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The role of the tumor microenvironment in tumor cell intravasation and dissemination.

ABSTRACT: Metastasis, a process that requires tumor cell dissemination followed by tumor growth, is the primary cause of death in cancer patients. An essential step of tumor cell dissemination is intravasation, a process by which tumor cells cross the blood vessel endothelium and disseminate to distant sites. Studying this process is of utmost importance given that intravasation in the primary tumor, as well as the secondary and tertiary metastases, is the key step in the systemic spread of tumor cells, and that this process continues even after removal of the primary tumor. High-resolution intravital imaging of the tumor microenvironment of breast carcinoma has revealed that tumor cell intravasation exclusively occurs at doorways, termed "Tumor MicroEnvironment of Metastasis" (TMEM), composed of three different cell types: a Tie2^high/VEGF^high perivascular macrophage, a Mena overexpressing tumor cell, and an endothelial cell, all in direct contact. In this review article, we discuss the interactions between these cell types, the subsequent signaling events which lead to tumor cell intravasation, and the role of invadopodia in supporting tumor cell invasion and dissemination. We end our review by discussing how the knowledge acquired from the use of intravital imaging is now leading to new clinical trials targeting tumor cell dissemination and preventing metastatic progression.

SUBMITTER: Borriello L

PROVIDER: S-EPMC7431678 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Intravasation, the active entry of primary tumor cells into the vasculature, remains the least studied step in the metastatic cascade. Protease-mediated escape and stromal invasion of tumor cells represent widely accepted processes leading up to the intravasation step. However, molecular factors that contribute directly to tumor cell vascular penetration have not been identified. In this study, the in vivo role of the collagenolytic protease, MMP-1, in cancer cell intravasation and metastasis was analyzed by using a highly disseminating variant of human HEp3 epidermoid carcinoma, HEp3-hi/diss. Although naturally acquired or experimentally induced MMP-1 deficiency substantially suppressed HEp3-hi/diss intravasation, supplementation of recombinant MMP-1 to MMP-1-silenced primary tumors restored their impaired vascular dissemination. Surprisingly, abrogation of MMP-1 production and activity did not significantly affect HEp3-hi/diss migration or matrix invasion, suggesting noncollagenolytic mechanisms underlying MMP-1-dependent cell intravasation. In support of such noncollagenolytic mechanisms, MMP-1 silencing in HEp3-hi/diss cells modulated the microarchitecture and integrity of the angiogenic vasculature in a novel microtumor model. Concomitantly, MMP-1 deficiency led to decreased levels of intratumoral vascular permeability, tumor cell intravasation, and metastatic dissemination. Taking advantage of PAR1 deficiency of HEp3-hi/diss cells, we further show that endothelial PAR1 is a putative nontumor-cell/nonmatrix target, activation of which by carcinoma-produced MMP-1 regulates endothelial permeability and transendothelial migration. The inhibitory effects of specific PAR1 antagonists in live animals have also indicated that the mechanisms of MMP-1-dependent vascular permeability in tumors involve endothelial PAR1 activation. Together, our findings mechanistically underscore the contribution of a tumor MMP-1/endothelial PAR1 axis to actual intravasation events manifested by aggressive carcinoma cells.

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The role of the tumor microenvironment in tumor cell intravasation and dissemination.

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