Intravasation

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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]

Contents

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 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 and intravasation

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]

Related Research Articles

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

<span class="mw-page-title-main">Wound healing</span> Series of events that restore integrity to damaged tissue after an injury

Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.

Durotaxis is a form of cell migration in which cells are guided by rigidity gradients, which arise from differential structural properties of the extracellular matrix (ECM). Most normal cells migrate up rigidity gradients.

<span class="mw-page-title-main">Selectin</span> Family of cell adhesion molecules

The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.

The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.

<span class="mw-page-title-main">P-selectin</span> Type-1 transmembrane protein

P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.

<span class="mw-page-title-main">E-selectin</span>

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.

<span class="mw-page-title-main">MMP2</span> Protein-coding gene in the species Homo sapiens

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

<span class="mw-page-title-main">CD47</span> Protein-coding gene in humans

CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.

<span class="mw-page-title-main">LYVE1</span> Protein may function in lymphatic hyaluronan transport and have a role in tumor metastasis

Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), also known as extracellular link domain containing 1 (XLKD1) is a Link domain-containing hyaladherin, a protein capable of binding to hyaluronic acid (HA), homologous to CD44, the main HA receptor. In humans it is encoded by the LYVE1 gene.

<span class="mw-page-title-main">Invadopodia</span>

Invadopodia are actin-rich protrusions of the plasma membrane that are associated with degradation of the extracellular matrix in cancer invasiveness and metastasis. Very similar to podosomes, invadopodia are found in invasive cancer cells and are important for their ability to invade through the extracellular matrix, especially in cancer cell extravasation. Invadopodia are generally visualized by the holes they create in ECM -coated plates, in combination with immunohistochemistry for the invadopodia localizing proteins such as cortactin, actin, Tks5 etc. Invadopodia can also be used as a marker to quantify the invasiveness of cancer cell lines in vitro using a hyaluronic acid hydrogel assay.

<span class="mw-page-title-main">Desmoplasia</span> Growth of fibrous or connective tissue

In medicine, desmoplasia is the growth of fibrous or connective tissue. It is also called desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, or scar tissue (adhesions) within the abdomen after abdominal surgery.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

<span class="mw-page-title-main">Tumor microenvironment</span>

The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

A cancer-associated fibroblast (CAF) is a cell type within the tumor microenvironment that promotes tumorigenic features by initiating the remodelling of the extracellular matrix or by secreting cytokines. CAFs are a complex and abundant cell type within the tumour microenvironment; the number cannot decrease, as they are unable to undergo apoptosis.

For cancer, invasion is the direct extension and penetration by cancer cells into neighboring tissues. It is generally distinguished from metastasis, which is the spread of cancer cells through the circulatory system or the lymphatic system to more distant locations. Yet, lymphovascular invasion is generally the first step of metastasis.

The host response to cancer therapy is defined as a physiological response of the non-malignant cells of the body to a specific cancer therapy. The response is therapy-specific, occurring independently of cancer type or stage.

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. PMC   2760965 . PMID   19738043.
  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. PMID   17454296. S2CID   22158818.
  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 (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. 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. PMC   2516896 . PMID   18467655.
  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. 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. 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. 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. 1 2 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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