Abstract
Meta-analyses from 2018–2022 have shown that obesity increases the risk of various cancers such as acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, non-Hodgkin's lymphoma, bladder, breast, cholangiocarcinoma, colorectal, ovarian, esophageal, kidney, liver, prostate, thyroid, and uterus. Contextually, obesity, and its comorbidities, is the largest, most lethal pandemics in the history of mankind; hence, identification of underlying mechanisms is needed to adequately address this global health threat. Herein, we present the metabolic and hormonal mechanisms linked to obesity that might etiologically contribute to neoplasia, including hyperinsulinemia and putative places in the insulin-signaling pathway. Excess insulin, acting as a growth factor, might contribute to tumorigenesis, while abundant ATP and GDP supply the additional energy needed for proliferation of rapidly dividing cells. Our observations in the Ecuadorian cohort of subjects with Laron syndrome (ELS) prove that obesity does not always associate with increased cancer risk. Indeed, despite excess body fat from birth to death, these individuals display a diminished incidence of cancer when compared to their age- and sex-matched relatives. Furthermore, in cell cultures exposed to potent oxidizing agents, addition of ELS serum induces less DNA damage as well as increased apoptosis. ELS individuals have absent growth hormone (GH) counter-regulatory effects in carbohydrate metabolism due to a defective GH receptor. The corresponding biochemical phenotype includes extremely low basal serum concentrations of insulin and insulin-like growth factor-I, lower basal glucose and triglyceride (TG) levels, and diminished glucose, TG, and insulin responses to orally administered glucose or to a mixed meal.
Background
The Ecuadorian cohort of subjects with Laron syndrome (ELS) is the world’s most numerous and genetically homogenous group of individuals with this condition. The ELS clinical phenotype is one of severe short stature and obesity, and it is accompanied by a series of apparent clinical paradoxes. Some of them were noted in the description of the first individuals (Rosenbloom et al. 1990) and of the entire cohort (Guevara-Aguirre et al. 1993, Rosenfeld et al. 1994) as well as in recent years (Guevara-Aguirre et al. 2021a,b ). Indeed, some coexistent clinical inconsistencies such as normal birth size and severe adult short stature; poor muscular development in childhood despite normal activity; delayed puberty despite normal luteinizing hormone/follicle-stimulating hormone axis; and normal intelligence despite very low insulin-like growth factor-I (IGF-I) levels were initially noted (Guevara-Aguirre et al. 2021a,b ). Nevertheless, apparent paradoxical findings in the metabolic phenotype are the most interesting. They include normal carbohydrate (CHO) metabolism despite low insulin secretion, diminished incidence of type 2 diabetes mellitus (T2D) and metabolic syndrome despite obesity, and diminished incidence of cancer despite obesity as a risk factor.
As noted, while the most striking clinical association observed in the ELS subjects is that of obesity and low T2D incidence, the diminished incidence of malignancies despite the risk factor posed by increased body fat is also relevant, and it is the focus of this review. This matter is especially important considering that in 1997 the WHO declared obesity and related illnesses as a major health public problem and a global epidemic. We hope that identification of underlying basic mechanisms will help in understanding and solving these major health catastrophes.
In the last few years, the association of obesity and increased cancer risk has been recognized (Wolin et al. 2010). Along with it, characteristic hyperinsulinemia and elevated serum concentration of free IGF-I despite normal total IGF-I levels have been noted (Nam et al. 1997). These mitogenic agents, especially insulin, contribute to higher cell proliferation and neoplastic changes (Boguszewski & Ayuk 2016). Concomitantly, increased serum levels of glucose, triacylglycerol, and other metabolic substrates, which are often raised in obesity, supply the additional energy needed for the proliferation of rapidly dividing cells.
The phenotype of elevated circulating insulin (and possibly free IGF-I), along with abundant energy sources (Colao et al. 2004), should generate and maintain a higher mitogenic rate and faster new cell formation. Together, this raises the possibility of excess DNA breaks, inefficient DNA repair, augmented cell oxidation, diminished apoptosis, and inefficient disposal of abnormal cells, including malignant clones (Birsoy et al. 2014).
Despite their obese clinical phenotype, subjects in the ELS cohort provide the unique opportunity of observing a biochemical profile that is opposite to that of typical obesity. Indeed, while all ELS individuals have excess percent body fat content, surprisingly, their biochemical phenotype is one of diminished insulin resistance and extremely low basal serum concentrations of insulin and IGF-I. Moreover, along with lower basal glucose and triglyceride (TG) levels, these individuals display normal or even diminished serum glucose, TG, and insulin responses to orally administered glucose or standard breakfast (Guevara-Aguirre et al. 2015). We believe that the study of the metabolic phenotype of ELS individuals might highlight basic mechanisms underlying obesity and carcinogenesis.
To understand some of the reasons for the combination of obesity with a normal hormonal and metabolic profile, we have observed for more than three decades subjects in the ELS cohort and compared them to their relatives in the southern Ecuador. Relevantly, these individuals share the same genetic ancestry as well as similar nutritional, social, and environmental circumstances, including, in most cases, the same household. We believe that, despite the risk posed by their lifelong presence of excess body fat and adolescent and adult obesity (Guevara-Aguirre et al. 2011), the main influence for the diminished incidence of cancer observed in these subjects is intrinsically linked to their distinct biochemical and hormonal profile.
Epidemiology of obesity-related cancer
Risk for obesity-related cancer was examined in various 2018–2022 meta-analyses presented below. While most of these studies suggested an increased risk, a neutral and even a diminished cancer probability was observed. In any case, when an augmented cancer risk is present, it appears dependent on the discrete malignancy type.
