs for other cancers were as follows: lung (0.8; 95% CI, 0.5–1.2), prostate (1.2; 95% CI, 0.8–1.9), and hematological cancers (1.3; 95% CI, 0.8–2.3).
Based on a review of the literature, Boguszewski & Ayuk (2016) concluded that thyroid cancer behaves not differently in acromegalic vs non-acromegaly patients. Both study groups had good prognoses and low mortality rate, and only a few patients had aggressive, multifocal, or anaplastic tumors. Interestingly, in acromegaly-associated papillary thyroid cancer, the frequency of BRAF mutations was not increased and might even be decreased.
In a cohort study, Danilowicz et al. (2020) found that most patients with both acromegaly and differentiated thyroid cancer (DTC) had a low initial RR (relative risk). Moreover, when compared with the control group, patients with DTC and acromegaly had a similar disease outcome. Nevertheless, in their metaanalysis and systematic review, Wolinski et al. (2014) found that patients with acromegaly are at an increased risk of thyroid nodular disease and thyroid cancer. These results indicate that careful and periodic thyroid US examination must be routinely done in patients with acromegaly.
Dworakowska & Grossman (2019) found an association with acromegaly and benign and malignant colonic neoplasms. This observation has recently been updated (Kasuki et al. 2022). It is known that signs and symptoms leading to an acromegaly diagnosis occur after various years of GH hypersecretion, and it is assumed that excess circulating GH and IGF-I leads to the development of colonic polyps as well as to colonic cancer. Concordantly, successful control of GH and IGF-I is associated with mortality reduction, especially when a multimodal and integrated approach is used (Giustina et al. 2020). Based on similar considerations, Terzolo et al. (2020) recommended that, regardless of age, colonoscopy be performed in all patients with acromegaly at the time of diagnosis. This exam should be done in all subjects, especially considering that neoplasm risk might be higher in younger patients who also have a more aggressive form of the disease.
Regarding prostate cancer, Correa et al. (2009) performed a systematic review and described five studies where no increase in cancer risk was found. Nevertheless, in Bolfi’s metaanalysis of 17 studies published before 2008, mortality in acromegaly was increased, while in 9 studies published after 2008 mortality was like that of the general population (standardized mortality ratio; SMR: 1.35, CI: 0.99–1.85). Relevantly, in six studies where somatostatin analogs were used, mortality was not increased (SMR: 0.98, CI: 0.83–1.15), whereas in series including only patients treated with surgery and/or radiotherapy, mortality was significantly higher (SMR: 2.11; CI: 1.54–2.91) (Bolfi et al. 2018). It is known that patients who achieve normal levels of GH and IGF-I have a better prognosis than those with higher concentrations of these growth peptides (Tonjes et al. 2023). In this context, the use of the GHR antagonist Somavert (Pegvisomant for injection) has been found safe and effective in the treatment of acromegalic patients refractory to standard therapies. Moreover, this drug might even lower cancer incidence in these patients (Giustina et al. 2014).
Overall, the cited studies show that acromegaly is associated with an increase in the risk of thyroid nodular pathology and of cancer in general. While strong links for colorectal and thyroid cancer exist, these risks also appear relevant for gastric, breast, and urinary tract cancer. Furthermore, these associations were not noticed in previous large studies. On the other hand, there is no statistically significant association for lung, prostate, and hematological malignancies. The evidence also supports that treatments that lower serum GH and IGF-I decrease cancer mortality. Finally, and possibly because of the rarity and peculiarities of the disease, there are no large studies evaluating the risk of cancer in patients with gigantism.
Cancer in growth hormone deficiency
Congenital or acquired GHD is a clinical denomination for a series of medical conditions associated with diminished or absent GH action in the human body (Dattani & Malhotra 2019).
Among others, congenital GHD depends on miscellaneous causes, including isolated GHD (Ghizzoni et al. 1994), biologically inactive GH (Takahashi et al. 1997, Besson et al. 2005), and MPHD (Castinetti et al. 2016). These GHD forms are further subdivided into various clinical forms each due to an underlying gene defect (Cogan et al. 1994, 1995, Duriez et al. 1994, Stewart et al. 2008, Castinetti et al. 2016). In addition, GHRHR mutations also generate isolated GHD (Aguiar-Oliveira et al. 2010).
