Volume 22, Issue 2

Higher body fatness is not only associated with a higher risk of hypertension, type 2 diabetes, and coronary heart disease but also with certain types of cancer. The scope of this review is to summarize the epidemiological evidence for an association between body fatness and specific types of cancer and to outline the mediating role of obesity-related biomarkers in this context. Epidemiological studies have gathered convincing evidence that greater body fatness is associated with a higher risk of colorectal cancer, postmenopausal breast cancer, endometrial cancer, esophageal adenocarcinoma, renal cell carcinoma, and pancreatic cancer. Further, evidence for an association between higher body fatness and higher risk of ovarian cancer, advanced prostate cancer, and hepatocellular carcinoma is growing. Abdominal obesity is an independent risk factor for colorectal cancer beyond general obesity, whereas an independent role is less clear for other obesity-related cancer types. Epidemiological biomarker studies have shown that the positive association between body fatness and risk of cancer may be partly explained by hyperinsulinemia and altered concentrations in adipokines and sex-steroid hormones. In addition, obesity-associated low-grade inflammation plays a role in colorectal carcinogenesis. While epidemiology has contributed substantially to the understanding of the role of higher body fatness and related metabolic alterations in the development of cancer, further epidemiological biomarker studies are necessary to elucidate the complex interrelations between mediating pathways as well as to study novel pathways. Knowledge resulting from this research may help identify an obesity phenotype that is particularly strongly associated with cancer risk and thus pave the way for targeted prevention of cancer morbidity and mortality.

Obesity is a significant risk factor for the development of different cancer types and has been associated with poorer response to oncotherapies and linked to earlier recurrence of the neoplastic disease. While molecular mechanisms of these associations are still under investigation, functional dysregulation of two major fat tissue-derived adipokines, leptin and adiponectin, appears to play an important role. Leptin is known to activate carcinogenic pathways, while adiponectin appears to exert antineoplastic activities and interfere with leptin-induced processes. Because excess body fat is associated with increased leptin expression and adiponectin downregulation, therapeutic rebalancing of these pathways may benefit cancer patients, especially the obese subpopulations. This review focuses on our novel leptin receptor antagonists and adiponectin receptor agonists designed for therapeutic modulation of obesity-associated pathways in cancer.

Obesity or overweight is a risk factor for several health disorders such as type 2 diabetes, hypertension, and certain cancers. Furthermore, obesity affects almost all body systems including the extracellular matrix (ECM) by generating a pro-inflammatory environment, which are associated with abnormal secretions of several cytokines or hormonal substances, for example, insulin-like growth factors (IGFs), leptin, and sex hormones. These chemical mediators most likely have a great impact on the ECM. Accumulating evidence suggests that both obesity and ECM can influence tumor growth and progression through a number of chemical mediators. Conversely, cells in the connective tissue, namely fibroblasts and macrophages, support and aggravate the inflammatory situation in obesity by releasing several cytokines or growth factors such as vascular endothelial growth factor, epidermal growth factor, and transforming growth factor-beta (TGF-β). A wide range of functions are performed by TGF-β in normal health and pathological conditions including tumorigenesis. Breast cancer in postmenopausal women is a classic example of obesity-related cancer wherein several of these conditions, for example, higher levels of pro-inflammatory cytokines, impairment in the regulation of estrogen and growth factors, and dysregulation of different ECM components may favor the neoplastic process. Aberrant expressions of ECM components such as matrix metalloproteinases or matricellular proteins in both obesity and cancer have been reported by many studies. Nonstructural matricellular proteins, viz., thrombospondins, secreted protein acidic and rich in cysteine (SPARC), and Cyr61-CTGF-Nov (CCN), which function as modulators of cell-ECM interactions, exhibit protean behavior in cancer. Precise understanding of ECM biology can provide potential therapeutic targets to combat obesity-related pathologies.

Fructose consumption has dramatically increased in the last 30 years. The principal form has been in the form of high-fructose corn syrup found in soft drinks and processed food. The effect of excessive fructose consumption on human health is only beginning to be understood. Fructose has been confirmed to induce several obesity-related complications associated with the metabolic syndrome. Here we present an overview of fructose metabolism and how it contrasts with that of glucose. In addition, we examine how excessive fructose consumption can affect de novo lipogenesis, insulin resistance, inflammation, and reactive oxygen species production. Fructose can also induce a change in the gut permeability and promote the release of inflammatory factors to the liver, which has potential implications in increasing hepatic inflammation. Moreover, fructose has been associated with colon, pancreas, and liver cancers, and we shall discuss the evidence for these observations. Taken together, data suggest that sustained fructose consumption should be curtailed as it is detrimental to long-term human health.

Background: Breast cancer is the second leading cause of cancer-related mortality in women. Glucocorticoids (GCs) have the potential to directly affect breast cancer or indirectly via changes to the tumor growth microenvironment a breast cancer is exposed to. The role of GCs in breast cancer progression by direct and indirect means are not fully understood. Aim: To study the direct and indirect effects of GCs on breast cancer cell cycle regulation. Methods: MCF7 breast cancer cells were incubated with increasing concentrations of corticosterone (CORT) to investigate the direct effects. In addition, MCF7 cells were cultured in conditioned media (CM) from primary adipose tissue excised from CORT-supplemented lean and obese male rats. Results: CORT alone resulted in dose-dependent increases in p27 and hypophosphorylated retinoblastoma protein (Rb) which was accompanied by a reduction in the number of cells in S-phase. CM prepared from adipose tissue overrode these direct CORT effects, suggesting that the tumor growth microenvironment created in the CM dominates MCF7 cell cycle regulation. Conclusions: The direct inhibitory effects of CORT on cancer cell cycle progression are largely limited by the hormone’s effects on adipose tissue biology.