Pulmonary Vascular Destabilization in the Premetastatic Phase Facilitates Lung Metastasis

Abstract

Before metastasis, certain organs have already been influenced by primary tumors. However, the exact alterations and regulatory mechanisms of the premetastatic organs remain poorly understood. Here, we report that, in the premetastatic stage, angiopoietin 2 (Angpt2), matrix metalloproteinase (MMP) 3, and MMP10 are up-regulated in the lung by primary B16/F10 tumor, which leads to the increased permeability of pulmonary vasculatures and extravasation of circulating tumor cells. Subsequent studies show that Angpt2, MMP3, and MMP10 have a synergistic effect on disrupting vascular integrity in both in vitro and in vivo models. Lentivirus-based in vivo RNA interference of Angpt2, MMP3, and MMP10 attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells in the premetastatic lung. Moreover, knocking down these factors significantly inhibits the spontaneous lung metastasis in the model by orthotopic implantation of MDA-MB-231-Luc-D3H1 cells in nude mice. Further investigations reveal that the malignancy of tumor cells is positively correlated with their capabilities to induce the expression of Angpt2, MMP3, and MMP10. Luciferase reporter assay and chromatin immunoprecipitation assay also suggest that transforming growth factor-B1 and tumor necrosis factor-A signaling are involved in the regulation of these premetastatic factors. Our study shows that pulmonary vascular destabilization in the premetastatic phase promotes the extravasation of tumor cells and facilitates lung metastasis, which may provide potential targets for clinical prevention of metastasis.

Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation

“…However, the exact molecular mechanisms responsible for this heterogeneity remain elusive. Multiple secreted factors-often overexpressed in tumors (e.g., VEGF, TGF-β, TNF-α, and angiopoietin-2)-can promote vascular permeability in the lungs (5)(6)(7)(8)(9)(10)(11). VEGF released from lung metastasizing cancer cells can activate the Src-FAK complex in lung endothelial cells and promote vascular hyperpermeability, up-regulation of endothelial adhesion molecules, and cancer cell homing (27,28).…”

“…Recent reports have shown the lung "soil" may be "prepared" by distant primary tumors before metastatic cancer cell arrival. Although the role of various molecular players in this process is not resolved, this process occurs through microenvironmental changes in the lung in response to factors secreted by the primary tumors during a socalled "premetastatic" phase (5)(6)(7)(8)(9)(10)(11)(12)(13). "Premetastatic" events are presumed to affect the lung in a diffuse fashion, as all pulmonary microvessels are exposed to factors and cells originating from the primary tumor (14,15).…”

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

“…Microarray-based gene expression analysis of premetastatic lungs of B16 melanoma-bearing mice revealed the upregulation of Angpt2, MMP3 and MMP10, but not VEGF, with a concomitant lung-specific fibrin deposit, suggesting vascular destabilization. 29 Primary tumor-derived TNF-a and TGF-b were assumed to be responsible for the upregulation of these three genes. In primary tumors, tumor cells express a tissue factor that activates the extrinsic coagulation pathway, and a fibrin deposit is observed on the surface of TAM.…”

The miR-30 Family Inhibits Pulmonary Vascular Hyperpermeability in the Premetastatic Phase by Direct Targeting of Skp2

“…Among the multiple factors underlying metastasis, it is well-recognized that a process called premetastatic niche formation (1)(2)(3) is crucial for the development of metastasis. Previous studies have described 2 primary premetastatic events in the lung: bone marrow-derived cell (BMDC) mobilization (2,4) and vascular hyperpermeability (5). Induction of vascular destabilization is crucial for the extravasation of tumor cells and subsequent colonization.…”