Cell
Volume 140, Issue 2, 22 January 2010, Pages 268-279
Journal home page for Cell

Article
Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development

https://doi.org/10.1016/j.cell.2009.12.046Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► Activated Ras induces VEGFR, leading to cell-autonomous growth of skin tumor cells ► The autocrine function of VEGF in tumor growth is independent of angiogenesis ► VEGFR and EGFR signaling synergize to promote epidermal tumor growth ► A large fraction of human squamous cell carcinomas exhibits upregulation of VEGFR1

HUMDISEASE
SIGNALING

Cited by (0)

4

Present address: National Cancer Center, 11 Hospital Drive, 169610 Singapore, Republic of Singapore