Unexpected contribution of lymphatic vessels to promotion of distant metastatic tumor spread.

Abstract

Tumor lymphangiogenesis is accompanied by a higher incidence of sentinel lymph node metastasis and shorter overall survival in several types of cancer. We asked whether tumor lymphangiogenesis might also occur in distant organs with established metastases and whether it might promote further metastatic spread of those metastases to other organs. Using mouse metastasis models, we found that lymphangiogenesis occurred in distant lung metastases and that some metastatic tumor cells were located in lymphatic vessels and draining lymph nodes. In metastasis-bearing lungs of melanoma patients, a higher lymphatic density within and around metastases and lymphatic invasion correlated with poor outcome. Using a transgenic mouse model with inducible expression of vascular endothelial growth factor C (VEGF-C) in the lung, we found greater growth of lung metastases, with more abundant dissemination to other organs. Our findings reveal unexpected contributions of lymphatics in distant organs to the promotion of growth of metastases and their further spread to other organs, with potential clinical implications for adjuvant therapies in patients with metastatic cancer.

• Authors: Qiaoli Ma, Lothar C Dieterich, Kristian Ikenberg, Samia B Bachmann, Johanna Mangana, Steven T Proulx, Valerie C Amann, Mitchell P Levesque, Reinhard Dummer, Peter Baluk, Donald M McDonald, Michael Detmar
• Journal: Science advances (Sci Adv) Vol. 4 Issue 8 Pg. eaat4758 (08 2018) ISSN: 2375-2548 [Electronic] United States
• PMID: 30101193 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor C

Topics

• Animals
• Breast Neoplasms (blood supply, metabolism, pathology)
• Female
• Humans
• Lung Neoplasms (blood supply, metabolism, secondary)
• Lymphangiogenesis
• Lymphatic Metastasis
• Lymphatic Vessels (metabolism, pathology)
• Melanoma, Experimental (blood supply, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neovascularization, Pathologic (metabolism, pathology)
• Prognosis
• Retrospective Studies
• Survival Rate
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor C (metabolism)