Combined GHD might be also due to abnormalities in various genes such as PROP-1 (Carvalho et al. 2000), PIT-1 (Tatsumi & Amino 1999), HESX-1 (Fang et al. 2016), LHX3 (Ramzan et al. 2017), LHX4 (Tajima et al. 2013), OTX2 (Tajima et al. 2013), SOX3 (Burkitt et al. 2009), and SOX2 (Macchiaroli et al. 2014). Finally, LS (Laron & Pertzelan 1967, Guevara-Aguirre et al. 1993) due to miscellaneous mutations in the GHR gene (Berg et al. 1993) generate an absence of physiologic GH-induced signaling (Guevara-Aguirre et al. 2011). None of these genetically based GHD forms or IGF-I deficiency states is associated with increased cancer risk; moreover, malignancy incidence is diminished, and several underlying mechanisms have been suggested (Shevah & Laron 2007, Aguiar-Oliveira et al. 2010, Chhabra et al. 2011, Guevara-Aguirre et al. 2011, 2021, Werner et al. 2019, 2020).
Acquired GHD can be caused by head trauma (Kgosidialwa et al. 2019), cranial irradiation (Merchant et al. 2011), and hypothalamic–hypophyseal benign or malignant tumors (Boguszewski et al. 2021). In consequence, the acquired GHD is just an epiphenomenon of the original disease, and any consequence including malignancy does not depend on the actual GH status but rather stems from the nature of the main condition.
An international survey of individuals with congenital IGF-I deficiency generated by miscellaneous causes included subjects with isolated GHD, LS, GHRHR abnormalities, and MPHD. No cases of malignancy were found (Steuerman et al. 2011). Of note, when IGF-I deficiency was due to LS, affected subjects were compared to much older relatives. Regardless, isolated subjects with LS, GHD, and GHRHR deficiency display associated cancer risk protection (Aguiar-Oliveira et al. 2010).
IGF-I signaling and cancer
GH is secreted by the anterior pituitary in response to rising hypothalamic levels of GHRH (Mayo et al. 1995). Subsequent GH binding to its receptor (GHR) in the liver leads to the activation of Janus kinases (JAKs) and further recruitment of the 5a and 5b Signaling Transducers and Activator of Transcription (STAT) proteins, which eventually mediate the metabolic and proliferative actions of GH (Rotwein 2012, Carter-Su et al. 2016). Below, we exemplify various locations where mutated proteins, or distorted events along this signaling pathway, might be associated with carcinogenesis.
Physiologically, STAT 5b induces the synthesis of IGF-I (Woelfle & Rotwein 2004, Rotwein 2012). This growth peptide, along with IGF-binding protein 3 (IGFBP3), which is not transcriptionally regulated by GH in the liver (Olivecrona et al. 1999), and an acid labile subunit (ALS) circulate as a trimolecular 150 kilodalton (kD) complex (Giannakopoulos et al. 2021, Kim et al. 2022a ). After its release from the 150 kD unit, free IGF-I binds to the two extracellular α subunits of its receptor (IGFIR) (Elis et al. 2011), which activates the two intracellular β subunits followed by their autophosphorylation (Elis et al. 2011, Rotwein 2012, Kavran et al. 2014, Hakuno & Takahashi 2018, Giannakopoulos et al. 2021, Kim et al. 2022a ). Interestingly, distorted and constitutively activated STAT5 signaling has been found in certain cancers (Gu et al. 2010).
At the end of this typical ligand autophosphorylation cascade initiated by the IGF-I/IGFIR binding, phosphorylation of docking proteins such as IRS-1 occurs, and it is followed by the activation of the PI3K/AKT (Schiaffino & Mammucari 2011). In general, phosphorylated AKT has well-known anabolic effects that lead to GLUT4 transporter translocating to the cell membrane, which allows glucose entry to cells with subsequent glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation functioning (Liu et al. 2021). Overall, substantial amounts of reducing NADH power and high-energy compounds such as ATP and GTP are formed. Besides its anabolic function, fully active AKT regulates cell survival by inhibiting the phosphorylation of a forkhead transcription factor and by impeding BAD protein action, hence blocking apoptosis (Feng & Levine 2010, Liu et al. 2021). Of note, the abundance of copious amounts of available energy becomes ideal for the flourishing of rapidly dividing cells as well as of malignant clones (Feng & Levine 2010).
There are many examples where altered AKT might be involved in carcinogenic processes, including those that use NFƙB signaling (Fresno Vara et al. 2004, Joyceline et al. 2022). Similarly, altered IGF-I/IGFIR interaction might trigger the aberrant P13/AKT signaling pathway that upregulates clusterin, a cell stress-induced pro-survival protein that is elevated in early-stage carcinogenesis (Peng et al. 2019).
