MITIGATION OF INTESTINAL TUMORIGENESIS AND CANCER CACHEXIA IN APCMIN/+ MICE BY TABLE GRAPES (VITIS VINIFERA)
Open Access
- Author:
- Indukuri, Vijaya Varma
- Graduate Program:
- Food Science
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 10, 2019
- Committee Members:
- Joshua D. Lambert, Dissertation Advisor/Co-Advisor
Joshua D. Lambert, Committee Chair/Co-Chair
Jairam K.P. Vanamala, Committee Member
Gregory R. Ziegler, Committee Member
Mary J. Kennett, Outside Member - Keywords:
- Colon cancer
cancer prevention
β-catenin - Abstract:
- Colon cancer is the 3rd most prevalent cancer in the United States and it kills over 50,000 Americans every year. Conventional chemotherapies can significantly reduce tumor growth but can have serious adverse side effects. Emerging evidence suggests that phytonutrient-rich plant foods reduce the risk of colon cancer. Grapes, one of the most widely consumed fruits in the world, contain a variety of phytonutrients such as anthocyanins, proanthocyanidins, stilbenes, flavonols, and flavanols. We have recently shown that grape compounds (resveratrol and grape seed extract) and grape powder extract can target cancer stem cells in vitro and in vivo using a carcinogen-induced rodent model of colon cancer. However, no information is available on the anti-colon cancer activity of multi-colored grapes in vivo. Herein, I have investigated the inhibitory efficacy of table grapes (freeze-dried grape powder – FDGP) against colon cancer stem cells (CSCs) in vitro and intestinal tumorigenesis in the APCMin/+ mouse, a model of genetically-induced intestinal tumorigenesis. CSCs have been shown to be responsible for the initiation and progression of tumors in a variety of cancers. Grape powder extract (GPE) made from FDGP suppressed proliferation, sphere formation, and elevated apoptosis in colon CSCs. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter the efficacy of GPE, which indicates that these anti-proliferative and pro-apoptotic effects are independent of p53. These findings demonstrate the potential colon CSC inhibitory efficacy of FDGP. Dietary supplementation of male APCMin/+ mice with FDGP (at 3 or 6% w/w) suppressed the total number of intestinal polyps by 55%. This level of inhibition was greater than aspirin (39% at 200 ppm), which is a drug used for the prevention of colon cancer in humans. FDGP supplementation also decreased polyp growth, where the number of polyps of 1 to 2 mm in size was significantly lower than control mice. Reduced tumorigenesis was associated with downregulation of targets in the Wnt/β-catenin pathway, such as cyclin D1, c-Jun, and c-myc expression. Expression of genes linked to angiogenesis, VEGF and HIF-1α, were also lower in FDGP-treated mice. We also looked at the effect of FDGP on cancer cachexia. Cancer-induced cachexia is a complex condition of tissue wasting which develops as a secondary disorder in cancer patients and leads to progressive functional impairment, accompanied by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. It accounts for ~30% of all cancer-related deaths. In addition, the radiotherapy used to treat colon cancer can exacerbate cachexia progression. The APCMin/+ mouse is an established model of colon cancer-induced cachexia. We found that dietary supplementation of APCMin/+ mice with FDGP ameliorated weight loss in APCMin/+ compared to control diet-treated mice. FDGP also countered other important markers of cancer cachexia such as endotoxemia, altered gut barrier function, and systemic inflammation in APCMin/+ mice. FDGP supplemented mice had lower levels of circulating endotoxins/lipopolysaccharides (LPS) and LPS binding protein LBP. FDGP also suppressed the systemic and tissue levels of pro-inflammatory cytokines and upregulated the levels of anti-inflammatory cytokines. We also observed that mice treated with FDGP had greater levels of fecal bacteria associated with reduced cachexia, and lower levels of those positively correlated with colon cancer-cachexia. These results suggest that FDGP ameliorated weight loss and other important markers of cancer-induced cachexia. In conclusion, the present study suggests the potential usefulness of table grapes for the chemoprevention of human intestinal/colorectal cancer and its associated cachexia.