Premetastatic lung "niche": is vascular endothelial growth factor receptor 1 activation required?

Abstract

Inflammatory pathways may mediate preparation of the "metastatic soil" in the lungs. Some of these pathways--activation and/or the recruitment of certain inflammatory cells--might depend on vascular endothelial growth factor receptor 1 (VEGFR1) activity. Thus, blocking the activity of VEGFR1 (or the interaction with its ligands) has emerged as a potential antimetastasis strategy to target not only angiogenesis and cancer cell survival and migration, but also the recruitment of tumor growth-promoting bone marrow-derived cells (BMDC). However, inhibition of VEGFR1 activity by blocking antibodies or by genetic deletion of the tyrosine kinase domain neither prevented nor changed the rate of spontaneous metastasis formation after surgical removal of primary tumors. Thus, development of VEGFR1-targeted agents should be pursued in selected tumors (e.g., by identifying cancers that depend on VEGFR1 signaling for survival) or in specific combination therapies. Preventing metastasis will likely require identification and blockade of additional or alternative proinflammatory pathways that mediate the priming of the metastatic soil and the growth of micrometastases.

Figure 1. Mechanisms of "pre-metastatic" lung activation

A, It has been proposed that tumor-derived factors create pre-metastatic “niches" by recruiting bone marrow-derived cells (BMDCs), which facilitate homing and growth of metastatic cells. B, Alternatively, paracrine interactions may occur between lung resident VEGFR1⁺ endothelial cells and resident myeloid BMDCs––e.g., macrophages––that "activate" the normal lung tissue in response to tumor-derived factors. (Drawings in A, B courtesy of Dr. Lance L. Munn.) C, Nonetheless, metastasis formation can occur independently of VEGFR1 activity in lung stromal cells. Once metastases become macroscopic, VEGFR1 activity modulates the recruitment of local/circulating myeloid BMDCs to the growing metastatic nodules. Green, green fluorescence protein (GFP)-positive BMDCs; blue, DAPI nuclear counterstaining of lung cells; black in red box, melanotic B16 melanoma metastases formed in lungs after primary tumor resection despite VEGFR1 blockade. Images in C are 512 µm across (courtesy of Dr. Michelle R. Dawson).