Among possible etiological influences driving carcinogenesis in obesity, dysregulation of baseline levels or signaling pathways of hormones and cytokines influencing proliferation of malignant cells and metastasis was suggested. Other direct influences were included in the fields of extracellular matrix remodeling, angiogenesis, and adrenergic signaling (Pellegata et al. 2022). Herein, we present a brief description of such meta-analysis.
Soltani and colleagues evaluated 13 studies describing 3,345,031 subjects with obesity and T2D. These authors found that each 5-unit BMI increase associates with a 6% increase in cancer events. Nevertheless, disaggregation showed a 12% higher incidence of BC, while no increase in pancreatic, colorectal, and prostate cancer was noted (Soltani et al. 2021).
Namazi and colleagues evaluated 12 studies describing 251,045 subjects. Combined adjusted multivariable relative risk (RR) for BC for lowest vs highest fat mass content was 1.44 for cohort studies, even though, case–control studies showed no significant association (Namazi et al. 2019).
In a meta-analysis of 27 studies, Lohman and colleagues investigated the association of obesity and overweight, at the time of diagnosis of non-metastatic BC, with disease-free survival (DFS) and overall survival (OS) in three groups of patients. Subjects included were hormone (estrogen and/or progesterone) receptor-positive/human epidermal growth factor receptor 2 (HER2)-positive, HER2-positive, and triple-negative BC groups. They found that obesity is modestly associated with worse DFS and OS in all groups (Lohmann et al. 2021).
In the 538,857 subjects included in an Asian cohort, Shin and colleagues observed that differentiated thyroid cancer (DTC) and BMI displayed a linear association only in men but not in women (Shin et al. 2022). Similarly, when evaluating 15 studies, O’Neill and colleagues found that obesity was associated with larger DTC tumor size, increased rates of multifocality, extrathyroidal extension and nodal spread (O'Neill et al. 2021). Similar findings were reported by Cui and colleagues (Cui et al. 2021).
Regarding genitourinary cancer, Shi overviewed 31 systematic reviews and meta-analysis. He found a linear relationship between obesity with bladder and kidney cancer incidence as well as with mortality (Shi et al. 2021). In the meta-analysis of renal cell carcinoma (RCC) cases performed by Callahan and colleagues, obesity was associated with increased risks of clear cell carcinoma and chromophobe RCC; nevertheless, no association with papillary RCC or any other subtype, was noted (Callahan et al. 2018). Similarly, Liu´s meta-analysis included 24 cohort studies, with a follow-up period ranging from 5.4 to 25 years. The analysis included 15,535 kidney cancer cases among 8,953,478 total subjects. An augmented risk for obese vs non-obese individuals was documented (Liu et al. 2018).
When evaluating 78 studies, Harrison and colleagues found that a 5 kg/m2 increase in BMI was associated only with advanced prostate cancer (hazard ratio = 1.06, 95% CI 1.01–1.12, P = 0.013), but no association was found in other sets of patients with prostate cancer (Harrison et al. 2020). In a different but related topic, Minlikeeva and colleagues analyzed source data from The Ovarian Cancer Association Consortium and found that obesity was associated with poorer survival (Minlikeeva et al. 2019).
During evaluation of gastrointestinal cancer risk in overweight subjects, Tian and colleagues meta-analyzed selected data from 25 articles. Information from 16,561 affected subjects with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EADC) was compared with data from 11,954,161 normal weight controls. The study observed that, when contrasted with controls, a decreased risk of ESCC and an increased EADC risk exist (Tian et al. 2020). Similarly, the meta-analysis from Yang and colleagues showed a liver cancer risk increase depending on the obesity level (Yang et al. 2020).
On a similar matter, Petrick and colleagues performed a pooled analysis of 13 US-based cohort studies that included 1,584,703 individuals. These studies searched for the association of obesity and T2D with intrahepatic cholangiocarcinoma (ICC) risk. Obesity/T2D were linked to a 62% increase in ICC risk. Furthermore, meta-analysis of 14 studies included in the same report found that obesity alone associates with a 49% ICC risk increase (Petrick et al. 2018).
The six-study meta-analysis from Li and colleagues of subjects with comparable BMI found that obesity associates with a 42% increased risk of colorectal cancer (Li et al. 2021). Different meta-analysis (Lei et al. 2021, O'Sullivan et al. 2022), including one of 2,546,556 participants and 19,563 early-onset colorectal cancer cases, found that obesity was a relevant risk factor (O'Sullivan et al. 2022). In a related analysis, Lazzeroni and colleagues found that subjects with Mut L Homolog1 (MLH1) mutations displayed a 49% higher risk for each 5 kg/m2 BMI increase. No association with Mut S Homolog 2 mutations was found (Lazzeroni et al. 2021).
To evaluate blood cancer risk increase associated with overweight/obesity, Abar and colleagues performed a 65-study meta-analysis of various blood cancers and found an RR increase associated with higher BMI. Malignancies included Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large beta cell lymphoma, multiple myeloma, leukemia, acute myeloid lymphoma, chronic myeloid lymphoma, and chronic lymphocytic leukemia (Abar et al. 2019).
Regarding lung cancer (LC), 15 cohort studies were included in the meta-analysis from Shen and colleagues, which included more than 15 million subjects. Among those, there were 28,273 deaths from LC. This author estimated that RR linearly increases for each 5 kg/m2 of higher BMI (Shen et al. 2017). Interestingly, Zhu and Zhang analyzed LC in non-smokers and found an inverse correlation with BMI (Zhu & Zhang et al. 2018). Furthermore, Jian and colleagues performed a large, pooled data base analysis that included 16 studies from the International Lung Cancer Consortium. A lower risk in obese patients was detected (Jiang et al. 2021). Similarly, a meta-analysis by Gao and colleagues performed in only-prospective trials, included 28 cohort studies, which included more than 28 million participants at baseline (Gao et al. 2019). There were 127,161 LC cases occurring in the 5–32 years follow-up observation period. It was found that BMI was inversely associated with LC risk (Gao et al. 2019).
