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

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

doi:10.1371/journal.pone.0119415

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

PLoS One. 2015 Mar 18;10(3):e0119415. doi: 10.1371/journal.pone.0119415. eCollection 2015.

Affiliations

¹ Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
² Institute of Microbial Chemistry (BIKAKEN), Tokyo, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan.
³ The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Grants and funding

This study was supported by MEXT KAKENHI Grant Number 23112522. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.