Adipose tissue and cancer

I’ve read the first third of this book, and it’s been a quite interesting read so far. Some parts have been easier to read than others and occasionally it gets a bit technical, but overall it’s a quite readable book for someone with my background and I’m certainly learning some new stuff by reading this.

Some observations from the book:

“obesity and metabolic syndrome are linked to various chronic diseases [6,7] including cardiovascular disease, type II diabetes, and the focus of this chapter, cancer. Importantly, not all obese individuals develop the metabolic dysregulation usually associated with obesity and metabolic syndrome, and these “metabolically healthy obese” individuals do not have elevated cancer risk. An estimated 30 % of obese individuals in the USA are metabolically healthy [8]. Conversely, some nonobese individuals can develop the metabolic perturbations usually associated with obesity, and these individuals appear to be more prone to chronic diseases including cancer [9]. Thus, an emerging hypothesis is that the obesity-related metabolic perturbations, and not specific dietary components or increased adiposity, are at the crux of the obesity–cancer connection.” […]

“Evidence-based guidelines for cancer prevention urge maintenance of a lean phenotype [10]. Overall, an estimated 15–20 % of all cancer deaths in the USA are attributable to overweight and obese body types [11]. Obesity is associated with increased mortality from cancer of the prostate and stomach in men; breast (postmenopausal), endometrium, cervix, uterus, and ovaries in women; and kidney (renal cell), colon, esophagus (adenocarcinoma), pancreas, gallbladder, and liver in both genders [11]. While the relationships between metabolic syndrome and specific cancers are less well established, first reports from the Metabolic Syndrome and Cancer Project, a European cohort study of ~580,000 adults, confirm associations between obesity (or BMI) in metabolic syndrome and risks of colorectal, thyroid, and cervical cancer [12].”

“During obesity, adipose tissue responds to the excess energy by increasing adipocyte size (hypertrophy) and enhancing adipocyte proliferation (hyperplasia) [14]. Adipocyte size strongly correlates with insulin resistance and secretion of proinflammatory cytokines [3]. Moreover, location of the adipose tissue also determines risk for metabolic diseases. […] Healthy adipose tissue must be able to rapidly respond to excess energy intake by inducing adipocyte hypertrophy and hyperplasia, remodeling of the extracellular matrix, and enhanced neovascularization to nourish the adipose tissue. In pathological states such as insulin resistance associated with obesity, rapid adipocyte hypertrophy occurs with restricted angiogenesis resulting in cellular hypoxia, and thereby resulting in local inflammation [15]. Macrophages surrounding necrotic adipocytes phagocytize fatty acids, which are released from the adipocyte. This produces bloated, lipid overburdened macrophages, which is characteristic of chronic inflammation and often observed in obese individuals [14]. […] inflammation is a recognized hallmark of cancer, and growing evidence continues to indicate that chronic inflammation is associated with increased cancer risk [75–77]. Several tissue-specific inflammatory lesions are established neoplastic precursors for invasive cancer, including gastritis for gastric cancer, inflammatory bowel disease for colon cancer, and pancreatitis for pancreatic cancer [78,79].”

“When lipid storage capacity in adipose tissue is exceeded, surplus lipids often accumulate within muscle, liver, and pancreatic tissue [16]. As a consequence, hepatic and pancreatic steatosis can develop; both have been positively associated with insulin resistance and ultimately lead to impairment of lipid processing and clearance within these tissues [16]. […] The term nonalcoholic fatty liver disease (NAFLD) refers to a disease spectrum that includes variable degrees of simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis [19,20]. Simple steatosis is benign, whereas NASH is defined by the presence of hepatocyte injury, inflammation, and/or fibrosis, which can lead to cirrhosis, liver failure, and hepatocellular carcinoma. […] NASH occurs in 20 % of cases of NAFLD and ~5–20 % of NASH cases progress to cirrhosis; 80 % of cryptogenic cirrhosis cases present with NASH [22]. Of this group, ~0.5 % will eventually progress to hepatocellular carcinoma […] In Western populations, overnutrition/obesity is the most common cause of NAFLD” […] NAFLD has evolved in parallel to the obesity pandemic as the most prevalent liver disease worldwide. Whereas the fact that chronic liver inflammation as observed in nonalcoholic steatohepatitis (NASH) finally leads to the development of hepatocellular carcinoma is well accepted [123], its association with increased formation of adenomatous polyps and CRC has just recently been established [124,125].”

“Hyperglycemia, a hallmark of metabolic syndrome, is associated with insulin resistance, aberrant glucose metabolism, chronic inflammation, and the production of other metabolic hormones such as IGF-1, leptin, and adiponectin [37]. […] In metabolic syndrome, the amount of bioavailable IGF-1 increases […] Elevated circulating IGF-1 is an established risk factor for many cancer types [38,39].”

VEGF [Vascular Endothelial Growth Factor], a heparin-binding glycoprotein produced by adipocytes and tumor cells, has angiogenic, mitogenic, and vascular permeability-enhancing activities specific for endothelial cells [83]. Circulating levels of VEGF are increased in obese, relative to lean, humans and animals, and increased tumoral expression of VEGF is associated with poor prognosis in several obesity-related cancers [84]. The need for nutrients and oxygen triggers tumor cells to produce VEGF, which leads to the formation of new blood vessels to nourish the rapidly growing tumor and may facilitate the metastatic spread of tumors cells [83].”