A study performed by Sun and colleagues in China used different BMI cutoff points to define overweight and obesity (24 and 28 kg/m2, respectively) (Sun et al. 2022). In any case, this meta-analysis of eight large-cohort studies, each with over 25,000 patients and more than 8 years of follow-up, found no global increase in death risk for cancer except for hepatocellular, colorectal, postmenopausal breast, and epithelial ovarian cancer. No increase in pancreatic cancer was noted (Sun et al. 2022).
Along with strong associations between obesity and cancer mortality documented in most epidemiological studies, a meta-analysis of 203 studies performed by Petrelli and colleagues (Petrelli et al. 2021) found that OS in obese subjects was significantly shorter than in non-obese individuals for cancer in general, with special relation to breast, colorectal, and uterine. Evidence of decreased mortality for LC and melanoma and neutral evidence for bladder, brain, gastroesophageal, head and neck, hepatobiliary, ovarian, pancreas, and prostate cancer were noted (Petrelli et al. 2021).
Most recently, Larsson and colleagues performed an analysis of large-cohort studies and a pooled analyses of cohort studies as well as Mendelian randomization studies. They found associations between BMI and site-specific cancer risk. Sources included recent reports by the International Agency for Research on Cancer Working Group. Increased cancer risk associated with obesity was documented for esophagus, stomach, colon and rectum, liver, gallbladder, pancreas, kidney, corpus uteri, postmenopausal breast, and prostate malignancies (Larsson et al. 2022).
Overall, these observations in large sets of data strongly suggest that obesity increases the risk of various cancer types, including acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, non-Hodgkin's lymphoma, bladder, breast, cholangiocarcinoma, colorectal, ovarian, esophageal, kidney, liver, prostate, thyroid, and uterus. In this paper, we present putative basic mechanisms that might help to explain these epidemiological findings.
The insulin-signaling pathway and cancer
The insulin-signaling pathway: metabolic and proliferative routes
The physiologic insulin-signaling pathway
Binding of insulin to its tetrameric receptor (insulin receptor; INSR) in the extracellular region near the cell membrane initiates signaling in target cells (Constanzo 2018). Phosphorylated INSR recruits insulin receptor substrate (IRS) proteins that trigger the activation of the phosphatidyl inositol 3 kinase (PI3K)/protein B (AKT) and of the RAS/mitogen-activated protein kinase (MAPK) routes (Topacio et al. 2019). While there are at least six IRS types, we will refer only to physiologic insulin action mediated by phosphorylated IRS-1 and IRS-2 (De Meyts 2020). In short, insulin/INSR physiologic interaction results in the activation of PI3K/AKT and RAS/MAPK, the metabolic and proliferative branches of the insulin-signaling pathway, respectively (Kearney et al. 2021).
The PI3K/AKT route generates metabolic and survival signals in target cells
After PI3K phosphorylation by IRS-1, PI3 inositol-dependent kinase (PDK-1) activates AKT (protein B), the main effector of the metabolic branch of the insulin-signaling pathway (Tsai et al. 2022). AKT participates in mammalian target of rapamycin (mTOR)-mediated protein and lipid synthesis but, mainly, drives the planting of cytosolic glucose transporter 4 (GLUT4) transporters in the cell membrane to allow glucose entrance and further processing in target cells. The net result is ATP and GTP generation, the most important energy sources for cell physiology. Interestingly, while tumor-suppressor protein phosphatase and tensin homolog (PTEN) physiologically inhibits the PI3K/AKT signaling route, AKT limits PI3K-mediated PIP3 synthesis (Xue et al. 2021) by IRS phosphorylation. While crosstalk between circular RNAs and the PI3K/AKT signaling branch appears as another relevant element in cancer progression (Xue et al. 2021, Tsai et al. 2022), overactivation of the PI3K/AKT route appears as a key element in carcinogenesis.
Cytosolic AKT inhibits the apoptosis-promoting BAD proteins, resulting in normal cell survival when nutrients and energy are abundant. However, AKT also inhibits the apoptosis of neoplastic and malignant cells, especially when energy is easily available (Nitulescu et al. 2018, Zhou et al. 2000). In addition, increased AKT activation associates with larger reactive oxygen species (ROS) concentration and oxidative stress in pathological conditions such as those found in carcinogenic processes (Shiau et al. 2022).
The RAS/MAPK route generates proliferation and growth signals in target cells
While the PI3K/AKT is the dominant effect after insulin/INSR binding, this interaction also promotes phosphorylation of the adaptor protein GRB2 which, in turn, activates the guanosine–nucleotide exchange protein known as Son of Sevenless (SOS). SOS then modifies the dormant rat sarcoma protein (RAS) (McClain 1991, Topacio et al. 2019) and drives inactive RAS to release GDP and become the active GTP–RAS form, the potent initiator of the RAS/MAPK cascade (Topacio et al. 2019).
