Obesity and Cancer: Linked Molecular Mechanisms

Although the available limited evidence suggested a protective role of APN on ovarian carcinogenesis, additional studies are necessary to elucidate its function in ovarian tumor onset and progression.

Low APN blood levels were also associated with an increased risk and a worse prognosis of endometrial cancer. Additionally, a low expression of AdipoR1 in endometrial cancer cells is associated with advanced tumor stage [Tumminia et al., 2019]. The mechanism by which APN inhibits the growth of endometrial cancer cells is unknown. However, several hypotheses have been formulated implying: i) activation of AMPK (resulting in cell growth suppression and apoptosis); ii) the extracellular signal-regulated protein kinase (ERK) and Akt pathway inhibition; iii) reduction of Cyclin D1 expression [Moon et al., 2011]; iv) a pro-apoptotic effect [Cust et al., 2007].

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Several studies highlight the central role of APN and its receptors in prostate cancer, even if some evidence appears to be contradictory [Hu et al., 2016]. APN concentration in prostate cancer patients was significantly lower than healthy controls; additionally, it was related to prostate cancer development and progression [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 cells proliferation [Gao et al., 2015]. In contrast with these results, several authors showed no significant association between APN expression and prostate malignancy [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 outside) than in subjects with T2 (confined within the prostate). Furthermore, some evidence indicates that AdipoR2 expression is directly associated with prostate cancer progression and metastasis [Rider et al., 2015]. Additional studies are needed to better clarify the role of APN in prostate cancer.

Adipose Tissue, Adiponectin and Low Chronic Inflammation

In adipose tissue form obese subjects, the balance between adipocytes and immune cells is lost. Clusters of enlarged adipocytes become distant from the blood vessels, leading to a local area of hypoxia that underlies the inflammatory response. Obesity, indeed, is a state of low- grade chronic inflammation [Boutari et al., 2018].

Several immune cell types are involved in the development of adipose tissue inflammation: neutrophils and mast cells promote inflammation whereas eosinophils and myeloid-derived suppressor cells are supposed to play a protective role. Recently, a prominent role emerged for B- and T-lymphocytes and natural-killer cells in adipose tissue inflammation. Additionally, an enhanced recruitment of M1 pro-inflammatory adipose tissue macrophages (ATMs) may occur during weight gain [Ouchi et al., 2011].

Infiltrating macrophages might surround and phagocytose damaged or necrotic adipocytes to form a syncytial arrangement, known as crown-like structures (CLSs). Macrophages constituting CLSs in adipose tissue have been associated with nuclear factor-kappa B (NF-B) activation and increased secretion levels of several pro-inflammatory mediators, thus creating a positive feedback to further sustain chronic inflammation [Ouchi et al., 2011].

The cross-talk between adipocytes and cancer cells is mediated by cytokines, specifically IL-1, IL-6 and TNF-, ROS generation, adipokines and other molecules released by adipose tissue contributing to local and systemic inflammation and able to control proliferation and invasion in different cancer cell types [Avgerinos et al., 2019]. On the other hand, malignant cells can induce phenotype alteration of adjacent adipocytes; reduction of their lipid content and release of adipokine and other tumor-promoting substances, such as matrix metalloproteinases [Dirat et al., 2011].

Recently, a role for inflammasome in the adipose tissue inflammation of obese subjects has also been described. Inflammasome, a macromolecular complex composed of Nod (Nucleotide-binding and oligomerization domain)-like receptors (NLRP1, NLRP3, and NLRC4), the adaptor apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and the enzyme caspase-1 (CASP-1), is a novel innate immune pathway required for triggering the maturation of proinflammatory cytokines, including IL-1_ and IL-18 [Lamkanfi et al., 2014]. Adipocytes express multiple inflammasome related genes, including Nod-like receptor pathway genes [NLRP3 and PYCARD (PYD-PYRIN-PAAD-DAPIN and CARD-caspase-recruitment Domain Containing)], CASP1, and other TLR (Toll-like receptor)-regulated genes [IL1B, CCL2 (C-C Motif Chemokine Ligand 2), and TNF] and this adipocyte signature significantly increased in obese versus lean subjects [Yin et al., 2014]. Activated inflammasome and increased IL-1 production in cancer-associated macrophages generates an inflammatory microenvironment promoting tumor growth and metastasis in animal and human cancer models [Guo et al., 2016]. The complicated function of inflammasomes raises new challenges for the treatment of obese cancer patients.

