Angiopellosis

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In cellular biology, angiopellosis (cell extravasation) is the movement of cells out of the circulatory system, into the surrounding tissue. This process is specific to non-leukocytic cells; white blood cells (leukocytes) employ diapedesis for movement out of circulation. Angiopellosis was discovered by studying the way that stem cells reach damaged tissue when injected or infused into the circulatory system. [1] It has been found that circulating tumor cells (CTCs) possess this ability to exit blood vessels through angiopellosis during the process of metastasis. [2]

Contents

Angiopellosis involves cell–cell recognition by the blood vessel wall (endothelial cells), and the active remodeling of the blood vessel to allow the cell to exit. [3]

Mechanism

Angiopellosis extravasation occurs as a means for cells that are not native to the circulation to exit. This includes adult stem cells that are injected intravenously for therapies. Cells that are normally found in circulation (i.e. blood cells) either extravasate through diapedesis (white blood cells), or do not extravasate and remain in circulation (red blood cells).

Angiopellosis was first observed by researchers studying the mechanism by which intravenously injected stem cells arrived at damaged tissue. [1] They discovered that the injected stem cells prompted the blood vessel walls to undergo extensive changes at the cellular level, resulting in the removal of the cell from within the vessel (lumen) into the surrounding tissue. [4]

Below is a brief summary of each of the steps currently thought to be involved in angiopellosis:

Upon entering the circulation, the cell (or clump of cells) travels through the circulatory system and eventually attaches to or becomes lodged within the blood vessel wall. This prompts a series of events that ends with the cell exiting circulation:

  1. The endothelial cells of the vessel recognize the cell through membrane-specific recognition. Recognition of the cell is vital, and is thought to be what prevents cells native to the circulation from randomly extravasating via angiopellosis.
  2. Once attached or lodged, the exiting cell(s) elicit activity from the endothelial cells of the blood vessel: the endothelial cells extend protrusions and actively remodel themselves around the exiting cells. [5]
  3. The exiting cell will then be either actively "pushed" from the inside of the blood vessel, or the vascular cells will remodel around the cell so that the cell no longer remains inside the vessel. [6]

Differences from Leukocyte Extravasation

The most notable difference is the physical mechanism the cells use to exit. During angiopellosis, the endothelial cells are the most active in the process, while in diapedesis it is the white blood cell that are the most physically active during the process.

During angiopellosis the extravasating cell remains round in morphology and only slightly changes shape as a result of the vasculature remodeling around it; during diapedesis, the white blood cells significantly change shape as they squeeze between the cells of the blood vessel wall.

Angiopellosis allows for the extravasation of multiple cells during a single event. The blood vessel will actively remodel around a cluster/group of cells and allow the cells to exit in a single event. Diapedesis only allows for a single white blood cell to migrate across the blood vessel wall at a given time. Although multiple white blood cells can leave simultaneously, they all elicit separate diapedesis extravasation events.

There are further temporal and molecular difference between the two processes. [7]

Role in the Cancer Exodus Hypothesis

Angiopellosis is a critical component of the Cancer Exodus Hypothesis, which posits that circulating tumor cells (CTCs) can extravasate as multicellular clusters rather than only as single cells. According to this hypothesis, CTC clusters maintain their cohesive structure throughout the process of metastasis, which enhances their metastatic potential. [8]

This hypothesis challenges traditional views that CTC clusters must dissociate to initiate metastasis. Studies show that these clusters are capable of exiting blood vessels through angiopellosis while maintaining their multicellular configuration, thus enhancing their ability to establish secondary tumors. [9] This cluster-based migration and extravasation may contribute to the increased treatment resistance observed in metastases, as CTC clusters can harbor a greater diversity of cell types than single CTCs. [10]

The Cancer Exodus Hypothesis underscores the importance of CTC clusters as biomarkers in liquid biopsy techniques, as their presence can be indicative of advanced metastatic disease and cancer aggressiveness. [11]

Stem cell infusion therapy

Stem cell infusion therapy is a type of infusion therapy in which stem cells are infused into the blood. These stem cells then exit the blood vessels and preferentially migrate to damaged tissue as part of the regeneration process. [12] Angiopellosis has been shown to be the mechanism by which stem cells extravasate and reach damaged tissue [13] [14]

See also

Related Research Articles

<span class="mw-page-title-main">Angiogenesis</span> Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

<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">Biopsy</span> Medical test involving extraction of sample cells or tissues for examination

A biopsy is a medical test commonly performed by a surgeon, an interventional radiologist, or an interventional cardiologist. The process involves the extraction of sample cells or tissues for examination to determine the presence or extent of a disease. The tissue is then fixed, dehydrated, embedded, sectioned, stained and mounted before it is generally examined under a microscope by a pathologist; it may also be analyzed chemically. When an entire lump or suspicious area is removed, the procedure is called an excisional biopsy. An incisional biopsy or core biopsy samples a portion of the abnormal tissue without attempting to remove the entire lesion or tumor. When a sample of tissue or fluid is removed with a needle in such a way that cells are removed without preserving the histological architecture of the tissue cells, the procedure is called a needle aspiration biopsy. Biopsies are most commonly performed for insight into possible cancerous or inflammatory conditions.

