Abstract
Fibroblast-like stromal cells modulate cancer cells through secreted factors and adhesion, but those factors are not fully understood. Here, we have identified critical stromal factors that modulate cancer growth positively and negatively. Using a cell co-culture system, we found that gastric stromal cells secreted IL-6 as a growth and survival factor for gastric cancer cells. Moreover, gastric cancer cells secreted PGE2 and TNFα that stimulated IL-6 secretion by the stromal cells. Furthermore, we found that stromal cells secreted glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Extracellular GAPDH, or its N-terminal domain, inhibited gastric cancer cell growth, a finding confirmed in other cell systems. GAPDH bound to E-cadherin and downregulated the mTOR-p70S6 kinase pathway. These results demonstrate that stromal cells could regulate cancer cell growth through the balance of these secreted factors. We propose that negative regulation of cancer growth using GAPDH could be a new anti-cancer strategy.
Highlights
Tumor tissues are composed of cancer cells and surrounding stroma
These results showed that the growth of well-differentiated gastric cancer cell lines was suppressed by gastric stromal cells and the growth of undifferentiated gastric cancer cell lines with high metastatic abilities was increased by gastric stromal cells
In this study we have found that Hs738 gastric stromal cells secrete IL-6 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for positive and negative regulation of cancer cells, respectively
Summary
Tumor tissues are composed of cancer cells and surrounding stroma. Since the myofibroblast content of tumor tissues correlates well with poor prognosis of some cancers [7], stromal cells, especially myofibroblasts, are significantly involved in the development of cancer. Recent reports have clarified the role of stromal cells in the maintenance of cancer stem cells [8], metastatic niches [9, 10], and chemoresistance [11, 12]. Due to such growing evidence, stromal cells are becoming an attractive target for anticancer strategies
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