Intravasation is the invasion of cancer cells through the basal 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. Cancer cell chemotaxis also relies on this migratory behavior to arrive at a secondary destination designated for cancer cell colonization.
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. uPA also activates multiple growth factors and matrix metalloproteinases (MMPs) that further contribute to ECM degradation, thus enabling tumor cell invasion and intravasation.
Tumor associated macrophages (TAMs) have been shown to be abundantly present in the microenvironments of metastasizing tumors. 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.
Active and passive intravasation
Tumors can use both active and passive methods to enter vasculature. Some studies suggest that cancer cells actively move towards blood or lymphatic vessels in response to nutrient or chemokine gradients, while others provide evidence for the hypothesis that metastasis in the early stages is more accidental.
In active intravasation, cancerous cells actively migrate toward and then into nearby blood vessels. The first step in this process is specific adhesion to venular endothelial cells, followed by adherence to proteins of the subendothelial basement membrane, such as laminin and types IV and V collagen. 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.
Passive intravasation refers to a process in which tumors metastasize through passive shedding. Evidence for this is seen when the number of tumor cells released into the blood stream increases when the primary tumor experiences trauma. Additionally, cells growing in restricted spaces have been shown to push against each other causing blood and lymphatic vessels to collapse, potentially forcing cells into the vessels.
Epithelial-mesenchymal transition and intravasation
Epithelial-mesenchymal transition (EMT) has been hypothesized to be an absolute requirement for tumor invasion and metastasis. However, 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.
- Tsuji, Takanori; Soichiro Ibaragi; Guo-Fu Hu (15 September 2009). "Epithelial-Mesenchymal Transition and Cell Cooperativity in Metastasis". Cancer Research. 69 (18): 7135–7139. doi:10.1158/0008-5472.CAN-09-1618.
- Soon, Lilian (2007). "A Discourse on Cancer Cell Chemotaxis: Where to from Here?". IUBMB Life. 59 (2): 60–67. doi:10.1080/15216540701201033.
- Iizumi, Megumi; Wen Liu; Sudha K Pai; Eiji Furuta; Kounosuke Watabe (December 2008). "Drug Development Against Metastasis-related Genes and Their Pathways: a Rationale for Cancer Therapy". Biochimica et Biophysica Acta. 1786 (2): 87–104. doi:10.1016/j.bbcan.2008.07.002.
- Condeelis, John; Jeffrey W. Pollard (27 January 2006). "Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis". Cell. 124 (2): 263–266. doi:10.1016/j.cell.2006.01.007.
- Pollard, Jeffrey W. (1 September 2008). "Macrophages Define the Invasive Microenvironment in Breast Cancer". Journal of Leukocyte Biology. 84 (3): 623–630. doi:10.1189/jlb.1107762.
- van Zijil, Franziska; Georg Krupitza; Wolfgang Mikulits (October 2011). "Initial Steps of Metastasis: Cell Invasion and Endothelial Transmigration". Mutation Research. 728 (1-2): 23–34. doi:10.1016/j.mrrev.2011.05.002. PMID 21605699.
- Bockhorn, Maximilian; Rakesh K Jain; Lance L. Munn (May 2007). "Active Versus Passive Mechanisms in Metastasis: Do Cancer Cells Crawl into Vessels, or Are They Pushed?". The Lancet Oncology. 8 (5): 444–448. doi:10.1016/S1470-2045(07)70140-7.
- Cavallaro, U; G. Christofori (30 November 2001). "Cell Adhesion in Tumor Invasion and Metastasis: Loss of the Glue is Not Enough". Biochimica et Biophysica Acta. 1552 (1): 39–45. doi:10.1016/s0304-419x(01)00038-5.
- Zetter, B R. (August 1993). "Adhesion Molecules in Tumor Metastasis". Seminars in Cancer Biology. 4 (4): 219–229.
- Liotta, L A; Saidel, M G; Kleinerman, J (March 1976). "The Significance of Hematogenous Tumor Cell Clumps in the Metastastic Process". Cancer Research. 36 (3): 889–894.