Obesity and its associated metabolic dysregulation are established risk factors for many cancers. However, the biologic mechanisms underlying this relationship remain incompletely understood. Given the rising rates of both obesity and cancer worldwide, and the challenges for many people to lose excess adipose tissue, a systematic approach to identify potential molecular and metabolic targets is needed to develop effective mechanism-based strategies for the prevention and control of obesity-driven cancer. Epidemiological, clinical, and preclinical data suggest that within the growth-promoting, pro-inflammatory microenvironment accompanying obesity, crosstalk between adipose tissue (comprised of adipocytes, macrophages and other cells) and cancer-prone cells may occur via obesity-associated hormones, cytokines, and other mediators that have been linked to increased cancer risk and/or progression. We report here a systematic review on the direct “crosstalk” between adipose tissue and carcinomas in humans. We identified 4,641 articles with n=20 human clinical studies which are summarized as: (a) breast (n=7), (b) colorectal (n=4), (c) esophageal (n=2), (d) esophageal/colorectal (n=1), (e) endometrial (n=1), (f) prostate (n=4), and (g) ear-nose-throat (ENT) cancer (n=1). Findings from these clinical studies reinforce preclinical data and suggest organ-dependent crosstalk between adipose tissue and carcinomas via VEGF, IL-6, TNF-alpha and other mechanisms. Moreover, visceral white adipose tissue (VAT) plays a more central role as it is more bio-energetically active and is associated with a more pro-cancer secretome than subcutaneous adipose tissue (SAT). Efforts to eavesdrop and ultimately interfere with this cancer-enhancing crosstalk may lead to new targets and strategies for decreasing the burden of obesity-related cancers.

Background Branched-chain amino acids (BCAA) have been previously linked to survival in colorectal cancer (CRC) patients. It is unclear whether BCAAs are prognostic biomarkers or surrogate markers for energy balance. Objectives We aimed to determine correlations of BCAAs with markers of energy balance over time and to investigate prognostic significance of BCAAs in CRC. Methods We used urinary samples from newly diagnosed CRC patients [n=163; (stage I – IV)] from the ColoCare study in Heidelberg, Germany, collected at surgery (n=163), 6 (n=83) and 12 months follow-up (n=54). Isoleucine, leucine, valine, (2Z)-3-methylglutaconic acid (3HM), 2-ethylhydracrylic acid (2EA), 2-methyl-3-hydroxybutyrate (2M3H) were detected using gas-chromatography mass-spectrometry and proton-nuclear-magnetic-resonance spectroscopy. Partial correlation coefficients between BCAAs with body mass index (BMI), physical activity (metabolic equivalent [MET]) and muscle area were computed and adjusted for sex and age at diagnosis. We used Cox proportional hazard models to investigate overall survival (OS) after 24 months of follow-up. Results We did not observe significant correlations between BCAAs and parameters of energy balance at all time points (correlation ranges: BMI: r= −0.13 to −0.01; METs: r=−0.14 to 0.02; dorsal muscle: r=−0.03 to 0.10). BCAAs were not associated with risk of death in stage I-III (e.g., valine: HRlog2=1.62, p=0.25) or in stage IV tumors. Elevated concentrations of 2EA and 2M3H were significantly associated with OS, independent of stage (2EA: stage I-III: HRlog2=0.42, p=0.04; stage IV: HRlog2=0.51, p=0.01). Conclusion Our study suggests that BCAAs in colorectal cancer patients do not reflect parameters of energy balance and may be independently associated with overall survival.