Tumor microenvironmental control of metastasis : effects of the immune cells and physical forces on cell migration

Abstract

Metastasis, which accounts for 90% of cancer deaths, critically depends on the ability of cancer cells to migrate through the dense extracellular matrix (ECM) surrounding the solid tumor. Recent advances in cancer biology have revealed that non-cancerous cells and biophysical forces in tumor microenvironment can influence metastasis. Specifically, macrophage, one of the most abundant tumor-associated stromal cell types, has been shown to assist cancer cell invasion. However, exactly how macrophages affect the different aspects (e.g. speed and persistence) of cancer cell migration, especially in 3D ECM that mimics the in vivo tumor microenvironment, remains largely unknown. In addition to macrophages, elevated interstitial flow (the flow of tissue fluid) within the tumor tissue has been shown to influence cancer cell and fibroblast migration. Nevertheless, the effects of this tumor-associated biophysical force on macrophages are still unknown. In this thesis, we first explored how macrophages control the subtle details (speed vs. persistence) of cancer cell migration. Using a microfluidic migration assay, we found that macrophage-released TNFa and TGF1 enhance cancer cell migration speed and persistence in 3D ECM in an MMP-dependent fashion via two distinct pathways. Specifically, macrophagereleased TGF1 enhances cancer cell migration speed via the induction of MTl-MMP expression in cancer cells. In contrast, macrophage-released TNFa and TGFp1 synergistically enhance cancer cell migration persistence via the induction of NF-KB-mediated MMP1 expression. Therefore, these results suggest that macrophages control different aspects of cancer cell migration in 3D differently, and both TNFa and TGFp1 released by macrophages need to be simultaneously inhibited to effectively limit macrophage-assisted cancer cell metastasis. In a separate study, we investigated how tumor-associated interstitial flow (IF) affects macrophage migration and protein expression. We discovered that IF promotes macrophage migration in 3D ECM via the flow-induced activation of FAK and Akt. Interestingly, IF also directs the preferential migration of macrophages against the direction of flow (upstream). Moreover, we show that IF polarizes macrophages toward a pro-metastatic M2 phenotype via integrin/Src-dependent STAT3/6 activation. Since IF emanates from tumor core to stromal tissue surrounding the tumor, these results suggest that IF can promote metastasis by not only recruiting macrophages from stroma into tumor, but also enhancing the M2 polarization of macrophages in the tumor microenvironment. Keywords: Tumor Microenvironment, Macrophages, Interstitial Flow, Migration, and Polarization.