Keywords

Introduction

White adipose tissue (WAT) was formerly studied in connection with caloric reserves, mechanic and thermal insulation, and sexual attraction. However, it is unquestionably a complex endocrine organ (Coelho et al. 2013). Adipocytes constitute 90% of the cells, whereas the stromal-vascular components include endothelial cells (10–20% of cells), pericytes (3–5%), fibroblasts, and others (15–30%). Stem and progenitor cells (0.1%) should not be neglected, along with T- and B-lymphocytes, macrophages, dendritic cells, and others (Cozzo et al. 2017). Sex steroid hormones, insulin resistance, growth factors, cytokines, and adipokines are all influenced by this cellular environment (Osborn and Olefsky 2012). Many cancer types are impacted by the same molecules and pathways (Sung et al. 2019).

Excessive body weight promotes elevated free fatty acids (FFA), triglycerides, glucose, insulin resistance, and insulin production, some of which could also stimulate cancer progression (Osborn and Olefsky 2012).

Comorbidities

Obesity predisposes to metabolic, cardiovascular diseases, as well as of several malignancies (Sung et al. 2019; Global BMI Mortality Collaboration et al. 2016; Goodwin and Stambolic 2015; GBD 2015 Obesity Collaborators et al. 2017), a phenomenon called as “adiponcosis” (Bifulco and Ciaglia 2017).

Cancers of digestive organs, like colon cancer, and tissues with endocrine links, such as breast, ovarian, endometrial, and prostate cancers, receive most attention (Sung et al. 2019; Kyrgiou et al. 2017; Tumminia et al. 2019). Cancer is the number two most fatal human condition, after cardiovascular disease, whereas obesity and related aberrations could be aggravating oncological mechanisms (Sung et al. 2019; Goodwin and Stambolic 2015).

Biological Mechanisms Linking Obesity to Cancer

Possible biological mechanisms comprise hyperinsulinemia/insulin resistance (IR) and abnormalities of the insulin-like growth factor-1 (IGF-1) signaling, sex hormones biosynthesis and pathway, alterations in adipokines pathophysiology, and subclinical chronic low-grade inflammation (Fig. 28.1).

Fig. 28.1
figure 1

Molecular pathways linking obesity and cancer. Insulin and insulin-like growth factor 1 (IGF-1) trigger off the phosphatidylinositol 3-kinase (PI3K) pathway, which in turn upregulates glycolysis and other metabolic pathways to generate energy needs for proliferation. Adipose tissue in the obese condition is a site of profound inflammatory activity using immune cells that secrete an abundance of cytokines that can influence on neighboring cancer cells to promote tumorigenesis through different metabolic levels.

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Hyperinsulinemia/Insulin Resistance

Insulin resistance is a common feature of obese patients resulting in a compensatory increase in systemic insulin and IGF-1 levels (Ackerman et al. 2017). The excess of body weight is not the only parameter determining hyperinsulinemia: the distribution of the extra weight and of visceral adipose tissue is also a key variable. Hyperinsulinemia induces the production of IGF-1 by hepatocytes and downregulates the secretion of IGF-1 binding proteins (IGFBPs), resulting in an increase in bioavailable IGF-1. Several cancer cell types respond to insulin and IGF-1 receptor binding, by activating PI3K and MAPK pathways or other downstream networks, promoting cell survival, growth, and motility (Di Zazzo et al. 2014; Ackerman et al. 2017).

Insulin resistance, hyperinsulinemia, and high IGF-1 levels increase the risk of endometrial, breast, colorectal, and prostate cancer (Goodwin and Stambolic 2015). When colorectal cancer-susceptible mice were treated with an IGF-1-receptor inhibitor disrupting downstream signaling, tumor burden was significantly reduced (Ackerman et al. 2017).

In adipose tissue, insulin controls lipid storage and inhibition of lipolysis. Once glucose and insulin levels are elevated for prolonged periods as a consequence of overeating or lack of exercise, insulin can induce lipid storage in non-adipose tissue such as skeletal muscle. This inappropriate accumulation of intramuscular fatty acids contributes to altered insulin signaling.

