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Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype
- Source :
- Cancer research. 69(1)
- Publication Year :
- 2009
-
Abstract
- 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 (VEGF-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. Furthermore, 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 VEGF-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 be a significant cause of lymph node metastasis. [Cancer Res 2009;69(1):349–57]
- Subjects :
- Cancer Research
Receptors, CCR7
Vascular Endothelial Growth Factor C
C-C chemokine receptor type 7
Breast Neoplasms
Biology
Paracrine signalling
Chemokine receptor
Cell Movement
Cell Line, Tumor
Humans
Neoplasm Invasiveness
Autocrine signalling
Lymphatic Vessels
Chemokine CCL21
Endothelial Cells
Receptor Cross-Talk
Vascular Endothelial Growth Factor Receptor-3
Lymphangiogenesis
Lymphatic system
Oncology
Vascular endothelial growth factor C
Lymphatic Metastasis
Cancer research
CCL21
Signal Transduction
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 69
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....8a570135e51f42211ca7f2348604e108