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Fibroblast Growth Factor Receptor 2 Limits and Receptor 1 Accelerates Tumorigenicity of Prostate Epithelial Cells¹

Center for Cancer Biology and Nutrition, Albert B. Alkek Institute of Biosciences and Technology and Department of Biochemistry and Biophysics, Texas A & M University, Houston, Texas 77030-3303

Progressive loss of the differentiated phenotype and communication with stroma accompanies the transition of nonmalignant rat prostate epithelial cells to anaplastic, malignant tumors. Here we show that cell surface expression of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase is reduced in malignant tumor cell populations (type II) and undetectable at the mRNA level in 30% of cells. This is in addition to the irreversible loss by splice switching of the FGFR2 ectodomain that abrogates response to FGF-7 and homologues from the stroma. One hundred % of type II malignant cells express FGFR1, which is normally expressed in the stroma. Expression of the FGFR1 kinase in premalignant type I tumor epithelial cells by transfection accelerated progression to the malignant phenotype. In contrast to the FGFR2 kinase fused to the ectodomain of FGFR1, the FGFR1 kinase failed initially to support a mitogenic response to FGF-2 in type I tumor cells. However, the FGFR1-transfected cells acquired a mitogenic response after extensive proliferation of the cell population. Resident FGFR2 and ectopic FGFR1 appeared to be partitioned in the type I cells, because neither full-length nor truncated isoforms of FGFR1 affected the mitogenic response of the other. Restoration of the FGFR2IIIb kinase to malignant cells expressing FGFR1 depressed tumor growth rates, restored responsiveness to stromal cells, and restored epithelial cell differentiation. These observations reveal that homologous FGFR1 and FGFR2 kinases play very different roles in cell growth and differentiation and in development and support of the malignant phenotype.

¹ This work was supported by NIH Grant CA59971 from the National Cancer Institute.

² Present address: Department of Urology, Hiroshima University School of Medicine, 1-2-3 Kasumi, Hiroshima 734, Japan.

³ To whom requests for reprints should be addressed, at Center for Cancer Biology and Nutrition, Alkek Institute of Biosciences and Technology, Texas A & M University, 2121 West Holcombe Boulevard, Houston, TX 77030-3303. Phone: (713) 677-7522; Fax: (713) 677-7512; E-mail: wmckeeha@ibt.tamu.edu.

Received 6/ 5/97. Accepted 10/ 3/97.

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