Activated GTP–RAS phosphorylates RAF which phosphorylates MEK that in turn activates ERK, the old MAPK (Topacio et al. 2019, De Meyts 2000). Phosphorylated ERK/MAPK enters the cell nucleus of target cells and activates ELK1 which, in turn, binds to another intranuclear protein, the serum reactive factor (SRF). After binding, combined ELK1/SRF becomes a transcription factor that initiates the expression of early-response genes such as JUN/FOS or MYC. Resultant proteins, cellular(c)-JUN, and c-FOS dimerize and re-enter the cell nucleus, triggering the expression of late-response genes (Topacio et al. 2019, De Meyts 2000, Escribano et al. 2017). Among expressed peptides, newly formed cyclin proteins allow cyclin-dependent kinases (CDKs) to phosphorylate Rb proteins, which are bound with members of the E2F transcription factors. Rb-E2F complexes inhibit the transcription of the E2F-regulated genes. Upon Rb phosphorylation by CDKs, released E2F promotes cell cycle progression and cell duplication (Topacio et al. 2019).
RAS activation is a powerful and tightly controlled cellular process. Interestingly, intrinsic RAS GTPase phosphatase activity, which converts GTP–RAS into GDP–RAS (the inactive form), is a precise but inefficient mechanism to deactivate GTP-RAS; however, it is potently amplified by a GTPase-activating-protein, a recognized tumor suppressor (Topacio et al. 2019, De Meyts 2000).
Role of insulin receptors in neoplasia
Insulin receptor isoform A (IR-A) and insulin receptor isoform B (IR-B) are the INSR isoforms that physiologically bind insulin. Its selective binding capacity derives from an alternative splicing of exon 11 on chromosome 19, which generates a 12-amino acid change in the alpha chain of the IR-A isoform (Belfiore et al. 2009). The IR-B type, mostly present in adult tissues, is the preferred physiologic route for metabolic insulin action. In contrast, the IR-A isoform is expressed in intrauterine life and induces mitogenic actions. In any case, dysregulation of both IRs isoforms, as frequently found in obesity and comorbidities, might associate with neoplasia and cancer (Belfiore et al. 2017).
Insulin receptors in normal and rapidly dividing cells
Physiologically, the insulin/INSR signaling pathway promotes energy generation as well as contributes to healthy proliferation, differentiation, growth, and survival of normal cells. Indeed, insulin exerts widespread anabolic bodily actions (Belfiore et al. 2009). However, hyperinsulinemia, dysregulation of INSR isoforms, and undue insulin interaction with the insulin-like growth factor-I receptor (IGF-IR), or with hybrid INSR/IGF-IR, can also trigger disease (Belfiore et al. 2017, Rahman et al. 2021). Studies of the IR-A/IR-B ratio in physiologic and pathologic conditions help to understand the subtleties of INSR expression and its role in health and disease (Chettouh et al. 2013).
While IR-A is mainly present in intrauterine life, adult tissues preferentially express IR-B, and the IR-A/IR-B ratio reflects those differences in normal cells. In malignant clones, however, an abnormal ratio is found (Chettouh et al. 2013). For example, in hepatocellular cancer, mitogenic IR-A is overexpressed. Increasing IR-A and decreasing IR-B receptor synthesis, or a combination of both, would further alter the IR-A/IR-B ratio (Chettouh et al. 2013). This phenomenon occurs in BC where increased IR-A and decreased IR-B synthesis is found (Aljada et al. 2015).
Besides IR-A and IR-B expression and its relative quantities, hyperinsulinemia might directly generate an abnormal ratio of IR-A/IR-B at the level of normal colorectal mucosa, which associates with increased adenoma formation risk (Santoro et al. 2014).
GTP and GDP in normal and neoplastic cells
When GHR function is normal, the complex interrelationship of obesity and cancer risk is related to hyperinsulinemia and excess fuel supply, in the presence of increased antiapoptosis and uninhibited DNA damage (Guevara-Aguirre & Rosenbloom 2015). Contextually, cell energy acquisition mainly depends on recruitment and docking of GLUT4 transporters from the cytosol to the cell membrane (Gonzalez & McGraw 2006). This key event leads to cytosolic glycolysis and to mitochondrial Krebs cycle and oxidative phosphorylation functioning, which results in ATP and GDP generation (Guo et al. 2012). It also suggests that insulin overactivation of the Pl3K/AKT signaling pathway most probably will lead to excess energy creation within cells. While ATP enhances cell activities, including those of rapidly dividing cells, the role of GTP in RAS activation (Osaka et al. 2021) is also in carcinogenesis (Maertens & Cichowski 2014), and mutated RAS is recognized as some of the most important influences in oncogenic processes (Prior et al. 2020).
Mutations in normal and rapidly dividing cells
In general, gene mutations are naturally occurring cellular events. They allow acquisition of new features required to adapt to ever-changing environmental conditions and are in the core of the evolution process (Babcock 1918, Hershberg 2015). Nevertheless, when deleterious mutations occur outside those boundaries, and among other detrimental effects, it can result in conversion of a protooncogene to an oncogene, resulting in uncontrolled cell mitosis that may result in neoplasia and cancer (Guo et al. 2012).
Neoplastic and cancer cells, typically, have faster mitogenic rate and larger number of mutations. They are phenotypically abnormal cells that avoid physiological mechanisms controlling the normal cell cycle (Tomlinson et al. 1996). These changes might result in benign as well as malignant tumors. Of note, the relevance of the mitogenic rate, estimated by simple algebraic methods, predicted the number of cancer events that might arise with normal as well as with faster mutation rates (Tomlinson et al. 1996, Calabrese & Shibata 2010).
