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

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 ApcMin/+ 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.

肿瘤微环境中的先天免疫细胞被认为可控制从良性到恶性阶段的转变。在许多癌症中，自然杀伤（NK）细胞浸润增加与良好预后相关。尽管NK细胞抑制结直肠癌（CRC）的机制尚不清楚，但当前研究表明涉及Smad4。我们发现未经治疗的转移性CRC患者循环NK细胞中Smad4表达受到抑制。此外，NK细胞特异性Smad4缺失促进了经葡聚糖硫酸钠（DSS）处理的ApcMin/+小鼠的结肠腺瘤以及经氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）处理的小鼠的腺癌。其他研究表明，结肠上皮中Smad4缺失或弱表达与CRC患者预后不良相关。因此，针对结肠上皮和NK细胞中的Smad4可能为治疗CRC提供绝佳机会。为此，我们发现食用黑树莓（BRBs）进行饮食干预可增加家族性腺瘤性息肉病（FAP）或CRC患者以及两种CRC小鼠模型结肠上皮中Smad4的表达。此外，黑树莓的苯甲酸代谢物，如马尿酸盐，可上调Smad4和颗粒酶B（Gzmb）的表达，这可能增强原代人NK细胞的细胞毒性。值得注意的是，马尿酸盐水平升高是人类健康肠道微生物群的代谢组学标志物，并且马尿酸盐也具有抗肿瘤作用。总之，我们的研究提出了一种植物性食物来源的苯甲酸代谢物作用的新机制。这种机制可在临床上加以利用，以上调结肠上皮和NK细胞中的Smad4，从而延缓CRC进展。