Tumor cell intravasation

Abstract

The process of entering the bloodstream, intravasation, is a necessary step in the development of distant metastases. The focus of this review is on the pathways and molecules that have been identified as being important based on current in vitro and in vivo assays for intravasation. Properties of the vasculature which are important for intravasation include microvessel density and also diameter of the vasculature, with increased intravasation correlating with increased vessel diameter in some tumors. TGFB signaling can enhance intravasation at least in part through induction of EMT, and we discuss other TGFB target genes that are important for intravasation. In addition to TGFB signaling, a number of studies have demonstrated that activation of EGF receptor family members stimulates intravasation, with downstream signaling through PI3K, N-WASP, RhoA, and WASP to induce invadopodia. With respect to proteases, there is strong evidence for contributions by uPA/uPAR, while the roles of MMPs in intravasation may be more tumor specific. Other cells including macrophages, fibroblasts, neutrophils, and platelets can also play a role in enhancing tumor cell intravasation. The technology is now available to interrogate the expression patterns of circulating tumor cells, which will provide an important reality check for the model systems being used. With a better understanding of the mechanisms underlying intravasation, the goal is to provide new opportunities for improving prognosis as well as potentially developing new treatments.

Keywords: EGFR; TGFB; angiogenesis; intravasation; metastasis; uPA.

Fig. 1.

Two views of an MDA-MB-231 breast cancer cell (green) crossing an endothelial cell layer (blue) in association with a macrophage (red) in the Transwell in vitro intravasation assay (99). The basal side of the endothelium is on the right.

Fig. 2.

Summary of intravasation mechanisms. A: diagram summarizing basic contributors to intravasation. B: interaction network of the major mechanisms described in this review. Major stimulators of intravasation are noted in blue and key properties regulating intravasation are indicated in orange.