PMID- 14519655
OWN - NLM
STAT- MEDLINE
DCOM- 20040817
LR  - 20220310
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 9
IP  - 11
DP  - 2003 Sep 15
TI  - Reduction of stromal fibroblast-induced mammary tumor growth, by retroviral 
      ribozyme transgenes to hepatocyte growth factor/scatter factor and its receptor, 
      c-MET.
PG  - 4274-81
AB  - 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.
FAU - Jiang, Wen G
AU  - Jiang WG
AD  - Metastasis Research Group, University Department of Surgery, University of Wales 
      College of Medicine, Cardiff CF14 4XN, Wales, UK. jiangw@cf.ac.uk
FAU - Grimshaw, David
AU  - Grimshaw D
FAU - Martin, Tracey A
AU  - Martin TA
FAU - Davies, Gaynor
AU  - Davies G
FAU - Parr, Christian
AU  - Parr C
FAU - Watkins, Gareth
AU  - Watkins G
FAU - Lane, Jane
AU  - Lane J
FAU - Abounader, Roger
AU  - Abounader R
FAU - Laterra, John
AU  - Laterra J
FAU - Mansel, Robert E
AU  - Mansel RE
LA  - eng
GR  - 2001:233/BCN_/Breast Cancer Now/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (RNA, Catalytic)
RN  - 0 (hammerhead ribozyme)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/blood supply/*pathology
MH  - Cell Division
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Female
MH  - Fibroblasts/*cytology
MH  - Genetic Vectors
MH  - Hepatocyte Growth Factor/*genetics
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Invasiveness
MH  - Neovascularization, Pathologic/prevention & control
MH  - Proto-Oncogene Proteins c-met/*genetics
MH  - RNA, Catalytic/genetics
MH  - Restriction Mapping
MH  - Retroviridae
MH  - Stromal Cells/*cytology/pathology
MH  - Transfection
MH  - Transplantation, Heterologous
EDAT- 2003/10/02 05:00
MHDA- 2004/08/18 05:00
CRDT- 2003/10/02 05:00
PHST- 2003/10/02 05:00 [pubmed]
PHST- 2004/08/18 05:00 [medline]
PHST- 2003/10/02 05:00 [entrez]
PST - ppublish
SO  - Clin Cancer Res. 2003 Sep 15;9(11):4274-81.