Current mechanisms in obesity and tumor progression

Abstract

Purpose of review

Hyperadiposity, as present in obesity, is a substantial threat to cancer risk and prognosis. Studies that have investigated the link between obesity and tumor progression have proposed several mechanistic frameworks, yet, these mechanisms are not fully defined. Further, a comprehensive understanding of how these various mechanisms may interact to create a dynamic disease state is lacking in the current literature.

Recent findings

Recent work has begun to explore not only discrete mechanisms by which obesity may promote tumor growth (for instance, metabolic and growth factor functions of insulin; inflammatory cytokines; adipokines; and others), but also how these putative tumor-promoting factors may interact.

Summary

This review will highlight the present understanding of obesity, as it relates to tumor development and progression. First, we will introduce the impact of obesity in cancer within the dynamic tumor microenvironment, which will serve as a theme to frame this review. The core of this review will discuss recently proposed mechanisms that implicate obesity in tumor progression, including chronic inflammation and the role of pro-inflammatory cytokines, adipokines, hormones, and genetic approaches. Furthermore, we intend to offer current insight in targeting adipose tissue during the development of cancer prevention and treatment strategies.

INTRODUCTION

Obesity, characterized as a BMI of 30 or more and typically because of hyperadiposity [1], is a growing global disease and a risk factor for many complications, including metabolic syndrome, hepatic steatosis, cardiovascular disease, diabetes, poor bone health, and cancer [2–5]. Although epidemiologic links between obesity and cancer have been established, the pathophysiological mechanisms are not clear. Pro-inflammatory processes and obesity-related endocrine disorders have been widely studied in breast cancer, a tumor type, which is linked to obesity [6], but these mechanisms are not well defined in other cancer types. Further, although several physiologic links are offered, the molecular interactions underlying those mechanisms are still widely unknown.

Current studies suggest that most mechanisms underlying tumor growth are because of tumor microenvironment alterations [7]. This is often manifested as an upregulation of various factors including inflammatory cytokines and immune cells (IL-6, IL-1β, T cells, B cells, macrophages), disruption of normal extracellular matrix (ECM), and endothelial cell function [8].

In obesity, both the number and size of adipocytes increases, leading to chronic subclinical inflammation [9,10]. This low-grade inflammatory state in adipose tissue is comparable to the tumor microenvironment (TM), which may suggest its ability to support tumor growth. For example, recruitment of inflammatory factors and stimulation of the coagulation cascade is activated in obesity, as it is in the TM [2,11].

Here, we aim to compile current literature regarding obesity-related tumor progression. We discuss the present understanding of the mechanisms fundamental to these links within the framework of the TM. To conclude, we address current investigational therapeutics and other areas that warrant further investigation.

TUMOR MICROENVIRONMENT AND OBESITY

The TM is composed of diverse constituents, like cytotoxic immune cells, and antigen-presenting cells, like macrophages, which interact generating an inflamed state similar to an injured tissue [11]. During uncontrolled cell proliferation, cancer cells hijack the regulatory systems of noncancerous cells [9], initiating an infiltration of pro-inflammatory factors, like cytokines and growth factors, immune cells and injury-response processes like the coagulation cascade and platelet activation factors, often leading to endothelial dysfunction and fibrosis [10,12]. Breast cancer progression is sustained by hypoxia-related oxidative stress and infiltration of pro-inflammatory mediators, such as TNF-α, IL-6, and cyclooxygenase-2 (COX-2) [13].

Metabolic reprogramming within the TM also plays a role in tumor growth. The Warburg effect is a phenomenon whereby a tumor cell favors glycolysis over oxidative phosphorylation even in an aerobic environment [9]. Although glycolysis provides less ATP per glucose molecule, tumor cells rely on aerobic glycolysis to garner building blocks necessary for cell division and metastasis [14] as well as to promote lactate secretion. Changes to signaling cues within oncogenic pathways allow the tumor cell to outsource materials into the TM for survival, as well as to expand within surrounding tissues.