<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.

<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.

Intravasation is the invasion of cancer cells through the basement 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.

<span class="mw-page-title-main">E-selectin</span> Mammalian protein found in Homo sapiens

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.

High endothelial venules (HEV) are specialized post-capillary venules characterized by plump endothelial cells as opposed to the usual flatter endothelial cells found in regular venules. HEVs enable lymphocytes circulating in the blood to directly enter a lymph node.

<span class="mw-page-title-main">CD146</span> Protein found in humans

CD146 also known as the melanoma cell adhesion molecule (MCAM) or cell surface glycoprotein MUC18, is a 113kDa cell adhesion molecule currently used as a marker for endothelial cell lineage. In humans, the CD146 protein is encoded by the MCAM gene.

<span class="mw-page-title-main">MMP2</span> Protein-coding gene in humans

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.

Extravasation is the leakage of a fluid out of its contained space into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells through the capillary wall, into the surrounding tissues. This is known as leukocyte extravasation, also called diapedesis. In the case of cancer metastasis, it refers to cancer cells exiting the capillaries and entering other tissues, where secondary tumors may form. The term is commonly used in a medical context.

<span class="mw-page-title-main">Sean J. Morrison</span>

Sean J. Morrison is a Canadian-American stem cell biologist and cancer researcher. Morrison is the director of Children's Medical Center Research Institute at UT Southwestern (CRI), a nonprofit research institute established in 2011 as a joint venture between Children’s Health System of Texas and UT Southwestern Medical Center. With Morrison as founding director, CRI was established to perform transformative biomedical research at the interface of stem cell biology, cancer and metabolism to better understand the biological basis of disease. He is a Howard Hughes Medical Institute Investigator, has served as president of the International Society for Stem Cell Research, and is a member of the U.S. National Academy of Medicine, U.S. National Academy of Sciences and European Molecular Biology Organization.

<span class="mw-page-title-main">Circulating tumor cell</span> Cell from a primary tumor carried by blood circulation

A circulating tumor cell (CTC) is a cell that has shed into the vasculature or lymphatics from a primary tumor and is carried around the body in the blood circulation. CTCs can extravasate and become seeds for the subsequent growth of additional tumors (metastases) in distant organs, a mechanism that is responsible for the vast majority of cancer-related deaths. The detection and analysis of CTCs can assist early patient prognoses and determine appropriate tailored treatments. Currently, there is one FDA-approved method for CTC detection, CellSearch, which is used to diagnose breast, colorectal and prostate cancer.

<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.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to 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.

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

Vasculogenic mimicry (VM) is a strategy used by tumors to ensure sufficient blood supply is brought to its cells through establishing new tumor vascularization. This process is similar to tumor angiogenesis; on the other hand vascular mimicry is unique in that this process occurs independent of endothelial cells. Vasculature is instead developed de novo by cancer cells, which under stress conditions such as hypoxia, express similar properties to stem cells, capable of differentiating to mimic the function of endothelial cells and form vasculature-like structures. The ability of tumors to develop and harness nearby vasculature is considered one of the hallmarks of cancer disease development and is thought to be closely linked to tumor invasion and metastasis. Vascular mimicry has been observed predominantly in aggressive and metastatic cancers and has been associated with negative tumor characteristics such as increased metastasis, increased tissue invasion, and overall poor outcomes for patient survival. Vascular mimicry poses a serious problem for current therapeutic strategies due to its ability to function in the presence of Anti-angiogenic therapeutic agents. In fact, such therapeutics have been found to actually drive VM formation in tumors, causing more aggressive and difficult to treat tumors to develop.

A pre-metastatic niche is an environment in a secondary organ that can be conducive to the metastasis of a primary tumor. Such a niche provides favorable conditions for growth, and eventual metastasis, in an otherwise foreign and hostile environment for the primary tumor cells. This concept demonstrated the fundamental role of the microenvironment in regulating tumor growth and metastasis. The discovery of the pre-metastatic niche has fostered new research regarding the potential treatment of metastases, including targeting myeloid derived suppressor cells, and stromal cell plasticity including fibroblasts and pericytes and perivascular smooth muscle cells and (attempts to stop the flow of vesicles from primary tumors to pre-metastatic niches in secondary organs and different combinations of microenvironment targeted therapies.

<span class="mw-page-title-main">Invasion (cancer)</span> Direct extension and penetration by cancer cells into neighboring tissues

Invasion is the process by which cancer cells directly extend and penetrate into neighboring tissues in cancer. 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.