The inflammatory environment of obesity is mitigated by weight loss, as demonstrated by an attenuation of endothelial dysfunction in women that lost weight [Hagman et al., 2017].

The “Obesity paradox”

Obesity is associated with a greater cancer reoccurrence risk, a poorer cancer prognosis and a reduced survival compared to normal-weight patients [Lennon et al., 2016]. However, some opposite evidence shows that obesity reduce cancer incidence and improve cancer survival. The controversial results indicate that the association between obesity and cancer biology is complex. Recently, a study excluded obesity alone as a risk factor for increased cancer mortality in both genders [Kuk et al., 2018]. Additionally, body fatness reduced the nerve sheath cancer risk [Wiedmann et al., 2017]; overweight or obesity represent a protective factor, and reduce the mortality of bladder [Pavone et al., 2018] and lung cancer patients [Zhang et al., 2017] after surgery or chemotherapy. A meta‐analysis also showed that obese patients with esophageal cancer had better long-term survival than non-obese patients [Kayani et al., 2012]. This finding is termed “obesity paradox”. Potential explanations of the obesity paradox in cancer patients may include methodologic issues such as the use of BMI as a measure of adiposity that does not fully characterize the intricate biology and physiology of excess body fat. BMI cannot differentiate between lean mass and adipose tissue, and show high variation depending upon gender, age, ethnicity and race. Additionally, BMI may underestimate the Visceral Adipose Tissue (VAT), resulting in potential biases of the association between obesity/overweight and cancer towards the null effect. Computed tomography represents the gold standard method for direct quantification of VAT but it is not feasible for population-based studies [Allott et al., 2015]. Somatometric measures, such as Waist Circumference (WC) and Waist-to Hip Ratio (WHR), surrogates of visceral adiposity, may be better indicators for cancer risk, particularly colon and postmenopausal breast cancers, than BMI [Sung et al, 2019]. However, also WC and WHR poorly approximate visceral adiposity, because they characterize both VAT and subcutaneous adipose tissue (SAT) at the waist level [Avgerinos et al., 2019].

Obesity and therapy

Obesity is characterized by a systemic and local environment (i.e. dysglycemia, abnormal blood pressure, dyslipidemia, hyperinsulinemia and etc.) that could reduce the response to chemotherapy. For example, 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 mCRC patients, high visceral fat and BMI were significantly associated with absence of a response and increased-progression. BMI was negatively associated to 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., 2017]. Additionally, hyperinsulinemia, by stimulating the proliferation of many cancer cells, could contributes to chemoresistance to 5-fluorouracil, antracyclines, taxanes, and other drugs upregulating P-glycoprotein [Wei et al., 2015]. The main concern is that obese patients are not adequately represented in pharmacokinetic studies, so there is no satisfactory information about the clinical setting. The most common strategy in order to treat obese patients is based on dose-capping or dose-fixed regimens. The first consequence of this “depotentiation” attitude may be the use of subtherapeutic strategies, associated with disease recurrence and mortality. The America Society of Clinical Oncology suggest that standard attitude for dose calculation of chemotherapy (using the full weight) should be adopted in obese patients.

Specific Therapies for Obese Patient?

A healthy lifestyle characterized by the limited calories in the diet, physical exercise and moderate alcohol consumption should be considered as the most important prevention for obesity and cancer [Sung et al., 2019]. 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]

As the correlation between obesity and cancer become evident, there was an increased interest in testing diabetes and cholesterol-lowering drugs, commonly used by patients with obesity and metabolic syndrome.

