Intravasation

Intravasation is the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel.^[1] Intravasation is one of several carcinogenic events that initiate the escape of cancerous cells from their primary sites.^[2] Other mechanisms include invasion through basement membranes, extravasation, and colonization of distant metastatic sites.^[2] Cancer cell chemotaxis also relies on this migratory behavior to arrive at a secondary destination designated for cancer cell colonization.^[2]

One of the genes that contributes to intravasation codes for urokinase (uPA), a serine protease that is able to proteolytically degrade various extracellular matrix (ECM) components and the basement membrane around primary tumors.^[3] uPA also activates multiple growth factors and matrix metalloproteinases (MMPs) that further contribute to ECM degradation, thus enabling tumor cell invasion and intravasation.^[3]

A newly identified metastasis suppressor, p75 neurotrophin receptor (p75NTR), is able to suppress metastasis in part by causing specific proteases, such as uPA, to be downregulated.^[3]

Tumor-associated macrophages (TAMs) have been shown to be abundantly present in the microenvironments of metastasizing tumors.^[4][5] 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.^[5][6]

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.^[7][8][9]

Tumors can use both active and passive methods to enter the vasculature.^[10] Some studies suggest that cancer cells actively move towards blood or lymphatic vessels in response to nutrient or chemokine gradients,^[6] while others provide evidence for the hypothesis that metastasis in its early stages is more of a random behavior.^[11]

In active intravasation, cancerous cells actively migrate toward and then into nearby blood vessels.^[10] The first step in this process is specific adhesion to venous endothelial cells, followed by adherence to proteins of the subendothelial basement membrane, such as laminin and types IV and V collagen.^[12] 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.^[12]

Passive intravasation refers to a process in which tumors metastasize through passive shedding.^[10] Evidence for this is seen when the number of tumor cells released into the circulation increases when the primary tumor experiences trauma.^[13] 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.^[10]

Epithelial–mesenchymal transition (EMT) has been hypothesized to be an absolute requirement for tumor invasion and metastasis,^[1] although both EMT and non-EMT^{[clarification needed]} cells have been shown to cooperate to complete the spontaneous metastasis process.^[1] EMT cells with migratory phenotype degrade the ECM and penetrate local tissue and blood or lymphatic vessels, thereby facilitating intravasation.^[1] Non-EMT cells can migrate together with EMT cells to enter the blood or lymphatic vessels.^[1] 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.^[1]