Obesity leads to chronic inflammation and an inappropriate secretion of adipokines and hormones, including leptin, adiponectin, and estrogen [15]. This altered, often unchecked, state within adipose tissue creates an inflamed environment susceptible to tumor infiltration. Chronic inflammation in adipose tissue allows cancer cells to co-opt pro-inflammatory substrates and tissue repair mechanisms to feed into their own energy demands [11], as discussed in the following section.

ADIPOSE TISSUE INFLAMMATION AND TUMOR GROWTH

Adipose tissue is a dynamic endocrine organ, broadly characterized as white (WAT) or brown (BAT) adipose tissue [2]. WAT is further distinguished as visceral (situated around ectopic organs) and subcutaneous (distributed under the skin)WAT. Activity of these fat depots is largely guided by their location. Initially considered solely an energy reservoir, adipose tissue is vital to maintaining energy homeostasis, immune function, and reproduction, and mediating systemic interactions involving lipid metabolism, insulin sensitivity, and angiogenesis [10,16].

Figure 1 describes key alterations to adipose tissue that occur in obesity. adipose tissue dysfunction appears early in obesity and often includes WAT hypoxia [2,10]. A dysfunctional adipose tissue environment is much like a TM, leaving adjacent tissues and organs susceptible to infiltration and damage [17^▪]. Interactions between adipose tissue and tumor cells allow tumor cells to acquire key energy substrates, such as lactate, fatty acids, and amino acids [2]. In breast cancer, hypoxic conditions within chronic adipose tissue inflammation leads to the activation of hypoxia-induced factor-1, which has been associated with poor outcomes in obese breast cancer patients [18^▪]. Hypoxic conditions also drive leptin secretion from adipose tissue [2]. The role of leptin as a driver of tumor progression will be more comprehensively discussed later.

FIGURE 1.

Obesity and adipose tissue inflammation. Obesity-induced inflammation in adipose tissue leads to dysfunction of several processes in adipose tissue. Obesity-induced inflammation increases in both the size and number of adipocytes, leading structural and functional damage, hypoxia, oxidative stress and increased cancer risk. Increase in hormone signaling leads to upregulation of metabolic pathways like JAK/STAT3 and AMPK. Inflamed adipose tissue incites abnormal adipokine secretion, including leptin and adiponectin. In a state of chronic injury, inflamed adipose tissue is infiltrated by pro-inflammatory factors, such as macrophages, IL-6 and TNFα. Systemic changes in obesity such as increased insulin resistance and cancer risk are mediated by this altered adipose tissue state. IL-6, interleukin-6; TNFα, tumor necrosis factor-α.

As adipose tissue dysfunction persists, disordered functioning is coupled with chronic tissue injury, activating proinflammatory processes that support tumor growth and metastasis (Fig. 2). WAT inflammation has been widely regarded as a key factor in tumor proliferation in multiple cancer types [10,17^▪]. Adipose tissue inflammation arises and is perpetuated through increases in macrophages, lymphocytes, and mediators, such as IL-1β, COX-2, and TNFα. Abnormal expression and functioning of these molecules alter secretion of adipokines, which leads to dysregulation of key signaling pathways, like JAK/STAT3 and P13K. Further, pro-inflammatory factors can be used by adjacent tumor sites as substrates that feed into and support the tumor ecosystem [16,19].

FIGURE 2.

Adipose tissue inflammation and the tumor microenvironment. In the presence of the tumor microenvironment, the obesity-induced altered adipose tissue state becomes a source of energy substrates and structural support for the growing tumor. Tumor tissue induce a transformation from adipocytes to CAAs where resources are shuttled to the tumor. Various mechanisms support tumor sustenance and metastasis, including increased adipocyte lipolysis, secretion of inflammatory cytokines, and metabolic reprogramming. The inflamed adipose tissue creates a pro-tumor environment where the tumor can adopt a more aggressive and invasive phenotype. AT, adipose tissue; CAA, cancer-associated adipocyte.