Sex Hormones

Peripheral adipose tissue performs steroids aromatization: androgens and androgenic precursors are converted to estradiol by aromatase. In obesity, the excess of adipose tissue and the increased aromatase activity lead to a higher conversion rate, resulting in higher levels of circulating estrogens (Gérard and Brown 2018). In men and in postmenopausal women, the conversion of androgens to estrogens is dependent upon adipose tissue mass. Estrogen signaling has several consequences in tumor growth promotion. Indeed, estradiol is able to stimulate cell proliferation of breast epithelial and endometrial cells, to inhibit apoptosis, and to induce angiogenesis (Andò et al. 2019). Additionally, obesity is associated with lower plasma levels of sex hormone-binding globulin (SSBG), thus increasing bioavailable concentrations of estradiol and testosterone, resulting in a greater cancer risk (Di Zazzo et al. 2018).

Adipokines and Cancer

Adipokines are bioactive molecules released by WAT that acts locally in an autocrine and paracrine manner, but they also have a systemic, endocrine effect through blood circulation (Diedrich et al. 2015). Adipokines include adiponectin (APN), leptin, resistin, omentin, and chemerin; under physiological conditions, they regulate several processes such as energy balance, lipid metabolism, insulin sensitivity, inflammation, innate and adaptive immunity, angiogenesis, hematopoiesis, and cell proliferation (Schrover et al. 2016).

Abnormal accumulation of adipose tissue induces adipocyte dysfunctions, resulting into the alteration of its endocrine functions and consequently affecting the secretion of different adipokines, usually leading to increased leptin and decreased APN blood concentration. Abnormal adipokine secretion often represents a factor leading to cancer (Fig. 28.1) ( Di Zazzo et al. 2019). Upon analysis of a panel of 14 obesity-related hormones, cytokines, coagulation factors, and other biomarkers, C-peptide, IL-6, and TNF-α pointed toward clear-cell renal carcinoma risk (Wang et al. 2019).

Adiponectin and Cancer

APN behaves as insulin-sensitizing, anti-apoptotic, and immune regulatory (Ackerman et al. 2017). Various homo-oligomers are recognized, and as adiposity accumulates, APN diminishes in the same proportion (Di Zazzo et al. 2019). APN usual receptors, AdipoR1 and AdipoR2, are physiologically highly relevant. Hexameric and multimeric APN binds to a different receptor, from the cadherin superfamily (Di Zazzo et al. 2019).

Signaling pathways for cellular responses include AMPK, mTOR, PI3K/AKT, MAPK, STAT3, and NF-kB, (Di Zazzo et al. 2019). AdipoR1 and AdipoR2 also impact energy balance, including insulin sensitization (Di Zazzo et al. 2019). Ceramidase stimulatory activity, which depletes intracellular ceramide, inhibits apoptosis (Holland et al. 2011).

Hypoadiponectinemia

Poor response to APN during excessive adiposity could be explained by low receptor values (Yamauchi et al. 2014). The same tends to occur during inflammation linked to diabetes and atherosclerosis (Di Zazzo et al. 2019). APN is usually classified as an anti-cancer molecule, with anti-inflammatory, anti-proliferative, and pro-apoptotic impact (Porcile et al. 2014; Di Zazzo et al. 2019).

Breast Cancer

Breast Cancer (BC) risk is heightened during advanced adiposity: (i) aromatization of androgens to estrogens stimulates growth of mammary cells; (ii) interference with APN physiology prevents its protective response (Avgerinos et al. 2019). Low APN levels are certainly deleterious in this context (Ye et al. 2014), including cancer growth and virulence. In the ERα-negative human BC cell line MDA-MB-231, Genes involved in cell cycle progression and apoptosis are one of the possible mechanisms (Mauro et al. 2014).

In an ERα-positive cell culture, APN leads to expression of ERα and cell growth (Mauro et al. 2014). Cross talk between APN/AdipoR1, IGF-IR, and ERα seems relevant (Mauro et al. 2015). Insulin and estrogen elevation, which favor cancer progression, contrast with depressed APN, including postmenopausal and ER-positive breast tumors (Di Zazzo et al. 2014; Mauro et al. 2014). APN modulates cell migration and invasion (Jia et al. 2014), AdipoR2 signals lymphatic and vascular penetration, and all of them are markers of metastatic disease (Jeong et al. 2011).

