Reciprocal Reprogramming of Cancer Cells and Associated Mesenchymal Stem Cells in Gastric Cancer.

We utilized gastric cancer cells (GSC1) to demonstrate subversion of naïve Mesenchymal Stem Cells (MSC) from adjacent tissue, which are reprogrammed to express a tumor-promoting phenotype, whose cardinal manifestation is to sustain cancer stem cells. Paracrine effects of such primed MSC are sufficient to enable 2D growth of GSC1, while cell-cell interactions are necessary for 3D growth or in vivo tumor formation. Increased expression of R-spondin in primed MSC mediated elevation of Lgr5 expression in GSC1, activation of the WNT/β-catenin signaling pathway and translocation of β-catenin into the nucleus of most Lgr5 positive cells. Subversion of MSC in the tumor microenvironment (TME) by cancer cells, appears to be a prominent means to sustain the cancer stem cell underpinning of tumor progression. Examination of the alteration in gene expression in naïve MSC recruited into the tumor site by the cancer cells and reprogramming them into a tumor promoting stroma. Alterations were identified in the original tumor-derived MSC to identify the mechanism of sustaining tumor grow and maintenance of stemness properties in the cancer cells by the tumor stromal MSC.