Cross-talk between inflamed WAT and cancer cells not only provides an avenue to siphon energy resources and metabolites to the tumor but also affects the TM itself. Under normal conditions, WAT plays a crucial role in secreting structural and mechanical support factors for the ECM surrounding adipose tissue. However, adipose tissue inflammation can lead to endocrine receptor stress and ECM stiffness, triggering fibrosis [10]. In the presence of a breast tumor, molecules secreted by the WAT, like collagen type VI, promote tumor progression [20]. Inflamed WAT secretion of these mediators in the presence of tumorcells also leads to destruction of the adipose tissue: matrix metalloproteinases (MMPs) actively suppress adipocyte differentiation and promote dedifferentiation, allowing tumor invasion.

AT inflammation in obesity contributes to tumor progression through the development of cancer-associated adipocytes (CAA) [18^▪]. Due to pressure from malignant cells, CAAs repurpose adipocyte-derived factors like leptin and fatty acids in favor of tumor development [18^▪]. Cancer cells take up CAA-secreted factors, which in turn promote metastasis [17^▪]. CAAs’ function to sustain inflammation and fibrosis is often retained even when engulfed by the tumor. They lead to increases in IL-6, MMP-11, and HIF-1, all of which promote tumor progression [16,17^▪]. In melanoma, CAAs are linked to malignant cells via exosomes. These membrane-bound vesicles are used to transfer functional material from the CAA to the tumor cell [18^▪].

ADIPOKINES AND HORMONES IN CANCER

Excess adipose tissue contributes to the TM and tumor progression via secretion of endocrine-signaling factors. Among known adipokines, leptin and adiponectin are widely implicated as two prominent factors in tumorigenesis, especially as inflammatory mediators.

Leptin

Elevated leptin is derived from WAT, is almost universally present in obesity, and is responsible for regulating energy homeostasis by controlling food intake [2,21], and energy expenditure [22]. In addition, leptin contributes to tumor initiation and metastasis in various cancer types, including breast cancer, hepatocellular carcinoma, lung cancer, prostate cancer, colorectal cancer, and renal carcinoma [13,23] – most of which, interestingly, are obesity-associated tumor types. Recent studies have targeted overexpression of leptin and its receptor in its promotion of tumor migration, interactions with the ECM, and the epithelial–mesenchymal transition (EMT) [23]. Further, leptin has been shown to lead to the degradation of ECM components, via activation of proteolytic cleavage enzymes [23]. There are numerous studies correlating leptin to breast cancer, in which leptin effects pathways including JAK/STAT3, MAPK, and AMPK, promoting cancer proliferation [2]. Upregulation of these pathways leads to enhanced expression of tumorigenesis genes [20]. Additionally, leptin has been shown to participate in breast cancer cell growth by enhancing estrogen action via crosstalk with aromatase [24]. Current data demonstrate that leptin upregulates antiapoptotic proteins, inflammatory markers, and hypoxic factors, as well as potentiate estrogen signaling [8,13,25,26]. As breast cancer exists in an adipose tissue-rich milieu, leptin is a particularly attractive pro-cancer factor in this tumor type.

Adiponectin

Secreted by the adipose tissue, adiponectin improves insulin sensitivity and suppresses inflammation [15], but its levels decline in obesity. Adiponectin is a protective factor against multiple cancer types, including endometrial, prostate, thyroid, and ovarian cancer [15,27–29], each of which has been associated with obesity (endometrial [30–32], prostate [33,34], thyroid [35,36], ovarian [32]). Decreased local and intra-tumor adiponectin also promotes breast cancer via reduced inhibition of energy metabolism pathways, like AMPK/MTOR/SK6 [20,28,37]. Although adiponectin-based therapies have been posed as a potential tool in cancer treatment, the paradigm that adiponectin inhibits tumor growth must be further investigated.