Gastrointestinal Malignancies

Strong correlation between obesity and the development of gastrointestinal (GI) cancers is reported (Murphy et al. 2018). The largest adipose intra-abdominal depot is the omentum, the so-called fatty apron connecting the stomach to the colon, enriched with immune cells and responsible for local inflammation. Obesity disrupts the homeostatic profiles of innate and adaptive immune cell populations within the omentum (O’Sullivan et al. 2018). APN plasma levels were found decreased in patients with GI cancers (Nagaraju et al. 2015). APN is suggested to be involved in esophageal mucosa remodeling, and it might have a protective role against cancer transformation, contributing to the link between obesity and lower esophageal carcinoma (EC) (Almers et al. 2015). Patients with metabolic syndrome, associated with increased leptin and decreased APN serum levels, are prone to Barrett’s esophagus, a metaplastic change occurring in response to gastroesophageal reflux disease that can potentially lead to the EC. Moreover, high levels of LMW-APN are associated with a decreased risk of Barrett’s esophagus (Tilg and Moschen 2014).

Beales and colleagues demonstrated that in OE33, an esophageal carcinoma cell line, leptin was able to induce proliferation, invasion, and migration and inhibit apoptosis in a STAT3-dependent manner and, by contrast, APN inhibited leptin-stimulated proliferation via AdipoR1 (Beales et al. 2014). In gastric cancer, APN inhibited proliferation in vitro with most prominent effects in AZ521 and HGC27 gastric cell lines expressing high levels of AdipoR1/R2 mRNA. Moreover, higher concentrations of APN significantly reduce tumor volume and peritoneal metastases in vivo (Ishikawa et al. 2007), consistent with previous findings suggesting an anti-angiogenic and tumor suppressive role for this adipokine (Bråkenhielm et al. 2004). In the same models, APN elicits its biological effects through AdipoR1/R2 activation, whose expression was significantly associated with histological type and overall survival (Ishikawa et al. 2007). Negative AdipoR1 immunostaining was found in patients with lymphatic metastasis and peritoneal dissemination, while positive AdipoR1 expression corresponded to a longer survival rate (Tsukada et al. 2011).

Circulating APN levels have been also associated with increased risk of pancreatic cancer (Pothuraju et al. 2018). APN exerted its inhibitory effect through modulation of the β-catenin signaling pathway. In BxPC-3 and CFPAC-1, pancreatic cell lines both expressing the AdipoRs, APN reduced serum-induced phosphorylation of GSK-3β, decreased the nuclear accumulation of β-catenin, and downregulated the expression of cyclin D1. Knockdown of AdipoRs abolished the growth-inhibiting effect induced by APN in vitro and in xenograft models (Jiang et al. 2019).

Colorectal Cancer

Low APN is a marker of colorectal cancer (CRC) (Di Zazzo et al. 2019). Both AdipoR1 and AdipoR2 in turn could signal lymphatic metastasis (Ayyildiz et al. 2014), as well as (for AdipoR1) the ability to survive the illness (Choe et al. 2018). APN negatively controls CRC growth, by inhibiting the mechanistic target of rapamycin (mTOR) via AMPK phosphorylation, and decreasing PI3K and Akt phosphorylation (Parida et al. 2019).

In CRC models, APN knockdown resulted in increased multiplicity of aggressive colorectal polyps. In an APN-deficient mice model, APN treatment inhibited cancer progression and angiogenesis (Moon et al. 2013). APN deficiency also aggravated azoxymethane-induced colon cancer in C57BL/6J mice (Mutoh et al. 2011).

APN conferred protection against inflammation-induced colon cancers by preventing apoptosis in the goblet cells and promoting conversion of epithelial to goblet cells (Saxena et al. 2012). In HCT116, HT29, and LoVo CRC cell lines, APN induced G1/S cell cycle arrest with concomitant overexpression of p21 and p27 via AMPK phosphorylation; inhibition of AdipoRs released cells from APN-induced growth blockade (Kim et al. 2010). APN anti-cancer effect is glucose-dependent, possibly explaining why CRC survival is enhanced in a low glucose medium; however, the opposite occurs with APN in high glucose conditions (Habeeb et al. 2011).

