Loss of Caveolin-1 in Metastasis-Associated Macrophages Drives Lung Metastatic Growth through Increased Angiogenesis

Abstract

Summary: Although it is well established that tumor-associated macrophages take part in each step of cancer progression, less is known about the distinct role of the so-called metastasis-associated macrophages (MAMs) at the metastatic site. Previous studies reported that Caveolin-1 (Cav1) has both tumor-promoting and tumor-suppressive functions. However, the role of Cav1 in bone-marrow-derived cells is unknown. Here, we describe Cav1 as an anti-metastatic regulator in mouse models of lung and breast cancer pulmonary metastasis. Among all the recruited inflammatory cell populations, we show that MAMs uniquely express abundant levels of Cav1. Using clodronate depletion of macrophages, we demonstrate that macrophage Cav1 signaling is critical for metastasis and not for primary tumor growth. In particular, Cav1 inhibition does not affect MAM recruitment to the metastatic site but, in turn, favors angiogenesis. We describe a mechanism by which Cav1 in MAMs specifically restrains vascular endothelial growth factor A/vascular endothelial growth factor receptor 1 (VEGF-A/VEGFR1) signaling and its downstream effectors, matrix metallopeptidase 9 (MMP9) and colony-stimulating factor 1 (CSF1). : Celus et al. show an intrinsic anti-metastatic surveillance mechanism in the lung microenvironment whereby upregulation of Caveolin-1 in metastasis-associated macrophages specifically controls the excessive exposure of VEGFR1 at the cell surface and thereby limits downstream MMP9 and CSF1 expression, angiogenesis, and metastatic growth. Keywords: Caveolin-1, macrophages, metastasis, angiogenesis, VEGFR1, MMP9, CSF1, VEGF-A