Direct cancer-stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells.
BACKGROUND
Scirrhous-type gastric carcinoma (SGC) exhibits an extensive submucosal fibrosis and extremely poor patient prognosis. We investigated the importance of the cancer-stromal interaction in the histogenesis of SGC.


METHODS
Gastric fibroblasts NF-25 and intestinal fibroblasts NF-j2 were co-cultured with SGC-derived (HSC-39) or non-SGC-derived (HSC-57 and HSC-64) cells. To identify genes that are up- or downregulated in NF-25, complementary DNA (cDNA) microarray analysis was performed. The antibody against vascular-cell adhesion molecule-1 (VCAM-1) was used for cell growth test and immunohistochemistry. Moreover, the impact of interaction with NF-25 fibroblasts on HSC-39 cells was investigated using western blot and reverse transcription-polymerase chain reaction.


RESULTS
HSC-39 cells stimulated growth of NF-25 but not NF-j2 when co-cultured. Induction of VCAM-1 in NF-25 fibroblasts was identified, which was specific when co-cultured with HSC-39 but not with non-SGC-derived HSC-57 and HSC-64 cells. Neutralising antibody to VCAM-1 suppressed NF-25 growth in dose-dependent manners. In tissue samples, positive immunoreactivity of VCAM-1 in SGC-derived fibroblasts was significantly higher than that in non-SGC-derived fibroblasts. Furthermore, interaction with NF-25 fibroblasts not only induced the epithelial-mesenchymal transition-like change, but also expressions of matrix metalloproteinase- related genes in HSC-39 cells.


CONCLUSIONS
Direct interaction between SGC cells and gastric fibroblasts establishes the tumour microenvironment and reinforces the aggressiveness of SGC.
Semba
S
S
Department of Pathology, Division of Pathology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
Kodama
Y
Y
Ohnuma
K
K
Mizuuchi
E
E
Masuda
R
R
Yashiro
M
M
Hirakawa
K
K
Yokozaki
H
H
D000368:Aged; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D039441:Integrin alpha4 / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology*; D017154:Stromal Cells / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics / Q000502:physiology
D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D020778:Matrix Metalloproteinase 2