Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development
Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development
复制标题
DOI：
10.1016/j.cell.2009.12.046
复制
发表时间：
2010-01-22
期刊：
影响因子：
64.5
通讯作者：
Sibilia, Maria
中科院分区：
文献类型：
--
作者：
Lichtenberger, Beate M.;Tan, Poi Kiang;Sibilia, Maria
已经确定肿瘤细胞来源的VEGF作用于内皮细胞以促进血管生成和肿瘤生长。在这里，我们证明了在K5-SOS依赖性小鼠皮肤肿瘤中，自分泌VEGF是肿瘤细胞以细胞自主和血管生成独立的方式增殖所必需的。VEGF在表达SOS的肿瘤中上调，其在表皮细胞中的缺失通过抑制血管生成和肿瘤细胞增殖来延迟肿瘤发生。表皮特异性Flt 1缺失也损害肿瘤发生和增殖。令人惊讶的是，在EGFR突变小鼠中，在不存在VEGF的情况下发生完全的肿瘤抑制，表明VEGFR和EGFR在肿瘤细胞中协同作用以促进肿瘤生长。从机制上讲，K5-SOS以Erk依赖性方式上调VEGF、Flt 1和Neuropilin-1，从而激活自分泌增殖循环，而EGFR则阻止肿瘤细胞凋亡。此外，Flt 1在人SCC中上调，其在SCC细胞中的抑制损害增殖。因此，除了调节血管生成外，VEGF还被认为是表皮肿瘤的有效生长因子。
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.