Emerging evidence showed that metformin could decrease incidence and mortality of cancer in patients affected by type-2 diabetes and is associated to a less aggressive clinical cancer outcome. The positive effects of metformin could be related to a general metabolic normalization, by inducing hepatic gluconeogenesis and reducing IR of peripheral tissues resulting in lower insulin and IGF-1 levels [Gallagher et al., 2015]. In vitro evidence suggests that metformin restricts tumor growth and induces apoptosis through insulin-independent mechanisms, involving the activation of the AMPK affecting the mTOR pathway which plays a crucial role in tumor development, progression and resistance to chemotherapy [Safe et al., 2018]. Furthermore, metformin decreases cancer recurrence by directly inducing cancer stem cell death [Gallagher et al., 2015].

In addition, glycemic control with metformin can restore adipokines concentrations, increasing APN and decreasing pro-inflammatory adipokine levels in both humans and mice [Avgerinos et al., 2019]. Meta-analyses indicate that metformin is associated with decreased cancer risk and mortality [Wu et al., 2015]. Clinical trials using metformin alone or in combination with standard therapy in several cancer types, either as a preventive or therapeutic strategy are ongoing [Heckman-Stoddard et al., 2017]. However, the design of most trials has been questioned because of the insufficient underlying molecular rationale and the wide inclusion criteria [Mazzarella et al, 2015].

Thiazolidinediones (TZDs), pharmacological agents acting as peroxisome proliferator-activated receptor gamma (PPARγ) agonists, were extensively used to treat diabetes in the past. 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 [Vella et al., 2017]. 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]. TZDs can also induce cancer cell cycle blockade by activating the phosphatase and tensin homolog (PTEN), and can sensitize cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced death by repressing cyclin D3 expression in a PPARγ- independent manner. TZD treatment causes cell growth arrest and apoptosis of non-small cell lung carcinoma cells by a mechanism involving growth arrest and DNA damage inducible protein (GADD153) [Ackerman et al., 2017]. Nevertheless, the use of PPAR-γ agonists as anti-neoplastic agents have reached conflicting results in clinical trials [Vella et al., 2017].

Therapies targeting APN

Hypoadiponectinemia has been consistently associated with a higher risk of cancer [Tumminia et al, 2019]. Several studies demonstrated that increasing plasma APN levels or mimicking some of its cancer-protective properties are able to mitigate the deleterious effects of metabolic dysfunctions on tumor development and progression [Vansaun et al., 2013]. Therefore, pharmacological increase of 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, taxifoliol, 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 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].

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 unfavorable effects. In this regard, several possible side effects derived from chronic APN treatment such as infertility, cardiac damage and reduced bone density [Holland et al., 2013]. Further studies are needed to elucidate the clinical relevance of such therapeutic approaches.

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. Among them, Ramipril, Quinapril, Losartan, Telmisartan, Irbesartan and Candesartan have 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].

CONCLUSIONS

A growing body of basic, translational, and clinical investigation explored the connections between obesity and cancer. There is strong evidence for more than one mechanism involved: obesity-driven chronic inflammation, abnormal insulin/IGF-1 axis, dysregulated hormonal signaling, altered production of several adipokines, fatty acid metabolism or a combination of these. However, their relative importance and details of their molecular basis need more investigation. Reversing obesity-associated dysfunction and inflammation of the adipose tissue by lifestyle interventions such as weight loss, physical activity and dietary modifications as well as bariatric surgery could represent a public health relevant contribution to decrease cancer risk or progression. Further studies in basic and translational research are essential to delineate the ontological role of adipokines and their interplay in obesity-related cancer pathogenesis. Additional prospective and longitudinal studies could reveal the clinical utility of obesity related biomarkers in cancer prognosis and monitoring. Finally, novel more effective and adipokine-oriented therapeutic interventions could open the way for targeted oncotherapy.