RRC ID 36880
Author Saito S, Morishima K, Ui T, Hoshino H, Matsubara D, Ishikawa S, Aburatani H, Fukayama M, Hosoya Y, Sata N, Lefor AK, Yasuda Y, Niki T.
Title The role of HGF/MET and FGF/FGFR in fibroblast-derived growth stimulation and lapatinib-resistance of esophageal squamous cell carcinoma.
Journal BMC Cancer
Abstract BACKGROUND:Although advanced esophageal squamous-cell carcinoma (ESCC) is treated using a multidisciplinary approach, outcomes remain unsatisfactory. The microenvironment of cancer cells has recently been shown to strongly influence the biologic properties of malignancies. We explored the effect of supernatant from esophageal fibroblasts on the cell growth and chemo-resistance of ESCC cell lines.
METHODS:We used 22 ESCC cell lines, isolated primary human esophageal fibroblasts and immortalized fibroblasts. We first examined cell proliferation induced by fibroblast supernatant. The effect of supernatant was evaluated to determine whether paracrine signaling induced by fibroblasts can influence the proliferation of cancer cells. Next, we examined the effects of adding growth factors HGF, FGF1, FGF7, and FGF10, to the culture medium of cancer cells. These growth factors are assumed to be present in the culture supernatants of fibroblasts and may exert a paracrine effect on the proliferation of cancer cells. We also examined the intrinsic role of HGF/MET and FGFs/FGFR in ESCC proliferation. In addition, we examined the inhibitory effect of lapatinib on ESCC cell lines and studied whether the fibroblast supernatants affect the inhibitory effect of lapatinib on ESCC cell proliferation. Finally, we tested whether the FGFR inhibitor PD-173074 could eliminate the rescue effect against lapatinib that was induced by fibroblast supernatants.
RESULTS:The addition of fibroblast supernatant induces cell proliferation in the majority of cell lines tested. The results of experiments to evaluate the effects of adding growth factors and kinase inhibitors suggests that the stimulating effect of fibroblasts was attributable in part to HGF/MET or FGF/FGFR. The results also indicate diversity in the degree of dependence on HGF/MET and FGF/FGFR among the cell lines. Though lapanitib at 1 μM inhibits cell proliferation by more than 50% in the majority of the ESCC cell lines, fibroblast supernatant can rescue the growth inhibition of ESCC cells. However, the rescue effect is abrogated by co-treatment with FGFR inhibitor.
CONCLUSION:These results demonstrate that cell growth of ESCC depends on diverse receptor tyrosine kinase signaling, in both cell-autonomous and cell-non-autonomous manners. The combined inhibition of these signals may hold promise for the treatment of ESCC.
Volume 15
Pages 82
Published 2015-2-25
DOI 10.1186/s12885-015-1065-8
PII 10.1186/s12885-015-1065-8
PMID 25884729
PMC PMC4345039
MeSH Carcinoma, Squamous Cell / drug therapy Carcinoma, Squamous Cell / metabolism* Carcinoma, Squamous Cell / pathology Cell Culture Techniques Cell Line, Tumor Cell Proliferation / drug effects Cells, Cultured Culture Media, Conditioned / pharmacology Drug Resistance, Neoplasm* / drug effects Esophageal Neoplasms / drug therapy Esophageal Neoplasms / metabolism* Esophageal Neoplasms / pathology Esophageal Squamous Cell Carcinoma Esophagus / cytology Fibroblast Growth Factors / genetics Fibroblast Growth Factors / metabolism* Fibroblast Growth Factors / pharmacology Fibroblasts / cytology Fibroblasts / metabolism* Hepatocyte Growth Factor / genetics Hepatocyte Growth Factor / metabolism* Humans Lapatinib Molecular Sequence Data Paracrine Communication / drug effects Proto-Oncogene Proteins c-met / metabolism Pyrimidines / pharmacology Quinazolines / pharmacology* Receptors, Fibroblast Growth Factor / antagonists & inhibitors Receptors, Fibroblast Growth Factor / metabolism
IF 3.288
Times Cited 13
WOS Category ONCOLOGY
Resource
Human and Animal Cells TE-1(RCB1894) TE-4(RCB2097) TE-5(RCB1949) TE-6(RCB1950) TE-8(RCB2098) TE-9(RCB1988) TE-10(RCB2099) TE-11(RCB2100) TE-14(RCB2101) TE-15(RCB1951) EC-GI-10(RCB0774)