title: 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.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawada
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Ohba
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
authors.forename: Junjiro
authors.initials: J
authors.lastname: Yoshida
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Tokyo, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
authors.forename: Ihomi
authors.initials: I
authors.lastname: Usami
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Tokyo, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Abe
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Tokyo, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Tokyo, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Shibasaki
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Nomoto
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology
chemical_list: D015820:Cadherins; C508600:IL6 protein, human; D015850:Interleukin-6; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D015232:Dinoprostone