Endothelial cell dysfunction in cancer: a not-so-innocent bystander

Submitted: 15 January 2024
Accepted: 29 April 2024
Published: 16 May 2024
Abstract Views: 891
PDF: 127
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

The body’s homeostasis depends on the vascular endothelium, which controls angiogenesis, vascular tone, inflammation, cell trafficking, hemostasis, and the movement of nutrients and waste out of the body. Endothelial cells (ECs) are the primary gatekeepers of many of these vessel wall functions, despite only having a single cell’s thickness. Normally quiescent ECs in the context of cancer are activated by anti-cancer therapies, the tumor microenvironment, and factors secreted by the tumor. Crucially, this dysfunctional endothelium actively participates in tumor metastasis and progression rather than just acting as a passive bystander. Compared to the healthy vasculature, ECs in the tumor vasculature are heterogeneous and have a different gene expression profile. Tumor-associated ECs, in particular, exhibit increased pro-angiogenic characteristics and upregulated expression of adhesion molecules and proinflammatory cytokines, facilitating the intra- and extravasation of spreading tumor cells. Furthermore, the downregulation of important anticoagulant molecules and increased endothelial secretion of prothrombotic molecules can directly encourage cancer-associated thrombosis. Many anti-cancer therapies are also less effective in their delivery and function when there is dysfunction in the tumor endothelium. The review highlights some of the most recent research showing how tumor-associated ECs influence angiogenesis, inflammation, coagulation, and metastasis to contribute to the progression of tumors. Undoubtedly, a better understanding of how the tumor microenvironment subverts quiescent ECs and how phenotypic alterations in the vessel wall support the survival and spread of tumor cells will aid in the identification of new therapeutic targets to slow the advancement of cancer.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Ibrahim A, Arany Z. Does endothelium buffer fat? Circ Res 2017;120:1219-21. DOI: https://doi.org/10.1161/CIRCRESAHA.117.310865
Hsu T, Nguyen-Tran H-H, Trojanowska M. Active roles of dysfunctional vascular endothelium in fibrosis and cancer. J Biomed Sci 2019;26. DOI: https://doi.org/10.1186/s12929-019-0580-3
Aird WC. Phenotypic heterogeneity of the endothelium. Circ Res 2007;100:158-73. DOI: https://doi.org/10.1161/01.RES.0000255691.76142.4a
Terwoord JD, Beyer AM, Gutterman DD. Endothelial dysfunction as a complication of anti-cancer therapy. Pharmacol Ther 2022;237:108116. DOI: https://doi.org/10.1016/j.pharmthera.2022.108116
Kazmi RS, Boyce S, Lwaleed BA. Homeostasis of hemostasis: the role of endothelium. Semin Thromb Hemost 2015;41:549-55. DOI: https://doi.org/10.1055/s-0035-1556586
Dhami SPS, Patmore S, O’Sullivan JM. Advances in the management of cancer-associated thrombosis. Semin Thromb Hemost 2021;47:139-49. DOI: https://doi.org/10.1055/s-0041-1722863
Riera-Domingo C, Leite-Gomes E, Charatsidou I, et al. Breast tumors interfere with endothelial trail at the premetastatic niche to promote cancer cell seeding. Sci Adv 2023;9: eadd5028. DOI: https://doi.org/10.1126/sciadv.add5028
Li M, van Esch BCAM, Wagenaar GTM, et al. Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. Eur J Pharmacol 2018;831:52-9. DOI: https://doi.org/10.1016/j.ejphar.2018.05.003
Fang J, Lu Y, Zheng J, et al. Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: New insights and therapeutic implications. Cell Death Dis 2023;14:586. DOI: https://doi.org/10.1038/s41419-023-06119-x
Lei Z, Hu X, Wu Y, et al. The role and mechanism of the vascular endothelial niche in diseases: a review. Front Physiol 2022;13. DOI: https://doi.org/10.3389/fphys.2022.863265
