Tumor-associated endothelial cell

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A visualization of tumor-associated blood vessels in the human breast

Tumor-associated endothelial cells or tumor endothelial cells (TECs) refers to cells lining the tumor-associated blood vessels that control the passage of nutrients into surrounding tumor tissue. [1] Across different cancer types, tumor-associated blood vessels have been discovered to differ significantly from normal blood vessels in morphology, gene expression, and functionality in ways that promote cancer progression. [2] [3] [4] There has been notable interest in developing cancer therapeutics that capitalize on these abnormalities of the tumor-associated endothelium to destroy tumors. [3]

Contents

Abnormal morphology

Tumor endothelial cells (TECs) have been documented to demonstrate abnormal morphological characteristics such as ragged margins and irregular cytoplasmic projections. [1] In normal blood vessels, it is known that endothelial cells form regular monolayers with tight junctions without overlap, but TECs create disorganized and loosely connected monolayers, often branching and extending across the lumen to overlap with their neighbors. [5] In addition to this, TECs are showing distinct molecular signature which clearly separates them from physiological endothelial cells. [2] The tumor endothelium is often described as mosaic due to its aberrant expression of traditional endothelial cell markers (CD31 and CD105), [2] supporting the existence of irregular gaps between endothelial cells. [6] At a more macro level, beyond the observation of small intercellular openings between nearby TECs, larger gaps in the walls of tumor blood vessels have been described. [1]

Causes of abnormalities

Many tumors are characterized by high expression of vascular endothelial growth factor (VEGF), which is a strong vasodilator. VEGF has been indicated to stimulate sprouting and tip branching in endothelial cells, leading to defective endothelial monolayers. [7] Research supports that compression of tumor vessels by surrounding tumor cells results in mechanical tension and changes in blood flow. [8] It has been suggested that these flow-mediated changes cause abnormal expression of transcription factors which promotes aberrant endothelial morphology, size, and differentiation. [9]

Smaller capillaries are often surrounded by supporting pericytes which help with vessel stability. [10] Loss of pericyte growth factor (PDGFB) and its receptor on endothelial cells are molecular-level changes that can account for this abnormal loss in pericyte support. [11] Lower quantity of pericytes surrounding the tumor-associated endothelium has been associated with blood vessel instability and leakiness. [12]

Abnormal function

Blood vessel leakiness

Where these branched tumor-associated endothelial cells form small gaps in the blood vessel wall, erythrocytes often pool and form blood lakes. [13] These cellular openings contribute to tumor vessel "leakiness", potentially allowing the entry and delivery of therapeutic agents to tumor sites. [14] [5] For many tumors, it has been discovered associated endothelial cells have significantly increased permeability. [15] [16]

Enhanced permeability and retention (EPR) effect

Illustration of the Enhanced Permeation and Retention (EPR) effect of macromolecular structures as drug delivery systems in malignant tissue. Enhanced Permeation and Retention (EPR) effect.svg
Illustration of the Enhanced Permeation and Retention (EPR) effect of macromolecular structures as drug delivery systems in malignant tissue.

The increased permeability of tumor-associated endothelial cells permits macromolecules to leave the blood system and directly enter the tumor interstitial space. There is also a retention effect that allows these macromolecules to stay at tumor sites due to the suppression of lymphatic infiltration. [17] This observation has been termed the enhanced permeability and retention (EPR) effect and has been exploited for cancer nano-therapeutics. [18] Unfortunately the effectiveness of this mechanism for drug nano-carriers remains inconsistent due to the heterogeneity of this EPR effect within and amongst different tumors. [19] Tumor type, size, and location affect the nature of the surrounding vasculature and stroma and contribute to this heterogeneity in EPR effect. [19]

Roles in tumor progression

Angiogenesis

The idea of tumors promoting angiogenesis, or the process of forming new blood vessels, has been around since the discovery of VEGF in 1989. [20] The branching patterning of tumor-associated endothelial cells has been implicated in the initiation of angiogenesis. [21] Dr. Judah Folkman played an important role in studying the role of angiogenesis in promoting tumor growth. [22] [23] He identified tumor's response to hypoxia as a leading contributor to angiogenesis and cancer growth. [22]

Angiogenesis was originally introduced as a Hallmark of Cancer based on assumptions that the underlying processes were similar amongst different tumor types. [24] However, there are now multiple studies that illustrate the complexity behind these previous simple conceptions of angiogenesis, indicating that the way cancer cells interact with and co-opt new blood vessel growth varies amongst cancer types and must be studied. [2] [25] This must be studied in order to improve clinical design strategy and select for patients with tumors that are more likely to benefit from anti-angiogenic drugs. [2] [25]

