Intratumoral Cancer Cell Intravasation Can Occur Independent of Invasion into the Adjacent Stroma

Summary: Intravasation, active entry of cancer cells into the circulation, is often considered to be a relatively late event in tumor development occurring after stromal invasion. Here, we provide evidence that intravasation can be initiated early during tumor development and proceed in parallel to or independent of tumor invasion into surrounding stroma. By applying direct and unbiased intravasation-scoring methods to two histologically distinct human cancer types in live-animal models, we demonstrate that intravasation takes place almost exclusively within the tumor core, involves intratumoral vasculature, and does not involve vasculotropic cancer cells invading tumor-adjacent stroma and migrating along tumor-converging blood vessels. Highlighting an additional role for EGFR in cancer, we find that EGFR is required for the development of an intravasation-sustaining intratumoral vasculature. Intratumoral localization of intravasation supports the notion that overt metastases in cancer patients could be initiated much earlier during cancer progression than appreciated within conventional clinical tumor staging systems. : Deryugina and Kiosses investigate the localization of intravasation within primary tumors. They find that the majority of intravasation events occur within the tumor core and not at the invasive edge within tumor outgrowths into adjacent stroma in the models examined. Mechanistically, EGFR appears to impact intratumoral intravasation by regulating development of a fully interconnected angiogenic vasculature. Keywords: cancer metastasis, cell intravasation, tumor invasion, stromal invasion, tumor cell migration, tumor angiogenesis, EGFR, animal models of cancer, mouse ear tumor model, chorioallantoic membrane mode