期刊
ONCOGENE
卷 31, 期 42, 页码 4499-4508出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.602
关键词
lymphangiogenesis; metastasis; lymph node; VEGF-C; VEGF; therapy
资金
- Swiss National Science Foundation [3100A0108207, 31003A-130627]
- Commission of the European Communities [LSHCCT2005518178]
- Advanced European Research Council
- Oncosuisse
- Krebsliga Zurich
Metastatic spread of cancer through the lymphatic system affects hundreds of thousands of patients yearly. Growth of new lymphatic vessels, lymphangiogenesis, is activated in cancer and inflammation, but is largely inactive in normal physiology, and therefore offers therapeutic potential. Key mediators of lymphangiogenesis have been identified in developmental studies. During embryonic development, lymphatic endothelial cells derive from the blood vascular endothelium and differentiate under the guidance of lymphatic-specific regulators, such as the prospero homeobox 1 transcription factor. Vascular endothelial growth factor-C (VEGF-C) and VEGF receptor 3 signaling are essential for the further development of lymphatic vessels and therefore they provide a promising target for inhibition of tumor lymphangiogenesis. Lymphangiogenesis is important for the progression of solid tumors as shown for melanoma and breast cancer. Tumor cells may use chemokine gradients as guidance cues and enter lymphatic vessels through intercellular openings between endothelial cell junctions or, possibly, by inducing larger discontinuities in the endothelial cell layer. Tumor-draining sentinel lymph nodes show enhanced lymphangiogenesis even before cancer metastasis and they may function as a permissive 'lymphovascular niche' for the survival of metastatic cells. Although our current knowledge indicates that the development of anti-lymphangiogenic therapies may be beneficial for the treatment of cancer patients, several open questions remain with regard to the frequency, mechanisms and biological importance of lymphatic metastases.
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