1. Obesity and Cancer Development
Obesity is an epidemiologic problem that will continue to grow in the coming years. CDC data reported that 42.4% of American adults were obese in 2018, and that number increased from 30.5% in 2000 [
22]. As well as the negative public health care impacts, obesity is a significant strain on health care spending, with 147 billion dollars spent in 2008 [
22]. Much of this spending is secondary to the diseases often concomitant with obesity, such as heart disease [
23], type 2 diabetes [
24], hypertension [
25], asthma [
26,
27], and cancers [
28,
29]. When the costs of inpatient care, outpatient care, emergency care, dental care, and prescriptions were analyzed, it was found that obesity (BMI > 30) accounted for 149.4 billion dollars in 2014 [
28].
An early association between obesity and cancer risk was made in 1966 by analyzing trends in endometrial cancer [
30]. The authors proposed increased estrogen exposure as the pathogenesis of the heightened oncologic risk in obese women [
30]. Since that time, many groups have shown associations between increased BMI and the development of cancer. Obesity is a major cause of the non-alcoholic fatty liver disease (NAFLD), a leading cause of hepatocellular carcinoma (HCC) [
31,
32,
33]. Obesity increases the risk of non-Hodgkin lymphomas [
34,
35], particularly diffuse large B-cell lymphomas (DLBCL) [
36]. Obesity showed a significant increase in the incidence of gastric cardia cancer [
37], thyroid cancer [
38], colon cancer [
39], renal cancer [
40,
41,
42], liver cancer [
43], malignant melanoma [
44], multiple myeloma [
45], rectal cancer [
39], gallbladder cancer [
46], leukemia [
47], esophageal cancer [
37], and, as previously mentioned, non-Hodgkin lymphoma [
48].
It has been suggested that childhood obesity contributes to increased cancer risk and cardiovascular disease risk in adulthood [
49]. This is concerning because childhood obesity was pronounced an epidemic affecting 17% of the children [
50] in the US. It is likely related to the fact that if a person is obese as a child, they also tend to be obese as an adult. Increased BMI as a teen was associated with a higher risk for leukemia (OR = 1.32, 95% CI 1.15–1.53) [
51,
52], Hodgkin’s disease (HR = 1.25, 95% CI 1.13–1.37) [
49,
53], and colon cancer (39% increase in men and 19% increase in women) [
54].
The increase in cancer development has been proposed to be secondary to immunologic and metabolic derangements in the tumor microenvironment [
55]. Obesity has been said to create a “meta-inflammatory” state through the body, leading to impaired immunologic recruitment, coordination, and response [
56]. Obesity has been shown to contribute to increased cytokine production, aberrant macrophage activity, and increased exhaustion phenotypes shown by immune cells [
57]. Obesity-associated inflammation contributes to increased myeloid-derived suppressors cells (MDSCs), which suppress innate and adaptive immune responses [
19,
20]. Usually, cells of myeloid lineage progress to become macrophages, granulocytes, and dendritic cells [
58]. If these cells instead become MDSCs, they may inhibit natural killer cells and T-cell cytotoxicity and increase regulatory T cells by liberating factors such as arginase-1 and inducible nitric oxide synthase [
59]. Natural killer cells defend the body against foreign matter and neoplasms by releasing cytoplasmic mediators or cytotoxic activity [
60,
61]. When the tumor microenvironment is altered so that there is an abundance of pro-inflammatory phenotypes and increased TGF-β, the natural killer cells are less protective against carcinogenesis [
62]. In particular, it has been shown that the natural killer cells in an obese patient struggle to activate glycolysis [
63], which is essential for activating their cytotoxic machinery. It was postulated that this is due to increased lipid uptake by the natural killer cells [
63]. It has been shown that adipose tissue serves as a reservoir for cytokines, including TNF-α, leading to inflammation [
64]. This effect is seen in animal models, with obese dogs exhibiting higher IL-6 and TNF-α levels and lower T-cell proliferation than healthy weight dogs [
65]. It has been suggested that increased adipose tissue promotes that pivoting of a Th2 phenotype to a Th1 and Th17 predominant phenotype [
66]. This shift and the increase in liberated cytokines contribute to a pro-inflammatory state [
55].