Ovarian Cancer

Ovarian cancer patients have a lower blood concentration of APN than healthy women (Jin et al. 2016); low APN concentration was associated with longer progression-free survival times and a better tumor responsiveness to chemotherapy (Diaz et al. 2013; Slomian et al. 2019). In addition, AdipoR1 expression level in ovarian cancer tissues could represent a marker of prognosis, being positively associated with overall patient’s survival (Li et al. 2017). Low APN plasma levels may favor ovarian cancer growth, induced by persistent activation of PI3K/Akt/mTOR signaling. Moreover, APN is able to repress human ovarian cancer cell growth and reverse the stimulatory effects of 17β-estradiol and IGF-1 on cell proliferation through the downregulation of their receptors (Hoffmann et al. 2018).

Endometrial Cancer

Low APN blood levels were associated with an increased risk and a worse prognosis of endometrial cancer (EMC). Low expression of AdipoR1 in endometrial cancer cells is associated with advanced tumor stage (Tumminia et al. 2019). Several hypotheses have been formulated the role of APN implying: (i) activation of AMPK (resulting in cell growth suppression and apoptosis); (ii) extracellular signal-regulated protein kinase (ERK) and Akt pathway inhibition; (iii) reduction of Cyclin D1 expression (Moon et al. 2011). Association seems more evident for type II EMC, and APN modulators are being explored for potential therapeutic avenues (Garikapati et al. 2019).

Prostate Cancer

Conflicting reports about APN exist (Hu et al. 2016). APN concentration in prostate cancer patients was low and connected to disease advent (Goktas et al. 2005). A lower AdipoR1 and AdipoR2 expression was observed in prostate neoplastic tissues compared with healthy prostate tissue (Michalakis et al. 2007). Growing evidence indicates that APN exerts an anti-proliferative action in prostate cancer cells, inhibiting dihydrotestosterone-activated cell proliferation (Bub et al. 2006). The ectopic overexpression of APN in prostate cancer cell lines inhibited mTOR-mediated neoplastic cell proliferation (Gao et al. 2015).

No links are also advocated (Baillargeon et al. 2006), or a significant positive correlation between APN concentrations and incidence of low- or intermediate-risk prostate cancer (Ikeda et al. 2015). Higher APN plasma levels were detected in subjects with cancer stage T3 (advanced) than in subjects with T2 (confined within the prostate). AdipoR2 findings could be a signal of cancer progression and metastasis (Rider et al. 2015).

Low Chronic Inflammation

Large adipocytes become distant from the blood supply, which can trigger chronic hypoxia and inflammation (Boutari and Mantzoros 2018).

Neutrophils and mast cells enhance inflammation whereas the opposite is expected from eosinophils and myeloid-derived suppressor cells. B- and T-lymphocytes and natural-killer cells are also engaged in the process, as well as M1 pro-inflammatory macrophages (ATMs) (Ouchi et al. 2011).

Macrophages constituting crown like structures elicit nuclear factor-kappa B (NF-κB) aggravating chronic inflammation (Ouchi et al. 2011). The cross talk between adipocytes and cancer engages IL-1, IL-6, and TNF-α, ROS generation, adipokines, and other molecules (Fig. 28.1) (Avgerinos et al. 2019). Cancer cells can also induce phenotype alteration of adjacent adipocytes, encompassing reduction of their lipid content and release of adipokine and matrix metalloproteinases (Dirat et al. 2011).

Inflammasome is an innate immune pathway activating proinflammatory cytokines, including IL-1 and IL-18 (Lamkanfi and Dixit 2014). Inflammasome-related genes are encountered in adipocytes (Yin et al. 2014), potentially stimulating cancer growth (Guo et al. 2016). Obesity treatment tends to ameliorate this negative profile (Hagman et al. 2017).

