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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 ORCID: https://orcid.org/0000-0002-3283-1111, Grimshaw, Alfred David, Martin, Tracey Amanda ORCID: https://orcid.org/0000-0003-2690-4908, Davies, Gaynor, Parr, Christian, Watkins, Gareth, Lane, Jane ORCID: https://orcid.org/0000-0002-1926-4909, Abounader, Roger, Laterra, John and Mansel, Robert Edward ORCID: https://orcid.org/0000-0002-8051-0726 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: 17 Oct 2022 08:25
URI: https://orca.cardiff.ac.uk/id/eprint/106

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