Physiologically, AKT signaling drives the activation of the serine/threonine kinase known as mammalian target of rapamycin (mTOR) (Schiaffino & Mammucari 2011). One of its isoforms, mTOR1, is a cell anabolic growth and proliferation mediator that, in the presence of normal levels of oxygen, ATP, amino acid, and glucose, along with physiological insulin and cytokine concentrations, induces and enhances the cell’s anabolic functions (Adegoke et al. 2012). mTOR forms a stoichiometric complex with Raptor, a nutrient-sensitive protein, to eventually form the mTOR1 complex (Sancak et al. 2008). This compounded unit exerts its anabolic actions on mRNA translation, aerobic glycolysis, and lipid and nucleotide synthesis, as well as on activation of the pentose phosphate pathway (Tsouko et al. 2014). Eventually, via ribosome biogenesis and generation of biosynthetic precursors such as amino acids and glycerol, mTOR1 action results in protein, cell membrane and nucleic acid synthesis (Adegoke et al. 2012). These net mTOR functions can be further stimulated by certain protooncogenes and some infectious agents and are inhibited by cell stress (Brüning et al. 2014, Zhang et al. 2015). Aberrant mTOR1 signaling has been linked to discrete carcinogenic events (Guertin & Sabatini 2007, Zoncu et al. 2011). Besides other functions, the other mTOR isoform, mTOR2/Rictor, is activated by insulin and IGF-I receptors via its tyrosine kinase branch (Hagiwara et al. 2012). Relevantly, mTOR2 also phosphorylates PDK1 thereby inducing a fully functional AKT form (Fu & Hall 2020).
Not only by a different route but also via active IRS, IGF-I/IGFIR binding conducts phosphorylation of GrB2 proteins, hence leading to the activation of the Son-of-Seven less (SOS) peptide, a guanine–nucleotide exchange inducer that activates the GDP/GTP exchange factor RAS and its downstream signaling intermediates (Hakuno & Takahashi 2018). These serial events include serine/threonine phosphorylation of MAP kinases that lead to the phosphorylation of ERK (extracellular signal-regulated kinase) and its entry to the nucleus where it triggers transcription of early- and late response genes, which eventually lead to DNA synthesis, pre-mitotic growth, mitosis, cytokinesis, and the eventual formation of daughter cells (Drosten et al. 2010, Hakuno & Takahashi 2018). Dysregulation and aberrant expression of any of these proteins might be found in malignant processes (Johnson et al. 1996). Indeed, RAS and the MAP kinases are normal protooncogenes that, if erroneously expressed, or mutated, can become potent oncogenes (Fang & Richardson 2005, Cipriano et al. 2014). RAS gene mutations are associated with roughly 20% of human cancers (Kiaris & Spandidos 1995), and mutated KRAS, one of the three RAS isoforms, is found in different cancer types such as colorectal malignancies (Jancík et al. 2010, Prior et al. 2020). In addition, other mutations on the B-RAF kinase have been observed in thyroid, melanoma, and colorectal cancer (Xing 2005, Dhomen & Marais 2007).
Normal IGF-I/IGFIR binding is central to physiologic cell proliferation, differentiation, and growth, as well as to the normal function of a variety of protooncogenes and tumor-suppressor genes (Ma et al. 2010, Werner et al. 2012, Hakuno & Takahashi 2018), IGF-I/IGFIR signaling also generates one of the most potent AKT-mediated anti-apoptotic systems that is essential for cell survival in humans (Schiaffino & Mammucari 2011, Liu et al. 2021). Concordantly, dysregulated or distorted IGF-I/IGFIR action may not only induce cellular proliferation but also upregulate anti-apoptotic events (Werner 2012), malignant cell spread (Lopez & Hanahan 2002), and defective cell migration (Takada et al. 2017).
In any case, it is of the utmost importance to consider that all and every rapidly dividing cell requires larger amounts of energy which is supplied by an efficient insulin concentration and action. Of note, elevated serum levels of glucose, triacylglycerol (TG), and other metabolites, often raised in conditions such as obesity, will provide the high energy requirements of fast dividing cells (Arthur et al. 2016, Kim et al. 2022c , Yustisia et al. 2022). In addition, high insulin levels should induce a higher mitogenic rate (Sanaki et al. 2020) and, thereby, an increased probability of cell division errors. This fundamental event, along with excess cell oxidation and diminished apoptosis, creates conditions suited for neoplastic genesis and development (Birsoy et al. 2014).
Low IGF-I associates with diminished cancer incidence in ELS
Cancer in humans has been linked to overexpression of pro-growth pathways, oxidative stress, genomic instability, and cellular damage (Saha et al. 2017). Concordantly, activation of stress resistance transcription factors and antioxidant enzymes contribute to the protection against age-associated damage and chronic illnesses in men (Longo & Finch 2003, Kim et al. 2022b ).
