Intervenolin suppresses gastric cancer cell growth through the induction of TSP-1 secretion from fibroblast-like stromal cells.

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 in vitro 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.