Yoshida Junjiro, Abe Hikaru, Watanabe Takumi, Kawada Manabu
Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Research Foundation, Tokyo 141-0021, Japan.
Oncol Lett. 2018 Nov;16(5):6777-6785. doi: 10.3892/ol.2018.9485. Epub 2018 Sep 21.
Fibroblast-like stromal cells modulate the growth of cancer cells, both positively and negatively. Growth modulation is achieved through the secretion of regulatory factors as well as by proteins within the extracellular matrix. Those cellular interactions present attractive targets for cancer chemotherapy. It was demonsrated a novel natural compound, intervenolin (ITV), inhibited the growth of human gastric cancer cells when co-cultured with stromal cells. Importantly, the inhibition was enhanced by the presence of stromal cells. The present study reported a mechanism of ITV action. Human gastric fibroblast-like stromal cells (Hs738) were treated with ITV. The resultant conditioned medium (ITV CM) inhibited the growth of human gastric cancer cells and suppressed the level of c-Myc protein. This result suggested that ITV negatively modulated cancer cell growth by upregulating the secretion of factors originating from stromal cells in the co-culture system. To better understand the mechanism, ITV CM was subjected to proteomic analysis. The data revealed that one of the candidate regulators was thrombospondin-1 (TSP-1). Recombinant human TSP-1 protein inhibited the growth of gastric cancer cells. Moreover, the growth-inhibitory activities of ITV CM as well as that of recombinant TSP-1 were blocked by neutralizing antibody targeting TSP-1. These results suggested that ITV inhibited the growth of gastric cancer cells through its modulation of stromal cell function.
成纤维细胞样基质细胞对癌细胞的生长具有正负两方面的调节作用。生长调节是通过分泌调节因子以及细胞外基质中的蛋白质来实现的。这些细胞间相互作用为癌症化疗提供了有吸引力的靶点。已证明一种新型天然化合物——间维诺林（ITV），在与基质细胞共培养时可抑制人胃癌细胞的生长。重要的是，基质细胞的存在增强了这种抑制作用。本研究报道了ITV的作用机制。用ITV处理人胃成纤维细胞样基质细胞（Hs738）。所得条件培养基（ITV CM）抑制人胃癌细胞的生长并抑制c-Myc蛋白水平。该结果表明，ITV通过上调共培养系统中源自基质细胞的因子分泌来负向调节癌细胞生长。为了更好地理解该机制，对ITV CM进行了蛋白质组学分析。数据显示，候选调节因子之一是血小板反应蛋白-1（TSP-1）。重组人TSP-1蛋白抑制胃癌细胞的生长。此外，靶向TSP-1的中和抗体阻断了ITV CM以及重组TSP-1的生长抑制活性。这些结果表明，ITV通过调节基质细胞功能来抑制胃癌细胞的生长。
