Intravasation

Intravasation is the invasion of cancer cells through the basal 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]

Contributing factors

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]

Active and passive intravasation

Tumors can use both active and passive methods to enter vasculature.[7] 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 the early stages is more accidental.[8]

In active intravasation, cancerous cells actively migrate toward and then into nearby blood vessels.[7] 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.[9] 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.[9]

Passive intravasation refers to a process in which tumors metastasize through passive shedding.[7] Evidence for this is seen when the number of tumor cells released into the blood stream increases when the primary tumor experiences trauma.[10] 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.[7]

Epithelial-mesenchymal transition and intravasation

Epithelial-mesenchymal transition (EMT) has been hypothesized to be an absolute requirement for tumor invasion and metastasis.[1] However, both EMT and non-EMT 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]

References

  1. 1 2 3 4 5 6 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.
  2. 1 2 3 Soon, Lilian (2007). "A Discourse on Cancer Cell Chemotaxis: Where to from Here?". IUBMB Life 59 (2): 60–67. doi:10.1080/15216540701201033.
  3. 1 2 3 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.
  4. ↑ 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.
  5. 1 2 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.
  6. 1 2 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.
  7. 1 2 3 4 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.
  8. ↑ 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.
  9. 1 2 Zetter, B R. (August 1993). "Adhesion Molecules in Tumor Metastasis". Seminars in Cancer Biology 4 (4): 219–229.
  10. ↑ 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.
This article is issued from Wikipedia - version of the Wednesday, March 09, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.