期刊
CANCER RESEARCH
卷 69, 期 1, 页码 349-357出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-1875
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资金
- Swiss National Science Foundation [107602]
- Department of Defense [W81XWH-05-1-0492]
- Oncosuisse grant [02114-08]
- Avon Foundation
- Novartis Foundation grant [06C71]
Most carcinomas spread to distant sites through lymphatic vessels. Several preclinical and clinical studies have shown a positive correlation between the incidence of lymph node metastasis and secretion of the lymphatic growth factor vascular endothelial growth factor-C (W-GF-C) by tumor cells, suggesting tumor lymphangiogenesis as an escape mechanism. However, recent evidence has shown VEGF receptor-3 (VEGFR-3) expression on tumor cells and autocrine signaling, which increase metastatic potential. Furthermorei there is growing evidence implicating lymphatic-homing chemokine receptors, particularly C-C chemokine receptor 7 (CCR7), in lymph node metastasis. We report here that expressions of VEGF-C and CCR7 by tumor cells act. synergistically to promote their invasion toward lymphatics. First, VEGF-C acts to increase lymphatic secretion of CCL21, which in turn drives CCR7-dependent tumor chemoinvasion toward lymphatics. Second, VEGF-C acts in an autocrine fashion to increase tumor invasiveness by increasing the proteolytic activity and motility of tumor cells in a three-dimensional matrix. Both of these effects are VEGFR-3 dependent and evident only in three-dimensional environments. We further verified that VEGF-C induces lymphatic CCL21 up-regulation in vivo by direct injection of VEGF-C protein intradermally in the mouse. Taken together, these results bridge the prometastatic functions of CCR7 and VFGF-C in tumors and show that, beyond lymphangiogenesis, VEGF-C promotes tumor invasion toward lymphatics by both autocrine and CCR7-dependent paracrine signaling mechanisms, which may he a significant cause of lymph node metastasis. [Cancer Res 2009;69(1):349-57]
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