Hyperinsulinemia of obesity and cancer
Hyperinsulinemia is defined as a fasting serum insulin level above 12.2 mIU/L (Polonsky et al. 1988). Fasting and postprandial values in obesity are above 20.16 and 67 mIU/L, respectively (Polonsky et al. 1988, Van Vliet et al. 2020). Obesity hyperinsulinemia is caused by chronic and dysregulated insulin secretion as well as by its inefficient hepatic clearance. In any case, hyperinsulinemia eventually results in insulin resistance and T2D (Corkey 2011, Cerf 2013, Thomas et al. 2019, Ludwig et al. 2020). Obesity hyperinsulinemia induces increased fat mass accretion, adipocyte dysfunction, hypertriglyceridemia, less energy expenditure, and a wide variety of other abnormalities in the CHO metabolism (Rajan et al. 2016, Chawla et al. 2018). Notably, hyperinsulinemia, by itself, is a risk for diabetes, cardiovascular disease, and cancer (Garg et al. 2014, Gallagher & LeRoith 2015, Poloz & Stambolic 2015, Chiefari et al. 2021).
Hyperinsulinemia and elevated fasting plasma glucose
Hyperglycemia and T2D are independently associated with increased cancer risk (Gallagher & LeRoith 2015, Poloz & Stambolic 2015, Chiefari et al. 2021). Elevations of fasting plasma glucose (FPG) and coexisting hyperinsulinemia associate with malignancy initiation and progress (Lohmann et al. 2016). Indeed, subjects with fasting FPG serum levels above 126 mg/dL have higher cancer death risks than those in the 100–126 mg/dL range. A distinct example is provided by LC and BC associated with higher FPG concentrations (Jee et al. 2005, Goodwin et al. 2009, Goodwin et al. 2012).
When comparing serum insulin and glucose concentrations, hyperinsulinemia above 10 IU/mL appeared as a stronger cancer risk than elevated FPG above 100 mg/dL. Cancer mortality in non-obese subjects, demonstrated that those with hyperinsulinemia are at a higher risk than those with either normal insulin or FPG levels (Perseghin et al. 2012, Walraven et al. 2013, Tsujimoto et al. 2017). Furthermore, long-lasting excess glucose and insulin serum levels result in the generation of advanced glycation end products that distort bodily proteins, hence originating permanent and usually irreversible tissue damage (Gallagher & LeRoith 2015).
Because of their higher mitogenic rate, cancer cells can alter their metabolism to maintain the typical high proliferation, growth, and survival pattern (Goodwin & Stambolic 2015). Moreover, due to these characteristics, cancer clones need a higher glucose uptake, which is then rapidly fermented to lactate, even in the presence of normal mitochondrial function. These derangements, which are advantageous for flourishment of malignant cells, are collectively known as the Warburg effect, an old but still poorly understood phenomenon (Vander Heiden et al. 2009, Koppenol et al. 2011).
Hyperinsulinemia also induces increased internalization of insulin receptors (INSR), resulting in lower quantities of available cell membrane-binding sites (Ferguson et al. 2012). These events further augment serum insulin levels while lowering malignant cell insulin sensitivity. Concomitantly, cancer cells promote a sharp increment in the amount of their own membrane GLUTs, resulting in overall augmented glucose uptake (Macheda et al. 2005, Hanahan & Weinberg 2011).
Notably, glucose by itself enhances the Wnt/β-catenin-signaling pathway, a route involved in tissue regeneration, stem cell proliferation, and differentiation. Nevertheless, its dysregulation or dysfunction is found in diverse types of cancer such as of colonic, hepatic, ovarian, melanoma, and others. Moreover, glucose induces β-catenin acetylation which, in turn, increases the amount of the hypoxia-inducible factor-1-alpha (HIF1α) (Chocarro-Calvo et al. 2013), a transcription peptide that promotes angiogenesis of malignant cells even when oxygen concentrations are low (Chocarro-Calvo et al. 2013, Garcia-Jimenez et al. 2013).
Hyperinsulinemia of obesity and dyslipidemia
In murine models of obesity and T2D, elevated levels of 27-hydroxicholesterol (27-OHC) and non-esterified fatty acids (NEFAs) associate with hyperinsulinemia. These molecules are estrogen receptor agonists and activate the AKT/glycogen synthase kinase (GSK)-3β/β-catenin-signaling pathway that promotes both proliferation and survival of cancer cells (He & Nelson 2017, Mollinedo & Gajate 2020).
In carcinogenic processes, dysregulation of signaling pathways along with altered free fatty acid (FFA) metabolism and chronic inflammation is found (Stone et al. 2018); moreover, hyperinsulinemia combined with high NEFA concentrations can unduly activate AKT–GSK-3β/β catenin, hence contributing to oncogenesis (Samuel et al. 2018).
The adipocyte and hyperinsulinemia
Obesity hyperinsulinemia induces abdominal and visceral fat mass accretion and contribute to deleterious changes in adipocyte progenitor cells. These abnormalities include increased nuclear size and DNA content (Kahn et al. 2019, Li et al. 2021). Furthermore, obesity-associated hyperinsulinemia generates adipocyte cell cycle abnormalities, resulting in cellular stress and dysfunction, eventually leading to accelerated senescence and associated neoplasia risks (Li et al. 2021).
Chronic inflammation, hypoxia, and hyperinsulinemia
Obesity and hyperinsulinemia are accompanied by chronic inflammation and overproduction of ROS, which are strongly associated with mutagenic and carcinogenic processes (Vakkila & Lotze 2004, Zheng et al. 2007). Furthermore, obesity-associated tissue hypoxia is linked to increased production and secretion of inflammatory cytokines such as tumor necrosis factor-alfa, an adipocytokine that promotes aromatase expression in the adipose tissue, hence augmenting serum estrogen levels, as seen in BC (Wang et al. 2017, Park et al. 2014).
Abnormalities of signaling pathways in hyperinsulinemia
Obesity hyperinsulinemia unduly activates metabolic signaling cascades that, along with excess energy and chronic inflammation, promote cell neoplastic growth and survival, which eventually results in the progression of benign and malignant neoplastic tumors (Orgel & Mittelman 2013, Poloz & Stambolic 2015, Cozzo et al. 2017, Chiefari et al. 2021).