Angiogenesis inhibitors

Various angiogenesis inhibitors have been developed to interfere with different steps in the process. [26] Bevacizumab (Avastin) is a monoclonal antibody that binds to VEGF, preventing the stimulation of the VEGF receptor. [27] Sorafenib and sutinib are additional angiogenesis inhibitors that bind and block receptors on endothelial cells that have important roles in downstream pathways contributing to angiogenesis progression. [28] An extensive amount of other compounds targeted towards halting angiogenesis are either currently in preclinical development, undergoing clinical trials, or in the process of getting approved by the United States Food and Drug Administration. [26]

Immune suppression

Immune therapies depend heavily on the abilities of effector lymphocytes to infiltrate tumors, and the tumor endothelium is a known crucial regulator of T-cell trafficking. The tumor-associated endothelium has been found to be able to function as an immune barrier to T-cells, inhibiting the effectiveness of immune therapies. [29] These tumor-associated endothelial cells have been found to over-express the endothelin B receptor, which suppresses T-cell adhesion and targeting to tumors upon activation by ET-1. [30]

Metastasis

The vasculature can promote metastasis by capturing cancer cells at their primary sites and providing for their delivery to secondary organs. [31] These tumor-associated endothelial cells can also release factors and supply nutrients that promote the growth of the primary tumor mass and its aggressive spread. [2] [31] Additionally, angiogenesis is intimately linked to metastasis, as delivery of nutrients and oxygen through blood vessels is required for invasive tumor growth and spread. [32]

