The role of HGF/MET and FGF/FGFR in fibroblast-derived growth stimulation and lapatinib-resistance of esophageal squamous cell carcinoma

BMC Cancer

Shin Saito¹  Kazue Morishima¹  Takashi Ui¹  Hiroko Hoshino⁴  Daisuke Matsubara⁴  Shumpei Ishikawa²  Hiroyuki Aburatani³  Masashi Fukayama⁵  Yoshinori Hosoya¹  Naohiro Sata¹  Alan K Lefor¹  Yoshikazu Yasuda¹  Toshiro Niki⁴ 

[1] Department of Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-City 329-0498, Tochigi, Japan

[2] Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo 113-0034, Tokyo, Japan

[3] Division of Genome Science, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904, Japan

[4] Department of Integrative Pathology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-City 329-0498, Tochigi, Japan

[5] Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo 113-0033, Tokyo, Japan

关键词: Chemo-resistance;    Lapatinib;    FGFs;    HGF;    Stromal fibroblasts;    Esophageal squamous-cell carcinoma;   

Others  :  1131607
DOI  :  10.1186/s12885-015-1065-8

 received in 2014-06-24, accepted in 2015-02-02,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Saito et al.; licensee BioMed Central.

【 图 表 】

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