Intravasation

Invasion of cancer cells into a blood or lymphatic vessel
Intravasation is the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel. Intravasation is one of several carcinogenic events that initiate the escape of cancerous cells from their primary sites. Other mechanisms include invasion through basement membranes, extravasation, and colonization of distant metastatic sites. uPA also activates multiple growth factors and matrix metalloproteinases (MMPs) that further contribute to ECM degradation, thus enabling tumor cell invasion and intravasation. Studies have revealed that macrophages enhance tumor cell migration and intravasation by secreting chemotactic and chemokinetic factors, promoting angiogenesis, remodeling the ECM, and regulating the formation of collagen fibers. Groups of three cell types (a macrophage, an endothelial cell, and a tumor cell) collectively known as tumor microenvironment of metastasis (TMEM) can allow tumor cells to enter blood vessels.

Tumors can use both active and passive methods to enter the vasculature. Some studies suggest that cancer cells actively move towards blood or lymphatic vessels in response to nutrient or chemokine gradients,

In active intravasation, cancerous cells actively migrate toward and then into nearby blood vessels. The final step is the adhesion of the metastatic tumor cell to connective tissue elements such as fibronectin, type I collagen, and hyaluronan, which is required for the movement of the tumor cell into the subendothelial stroma and subsequent growth at the secondary site of colonization. Cells growing in restricted spaces have been shown to push against each other, causing blood and lymphatic vessels to flatten, potentially forcing cells into the vessels.

Epithelial–mesenchymal transition (EMT) has been hypothesized to be an absolute requirement for tumor invasion and metastasis, although both EMT and non EMT cells have been shown to cooperate to complete the spontaneous metastasis process. EMT cells with migratory phenotype degrade the ECM and penetrate local tissue and blood or lymphatic vessels, thereby facilitating intravasation. Non EMT cells can migrate together with EMT cells to enter the blood or lymphatic vessels. Although both cell types persist in circulation, EMT cells fail to adhere to the vessel wall at the secondary site, while non EMT cells, which have greater adhesive properties, are able to attach to the vessel wall and extravasate into the secondary site.