See also

References

  1. 1 2 3 Dudley, Andrew C. (2012-03-01). "Tumor Endothelial Cells". Cold Spring Harbor Perspectives in Medicine. 2 (3): a006536. doi:10.1101/cshperspect.a006536. ISSN   2157-1422. PMC   3282494 . PMID   22393533.
  2. 1 2 3 4 5 6 Milosevic, Vladan; Edelmann, Reidunn J.; Fosse, Johanna Hol; Östman, Arne; Akslen, Lars A. (2022), Akslen, Lars A.; Watnick, Randolph S. (eds.), "Molecular Phenotypes of Endothelial Cells in Malignant Tumors" , Biomarkers of the Tumor Microenvironment, Cham: Springer International Publishing, pp. 31–52, doi:10.1007/978-3-030-98950-7_3, ISBN   978-3-030-98950-7 , retrieved 2022-07-13
  3. 1 2 Hashizume, H; Baluk, P; Morikawa, S; et al. (April 2000). "Openings between Defective Endothelial Cells Explain Tumor Vessel Leakiness". Am. J. Pathol. 156 (4): 1363–80. doi:10.1016/S0002-9440(10)65006-7. PMC   1876882 . PMID   10751361.
  4. ↑ Lu, Chunhua; Bonome, Tomas; Li, Yang; Kamat, Aparna A.; Han, Liz Y.; Schmandt, Rosemarie; Coleman, Robert L.; Gershenson, David M.; Jaffe, Robert B. (2007-02-16). "Gene Alterations Identified by Expression Profiling in Tumor-Associated Endothelial Cells from Invasive Ovarian Carcinoma". Cancer Research. 67 (4): 1757–1768. doi: 10.1158/0008-5472.can-06-3700 . PMID   17308118.
  5. 1 2 Hashizume, Hiroya; Baluk, Peter; Morikawa, Shunichi; McLean, John W.; Thurston, Gavin; Roberge, Sylvie; Jain, Rakesh K.; McDonald, Donald M. (2017-04-21). "Openings between Defective Endothelial Cells Explain Tumor Vessel Leakiness". The American Journal of Pathology. 156 (4): 1363–1380. doi:10.1016/S0002-9440(10)65006-7. ISSN   0002-9440. PMC   1876882 . PMID   10751361.
  6. ↑ di Tomaso, Emmanuelle; Capen, Diane; Haskell, Amy; Hart, Janet; Logie, James J.; Jain, Rakesh K.; McDonald, Donald M.; Jones, Rosemary; Munn, Lance L. (2005-07-01). "Mosaic tumor vessels: cellular basis and ultrastructure of focal regions lacking endothelial cell markers". Cancer Research. 65 (13): 5740–5749. doi: 10.1158/0008-5472.CAN-04-4552 . ISSN   0008-5472. PMID   15994949.
  7. ↑ Nagy, Janice A.; Dvorak, Ann M.; Dvorak, Harold F. (2007-01-01). "VEGF-A and the induction of pathological angiogenesis". Annual Review of Pathology. 2: 251–275. doi:10.1146/annurev.pathol.2.010506.134925. ISSN   1553-4006. PMID   18039100.
  8. ↑ Padera, Timothy P.; Stoll, Brian R.; Tooredman, Jessica B.; Capen, Diane; di Tomaso, Emmanuelle; Jain, Rakesh K. (2004-02-19). "Pathology: cancer cells compress intratumour vessels". Nature. 427 (6976): 695. Bibcode:2004Natur.427..695P. doi: 10.1038/427695a . ISSN   1476-4687. PMID   14973470.
  9. ↑ De Val, Sarah; Black, Brian L. (2009-02-01). "Transcriptional control of endothelial cell development". Developmental Cell. 16 (2): 180–195. doi:10.1016/j.devcel.2009.01.014. ISSN   1878-1551. PMC   2728550 . PMID   19217421.
  10. ↑ Hirschi, K. K.; D'Amore, P. A. (1996-10-01). "Pericytes in the microvasculature". Cardiovascular Research. 32 (4): 687–698. doi:10.1016/0008-6363(96)00063-6. ISSN   0008-6363. PMID   8915187.
  11. ↑ Hellström, M.; Gerhardt, H.; Kalén, M.; Li, X.; Eriksson, U.; Wolburg, H.; Betsholtz, C. (2001-04-30). "Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis". The Journal of Cell Biology. 153 (3): 543–553. doi:10.1083/jcb.153.3.543. ISSN   0021-9525. PMC   2190573 . PMID   11331305.
  12. ↑ Baluk, Peter; Hashizume, Hiroya; McDonald, Donald M (2005-02-01). "Cellular abnormalities of blood vessels as targets in cancer". Current Opinion in Genetics & Development. Oncogenes and cell proliferation. 15 (1): 102–111. doi:10.1016/j.gde.2004.12.005. PMID   15661540.
  13. ↑ Van den Brenk, H. A.; Crowe, M.; Kelly, H.; Stone, M. G. (1977-04-01). "The significance of free blood in liquid and solid tumours". British Journal of Experimental Pathology. 58 (2): 147–159. ISSN   0007-1021. PMC   2041288 . PMID   861165.
  14. ↑ Dvorak, H. F.; Nagy, J. A.; Dvorak, J. T.; Dvorak, A. M. (1988-10-01). "Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules". The American Journal of Pathology. 133 (1): 95–109. ISSN   0002-9440. PMC   1880651 . PMID   2459969.
  15. ↑ Jain, R. K. (1987-01-01). "Transport of molecules across tumor vasculature". Cancer and Metastasis Reviews. 6 (4): 559–593. doi:10.1007/bf00047468. ISSN   0167-7659. PMID   3327633. S2CID   20519826.