The Obesity Paradox in Cancer

Obesity negatively influences cancer recurrence, prognosis, and survival (Lennon et al. 2016). However, opposite evidence in certain circumstances suggests that obesity reduces cancer incidence and improves survival. Obesity has been ruled out as a risk for cancer mortality (Kuk et al. 2018). Body fatness reduced the nerve sheath tumor risk (Wiedmann et al. 2017); overweight or obesity attenuated mortality of bladder (Pavone et al. 2018); and lung cancer (Zhang et al. 2017) after surgery or chemotherapy. A meta-analysis also showed that obese patients with esophageal cancer had better long-term survival (Kayani et al. 2012).

The use of BMI as a measure of adiposity could partly explain the discrepancies, as it does not fully characterize the intricate biology and physiology of excess body fat. BMI cannot differentiate between lean mass and adipose tissue and depends upon gender, age, ethnicity, and race. Additionally, BMI does not estimate the visceral adipose tissue (VAT), which seems to be metabolically more relevant. Computed tomography and MRI are better alternatives for quantification of VAT; however, they are not always feasible (Allott and Hursting 2015). Anthropometric measures, such as waist circumference (WC) and waist-to-hip ratio (WHR), are viable techniques (Sung et al. 2019), however, not perfect ones, as both VAT and subcutaneous abdominal tissue (SAT) are lumped together in the results (Avgerinos et al. 2019).

Obesity and Therapy

Obesity and comorbidities like dysglycemia, hypertension, and dyslipidemia could reduce the response to chemotherapy. Elevated BMI was associated with poor prognosis in patients affected by colon cancer who received surgical resection of primary tumor and adjuvant chemotherapy with capecitabine and oxaliplatin (Lashinger et al. 2014). In bevacizumab-treated metastatic CRC patients, high visceral fat and BMI were significantly associated with absence of a response and increased progression. BMI was negatively associated with response to standard first-line chemotherapy with platinum and taxanes in ovarian cancer patients (Califano et al. 2014). These results could be related to the expression by adipose tissue of angiogenic factors (in particular VEGF) (Ottaiano et al. 2018). Hyperinsulinemia, a known growth factor, could trigger chemoresistance to 5-fluorouracil, anthracyclines, taxanes, and other drugs upregulating P-glycoprotein (Wei et al. 2015).

Drug Dosage

Pharmacokinetic studies rarely address the obese. The most common strategy is dose-capping or dose-fixed regimens. The consequence of this “depotentiation” attitude may be the use of subtherapeutic strategies, conducting to disease recurrence and mortality. According to the American Society of Clinical Oncology, full weight should be adopted for dosage calculation.

Specific Cancer Therapies for Obese and Diabetic Patients?

A balanced and healthy diet may control factors that sustain obesity-related disease (i.e., IGF-1, insulin, leptin) (Avgerinos et al. 2019). In addition, vigorous aerobic exercise leads to a peak of circulating APN levels (Saunders et al. 2012). Moreover, there is an increasing interest in testing diabetes and cholesterol-lowering drugs for cancer therapy. 

Metformin

Metformin could decrease incidence and mortality of cancer by inducing hepatic gluconeogenesis and reducing IR of peripheral tissues, resulting in lower insulin and IGF-1 levels (Gallagher and LeRoith 2015). Metformin blocks tumor growth and induces apoptosis through insulin-independent mechanisms (Safe et al. 2018). Furthermore, metformin decreases cancer recurrence by directly inducing cancer stem cell death (Gallagher and LeRoith 2015).

Glycemic control with metformin can restore adipokine concentrations, increasing APN, and decreasing pro-inflammatory adipokine levels in both humans and mice (Avgerinos et al. 2019). For prostate and breast malignancies, large meta-analyses failed to demonstrate benefits for metformin regarding cancer risk and mortality (Feng et al. 2019; Au Yeung and Schooling 2019; Wang et al. 2020). Yet in other contexts, such as rectal cancer treated by neoadjuvant chemoradiotherapy, better cancer response and lower risk of recurrence were elicited (Kim et al. 2020). Clinical trials are going on. Twelve of them address the following cancers: breast (five), along with head and neck, thyroid, endometrial, multiple myeloma, lymphocytic leukemia, and various gynecologic/ solid tumors (one of each) (www.cancer.gov, 2020).