The cancer exodus hypothesis establishes that circulating tumor cell clusters maintain their multicellular structure throughout the metastatic process. It was previously thought that these clusters must dissociate into single cells during metastasis. According to the hypothesis, CTC clusters intravasate, travel through circulation as a cohesive unit, and extravasate at distant sites without disaggregating, significantly enhancing their metastatic potential. This concept is considered a key advancement in understanding of cancer biology and CTCs role in cancer metastasis.

References

  1. 1 2 Allen, Tyler A.; Gracieux, David; Talib, Maliha; Tokarz, Debra A.; Hensley, M. Taylor; Cores, Jhon; Vandergriff, Adam; Tang, Junnan; de Andrade, James B.M. (January 2017). "Angiopellosis as an Alternative Mechanism of Cell Extravasation". Stem Cells. 35 (1): 170–180. doi:10.1002/stem.2451. ISSN   1066-5099. PMC   5376103 . PMID   27350343.
  2. ↑ Allen, Tyler A.; Asad, Dana; Amu, Emmanuel; Hensley, M. Taylor; Cores, Jhon; Vandergriff, Adam; Tang, Junnan; Dinh, Phuong-Uyen; Shen, Deliang; Qiao, Li; Su, Teng (2019-09-01). "Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential". Journal of Cell Science. 132 (17): jcs231563. doi:10.1242/jcs.231563. ISSN   0021-9533. PMC   6771143 . PMID   31409692.
  3. ↑ "Researchers Show How Stem Cells Exit Bloodstream | Medicilon Inc". www.medicilon.com. Retrieved 2019-08-01.
  4. ↑ "Stem Cell Finding May Improve Understanding of Metastatic Cancers". GEN - Genetic Engineering and Biotechnology News. 2016-06-29. Retrieved 2019-08-01.
  5. ↑ Valenzuela Alvarez, Matias; Gutierrez, Luciana M.; Correa, Alejandro; Lazarowski, Alberto; Bolontrade, Marcela F. (January 2019). "Metastatic Niches and the Modulatory Contribution of Mesenchymal Stem Cells and Its Exosomes". International Journal of Molecular Sciences. 20 (8): 1946. doi: 10.3390/ijms20081946 . PMC   6515194 . PMID   31010037.
  6. ↑ Tang, Jun-Nan; Cores, Jhon; Huang, Ke; Cui, Xiao-Lin; Luo, Lan; Zhang, Jin-Ying; Li, Tao-Sheng; Qian, Li; Cheng, Ke (2018). "Concise Review: Is Cardiac Cell Therapy Dead? Embarrassing Trial Outcomes and New Directions for the Future". STEM CELLS Translational Medicine. 7 (4): 354–359. doi:10.1002/sctm.17-0196. ISSN   2157-6580. PMC   5866934 . PMID   29468830.
  7. ↑ Poltavtseva, R. A.; Poltavtsev, A. V.; Lutsenko, G. V.; Svirshchevskaya, E. V. (2019-03-01). "Myths, reality and future of mesenchymal stem cell therapy". Cell and Tissue Research. 375 (3): 563–574. doi:10.1007/s00441-018-2961-4. ISSN   1432-0878. PMID   30456646. S2CID   53873894.
  8. ↑ Aceto, N. (2021). "Circulating Tumor Cell Clusters: Ready for Prime Time?". Cancer Discovery. 11 (5): 1056–1060. doi:10.1158/2159-8290.CD-21-0165.
  9. ↑ Allen, Tyler A. (2019). "Circulating Tumor Cells Maintain Multicellularity During Extravasation and Metastasis". Journal of Cell Science. 132 (17): jcs231563. doi:10.1242/jcs.231563. PMC   6771143 . PMID   31409692.
  10. ↑ Cheung, K. J. (2016). "Polyclonal Breast Cancer Metastases Arise from Collective Dissemination of Keratin 14-Expressing Tumor Cell Clusters". Proceedings of the National Academy of Sciences. 113 (37): E6546–E6555. doi:10.1073/pnas.1524448113. PMC   5024595 . PMID   27578862.
  11. ↑ Labelle, M. (2015). "CTC Clusters: Key Drivers of Cancer Progression and Therapy Resistance". Nature Methods. 12 (7): 587–589. doi:10.1038/nmeth.3404. PMC   4490017 .
  12. ↑ RegMedNet (2016-07-08). "Stem cell angiopellosis: the great escape". RegMedNet. Retrieved 2019-08-01.
  13. ↑ "New Way Out: Researchers Show How Stem Cells Exit Bloodstream". NC State News. Retrieved 2019-08-01.
  14. ↑ Tang, Junnan; Su, Teng; Huang, Ke; Dinh, Phuong-Uyen; Wang, Zegen; Vandergriff, Adam; Hensley, Michael T.; Cores, Jhon; Allen, Tyler; Li, Taosheng; Sproul, Erin (January 2018). "Targeted repair of heart injury by stem cells fused with platelet nanovesicles". Nature Biomedical Engineering. 2 (1): 17–26. doi:10.1038/s41551-017-0182-x. ISSN   2157-846X. PMC   5976251 . PMID   29862136.
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