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Reduction of Stromal Fibroblast-induced Mammary Tumor Growth, by Retroviral Ribozyme Transgenes to Hepatocyte Growth Factor/Scatter Factor and its Receptor, c-MET¹

Metastasis Research Group, University Department of Surgery, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom [W. G. J., D. G., T. A. M., G. D., C. P., G. W., Ja. L., R. E. M.], and Department of Neurology; Kennedy Krieger Institute and John Hopkins School of Medicine, Baltimore, Maryland 21205 [R. A., Jo. L.]

Purpose: Hepatocyte growth factor/scatter factor (HGF/SF) is known to increase the invasiveness and migration of cancer cells in vitro and induce angiogenesis. This study examined if inhibition of HGF/SF receptor expression by cancer cells and HGF/SF expression by stromal fibroblasts affects the growth of mammary cancer.

Experimental Design: Transgenes encoding ribozymes to specifically target human HGF/SF receptor (pLXSN-MET) or HGF/SF (pLXSN-HGF) were constructed using a pLXSN retroviral vector. Human mammary cancer cells MDA MB 231 was transduced with pLXSN-MET (MDA^+/+). A human fibroblast cell line MRC5, which produces bioactive HGF/SF, was transduced with pLXSN-HGF (MRC5^+/+). These cells were used in a nude mice breast tumor model.

Results: HGF receptor in MDA^+/+ cells and HGF in MRC5^+/+cells were successfully removed with respective ribozymes as shown by reverse transcription-PCR and Western blotting, respectively. MDA^+/+ was found to have reduced invasiveness when stimulated with HGF/SF. MRC5^+/+ exhibited a significant reduction in HGF/SF production. When injected into athymic nude mice, MDA^+/+ exhibited a slower rate of growth, compared with the wild type (MDA^-/-), and the cells transduced with control viral vector (MDA^+/-). The growth of MDA^-/- tumor was significantly enhanced when coimplanted with wild-type MRC5 (MRC5^-/-), and the stimulatory effect was reduced when MRC5^+/+ cells were coimplanted instead of MRC5^-/-. The reduction of tumor growth was accompanied by reduction of angiogenesis, as demonstrated by the staining of VE-cadherin in primary tumor tissues.

Conclusions: Retroviral ribozyme transgenes targeting HGF/SF in fibroblasts or its receptor cMET in mammary cancer cells can reduce the growth of mammary cancer and associated angiogenesis by inhibiting paracrine stromal–tumor cell interactions.