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]

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]

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]

Active and passive intravasation

Tumors can use both active and passive methods to enter 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 the early stages is more accidental.[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 venular 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 blood stream increases when the primary tumor experiences trauma.[13] 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.[10]

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. 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. PMC 2760965. PMID 19738043.
  2. Soon, Lilian (2007). "A Discourse on Cancer Cell Chemotaxis: Where to from Here?". IUBMB Life. 59 (2): 60–67. doi:10.1080/15216540701201033. PMID 17454296.
  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 (BBA) - Reviews on Cancer. 1786 (2): 87–104. doi:10.1016/j.bbcan.2008.07.002. PMC 2645343. PMID 18692117.
  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. PMID 16439202.
  5. 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. PMC 2516896. PMID 18467655.
  6. 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. PMC 4028085. PMID 21605699.
  7. Rohan; et al. (2014). "Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer". J Natl Cancer Inst. 106 (8). doi:10.1093/jnci/dju136. PMC 4133559. PMID 24895374.
  8. Boltz (2015). "Researchers identify tumor microenvironment of metastasis (TMEM) that allows breast cancer to metastasize".
  9. Karagiannis; et al. (2017). "Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism". Science Translational Medicine. 9 (397): eaan0026. doi:10.1126/scitranslmed.aan0026. PMC 5592784. PMID 28679654.
  10. 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. PMC 2712886. PMID 17466902.
  11. 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 (BBA) - Reviews on Cancer. 1552 (1): 39–45. doi:10.1016/s0304-419x(01)00038-5. PMID 11781114.
  12. Zetter, B R. (August 1993). "Adhesion Molecules in Tumor Metastasis". Seminars in Cancer Biology. 4 (4): 219–229. PMID 8400144.
  13. 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. PMID 1253177.
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