Suppression of in vitro invasion and in vivo growth of breast cancer induced by hepatocyte growth factor/scatter factor (HGF/SF) and HGF/SF producing fibroblasts, by viral hammerhead ribozymes targeting HGF/SF and its receptor cMET

W. G. Jiang, D. A. Grimshaw, J. Lane, T. A. Martin, J. Laterra, R. E. Mansel

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) is known to increase the migration and invasiveness of breast cancer cells. This study aimed to target the impact of HGF/SF on the growth of breast cancer, by using hammerhead ribozymes. Methods. Retroviral hammerhead ribozymes were constructed to specifically target human HGF/SF and its receptor cMET. A breast cancer cell, MDA MB 231, which expressed cMET was transduced with viral cMET ribozyme. A human fibroblast cell, MRC5, that produces bioactive HGF/SF was transduced with HGF/SF ribozyme. In vitro invasiveness of both wild and transduced breast cancer cells were analysed using a Matrigel invasion assay. Production of HGF/SF from wild and transduced fibroblasts was analysed using MDCK bioassay. Breast cancer cells (wild and stable transducants) were used in a nude mice model, to determine the growth of breast tumours. Results. MET ribozyme eliminated the expression of cMET mRNA, as shown by RT-PCR. The stably transduced MDA MB 231 cells lost its response to HGF/SF in the in vitro invasion assay (invasion index being 2.3±0.9 for wild, vs 0.99±0.18 in the transduced, p<0.05). HGF/SF ribozyme reduced production of bioactive HGF/SF from fibroblasts (62±31U/ml from wild vs 3.4±1.6 U/ml from the transduced, p<0.01). As a consequence, the transduced fibroblasts reduced their effect on the invasiveness on breast cancer cells, in a co-culture invasion assay (invasion index 3.1 ± 1 with wild fibroblasts vs 1.4±0.6 with transduced fibroblasts, p<0.01). In in vivo studies, MET-transduced breast cancer cells exhibited a significant reduction in growth (tumour volume 1.84±1.6mm3 with wild and 0.26±0.2mm3 with tranduced tumour cells over 4 wks period, p=0.05). Conclusion. Viral hammerhead ribozymes are effective in targeting HGF/SF receptor and HGF/SF production by fibroblasts. These ribozymes are therefore useful in suppressing HGF/SF induced invasion and tumour growth of breast cancer and may have potential therapeutic value.

Original languageEnglish (US)
Number of pages1
JournalBreast Cancer Research and Treatment
Volume69
Issue number3
StatePublished - Jan 1 2001
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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