title: Growth factor-mediated interaction between tumor cells and stromal fibroblasts in an experimental model of human small-cell lung cancer.
abstract: Malignant tumors induce development of their own stromal tissues during the processes of growth, progression and metastasis. Since the vascular architecture among the various stromal elements is well known to facilitate tumor growth and has been a target of therapy, the importance of stromal fibroblasts has recently been established. To elucidate the interaction between the tumor and its stromal fibroblasts, the present study took advantage of a unique experimental model consisting of a human small-cell lung cancer cell line, WA-ht, and its mouse stromal fibroblast cell line, WA-mFib, both originally derived from a xenograft tumor in a mouse subcutis. Co-culture with the WA-mFib cells significantly augmented the plating efficiency of WA-hT cells in vitro, and their co-inoculation in nude mice shortened latency and tumor doubling time. Histochemical detection of beta-gal, transfected into WA-mFib cells, demonstrated their contribution to the nude mouse xenograft tumor formation as its tumor stroma. Elevated hepatocyte growth factor (HGF) from fibroblasts followed by elevated production of vascular endothelial growth factor (VEGF) from both tumor cells and fibroblasts were demonstrated by ELISA in supernatants of their co-culture, accompanied by enhanced colonogenicity of the tumor cells; these enhanced features were not observed in their respective monocultures. Antisense oligonucleotides to HGF cancelled these augmentation effects with co-culture. The findings highlight the substantial roles of tumor stromal fibroblasts, interacting with soluble growth factors, in promoting the malignant propensity of the tumor.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kurosu
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.forename: Masako
authors.initials: M
authors.lastname: Minamihisamatsu
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kuriyama
mesh_terms: D000818:Animals; D001706:Biopsy; D018288:Carcinoma, Small Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003469:Culture; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007763:Lac Operon; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009841:Oligonucleotides / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D006133:Growth Substances; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D001616:beta-Galactosidase