LAUSR

Background: Tumor-stromal cell interactions are attractive targets for cancer chemotherapy because fibroblast-like stromal cells modulate cancer cells both positively and negatively through secreted factors as well as proteins of the extracellular matrix. We have focused on the negative regulation of cancer cells by secreted factors of stromal cells as it offers a novel strategy for discovering new cancer therapeutics. We used a coculture system to screen small molecules from natural sources such as microbial culture media, seeking molecules that modulated tumor-stromal cell interactions. In a recent study, we found a novel compound, intervenolin (ITV), from the culture medium of Nocardia sp. ML96-86F2. ITV inhibited the in vitro growth of human gastric cancer cells. Importantly, inhibition was greater when the cancer cells were cocultured with stromal cells. Here we report the mechanism of ITV action. Materials and Method: Human gastric cancer MKN-7 and MKN-74 cells were cultured with human gastric stromal Hs738 cells in the presence of ITV. The growth of MKN-7 and MKN-74 cells cultured in only CM taken from Hs738 cells treated with ITV (ITV CM) was also inhibited more strongly than it was cultured alone. We prepared serum-free CM from Hs738 cells to determine the anticancer factors secreted by ITV-treated HS738 cells using LC-MS/MS analysis. Results: Conditioned medium (CM) of ITV-treated Hs738 cells inhibited the growth of MKN-7 or MKN-74 cells and suppressed c-MYC protein level in MKN-74 cells. This result suggested that ITV induced the negative modulation of cancer cells through secreted factors from stromal cells. Proteome analysis of ITV-treated Hs738 CM revealed that one of the candidates could be thrombospondin-1 (TSP-1). As a result, recombinant TSP-1 inhibited the growth of gastric cancer cells and downregulated c-MYC. Conclusions: ITV inhibits gastric cancer cell growth through inducing TSP-1 secretion from Hs738 cells in coculture system in vitro. No conflict of interest. Citation Format: Junjiro Yoshida, Hikaru Abe, Takumi Watanabe, Manabu Kawada. Intervenolin suppresses gastric cancer cell growth via stromal secreted factors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B205.