De Sanctis F, Ugel S, Facciponte J, Facciabene A. The dark side of tumor-associated endothelial cells. Semin Immunol 2018;35:35-47. DOI: https://doi.org/10.1016/j.smim.2018.02.002
Saman H, Raza SS, Uddin S, Rasul K. Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers (Basel) 2020;12. DOI: https://doi.org/10.20944/preprints202004.0400.v1
Dhami SPS, Patmore S, Comerford C, et al. Breast cancer cells mediate endothelial cell activation, promoting von willebrand factor release, tumor adhesion, and transendothelial migration. J Thromb Haemost 2022;20:2350-65. DOI: https://doi.org/10.1111/jth.15794
Jiao S, Subudhi SK, Aparicio A, et al. Differences in tumor microenvironment dictate t helper lineage polarization and response to immune checkpoint therapy. Cell 2019;179:1177-90.e13. DOI: https://doi.org/10.1016/j.cell.2019.10.029
Roswall P, Bocci M, Bartoschek M, et al. Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-cc signaling. Nat Med 2018;24:463-73. DOI: https://doi.org/10.1038/nm.4494
Jain RK. Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nat Rev Cancer 2008;8:309-16. DOI: https://doi.org/10.1038/nrc2346
Liu T, Ma W, Xu H, et al. Pdgf-mediated mesenchymal transformation renders endothelial resistance to anti-vegf treatment in glioblastoma. Nat Commun 2018;9:3439. DOI: https://doi.org/10.1038/s41467-018-05982-z
Yao X, Zeng Y. Tumour associated endothelial cells: Origin, characteristics and role in metastasis and anti-angiogenic resistance. Front Physiol 2023;14:1199225. DOI: https://doi.org/10.3389/fphys.2023.1199225
Lundgren K, Holm C, Landberg G. Common molecular mechanisms of mammary gland development and breast cancer. Cell Mol Life Sci 2007;64:3233-47. DOI: https://doi.org/10.1007/s00018-007-7390-6
Ohmura-Kakutani H, Akiyama K, Maishi N, et al. Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype. PLoS One 2014;9:e113910. DOI: https://doi.org/10.1371/journal.pone.0113910
Carlson JC, Cantu Gutierrez M, Lozzi B, et al. Identification of diverse tumor endothelial cell populations in malignant glioma. Neuro Oncol 2021;23:932-44. DOI: https://doi.org/10.1093/neuonc/noaa297
Hida K, Maishi N, Takeda R, Hida Y. The roles of tumor endothelial cells in cancer metastasis. In: Sergi CM (ed.). Metastasis. Brisbane (AU): Exon Publications; 2022. DOI: https://doi.org/10.36255/exon-publications.metastasis.endothelial-cells
Bussolati B, Deambrosis I, Russo S, et al. Altered angiogenesis and survival in human tumor-derived endothelial cells. FASEB J 2003;17:1159-61. DOI: https://doi.org/10.1096/fj.02-0557fje
Butler JM, Kobayashi H, Rafii S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 2010;10:138-46. DOI: https://doi.org/10.1038/nrc2791
Ohga N, Ishikawa S, Maishi N, et al. Heterogeneity of tumor endothelial cells: Comparison between tumor endothelial cells isolated from high- and low-metastatic tumors. Am J Pathol 2012;180:1294-307. DOI: https://doi.org/10.1016/j.ajpath.2011.11.035
Geldhof V, de Rooij L, Sokol L, et al. Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast. Nat Commun 2022;13:5511. DOI: https://doi.org/10.1038/s41467-022-33052-y
Goveia J, Rohlenova K, Taverna F, et al. An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell 2020;37:21-36.e13. DOI: https://doi.org/10.1016/j.ccell.2019.12.001
Park HR, Shiva A, Cummings P, et al. Angiopoietin-2-dependent spatial vascular destabilization promotes t-cell exclusion and limits immunotherapy in melanoma. Cancer Res 2023;83:1968-83. DOI: https://doi.org/10.1158/0008-5472.CAN-22-2838
Angara K, Borin TF, Arbab AS. Vascular mimicry: a novel neovascularization mechanism driving anti-angiogenic therapy (AAT) resistance in glioblastoma. Transl Oncol.2017;10: 650-60. DOI: https://doi.org/10.1016/j.tranon.2017.04.007
Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 2020;77:1745-70. DOI: https://doi.org/10.1007/s00018-019-03351-7
Liu HL, Tang HT, Yang HL, et al. Oct4 regulates the transition of cancer stem-like cells to tumor endothelial-like cells in human liver cancer. Front Cell Dev Biol 2020;8:563316. DOI: https://doi.org/10.3389/fcell.2020.563316
