Stromal cells positively and negatively modulate the growth of cancer cells: stimulation via the PGE2-TNFα-IL-6 pathway and inhibition via secreted GAPDH-E-cadherin interaction.

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.

• Authors: Manabu Kawada, Hiroyuki Inoue, Shun-ichi Ohba, Junjiro Yoshida, Tohru Masuda, Manabu Yamasaki, Ihomi Usami, Shuichi Sakamoto, Hikaru Abe, Takumi Watanabe, Takao Yamori, Masakatsu Shibasaki, Akio Nomoto
• Journal: PloS one (PLoS One) Vol. 10 Issue 3 Pg. e0119415 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25785838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• IL6 protein, human
• Interleukin-6
• TNF protein, human
• Tumor Necrosis Factor-alpha
• Glyceraldehyde-3-Phosphate Dehydrogenases
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Dinoprostone

Topics

• Animals
• Cadherins (metabolism)
• Cell Growth Processes
• Cell Line, Tumor
• Coculture Techniques
• Dinoprostone (metabolism, physiology)
• Female
• Gene Expression Regulation, Neoplastic
• Glyceraldehyde-3-Phosphate Dehydrogenases (metabolism)
• Humans
• Interleukin-6 (metabolism, physiology)
• Mice
• Neoplasms (genetics, metabolism, physiopathology)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Signal Transduction
• Stromal Cells (metabolism, physiology)
• TOR Serine-Threonine Kinases (metabolism)
• Tumor Necrosis Factor-alpha (metabolism, physiology)