HGF Airway Over-expression Leads to Enhanced Pulmonary Vascularization without Induction of VEGF

Author(s): Cassandra Henry, Ariel Lopez-Chavez, Laura P. Stabile, Jill M. Siegfried.

Journal Name: Current Angiogenesis (Discontinued)

Volume 1 , Issue 1 , 2012

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Abstract:

The hepatocyte growth factor (HGF)/c-Met signaling pathway mediates angiogenesis. We have previously reported that airway expression of a human HGF transgene (HGF TG) produced mice that were more susceptible to lung tumorigenesis induced by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK). Here we show untreated HGF TG mice display enhanced vascularization (40 wks) and enhanced lymph vessel formation (20 wks) in the lungs compared to wild-type (WT) littermates, as ascertained by microvessel density. We profiled mRNA expression from HGF TG and WT mice for genes involved in angiogenesis. We consistently found significant decreases in expression of the VEGF family of angiogenic genes, including Vegfa, Vegfb, Vegfc, and Vegfd / Figf. Decreases were confirmed in whole lung protein extracts by immunoblot. Similar patterns of down-regulation were observed at 10, 20, and 40 wks of age. Vandetanib, an inhibitor of VEGFR2 and VEGFR3, did not prevent the increase in microvessel density observed in HGF TG mice. Reduction in VEGF pathway genes was also detected in lung tumors derived from NNK-treated HGF TG mice. HGF TG lung tumors also showed increased expression of five Cxcl family genes including Cxcl1 and Cxcl2 (murine forms of IL8). These results suggest increased vascularization produced by airway over-expression of HGF occurs through direct activation of c-Met on endothelial cells, rather than induction of VEGF pathways. Elevated HGF may also increase expression of inflammatory mediators that contribute to lung tumor progression.

Keywords: Angiogenesis, vascularization, HGF, non-small cell lung cancer, VEGF, c-Met

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Article Details

VOLUME: 1
ISSUE: 1
Year: 2012
Page: [52 - 63]
Pages: 12
DOI: 10.2174/2211552811201010052

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