Obesity As A Major Risk Factor For Cancer

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obesityObesity As A Major Risk Factor For Cancer
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Reports from the International Agency for Research into Cancer and the World Cancer Research Fund (WCRF) have shown that the strongest evidence exists for an association of obesity with the following cancer types: endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal, whereas the less common malignancies are leukemia, non-Hodgkin`s lymphoma, multiple myeloma, malignant melanoma, and thyroid tumours.Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. A dose-response meta-analysis (9 cohorts: 22 case-control studies) showed that the BMI-breast cancer association is stronger for oestrogen receptor positive/progesterone receptor-positive (ER+PR+) tumours (33% increase per 5 kg/m2 increment for postmenopausal breast cancer), while there were no significant BMI-cancer associations for ER−PR- and ER+PR-tumours.The prevalence of overweight and obesity is increasing worldwide, and the evidence base for a link between obesity and cancer is growing.  Other than from bone marrow, MSCs may arise from white adipose tissue (WAT) and other sources 102 It has been suggested that a higher frequency of MSCs in peripheral blood may well be a diagnostic marker for colorectal cancer 103 , and changes in circulating MSCs dependent on BMI, possibly mobilized from white adipose tissue, may be addressed to tumors, representing a link between obesity and cancer progression.Obesity is a leading modifiable risk factor for the development of several epithelial malignancies.  Not only do obese patients with different types of cancers have a worse prognosis but also they have an increased risk of metastatic disease and a shorter remission period after treatment, perhaps because angiogenesis may be exacerbated in obesity 104 In angiogenesis, there is an equilibrium between angiogenic factors, which stimulate the proliferation and migration of endothelial cells, and antiangiogenic factors, which inhibit these activities.Approximately 26% of men and 24% of women in England, and about 24% of men and 30% of women in Scotland are obese i Although obesity has been long associated with diabetes and heart conditions, it is also increasingly linked to cancer, as recent findings have shown.  Antiangiogenic factors such as angiostatin, endostatin, and adiponectin are also expressed in adipose tissue 82 An altered balance between vascular growth factors and inhibitors is typical of obesity, with expansion of the capillary bed in regional fat depots 105 , thus possibly contributing to the increased risk of metastatic disease in obese subjects with cancer.
The most important biological mechanisms mediating the unfavourable influence of the above factors are hyperinsulinemia and insulin resistance, the activities of IGFs and IGF binding proteins, sex hormones and SHBG, general and adipose tissue low-grade inflammation, changes in adipose tissue production of adipokines and vascular growth factors, oxidative stress, endocrine disruptors, and alterations in immune function.In the United States, quality-adjusted life years (QALY) lost due to obesity increased by 127% from 1993 to 2008, and are now slightly greater than the smoking-related loss in QALYs 2 The link between obesity and cancer has been demonstrated in numerous cohort studies 3 , 4 ; this article will provide an update of recent research, including updated meta-analyses of the link between obesity and cancer, weight loss interventions, and hypothesized mechanisms underlying the relationship.In 2005 and in 2007, the World Cancer Research Fund (WCRF) published comprehensive reviews of the international evidence that pointed to the relationship between food, nutrition, physical activity, and prevention of cancer 5 Evidence summarized in the 2007 WCRF review confirmed previous findings and added additional cancers that are related to obesity.Throughout different continents, the association between obesity and cancer was similar, except stronger associations for both premenopausal and postmenopausal breast cancer in the Asian-Pacific region 7•• Overall, Renehan`s study extended 2007 WCRF findings to less common cancer sites and found differences between genders regarding the magnitude of association between excess body weight and risks of certain cancers.In 2008, the International Agency for Research on Cancer concluded that evidence for an association between vitamin D and cancer was inconclusive, and highlighted the need for a clinical trial with specific focus on vitamin D and colorectal cancer 101 The inconsistent findings from two trials for which results are published to date 70 , 71 may be explained by the lower dose of vitamin D in the first study (i.e. 400 IU vs. 1100 IU).
Adiponectin may also indirectly protect against the development of insulin resistance by activating 5′-AMP-activated protein kinase (AMPK), leading to increased fatty acid oxidation and decreased influx of FFAs into the liver, which contributes to reduced hepatic glucose production and VLDL synthesis ( 27 ). Conceivably, the paradoxical decrease in adiponectin levels in obesity ( 28 ) may play an important role in the development of insulin resistance.Abdominal adipose tissue, which is strategically located to the liver, is especially associated with an abnormal metabolic profile ( 37 ). Elevated macrophage infiltration in omental versus subcutaneous adipose tissue and increased concentrations of IL-6 in the portal circulation in obese subjects contribute to systemic inflammation as seen in abdominal obesity ( 38 , 39 ). Furthermore, serum levels of IL-6, associated with visceral adipose tissue, influence insulin levels ( 40 ).Adiponectin, an adipokine that is exclusively derived from adipocytes, has significant anti-inflammatory and insulin-sensitizing effects ( 62 , 63 ). Plasma concentrations of adiponectin are reduced in obesity ( 28 ), and clinical studies point toward there being an inverse relation between serum levels of adiponectin and the risk of breast, endometrial, prostate, colorectal, and kidney cancer ( 64 - 68 ). The role of adiponectin in cancer etiology in not yet fully understood.In vitro, adiponectin inhibits the growth of several breast cancer cell lines ( 73 ) and induces apoptosis of myelomonocytic (leukemia) lineage cells ( 74 ). Adiponectin also has been shown to inhibit tumor angiogenesis in in vitro experiments ( 75 ). These effects appear to be partially mediated through the activation of a cascade of apoptosis executor proteins, caspase-8,-9, and -3, leading to apoptosis in vascular endothelial cells.Inhibition of MAPK and PI3-K inhibited these effects, indicating that these pathways underlie the growth-promoting effect of leptin ( 90 , 91 ). Although leptin appears to favor cancer cell growth locally, more studies are required to assess the clinical significance of elevated levels of this pleiotropic hormone in relation to the link between obesity and cancer.