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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-MET

Jiang, Wen Guo, Grimshaw, Alfred David, Martin, Tracey Amanda, Davies, Gaynor, Parr, Christian, Watkins, Gareth, Lane, Jane, Abounader, Roger, Laterra, John and Mansel, Robert Edward 2003. Reduction of stromal fibroblast-induced mammary tumor growth, by retroviral ribozyme transgenes to hepatocyte growth factor/scatter factor and its receptor, c-MET. Clinical Cancer Research 9 (11) , pp. 4274-4281.

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
ISSN: 1078-0432
Last Modified: 18 Oct 2017 08:12
URI: http://orca-mwe.cf.ac.uk/id/eprint/106

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