Insulin activates the two isoforms of INSR receptors – IR-A is a 1370-amino-acid residue protein that lacks residues encoded by exon 11 and IRB is a 1382-residue IR-B isoform (Ebina et al. 1985, Ullrich et al. 1985). Of note, insulin binds to IR-A with higher affinity than with IR-B. IR-A also binds proinsulin and IGF-II (Mosthaf et al. 1990, Yamaguchi et al. 1991, Pandini et al. 2003) and has been found to be elevated in several types of cancers (Belfiore et al. 2017, Haeusler et al. 2018) such as lung (Ferguson et al. 2012), breast (Harrington et al. 2012, Aljada et al. 2015), ovaries, cervix, endometrium (Wang et al. 2012, Wang et al. 2013, Sun et al. 2016), gastric (Huang et al. 2019), esophageal (Arcidiacono et al. 2018), pancreatic (Dugnani et al. 2016), colorectal (Kaaks et al. 2000), and prostatic (Perks et al. 2016). In general, hyperinsulinemia induces overexpression of the mitogenic effects of activated IR-A in tumor cells (Vigneri et al. 2016).
Notably, INSR can form hybrids with the IGFI-IR. Since INSR/IGFIR hybrids indiscriminately bind insulin, IGF-I and IGF-II, they might also activate several mitogenic signaling pathways (Novosyadlyy et al. 2010). Notably, excess IGF-I induces prolonged IGF-IR and INSR/IGFIR activation, which induces further growth of malignant and premalignant lesions as well as antiapoptotic effects. Insulin might also promote tumorigenesis and antiapoptotic effects using similar mechanisms (Arcidiacono et al. 2012, Vigneri et al. 2016).
Besides promoting normal antiapoptotic mechanisms, insulin and IGF-I binding to its corresponding receptors physiologically activate the metabolic PI3K/AKT as well as the proliferative RAS/MAPK-signaling pathways (Novosyadlyy et al. 2010). Subsequently, these activated cascades induce AKT, RAS, and mTOR signaling activation that results in distinct normal metabolic and growth-promoting activities. Nevertheless, distortion of these signals by hyperinsulinemia can contribute to undue apoptosis inhibition, tumorigenesis, and metastatic growth (Gallagher et al. 2012, Simpson et al. 2017). Furthermore, hyperinsulinemia can provoke undue RAS farnesylation, an important event for RAS interaction with PI3K, hence resulting in a potent membrane-activated RAS isoform that stimulates malignant growth (Draznin 2011).
Hyperinsulinemia increases hepatic IGF-I synthesis and bioactivity while diminishing IGFBP1 and IGFBP2 levels. These events result in higher available serum IGF-I concentrations (Clemmons & Underwood 1991, Leung et al. 2000, Kaaks & Lukanova 2001, Pollak 2008, Draznin 2011, Simpson et al. 2017). Similarly, insulin and IGF-I inhibit steroid hormone binding globulin (SHBG) synthesis and increase estrogen availability for the mammary gland and endometrium, circumstances that might promote proliferative and undue antiapoptotic effects (Pollak 2008, Kim & Scherer 2021).
Hyperinsulinemia and the tumoral microenvironment
Hyperinsulinemia, obesity, and abnormal adipocytes influence tumoral microenvironment and promote further proliferation, angiogenesis, invasion, cell migration, and metastatic growth (Kahn et al. 2019, Wu et al. 2019, Kim & Scherer 2021). In addition, tumor-derived factors contribute to adipocyte lipid content loss, resulting in a new phenotype (cancer-associated adipocytes (CAAs)) as well as in diminished expression of adiponectin and subsequent hypothalamic appetite distortion (Ramos et al. 2020). Furthermore, tumor-derived influences induce overexpression of fatty acid-binding protein-4 (FABP-4) that not only associates with cardiovascular and metabolic disease but has also been implicated in the genesis and progression of various cancers (Park et al. 2014). In addition, CAAs receive tumor-derived paracrine influence, which results in FFA, inflammatory cytokine, and growth factor overproduction that benefits tumoral microenvironment, clone proliferation, and malignant cell survival (Wu et al. 2019).
Obesity, hyperinsulinemia and prediabetes are associated with lower levels of the key circadian transcription factor known as brain and muscle arnt-like-1 protein (BMAL1). This circadian peptide regulates cytosolic translation to promote general protein synthesis. A non-canonical function of BMAL1 ameliorates the effects of obesity in certain types of BC by influencing the respiratory cycle. Decreased levels of BMAL1 not only benefit intrinsic mitochondrial metabolism but also favor the inflamed extrinsic microenvironment, hence stimulating metastasis and invasion, as seen in BC (Ramos et al. 2020).
In summary, nutritional defects, especially excess consumption of refined sugars, contribute to obesity and hyperinsulinemia (Lozano et al. 2016, Janssen 2021, Zhang et al. 2021). Obesity comorbidities include CHO intolerance, T2D, the metabolic syndrome, and cardiovascular disease, the well-known metabolic effects of obesity and coexisting hyperinsulinemia (Lozano et al. 2016, Mirabelli et al. 2020, Mili et al. 2021, Scully et al. 2021, Zhang et al. 2021). Nevertheless, the mitogenic effects of obesity-related hyperinsulinemia appear to have a central, unique role in carcinogenesis, tumor growth, and metastatic disease.
The obese ELS cohort and cancer
Background
As stated earlier in this review, the distinct clinical phenotype of all ELS subjects is one of decreased lean mass and increased body fat that result in overweight and frank obesity. Excess adiposity can be seen in most individuals from birth, early childhood, and adolescence to adult life. Notably, even in subjects with apparent normal weight, a decreased muscle and excess fat mass can be clinically detected.