Estrogen

The systemic effects of estrogen are primarily regulated by estrogen receptors α and β (ER-α and ER-β). The obesity-induced hyper-inflammatory state alters estrogen production and signaling, which leads to DNA damage, cell proliferation, angiogenesis, and mutagenesis in multiple cancers [8]. Increased estrogen bioavailability and estrogen signaling is variable and seemingly dependent on the tumor type. In breast cancer, ER-α activation leads to targeted expression of genes and metabolic pathways that regulate cell survival, growth, and plasticity, including upregulation of P13K and MAPK [38,39]. Similarly, ER-α promotes aggressive tumor phenotypes in endometrial carcinoma via stromal cell interactions [40]. Recent evidence has linked ER-α to promoting cell proliferation and migration in prostate cancer [41,42]. ER-α is suggested to be a prognostic marker of these cancer types. The role of ER-β in cancer disorders is less clear but is suggested to be antiproliferative and tumor-suppressive. There is evidence that ER-β-induced apoptosis and autophagy inhibits metastasis in osteosarcoma through regulation of various molecular factors, such as inhibitors of apoptotic proteins (IAP), caspase-3, LC3, and p62 [43^▪]. In breast cancer, ER-β supports the EMT and perhaps reduces ER-α induced tumor proliferation and tumor growth [44]. ER-β also plays a protective role in colon cancer, where it is essential for maintaining cellular homeostasis, as wells as activating p53 signaling and increased apoptosis [44]. Further, within the TM, coordination between ER-α and ER-β lead to remodeling of the ECM by inducing changes in the expression profiles of ECM mediators, including MMPs and tyrosine kinase receptors [44].

Insulin

Hyperinsulinemia is common in obese individuals, usually caused by insulin resistance, and poses unique risks in cancer appearance and metastasis. Elevated insulin frequently occurs in concert with elevated insulin-like growth factor-1 (IGF-1). IGF-1 has antiapoptotic properties and also activates the P13K and MAPK pathways, all of which are cancer-promoting [2,7,8]. Obese patients with breast cancer who had poorer survival outcomes also presented with increased insulin and IGF-1 [8]. Insulin also interacts with leptin, adiponectin, and estrogen signaling to induce tumor promotion and survival via these metabolic pathways. Further, hyperinsulinemia is pro-inflammatory, leading to disruption to the TM, as described above. This state of metabolic instability and high oxidative stress is not remediated via processes that limit insulin utilization by other tissues (i.e. impaired insulin sensitivity), and consequently promotes tumor survival [45].

Targeting hyperinsulinemia within obesity-based cancers has provided some insight to potential insulin-dependent tumor growth mechanisms and insulin-based therapies. Huang et al. [46] suggest that hyperinsulinemia inhibits tumor autophagy. In hyperinsulinemic conditions, hepatocellular carcinoma cells exhibited increased growth, proliferation and invasion into HepG2 cells, in a concentration-dependent manner [46]. Hyperinsulinemia has been implicated in obesity-associated pancreatic cancer [47] via P13K/AKT and ERK1/2 activation in human pancreatic duct-derived cells, which led to tumor cell migration and invasion and reduced cell survival [48]. Rabin-Court et al. [49^▪▪] suggest that obesity-related tumors can be distinguished by their physiologic response to insulin. When grown in insulin, the obesity-related (breast [6,32], colon [50,51], and prostate [33,34]) cancer cell lines increased glucose uptake and oxidation as well as cell division, in contrast to nonobesity-related (melanoma, lymphoma, and lung) cell lines, in which insulin did not affect glucose metabolism or cell division [49^▪▪]. Nasiri et al. [52^▪▪] describe an insulin-dependent promotion of breast and colon cancer progression in obese mice, which was reduced by SGLT2 inhibition in an insulin-dependent manner, suggesting a potential therapeutic role of glucose and insulin-lowering agents. Further, hyperinsulinemia and hyperglycemia promoted oncogenic signaling in bladder epithelial cells and were not abrogated by insulin-sensitizing and glucose-lowering agents, metformin and pioglitazone. Certain amino-acid signatures, like increased glutamine, glycine and serine, have also been proposed to mediate the links between insulin and obesity-related cancers [53].