Wei X, Chen Y, Jiang X, et al. Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments. Mol Cancer 2021;20:7. DOI: https://doi.org/10.1186/s12943-020-01288-1
He X, You J, Ding H, et al. Vasculogenic mimicry, a negative indicator for progression free survival of lung adenocarcinoma irrespective of first line treatment and epithelial growth factor receptor mutation status. BMC Cancer 2021;21:132. DOI: https://doi.org/10.1186/s12885-021-07863-z
Ünlü B, Versteeg HH. Effects of tumor-expressed coagulation factors on cancer progression and venous thrombosis: Is there a key factor? Thromb Res 2014;133:S76-84. DOI: https://doi.org/10.1016/S0049-3848(14)50013-8
Palumbo JS, Talmage KE, Massari JV, et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms. Blood 2007;110:133-41. DOI: https://doi.org/10.1182/blood-2007-01-065995
Graf C, Wilgenbus P, Pagel S, et al. Myeloid cell-synthesized coagulation factor x dampens antitumor immunity. Sci Immunol 2019;4. DOI: https://doi.org/10.1126/sciimmunol.aaw8405
Comerford C, Glavey S, Quinn J, O’Sullivan JM. The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies. J Thromb Haemost 2022;20:1766-77. DOI: https://doi.org/10.1111/jth.15773
Patmore S, Dhami SPS, O’Sullivan JM. Von willebrand factor and cancer; metastasis and coagulopathies. J Thromb Haemost 2020;18:2444-56. DOI: https://doi.org/10.1111/jth.14976
Obermeier HL, Riedl J, Ay C, et al. The role of adamts-13 and von willebrand factor in cancer patients: Results from the vienna cancer and thrombosis study. Res Pract Thromb Haemost 2019;3:503-14. DOI: https://doi.org/10.1002/rth2.12197
Bauer AT, Suckau J, Frank K, et al. Von willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans. Blood 2015;125: 3153-63. DOI: https://doi.org/10.1182/blood-2014-08-595686
Feinauer MJ, Schneider SW, Berghoff AS, et al. Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model. Blood 2021;137:1219-32. DOI: https://doi.org/10.1182/blood.2020005710
Ünlü B, Kocatürk B, Rondon AMR, et al. Integrin regulation by tissue factor promotes cancer stemness and metastatic dissemination in breast cancer. Oncogene 2022;41:5176-85. DOI: https://doi.org/10.1038/s41388-022-02511-7
Hisada Y, Mackman N. Cancer cell-derived tissue factor-positive extracellular vesicles: Biomarkers of thrombosis and survival. Curr Opin Hematol 2019;26:349-56. DOI: https://doi.org/10.1097/MOH.0000000000000521
Hassan N, Efing J, Kiesel L, et al. The tissue factor pathway in cancer: Overview and role of heparan sulfate proteoglycans. Cancers (Basel) 2023;15. DOI: https://doi.org/10.3390/cancers15051524
Xing M, Yang Y, Huang J, et al. TFPI inhibits breast cancer progression by suppressing erk/p38 mapk signaling pathway. Genes Genom 2022;44:801-12. DOI: https://doi.org/10.1007/s13258-022-01258-5
Fei X, Wang H, Yuan W, et al. Tissue factor pathway inhibitor-1 is a valuable marker for the prediction of deep venous thrombosis and tumor metastasis in patients with lung cancer. Biomed Res Int 2017;2017:8983763. DOI: https://doi.org/10.1155/2017/8983763
Darwish NHE, Godugu K, Mousa SA. Sulfated non-anticoagulant low molecular weight heparin in the prevention of cancer and non-cancer associated thrombosis without compromising hemostasis. Thromb Res 2021;200: 109-14. DOI: https://doi.org/10.1016/j.thromres.2021.01.015
Sudha T, Yalcin M, Lin HY, et al. Suppression of pancreatic cancer by sulfated non-anticoagulant low molecular weight heparin. Cancer Lett 2014;350:25-33. DOI: https://doi.org/10.1016/j.canlet.2014.04.016
Feng K, Wang K, Zhou Y, et al. Non-anticoagulant activities of low molecular weight heparins-a review. Pharmaceuticals (Basel) 2023;16. DOI: https://doi.org/10.3390/ph16091254
Phillips PG, Yalcin M, Cui H, et al. Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin. Anticancer Res 2011;31:411-9.
