Colorectal cancer (CRC) is the third most frequently diagnosed malignancy in the United States. Given the global obesity epidemic, and the fact that obesity is associated with increased CRC risk, incidence and mortality, it is imperative that we discover and develop agents with efficacy against CRC under obese conditions. Thus, an agent with both anti-obesogenic and anti-CRC activities would be ideal to impair different facets of CRC interactions with adipose tissue secretions resulting in CRC chemoprevention under obese conditions. Our extensive in vitro and in vivo studies investigating the benefits of grape seed extract (GSE) consumption against CRC have shown that it exerts strong inhibitory activity in different CRC pre-clinical models. Recently, we also explored GSE potential to modulate the growth promoting tumorigenic secretions of adipocytes on CRC and colon cancer stem cells (CSCs). Results indicated that GSE significantly reduces the growth and invasion promoting effects of both mouse and human adipocytes on these cells which was associated with a decrease in CSC-associated markers and transcription factors. Notably, GSE effects on adipocytes were not due to changes in lipid content, but mechanistic studies showed that GSE causes differential modulation of adipogenesis-related proteins during different stages of adipocyte differentiation and induces the ‘browning’ of adipocytes as evidenced by an increase in UCP1 mRNA level and mitochondriogenesis. To further establish that indeed GSE has the potential to modify adipose tissue secretions, we fed GSE to obese mice and evaluated its anti-obesogenic effect. Briefly, short-term GSE feeding (200mg/ Kg body weight) for two weeks by oral gavage to diet-induced obese mice suppressed body weight, decreased the weight of fat pads, and improved associated metabolic abnormalities. During the high-fat-diet induced hyperlipidemia, GSE normalized total cholesterol in serum with a concomitant increase in high density cholesterol. Furthermore, our findings showed that GSE feeding significantly modulated the serum levels of adipokines/cytokines; specifically, GSE lowered the circulating leptin, resistin, pentraxin-2, lipocalin-2, and IGF-1 serum levels, while increasing IGFBP-1 levels. These results are significant as presence of meta-inflammation in obese people suggests that reversal of white adipose tissue dysfunction and modulation of visceral obese adipose tissue-driven pro-inflammatory adipokines/cytokines signaling provide unique opportunities for the preventive intervention of CRC in obese conditions. Based on these notable biological effects, GSE is a strong candidate agent to be studied further for its potential use against CRC growth and progression under obese conditions.

Citation Format: Komal Raina, Sushil Kumar, Dileep Kumar, Ranganatha R. Somasagara, Reenu Punia, Rama Kant, Rajesh Agarwal, Chapla Agarwal. Grape seed extract decreases visceral adiposity and impairs the pro-tumorigenic adipose tissue secretions affecting colorectal cancer growth and progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 901. doi:10.1158/1538-7445.AM2015-901