Thiazolidinediones (TZDs) and Other Agents

Activation of PPAR-γ by TZDs could restrict cell proliferation by decreasing insulin concentration and also influencing key pathways of the Insulin/IGF-1 axis, such as MAPK, PI3K/mTOR, and Glycogen synthase kinase (GSK)3-β/Wnt/β-catenin cascades, which modulate cancer cell survival and differentiation. Additionally, the PPARγ agonists TZDs, rosiglitazone, and pioglitazone augment the circulating level of APN directly, enhancing its gene and protein expression in a dose-dependent manner (Parida et al. 2019). Yet, meta-analysis results are conflicting.

For bladder cancer, an increased risk with pioglitazone was announced, possibly dose and time dependent (Tang et al. 2018). As regards colorectal cancer, no advantages were detected with pioglitazone, whereas other PZDs seemed moderately protective (Liu et al. 2018). A lack of association with breast cancer risk is reported (Du et al. 2018). This last outcome is consistent with a meta-analysis addressing digestive cancers, in which the risk did not differ for incretin mimetics, insulin, metformin, sodium-glucose co-transporter 2, sulfonylureas, TZDs, alpha-glucosidase inhibitors, or placebo (Chai et al. 2019).

Therapies Targeting APN

Increasing plasma APN levels or mimicking some of its cancer-protective properties could mitigate the deleterious effects of metabolic dysfunctions on tumor development and progression (Vansaun 2013; Tumminia et al. 2019). Therefore, pharmacological increase in serum APN levels, up-regulation of AdipoRs expression, or synthesis of AdipoRs agonists could represent promising therapeutic strategies.

Using a high-throughput assay, several natural compounds showing AdipoRs agonist activity were identified. These compounds, acting preferably on AdipoR1 (e.g., matairesinol, arctiin, arctigenin, gramine) or AdipoR2 (e.g., syringin, parthenolide, taxifolion, deoxyschizandrin), shared important anti-cancer properties, including anti-proliferative and anti-inflammatory effects (Sun et al. 2013). ADP355, a peptide-based APN receptor agonist, prevented the proliferation of AdipoRs-positive cancer cell lines. ADP 355 showed high affinity with AdipoR1, and through the regulation of the canonical APN-regulated pathways (i.e., AMPK, Akt, STAT3, and ERK1/2), reduced breast tumor growth both in vitro and in vivo (Otvos Jr et al. 2015). Additionally, three peptides BHD1028, BHD43, and BHD44 have been designed to mimic APN actions. BHD1028 showed the highest affinity with AdipoR1 and the main activation of AMPK already at low concentration, more than ADP 355 (Kim et al. 2018).

Oral Adiponectin Receptor Agonist

AdipoRon (AdipoR) is the first oral AdipoRs agonist able to bind and activate AdipoR1 and AdipoR2 that successfully re-established APN functions, mainly activating AMPK and PPARγ pathways in obesity-related type 2 diabetes (Okada-Iwabu et al. 2013). Initial reports have also investigated the possible anti-cancer role of AdipoR in preclinical models, especially in pancreatic and ovarian cancer (Akimoto et al. 2018; Ramzan et al. 2019). However, modifying AdipoRs interactions could also result in infertility, cardiac damage, and reduced bone density (Holland and Scherer 2013).

Statins and Assorted Drugs

Statins have been reported to be effective in increasing circulating APN levels. Statins function by releasing cellular oxidative stress, resulting in increased APN multimerization and secretion. Angiotensin converting enzyme inhibitors as well as angiotensin receptor antagonists Ramipril, Quinapril, Losartan, Telmisartan, Irbesartan, and Candesartan have similarly shown promising results in clinical trials. They function by enhancing APN secretion via PPARγ, though some of them are also known to induce transcription. Other potential drugs include non-statin anti-hyperlipidemic drugs like Fenofibrate and Zetia, non-TZD anti-diabetic drugs, such as Acarbose and the sulfonylurea Glimepiride and Sulfonylureas (Parida et al. 2019).