Lipid metabolism and free fatty acids

Obesity is associated with increased lipid metabolism, leading to higher circulating free fatty acids (FFA). Excess circulating FFAs are transported to the cancer cell and used as a metabolic substrate and/or as a structural element in the proliferating cancer membrane [10]. Fatty acid oxidation, induced by STAT3 activation, has been shown to be crucial in breast cancer tumor growth [54]. Further, cancer cells induce lipid metabolism from compromised adipocytes and CAAs and store them as long-chain fatty acids [2]. FFAs are increased in mice with prostate cancer, which was associated with increased tumor growth [55]. Similarly, Ha et al. [56] found a positive association between circulating FFA and cancer proliferation, migration and invasion. They postulate that this effect is mediated by an upregulation of peroxisome proliferator-activated receptor gamma, which promotes glucose and lipid metabolism in favor of the tumor cell [56].

MOLECULAR IMPLICATIONS

Genetic and molecular mechanisms, like long non-coding RNAs (lncRNA), are also implicated in tumor progression. LncRNAs, transcribed by RNA polymerase, were shown to be dysregulated in obese patients [14,57]. Oncogenic lncRNAs (e.g. h19, ANRIL, and HOTAIR) have been previously identified, and are well characterized as regulators of nutrient availability in obesity-related tumors [57–60]. Recent in-vitro and in-vivo studies show upregulation of cancer-associated lncRNAs within obesity-related tumors leading to tumor metastasis [61–69]. Liu et al. show that expression of lncRNAs for genes related to tumor proliferation were upregulated and genes responsible for mediating normal metabolic functioning and oxidative stress were down-regulated, suggesting potential effects at the genetic and epigenetic level [70]. In addition to the target genes of the predominant metabolic pathways in energy homeostasis (JAK/STAT, AMPK, MTOR), upregulation of fibroblast, inflammatory, ECM-specific genes are shown to be implicated in tumor pathogenesis [71,72^▪▪,73].

FUTURE CONSIDERATIONS

The recent studies highlighted above have provided crucial insight into the pathophysiological mechanism linking obesity to tumor progression (Fig. 3). However, a majority of these studies explore only a few main obesity-related cancers (breast cancer, colon cancer, pancreatic cancer). Future research is needed to understand these mechanisms in the context of other obesity-related cancers. Additionally, work is needed to clarify the molecular interactions among these implicated mechanisms to better understand how they interact to form the dynamic disease state. As highlighted in Table 1, studies that outline potential therapeutics to combat tumor progression in obesity-related cancers help link known mechanism to clinical progress but extensiveness of these studies is lacking.

FIGURE 3.

Mechanisms by which adipocyte dysfunction may promote tumor growth. In obesity, the hyperplastic, hypertrophic adipocytes – including CAAs – promote inflammation, ECM remodeling, and oxidative stress. These phenomena promote a variety of pathologic properties, including increases in adipokine and cytokine secretion, increased circulating insulin, leptin, and estrogen concentrations, and long noncoding RNAs. Together, each of these perturbations has been proposed to promote tumor pathogenesis. CAA, cancer-associated adipocyte; ECM, extracellular matrix; FFA, free fatty acids; lncRNAs, long noncoding RNAs.

Table 1.

