Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development.
It is established that tumor cell-derived VEGF acts on endothelial cells to promote angiogenesis and tumor growth. Here, we demonstrate that in K5-SOS-dependent mouse skin tumors, autocrine VEGF is required for tumor cell proliferation in a cell-autonomous and angiogenesis-independent manner. VEGF is upregulated in SOS-expressing tumors, and its deletion in epidermal cells delays tumorigenesis by suppressing angiogenesis and tumor cell proliferation. Epidermis-specific Flt1 deletion also impairs tumorigenesis and proliferation. Surprisingly, complete tumor inhibition occurs in the absence of VEGF in EGFR mutant mice, demonstrating that VEGFR and EGFR synergize in neoplastic cells to promote tumor growth. Mechanistically, K5-SOS upregulates VEGF, Flt1, and Neuropilin-1 in an Erk-dependent manner, thereby activating an autocrine proliferation loop, whereas EGFR prevents tumor cells from apoptosis. Moreover, Flt1 is upregulated in human SCC, and its inhibition in SCC cells impairs proliferation. Thus, in addition to regulating angiogenesis, VEGF has to be considered as a potent growth factor for epidermal tumors.
Institute for Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Beate M
BM
Lichtenberger
Poi Kiang
PK
Tan
Heide
H
Niederleithner
Napoleone
N
Ferrara
Peter
P
Petzelbauer
Maria
M
Sibilia
D000818:Animals; D019898:Autocrine Communication; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D012878:Skin Neoplasms / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1