The gate to metastasis: key players in cancer cell intravasation

Abstract

Metastasis is a leading cause of cancer-related death and consists of a sequence of events including tumor expansion, intravasation of cancer cells into the circulation, survival in the bloodstream, extravasation at distant sites, and subsequent organ colonization. Particularly, intravasation is a process whereby cancer cells transverse the endothelium and leave the primary tumor site, pioneering the metastatic cascade. The identification of those mechanisms that trigger the entry of cancer cells into the bloodstream may reveal fundamentally novel ways to block metastasis at its start. Multiple factors have been implicated in cancer progression, yet, signals that unequivocally provoke the detachment of cancer cells from the primary tumor are still under investigation. Here, we discuss the role of intrinsic properties of cancer cells, tumor microenvironment, and mechanical cues in the intravasation process, outlining studies that suggest the involvement of various factors and highlighting current understanding and open questions in the field.

Keywords: cancer; circulating tumor cells; intravasation; metastasis.

Fig. 1

Metastasis consists of a series of steps including tumor expansion, intravasation of cancer cells into the circulation, their survival in the circulation, followed by extravasation and expansion at distant sites.

Fig. 2

The intravasation process is regulated by intrinsic, microenvironmental, and mechanical factors. Intrinsic properties include genetic mutations, epigenetic changes, gene expression, and metabolic profile alterations that give cells an intravasation advantage. The cellular microenvironment consists of fibroblasts, adipocytes, pericytes, platelets, and immune cells such as macrophages and neutrophils. These cells may regulate the intravasation of cancer cells by cell‐to‐cell signaling, altering the tumor microenvironment and direct participation in the invasion process. Mechanical cues such as tissue stiffness, stress, and interstitial fluid pressure may also affect cancer cell dissemination into the circulation.

Fig. 3

Summary of factors involved in the regulation of intravasation process: intrinsic cancer cell properties, cellular microenvironment, and mechanical properties.