The role of VEGFR1 in tumor lymphangiogenesis and metastasis.

摘要

Traditionally, cancer research has focused on the tumor cell, but recently, there has been a shift in focus beyond the tumor cells themselves to the surrounding stroma and matrix components in the tumor microenvironment and sites of future metastasis, where it is now recognized that changes occur prior to the formation of metastases. In both of these sites, bone marrow-derived cells (BMDCs) facilitate a number of processes, including blood and lymph vessel development, which enhance tumor survival. VEGFR1, a member of the vascular endothelial growth factor family of proteins that have various roles in vessel development, is expressed on a subset of BMDCs of the myeloid lineage. The research herein shows that VEGFR1-expressing cells play a critical role in tumor lymphangiogenesis, as well as lymph node and distant metastases.;We demonstrate that VEGFR1 expression in both myeloid-derived cells and lymphatic endothelial cells is essential for lymphangiogenesis. With VEGFR1 inhibition in metastasis models, significant defects were observed in lymph vessel development and lymph node metastases. These defects were accompanied by an increase in expression of lymphangiogenic factors in the lymph node, suggesting compensatory upregulation of these genes due to the lymphangiogenic deficiency that results from VEGFR1 inhibition. When VEGFR1 was inhibited in vitro via shRNA, a reduction in lymphatic endothelial cell branching was observed, partially due to decreased proliferation with VEGFR1 knockdown. The negative effect of VEGFR1 knockdown on lymphatic endothelial cells in the absence of BMDCs is a previously unrecognized function of VEGFR1.;VEGFR1+ cell mobilization and metastases to the lung were significantly enhanced in the context of primary tumor surgical resection in subcutaneous models of melanoma and lung cancer. In vitro, BM-derived progenitor cells migrated more effectively in response to plasma from surgery mice than controls, with ELISA analysis showing an increase in MCP-1 and M-CSF levels in the surgery plasma. A comparable elevation in the mobilization of VEGFR1+/CD34+ cells was observed in a cohort of breast cancer patients that had undergone lumpectomy. Together, these results show a significant role for VEGFR1-expressing cells in previously unidentified tumorigenic processes and suggest a new avenue of treatment for metastatic disease.