A role for the IGF-I signaling pathway in promoting age-dependent mutations that induce a shift from protooncogenes to oncogenes as well as an increased number of other deleterious mutations has been proposed as strong influences in carcinogenic processes (Werner et al. 2018). Concordantly, activating mutations in RAS and AKT, two potent enzymes downstream of the IGF-I/IGFIR signaling route, and those in the IGF-IR itself are found in human cancers (Yuan et al. 2018). Furthermore, various enzymes in the IGF-I pathway, including mTOR, S6K, RAS, adenylate cyclase, and PKA can induce DNA damage by increasing superoxide production, thereby contributing to carcinogenesis (Longo & Fontana 2010).
Conversely, mutations that impair GHR function are associated with a diminished incidence of cancer in humans (Shevah & Laron 2007, Guevara-Aguirre et al. 2011). In vitro studies demonstrated that human mammary cells treated with hydrogen peroxide and incubated with serum from ELS subjects had less DNA damage than those incubated with serum from ELS relatives (Guevara-Aguirre et al. 2011). ELS serum also induced reduced expression of RAS, PKA, and mTOR, as well as upregulation of superoxide dismutase-2 (Guevara-Aguirre et al. 2011). The antiapoptotic properties of serum IGF-I in humans suggest that excess IGF-I levels contribute to diminished self-destruction of malignant cells (Pollak 2012). Accordingly, in the study of the IGF-I-deficient ELS cohort, pathway analysis of global gene expression showed that apoptosis-regulating genes were upregulated, whereas those of RAS, PKA, and mTOR were downregulated (Guevara-Aguirre et al. 2011).
The diminished incidence of cancer in the ELS subjects, who were compared to their age-matched relatives (Guevara-Aguirre et al. 2011), as well as the comparison between young IGF-I-deficient subjects and much older controls made by Shevah et al. (2007) suggested that GHR signaling and serum IGF-I concentrations participate in carcinogenic processes. Interestingly, partial loss-of-function IGFI-R gene mutations are found in Ashkenazi Jewish centenarians, hence suggesting an association of low IGF-IR action and enhanced life span (Suh et al. 2008).
Altogether, the diminished incidence of cancer in the ELS subjects, who lack GHR signaling, supports the notion that excess or aberrant functioning of GHR is a contributor in carcinogenic processes. Indeed, ELS subjects exhibit low circulating concentrations of IGF-I, diminished DNA breaks, enhanced apoptosis, augmented expression of pro-apoptotic genes, and lower expression of RAS, PKA, and mTOR, as well as increased expression of SOD2. These findings are objective molecular events that support the notion that diminished GHR action underlies cancer protection in subjects belonging to the ELS cohort (Guevara-Aguirre et al. 2011).
Additionally, besides low serum IGF-I levels, individuals in the ELS cohort also have diminished serum levels of insulin and yet, are highly insulin sensitive. We believe that, overall, the cancer protection seen in this group must be due to dual low-IGF-I/low insulin serum levels, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic event. Importantly, despite their obesity, subjects in the ELS cohort who do not respond to GH display normoglycemia and hypoinsulinemia, along with a diminished incidence of cancer.
The intent of this review is to give the reader an overview of the still controversial relationship between cancer and GH. Results of large cohort studies and meta-analysis in GH excess and deficiency, along with studies on the discrete effects of those abnormalities on clinical, biochemical, and cellular parameters of affected individuals, are thereby provided.
We acknowledge that these matters are still under study and controversy, especially after recent updates of thyroid and colorectal malignancies in acromegaly as well as of recent reports of its associations with gastric, breast, urinary tract malignancies and cancer in general. In the same line, the observation that treatments that lower GH and IGF-I might be linked to cancer mortality decrease, are herein noted.
If the GH malignancy-associated phenomenon is observed from a different perspective, that derived of observing GH- and IGF-I-deficient states, similar conclusions might be attained. For all the above reasons, clinical, biochemical, and corresponding subcellular signaling routes, are also briefly described.
Nevertheless, among the hormonal distorted influences that have been associated with carcinogenesis, it is difficult to ascribe an exclusive role in malignancy etiology and development to abnormalities of the GH/IGF-I signaling pathway. This is especially relevant since rapidly dividing cells indispensably need excess energy to maintain their typically elevated mitogenic rate which elevates the possibility of cell division errors. In consequence, the distinct role of hyperinsulinemia and excess glucose, triglycerides, and other energy-supplier metabolites influencing both genesis and flourishing of malignant cells is highlighted. We believe that research in these areas is not only promising and warranted but, more importantly, it is urgently needed.
Declaration of interest
None of the authors have financial interest regarding this manuscript.
Funding
None of the authors have received funding for the preparation of this manuscript.
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