Obesity increases the liberation of leptin and other adipokines due to an increase in adipose tissue volume [
67]. Leptin has been shown to promote cancer growth in mice [
67]. Obesity decreases adiponectin levels, an adipokine that counters the cancer-promoting effects of leptin [
67]. In conjunction with increased leptin release, the downregulation of adiponectin allows increased growth and metastasis. Obesity alters levels of steroid hormones which can contribute to cancer growth [
67]. Estrogen can be produced by adipose tissue [
68]; in fact, it is the primary way estrogen is produced in postmenopausal women [
67]. Estrogen has been shown to induce cancer-promoting effects, such as inhibiting apoptosis and inducing angiogenesis [
67]. It has been shown that estrogen promotes tumor growth and angiogenesis in mice, even in cancer cells lacking the 17β-estradiol receptor [
68]. Obesity also reduces the sequestration of estrogen by downregulating levels of sex hormone-binding globulin, leading to increased circulating unbound estrogen [
69]. Obesity leads to the dysregulation of insulin signaling, negatively impacting cellular signaling pathways and promoting cancer growth. Obesity causes increased insulin release due to decreased insulin responsiveness [
70]. In addition to its metabolic effects, insulin promotes mitosis [
67]. Cancer cells exposed to insulin divide faster, leading to increased tumor growth [
71]. Insulin signals through the PI3K and MAPK pathways are common to many crucial signaling cascades that regulate cellular functioning and metabolism [
67]. Consequently, dysfunction in these pathways secondary to improper insulin signaling can lead to derangements in normal cell development and cancer [
67]. Increased levels of IGF-2 (insulin-like growth factor 2) methylation are correlated with obesity and insulin resistance [
72,
73]. IGF-2 may bind to IR-A (insulin receptor A) or IGF1R (insulin-like growth factor 1 receptor) to increase glucose uptake and activate anabolic pathways, leading to energy production, cell growth, and division [
67]. Furthermore, high-fat diet-induced obesity leads to a metabolic competition between tumor and CD8 T cells for lipids, leading to increased lipid uptake by tumor cells than T cells, thereby impairing CD8 T-cell infiltration and function [
74].
2. Obesity and Cancer Prognosis
Along with increasing the incidence of cancers, obese patients tend to have compromised survival and increased complications following cancer treatment. Prostate cancer-specific mortality and biochemical recurrence were increased by 15% and 21%, respectively, with a 5 kg/m
2 weight gain [
75]. In colorectal cancer, obese patients have elevated all-cause mortality, cancer-specific mortality, disease recurrence, and decreased disease-free survival [
76]. These negative prognostic factors were not seen when analyzing patients with BMIs characterized as overweight [
76]. Obesity compromised survival and post-operative outcomes of recurrent hepatocellular carcinoma [
77]. When operated on for hepatic metastasis of colorectal cancer, obese patients spent a longer time in the operating room and had higher estimated blood loss, morbidity, and reintervention rates when compared to non-obese peers [
78]. A higher BMI was associated with extrathyroidal and vascular invasion of papillary thyroid carcinoma, suggesting obesity leads to a more aggressive phenotype [
79]. Obesity was associated with increased wound dehiscence, incisional site hernia, and stoma complications following colorectal surgery, and these patients were at higher risk for conversion to an open surgery [
80]. Obese patients were found to present with melanomas that were twice as thick as their non-obese peers [
81]. Following surgical resection of squamous cell carcinoma (SCC) of the tongue, obese patients had worse disease-specific survival (DSS), recurrence-free survival (RFS), and overall survival (OS) [
82]. Elderly female patients with B-cell lymphomas treated with RCHOP had a worse prognosis if they were obese [
83]. Following resection of gastric cancer, patients with a BMI > 30 experienced increased hospital length of stay (LOS), OR time, post-operative morbidity, and post-operative mortality [
84]. It was shown that the inflammation and desmoplasia caused by obesity led to a more aggressive phenotype of pancreatic adenocarcinoma that was resistant to chemotherapy and was prone to progression [
85]. It was also found that patients with a BMI >35 kg/m
2 were 12-fold more likely to have lymph node-positive disease and decreased DFS and OS [
86]. Obesity leads to poor prognosis in patients undergoing surgical resection of extremity soft-tissue sarcoma resection. This is likely due to poor wound healing, increased dehiscence, and increased infections [
87].