Contextually, excess serum insulin and maybe excess free IGF-I, frequently observed in obesity, contribute to higher cell proliferation and neoplastic changes (Perry et al. 2013, Boguszewski & Ayuk 2016). Concomitantly, increased serum levels of glucose, triacylglycerol (TG), and other metabolic substrates supply the additional energy needed for proliferation of rapidly dividing cells and generate an environment suitable for a higher mitogenic rate, hence increasing the possibility of DNA replication errors and inefficient DNA repair, along with augmented cell oxidation, diminished apoptosis, and insufficient disposal of abnormal cells, including malignant cells (Guevara-Aguirre et al. 2021b ).
Surprisingly, subjects in the ELS cohort display a biochemical profile opposite to that of typical obesity. Indeed, since the GH counter-regulatory effects on CHO metabolism are absent, they have less insulin resistance and display enhanced insulin sensitivity. These circumstances generate a phenotype of extremely low basal serum concentrations of insulin and IGF-I and normal to low basal glucose and TG, as well as diminished responses to orally administered glucose or to a standard breakfast, in terms of serum glucose, TG, and insulin (Guevara-Aguirre et al. 2015). Despite the risk posed by their lifelong presence of excess body fat and adolescent and adult obesity (Guevara-Aguirre et al. 2011), it is their biochemical and hormonal profile due to absent GHR signaling which better associates with the diminished incidence of cancer seen in these subjects.
Epidemiology
In a study published in 2011 (Guevara-Aguirre et al. 2011), we reported mortality findings in 99 ELS and 1606 relatives followed since 1988. Fifty-three subjects in the ELS cohort died before 1988 and nine since then. Most ELS subjects were homozygous for a splice site mutation at codon 180, exon 6 of the GHR, resulting in a defective GHR that lacks eight amino acids in its extracellular domain (Berg et al. 1992). The defective GHR signaling induces extremely low levels of serum IGF-I and IGF-II.
While the cancer-related aspects described in our 2011 report are extremely interesting, it is worth noting that the diminished incidence of T2D in the obese ELS subjects is the most surprising clinical finding we have made. Moreover, their low insulin serum levels might also be one of the most important mechanisms contributing to the low cancer incidence observed in this population.
Because ELS infants and young children frequently die of common diseases of childhood, only subjects that survived beyond 10 years of age (years) were considered for our morbidity and mortality 2011 analysis (Guevara-Aguirre et al. 2011). Surprisingly, despite the cancer risk posed by their obese phenotype, malignancy was not a cause for death in the ELS cohort, while it accounted for 20% of deaths in their relatives. The most common cancers diagnosed among them were those of stomach, uterus, prostate, lung, throat, liver, colon, cerebral, leukemia, breast, skin, and bone. Between 1988 and 2011, only one female ELS subject was diagnosed with a papillary serous epithelial tumor of the ovary and died in 2013. We believe that at least one more cancer case has been diagnosed and, if confirmed, it will be described in a follow-up report.
Mechanisms
We have suggested that the low cancer incidence in the ELS cohort is due to absent GHR signaling. Contextually, mutations in growth signaling pathways in yeast are associated with extended life span and less DNA damage as well as with decreased insulin resistance and cancer in mice (Guevara-Aguirre et al. 2011). In consequence, we considered the possibility that these signaling routes might be evolutionarily conserved throughout species and, perhaps, that they are also involved in disease genesis in humans. Interestingly, when serum from ELS individuals was added to human mammary cells treated with a potent oxidizing agent, there was reduced DNA damage and increased apoptosis. Concomitantly, reduced expression of RAS, protein kinase A, and mTOR as well as upregulation of superoxide dismutase 2 (SOD2) were observed (Guevara-Aguirre et al. 2011). Severely diminished IGF-I signaling in the ELS cohort was assumed to be the main etiologic reason for the absence of cancer and decreased insulin resistance as the explanation for diminished T2D incidence (Guevara-Aguirre et al. 2011). Nevertheless, the serum insulin levels seen in subjects belonging to the ELS cohort might have not only metabolic consequences but might also determine, in a discrete manner, appropriate proliferation, differentiation, growth, and survival of cells since only correct amounts of energy (ATP and GDP) are provided for these processes by the highly efficient but extremely low insulin levels in ELS individuals.
As stated above, the insulin/INSR interaction controls the RAS/MAPK signaling route that eventually activates early- and late-response genes influencing multiplication via CDKs (Lents et al. 2002). Importantly, activated AKT inhibits BAD proteins, thereby generating a cell antiapoptotic effect (Kennedy et al. 1999). Binding of insulin to its receptor also induces the potent PI3K/AKT signaling route to contribute to lipid and protein synthesis. However, the most relevant consequence of the insulin/INSR interaction is the AKT-mediated glucose entry into cells for subsequent ATP and GDP generation. Abnormalities of these physiologic events, especially hyperinsulinemia, might generate excess energy and undue fast cell proliferation, while normal functioning of the proliferative and metabolic branches of the INSR triggered by insulin induces salutary anabolic effects, as it occurs in the ELS subjects who distinctly have metabolic efficient hypoinsulinemia.
