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.
Department of Pathology, Division of Pathology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
S
S
Semba
Y
Y
Kodama
K
K
Ohnuma
E
E
Mizuuchi
R
R
Masuda
M
M
Yashiro
K
K
Hirakawa
H
H
Yokozaki
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