Journal Article

Black Raspberries Suppress Colorectal Cancer by Enhancing Smad4 Expression in Colonic Epithelium and Natural Killer Cells

Lin, Chien-Wei, Wang, Li-Shu, Mo, Yue Yang, Tsai, Susan, Huang, Yi-Wen, Bai, Weibin, Pan, Pan, Cao, Hui, Yu, Jianhua, Oshima, Kiyoko, Aldakkak, Mohammed, Wang, Hsin-Tzu, Xiao, Jianbo, Sun, Chongde, Echeveste, Carla Elena, Yearsley, Martha, Shan, Tianjiao, Du, Ming

2020

Overview

Innate immune cells in the tumor microenvironment have been proposed to control the transition from benign to malignant stages. In many cancers, increased infiltration of natural killer (NK) cells associates with good prognosis. Although the mechanisms that enable NK cells to restrain colorectal cancer (CRC) are unclear, the current study suggests the involvement of Smad4. We found suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Moreover, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated Apc Min/+ mice and adenocarcinomas in AOM/DSS-treated mice. Other studies have shown that Smad4 loss or weak expression in colonic epithelium associates with poor survival in CRC patients. Therefore, targeting Smad4 in both colonic epithelium and NK cells could provide an excellent opportunity to manage CRC. Toward this end, we showed that dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in patients with FAP or CRC and in the two CRC mouse models. Also, benzoate metabolites of BRBs, such as hippurate, upregulated Smad4 and Gzmb expression that might enhance the cytotoxicity of primary human NK cells. Of note, increased levels of hippurate is a metabolomic marker of a healthy gut microbiota in humans, and hippurate also has antitumor effects. In conclusion, our study suggests a new mechanism for the action of benzoate metabolites derived from plant-based foods. This mechanism could be exploited clinically to upregulate Smad4 in colonic epithelium and NK cells, thereby delaying CRC progression.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acids / Adenocarcinoma - diet therapy / Adenocarcinoma - immunology / Adenoma - diet therapy / Adenoma - immunology / Adult / Aged / Aged, 80 and over / Animal models / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Antitumor activity / Benzoic acid / black raspberries / Blood & organ donations / Cancer therapies / Cell Line, Tumor / Clonal deletion / Colon - pathology / colorectal (colon) cancer / Colorectal cancer / Colorectal Neoplasms - diet therapy / Colorectal Neoplasms - immunology / Cytotoxicity / Disease Models, Animal / Drinking water / Epithelial Cells - metabolism / Epithelial Cells - pathology / Epithelium / Female / Gene Expression Regulation, Neoplastic / Hippurates - pharmacology / Hippurates - therapeutic use / human clinical trials / Humans / Immunohistochemistry / Immunology / Intestinal microflora / Killer Cells, Natural - immunology / Male / Medical prognosis / Metabolites / Metabolomics / Metastases / Metastasis / Mice / Middle Aged / Natural killer cells / Nutrition research / Patients / Raspberries / Rubus - immunology / Smad4 / Smad4 protein / Smad4 Protein - genetics / Smad4 Protein - metabolism / Tissues / Tumor Microenvironment / Tumors / Up-Regulation