VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis

By S. Hirakawa, S. Kodama, R. Kunstfeld, K. Kajiya, L. Brown, Michael Detmar. Journal of Experimental Medicine, 2005

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The mechanisms of tumor metastasis to the sentinel lymph nodes are poorly understood. Vascular endothelial growth factor (VEGF)-A plays a principle role in tumor progression and angiogenesis; however, its role in tumor-associated lymphangiogenesis and lymphatic metastasis has remained unclear. We created transgenic mice that overexpress VEGF-A and green fluorescent protein specifically in the skin, and subjected them to a standard chemically-induced skin carcinogenesis regimen. We found that VEGF-A not only strongly promotes multistep skin carcinogenesis, but also induces active proliferation of VEGF receptor-2–expressing tumor-associated lymphatic vessels as well as tumor metastasis to the sentinel and distant lymph nodes. The lymphangiogenic activity of VEGF-A–expressing tumor cells was maintained within metastasis-containing lymph nodes. The most surprising finding of our study was that even before metastasizing, VEGF-A–overexpressing primary tumors induced sentinel lymph node lymphangiogenesis. This suggests that primary tumors might begin preparing their future metastatic site by producing lymphangiogenic factors that mediate their efficient transport to sentinel lymph nodes. This newly identified mechanism of inducing lymph node lymphangiogenesis likely contributes to tumor metastasis, and therefore, represents a new therapeutic target for advanced cancer and/or for the prevention of metastasis.

Subfields: Dermatology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/0b5924b2aa6ba6a23ec3956e0e91caeff7252b47

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Citations in the corpus

Integrins in angiogenesis and lymphangiogenesis (2008, background): “Like angiogenesis, lymphangiogenesis — the growth of new lymphatic vessels — promotes tumour metastasi”
Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. (2007, background): “2D); this could also inhibit lymph node lymphangiogenesis (33).”
The metastatic niche: adapting the foreign soil (2009, background): “Moreover, the onset of lymphangiogenesis within sentinel lymph nodes was demonstrated before tumour cell infiltratio”
Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. (2019, methodology): “The refined version of the AJCC staging and classification system which includes a sentinel node staging is the only internationally accepted classification system [7, 10] (Table 1).”
Cancer as an overhealing wound: an old hypothesis revisited (2008, background): “Surprisingly, VEGFA overexpression in the epidermis stimulated not only the growth of new blood vessels but also lymphangiogenesis in skin wounds and tumours, and the formation of lymphatic metastase”
Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. (2006, background): “VEGFR2 is expressed in lymph endothelial cells, thus, VEGFR2 might be partly involved in lymphangiogenesis (Veikkola, et al., 2001; Hirakawa et al., 2005).”
Angiogenesis in life, disease and medicine (2005, background): “By producing factors that induce lymph node lymphangiogenesis, primary tumours also prepare their future lymphatic metastatic transport to sentinel lymph node”
Lymphangiogenesis: Molecular mechanisms and future promise. (2010, background): “Importantly, damaged collecting lymphatic vessels can also be regenerated via lymphatic capillaries undergoing an intrinsic maturation program in response Cell 140, February 19, 2010 ©2010 Elsevier Inc. 465 to VEGF-C or VEGF-D stimulation (Ikomi et al., 2008; Tammela et al., 2007).”
Lymphangiogenesis in development and human disease (2005, background): “However, it should be noted that also VEGF can stimulate lymphatic metastasi”