“Epidemiological studies indicate that obesity represents a significant risk factor for the development of various cancers such as prostate and breast cancer, leading cancers in the Western world. An impressive body of evidence, however, also indicates that the risk of colorectal adenoma, and cancer (CRC) is increased in subjects with obesity and related metabolic syndrome [2,3]. […] Colorectal cancer is the second leading cancer death in the Western world and its death rate correlates with body mass index [5]. […] Recent CRC screening studies suggest that obesity and an increased body mass index are a significant additional risk factor for the development of colonic polyps with evidence that advanced adenomas arise in men almost a decade earlier than in women [7]. […] menopausal status appears to modify the relationship between BMI and colon cancer with a strong association between BMI and colon cancer risk seen in premenopausal but not postmenopausal women [21]. […] being obese prior to being diagnosed with colon cancer increases your risk of dying from the disease [29–32]. […] more and more studies are now demonstrating the location of body fat tissue is the best predictor of all-cause and colorectal cancer mortality […] colon cancer survival may be less likely for patients who are […] too thin at diagnosis [34].”

“In a meta-analysis of 52 studies (24 case–control and 28 cohort studies) examining the link between physical activity and colon cancer, a significant 24 % reduced risk of colon cancer in people who were most active compared with the least was found [48]. This supports other reviews of the association between physical activity and colon cancer in the Asian and European populations [49,50]. […] Physical activity also appears to affect disease outcome and recurrence after diagnosis and treatment with the greatest effect on colon cancer incidence [53]. […] new well-controlled clinical trials on obesity prevention and obesity treatment are necessary before therapeutic implications of WAT [White Adipose Tissue] reduction on cancer predisposition are completely understood. One of the possibly important considerations is the number of adipocytes and the accompanying stromal/vascular cells in WAT increasing in obesity and remaining increased even upon subsequent weight loss, which occurs via adipocyte size reduction. The pool of ASC [Adipose Stem Cells] is likely to remain intact and could contribute to cancer onset or progression despite calorie restriction and reduced adiposity.”

“There is general agreement that obesity is associated with an increased incidence of breast cancer in postmenopausal women (reviewed in [14–17]). […] The European Prospective Investigation into Cancer and Nutrition (EPIC) study [18], which had 57,923 postmenopausal participants, is of particular interest because of its large size, its prospective design, and the observations made concerning exogenous estrogens as a confounder. The results showed that a long-term weight gain was related to an increase in risk, but only in those who were not taking hormone replacement medication: compared with women with a stable body weight the relative risk for women who gained 15–20 kg was 1.5 with a confidence interval of 1.60–2.13. As reported by others, adiposity ceased to be a risk factor in current replacement therapy users, who were already at a high risk for breast cancer compared with nonusers. […] Preexisting obesity and postoperative weight gain are associated with poor prognosis in both premenopausal and postmenopausal breast cancer patients. […] A pivotal review of the literature by Chlebowski et al. [25] found that in 26 out of 34 studies individual studies, totaling 29,460 women, obesity was related to an increased risk of recurrence or reduced survival.”

“Daling et al. [29] have provided a major contribution to our understanding in the relationships between body fat mass and tumor biomarkers of progression in young breast cancer patients. In their study, not only was a combination of obesity and an absence of ER expression in premenopausal breast cancer patients aged younger than 45 years associated with an increased risk of dying from the disease, but those with BMI values in the highest quartile were more likely to have larger tumors of high histologic grade. This observation is particularly significant because it implies that large tumors in overweight/obese women grow at a faster rate than tumors of similar size from leaner women, rather than simply arising from delayed diagnosis due to palpation difficulty in obese women.”

“Wolf et al. [36] and Schott et al. [37] suggested that up to 16 % of breast cancer patients have diabetes, and that T2D may be associated with a 10–20 % excessive risk of breast cancer. […] There is ample epidemiological evidence that diabetes contributes to breast cancer risk [17,36–40]. […] Overall survival in cancer patients, with or without preexisting diabetes, has shown diabetes to be associated with an increased all-cause mortality risk. […] The Danish Breast Cancer Cooperative Group, with 18,762 newly diagnosed T2D cases, found that the recurrence with metastases was 46 % higher in obese women with a BMI of 30 kg/m^2 or greater beyond the first 5 years.”

The relationship between obesity and prostate cancer is a complicated one. […] The explanation for this confusion may rest, at least in part, in the reports that obesity as a positive risk factor for prostate cancer relates specifically with the aggressive phenotype [56–60] […] a meta-analysis by Discacciati et al. [61] of the results from 25 studies that examined disease stage and BMI showed not only a positive relationship between obesity and advanced prostate cancer but also a decrease in the risk for localized disease. The association between obesity and an aggressive prostate cancer phenotype is reflected in the relationship between the BMI and prostate cancer mortality rate. For example, in one large retrospective cohort study by Andersson et al. [62] […] there was a significantly larger prostate cancer mortality rate in the higher BMI categories”

Two studies have been reported in which meta-analysis was used to examine previously published investigations into the relationship between diabetes mellitus and prostate cancer risk [66,67]. […] [The first] meta-analysis showed that there was an inverse relationship between diabetes and prostate cancer risk, which translated to a 9 % reduction in risk. […] The overall conclusion […in the second meta-analysis] was the same: diabetic men have a significantly decreased risk of developing prostate cancer (RR = 0.84; 95% CI, 0.76–0.93). […] Gong et al. [69] reported a large prospective study of diabetes and prostate cancer from the USA after the two meta-analyses described above had been published that also took account of potential confounding by obesity. Men with diabetes had a 34 % lower risk of prostate cancer compared with men without diabetes that was not affected by adjustment for the BMI […] In contrast to these results, recently published studies have found that the presence of diabetes is positively associated with prostate cancers of high-grade [71–73] and late-stage tumors [72] ], a reversal in the observed relationship that needs to be considered in the context of the duration of the presence of T2D and the detection of prostate cancer by prostatic-specific antigen screening.”

October 1, 2013 - Posted by | books, cancer, diabetes, health, health care, medicine

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