Current findings: obesity and cancer therapeutics

Study	Cancer type	Subjects	Study design	Intervention	Details
Cohen et al. [74]	Ovarian/endometrial	F (n = 45)	Randomized case-controlled	Ketogenic diet	Ketogenic diet resulted in fat loss but retention in lean mass. Increased circulating ketones are suggested to be inhospitable to tumor microenvironment.
Cortesi et al. [75]	Breast	F (n = 430), obese	Single-arm, experimental	Weight loss, physical activity	Improved survival outcomes in obese women following a lifestyle intervention including weight loss and physical activity
Wang et al. [76▪▪]	LLC	C57BL/6 mice, HFD-fed, injected with LLC	In vivo	Aspirin	Aspirin reduced tumor growth in obese mice via targeting of glucose and glutamine metabolism
Pabona et al. [77]	Endometrial	Endometrial tumor cells derived from obese-nondiabetic women	In vitro	Metformin	Metformin-treated EC tumor cells showed increased antitumor biomarkers via altered signaling
Guo et al. [78]	Endometrial	LKB1fl/fl p53fl/fl mouse model of endometrial cancer	In vivo	Metformin	Metformin reversed upregulation of lipid and protein biosynthesis in obese mice
Dos Santos et al. [79]	Melanoma	Female HFD-fed mice	In vivo	Physical Activity	Tumor growth rate reduced with implementation of an exercise regimen
Zell et al. [80]	Colorectal	M (n = 23);F (n = 9), obese nondiabetic	Phase II clinical trial	Metformin	No differences in premetformin versus postmetformin rectal tissue mucosa following 12-week intervention
Jiang et al. [81]	Pancreatic	Human pancreatic BxPC-3 and CFPAC-1 cells	In vitro	Adiponectin	Activation of adiponectin signaling attenuates cell proliferation and β-catenin signaling
Shafa et al. [82]	Endometrial	Obese woman, 54 years old	Case study	Surgery	Combination of a hysterectomy and bariatric surgery resulted in sustained weight loss and improved tumor pathology
Demark-Wahnefried et al. [83]	Breast	F (n = 32), obese	Single blind, two-arm, randomized case-controlled	Weight Loss	Inconsistent effects caloric restriction of circulating cancer-related biomarkers. Improvement of P13K signaling and apoptotic gene expression after physical activity
Hsieh et al. [84]	Breast	4T1 breast cancer cells	In vitro	Aspirin	Aspirin attenuated breast cancer cell growth and migration by inhibiting obesity-induced inflammation
Hao et al. [55]	Prostate	LAPC-4-implanted mice	In vivo	Arctigenin	Arctigenin inhibits tumor growth in HF-fed mice. Induced reduction in serum FFA and subcutaneous fat depots
Yang et al. [85]	Obesity-related Cancers		Review	Herbal Medications	Review discusses novel findings regarding the antiproliferative effects of herbal medications including PD-L1 and resveratrol in obesity-related cancers
Kato et al. [86]	Colorectal	C57BL/KsJ–db/db mice	In vivo	Tofogliflozin	Suppression of colorectal cancer tumorigenesis after SGLT2-inhibitor treatment in azoxymethane-injected obese mice

Recent publications exploring cancer therapeutics in obese populations. EC, endometrial cancer; F, female; FFA, free fatty acid; HF, high fat; HFD, high-fat diet; LLC, Lewis lung carcinoma; M, male; PD-L1, programmed death-ligand 1; SGLT2, sodium-glucose transport protein 2.

CONCLUSION

In summary, there are several intertwined mechanisms that link obesity to tumor development and progression. Many of the involved factors, like chronic inflammation and upregulation of key circulating molecules, induce instability in the TM, promoting tumor survival. Upregulated adipokines and circulatory factors, like leptin, adiponectin, insulin and estrogen, also enhance tumor growth through activation of target genes and metabolic pathways, like JAK/STAT3, P13K/AKT, and MAPK. These recent findings lay groundwork to understanding the role of obesity in tumor growth and to developing targeted therapies.

KEY POINTS.

• Obesity impacts tumor progression via several mechanisms, including chronic inflammation, upregulation of secreted adipokines and circulatory factors, and genetic associations.

• Many of these mechanisms coexist and interact to alter the tumor microenvironment in support of tumor growth and metastasis.

• Therapeutic frameworks targeting these mechanisms in obesity-related cancers provide insight to tumor suppression but warrant further investigation.