The various obesity-induced CHO abnormalities in metabolism have been etiologically linked to coexisting hyperinsulinemia, which has also been identified as an independent cancer risk (Gallagher & LeRoith 2015, Tsujimoto et al. 2017). However, and as mentioned, despite being obese, subjects belonging to the ELS cohort display hypoinsulinemia, normal FPG, and reduced glucose and insulin responses to oral glucose and standard meal challenges (Guevara-Aguirre et al. 2015) (Fig. 1). Low to normal FPG is a relevant factor since subjects with serum glucose higher than 126 mg/dL have higher BC incidence (Pellegata et al. 2022). In addition, it is highly unlikely that the Warburg effect will develop in ELS subjects, considering their normal FPG; moreover, the ELS low serum insulin levels most probably maintain normal cell membrane INSR, thereby diminishing insulin resistance and keeping normal cell membrane GLUT transporters and adequate cell glucose uptake.
(A) Glucose and insulin serum concentrations as determined by 2-h oral glucose tolerance test (1.5 g/kg) in ELS. (B) Glucose and insulin serum concentrations as determined by 5-h glucose tolerance test after a standard breakfast in ELS.
Citation: Endocrine-Related Cancer 30, 6; 10.1530/ERC-22-0389
Considering that stomach, uterus, prostate, lung, throat, liver, colon, cerebral, leukemia, breast, skin, and bone cancers were diagnosed only in the relatives of the ELS cohort, there is no clinical evidence that the deleterious effects of distorted Wnt/β-catenin-signaling pathway are exerted in ELS individuals. Of note, this regeneration and proliferation route has been found dysregulated in colonic, hepatic, ovarian, melanoma, and other malignancies that are indeed present in the ELS relatives (Garcia-Jimenez et al. 2013). Moreover, normal FPG in ELS subjects should prevent beta-catenin acetylation and avoid transcription of HIF1α, a known cancer cell angiogenesis factor (Chocarro-Calvo et al. 2013). Given that cancer incidence, especially that of breast, is diminished, and that low insulin concentrations in ELS are found, there is no clinical evidence that the levels of 27-OHC and NEFA are elevated or that the AKT/GSK-3β/β-catenin signaling pathway is activated.
Fat mass in ELS subject
Subjects in the ELS cohort have diminished lean and excess body fat from birth to death. Surprisingly, and in an apparent paradox, increased adiposity does not increase their cancer risk, implying that the deleterious changes observed in adipocytes that are associated with obesity, and cancer in regular obesity, do not occur in these hypoinsulinemic subjects. Following the same pattern, the chronic inflammation accompanying obesity and overproduction of ROS, which are strongly associated with mutagenesis and carcinogenesis, is not present in these individuals because of their normal FPG and low insulin serum concentrations. Moreover, they have increased expression of SOD2, an important antioxidant enzyme (Guevara-Aguirre et al. 2011), and, because cancer incidence is diminished, there is no clinical evidence that cancer-associated inflammatory cytokines are overexpressed.
Obesity hyperinsulinemia induces the activation of several metabolic cascades that, when associated with chronic inflammation, might eventually provoke mutagenesis and cancer. Individuals in the ELS cohort have obesity, but the difference resides in that they are hypoinsulinemic.
Insulin normally binds to IR-A and IR-B, the INSR isoforms, and hyperinsulinemia is associated with lung (Ferguson et al. 2012), breast (Harrington et al. 2012, Sun et al. 2016), ovary, cervix, endometrium (Sun et al. 2016), stomach (Huang et al. 2019), esophageal (Arcidiacono et al. 2018), pancreatic (Dugnani et al. 2016), colorectal (Kaaks et al. 2000), and prostatic (Perks et al. 2016). The presence of cancers of stomach, uterus, prostate, lung, throat, liver, colon, cerebral, leukemia, breast, and skin in the ELS relatives and its absence in the ELS subjects support the notion that overexpression of the mitogenic effects of activated IR-A by hyperinsulinemia of obesity is, indeed, an important driver of carcinogenesis.
Obesity hyperinsulinemia might promote tumorigenesis not only by activating IR-A and possibly IGF-IR but also by exerting antiapoptotic effects. In this sense, the ELS serum displays increased apoptosis properties, linked in our study to lower IGF-I serum levels (Guevara-Aguirre et al. 2011). However, the role of low insulin concentrations might also have been a contributor to this phenomenon, and normal activation of the PI3K/AKT and RAS/MAPK routes can confidently be anticipated in ELS subjects. Similarly, normal activities in the RAS and mTOR signaling cascades are to be expected.
The mitogenic effects of obesity-related hyperinsulinemia appear to have a central, unique role in carcinogenesis, cancer growth, and metastatic disease. However, despite their obesity, the effects of hyperinsulinemia, including those on IGF-I synthesis and bioactivity, cannot be expected in these individuals simply because of their hypoinsulinemia. Similarly, because the presence of abnormal adipocytes, excess proliferation, angiogenesis, invasion, cell migration, overexpression of FABP-4, and inflammatory cytokines depends on excess circulating insulin concentrations, these abnormalities cannot be expected in these hypoinsulinemic ELS subjects.
Summary
As stated earlier in this review, data from the ELS cohort evidence that obesity does not always associate with augmented cancer risk and incidence and putative protective mechanism for this clinical 30-year observation have been presented. Briefly, the association of diminished cancer cases despite a clinically evident obese phenotype in ELS individuals depends more on their hormonal and metabolic profile, including low levels of IGF-I and insulin. Nevertheless, hypoinsulinemia, along with normal basal FPG and TG, and efficient glucose-induced responses in terms of these metabolic substances, appears as the dominant protective influence.
Identification of basic oncogenic mechanisms underlying obesity, and of those corresponding to the influence of insulin, free IGF-I, and GH on carcinogenesis, as well as of those inherent to the powerful actions of glucose, as the main energy source needed for faster cell proliferation, is urgently needed. This is especially relevant considering that obesity and its comorbidities, including cancer, are overstraining health systems worldwide and bringing about pain and death to millions of people every day.
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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