  16. ↑ Gerlowski, L. E.; Jain, R. K. (1986-05-01). "Microvascular permeability of normal and neoplastic tissues". Microvascular Research. 31 (3): 288–305. doi:10.1016/0026-2862(86)90018-x. ISSN   0026-2862. PMID   2423854.
  17. ↑ Maeda, H; Wu, J; Sawa, T; Matsumura, Y; Hori, K (2000-03-01). "Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review". Journal of Controlled Release. 65 (1–2): 271–284. doi:10.1016/S0168-3659(99)00248-5. PMID   10699287.
  18. ↑ Iyer, Arun K.; Khaled, Greish; Fang, Jun; Maeda, Hiroshi (2006-09-01). "Exploiting the enhanced permeability and retention effect for tumor targeting". Drug Discovery Today. 11 (17–18): 812–818. doi:10.1016/j.drudis.2006.07.005. PMID   16935749.
  19. 1 2 Prabhakar, Uma; Maeda, Hiroshi; Jain, Rakesh K.; Sevick-Muraca, Eva M.; Zamboni, William; Farokhzad, Omid C.; Barry, Simon T.; Gabizon, Alberto; Grodzinski, Piotr (2013-04-15). "Challenges and key considerations of the enhanced permeability and retention (EPR) effect for nanomedicine drug delivery in oncology". Cancer Research. 73 (8): 2412–2417. doi:10.1158/0008-5472.CAN-12-4561. ISSN   0008-5472. PMC   3916009 . PMID   23423979.
  20. ↑ Hall, A. P. (2005-03-01). "The role of angiogenesis in cancer". Comparative Clinical Pathology. 13 (3): 95–99. doi:10.1007/s00580-004-0533-3. ISSN   1618-5641. S2CID   31476527.
  21. ↑ Gerhardt, Holger; Golding, Matthew; Fruttiger, Marcus; Ruhrberg, Christiana; Lundkvist, Andrea; Abramsson, Alexandra; Jeltsch, Michael; Mitchell, Christopher; Alitalo, Kari (2003-06-23). "VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia". The Journal of Cell Biology. 161 (6): 1163–1177. doi:10.1083/jcb.200302047. ISSN   0021-9525. PMC   2172999 . PMID   12810700.
  22. 1 2 Zetter, Bruce R. (2008). "The scientific contributions of M. Judah Folkman to cancer research". Nature Reviews. Cancer. 8 (8): 647–654. doi:10.1038/nrc2458. ISSN   1474-1768. PMID   18633354. S2CID   8649851.
  23. ↑ Folkman, J. (1990-01-03). "What is the evidence that tumors are angiogenesis dependent?". Journal of the National Cancer Institute. 82 (1): 4–6. CiteSeerX   10.1.1.599.5748 . doi:10.1093/jnci/82.1.4. ISSN   0027-8874. PMID   1688381.
  24. ↑ Hanahan, Douglas; Weinberg, Robert A. (2011-03-04). "Hallmarks of Cancer: The Next Generation". Cell. 144 (5): 646–674. doi: 10.1016/j.cell.2011.02.013 . ISSN   0092-8674. PMID   21376230.
  25. 1 2 Pezzella, F; Harris, A L; Tavassoli, M; Gatter, K C (2015-12-21). "Blood vessels and cancer much more than just angiogenesis". Cell Death Discovery. 1: 15064. doi:10.1038/cddiscovery.2015.64. ISSN   2058-7716. PMC   4979496 . PMID   27551488.
  26. 1 2 Cook, Kristina M.; Figg, William D. (2010-07-01). "Angiogenesis inhibitors: current strategies and future prospects". CA: A Cancer Journal for Clinicians. 60 (4): 222–243. doi:10.3322/caac.20075. ISSN   1542-4863. PMC   2919227 . PMID   20554717.
  27. ↑ Shih, Ted; Lindley, Celeste (2006-11-01). "Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies". Clinical Therapeutics. 28 (11): 1779–1802. doi:10.1016/j.clinthera.2006.11.015. ISSN   0149-2918. PMID   17212999.
  28. ↑ Gotink, Kristy J.; Verheul, Henk M. W. (2010-03-01). "Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?". Angiogenesis. 13 (1): 1–14. doi:10.1007/s10456-009-9160-6. ISSN   1573-7209. PMC   2845892 . PMID   20012482.
  29. ↑ Buckanovich, Ronald J.; Facciabene, Andrea; Kim, Sarah; Benencia, Fabian; Sasaroli, Dimitra; Balint, Klara; Katsaros, Dionysios; O'Brien-Jenkins, Anne; Gimotty, Phyllis A. (2008-01-01). "Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy". Nature Medicine. 14 (1): 28–36. doi:10.1038/nm1699. ISSN   1078-8956. PMID   18157142. S2CID   14822376.
  30. ↑ Kandalaft, Lana E.; Facciabene, Andrea; Buckanovich, Ron J.; Coukos, George (2009-07-15). "Endothelin B Receptor, a New Target in Cancer Immune Therapy". Clinical Cancer Research. 15 (14): 4521–4528. doi:10.1158/1078-0432.CCR-08-0543. ISSN   1078-0432. PMC   2896814 . PMID   19567593.
  31. 1 2 Jahroudi, N.; Greenberger, J. S. (1995-01-01). "The role of endothelial cells in tumor invasion and metastasis". Journal of Neuro-Oncology. 23 (2): 99–108. doi:10.1007/bf01053415. ISSN   0167-594X. PMID   7543941. S2CID   24723243.
  32. ↑ Folkman, Judah (2002-12-16). "Role of angiogenesis in tumor growth and metastasis". Seminars in Oncology. 29 (6): 15–18. doi:10.1016/S0093-7754(02)70065-1. ISSN   0093-7754. PMID   12516034.

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