Quan Y, He J, Zou Q, et al. Low molecular weight heparin synergistically enhances the efficacy of adoptive and anti-pd-1-based immunotherapy by increasing lymphocyte infiltration in colorectal cancer. J Immunother Cancer 2023;11. DOI: https://doi.org/10.1136/jitc-2023-007080
Franses JW, Drosu NC, Gibson WJ, et al. Dysfunctional endothelial cells directly stimulate cancer inflammation and metastasis. Int J Cancer 2013;133:1334-44. DOI: https://doi.org/10.1002/ijc.28146
Wolf MJ, Hoos A, Bauer J, et al. Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell 2012;22:91-105. DOI: https://doi.org/10.1016/j.ccr.2012.05.023
Wieland E, Rodriguez-Vita J, Liebler SS, et al. Endothelial notch1 activity facilitates metastasis. Cancer Cell 2017;31: 355-67. DOI: https://doi.org/10.1016/j.ccell.2017.01.007
Zhao H, Wu L, Yan G, et al. Inflammation and tumor progression: Signaling pathways and targeted intervention. Signal Transduct Target Ther 2021;6:263. DOI: https://doi.org/10.1038/s41392-021-00658-5
Pitroda SP, Zhou T, Sweis RF, et al. Tumor endothelial inflammation predicts clinical outcome in diverse human cancers. PLoS One 2012;7:e46104. DOI: https://doi.org/10.1371/journal.pone.0046104
Cleveland AH, Fan Y. Reprogramming endothelial cells to empower cancer immunotherapy. Trends Mol Med 2024;30: 126-35. DOI: https://doi.org/10.1016/j.molmed.2023.11.002
Alsina-Sanchis E, Mülfarth R, Moll I, et al. Endothelial rbpj is essential for the education of tumor-associated macrophages. Cancer Res 2022;82:4414-28. DOI: https://doi.org/10.1158/0008-5472.CAN-22-0076
Wang Q, He Z, Huang M, et al. Vascular niche il-6 induces alternative macrophage activation in glioblastoma through hif-2α. Nat Commun 2018;9:559. DOI: https://doi.org/10.1038/s41467-018-03050-0
Shan Y, Ni Q, Zhang Q, et al. Targeting tumor endothelial hyperglycolysis enhances immunotherapy through remodeling tumor microenvironment. Acta Pharmaceutica Sinica B 2022;12: 1825-39. DOI: https://doi.org/10.1016/j.apsb.2022.02.014
Georganaki M, Ramachandran M, Tuit S, et al. Tumor endothelial cell up-regulation of ido1 is an immunosuppressive feed-back mechanism that reduces the response to cd40-stimulating immunotherapy. Oncoimmunology 2020;9: 1730538. DOI: https://doi.org/10.1080/2162402X.2020.1730538
Acharyya S, Oskarsson T, Vanharanta S, et al. A cxcl1 paracrine network links cancer chemoresistance and metastasis. Cell 2012;150:165-78. DOI: https://doi.org/10.1016/j.cell.2012.04.042
Tavora B, Reynolds LE, Batista S, et al. Endothelial-cell fak targeting sensitizes tumours to DNA-damaging therapy. Nature 2014;514:112-6. DOI: https://doi.org/10.1038/nature13541
Reymond N, d’Água BB, Ridley AJ. Crossing the endothelial barrier during metastasis. Nat Rev Cancer 2013;13:858-70. DOI: https://doi.org/10.1038/nrc3628
Alsina-Sanchis E, Mülfarth R, Fischer A. Control of tumor progression by angiocrine factors. Cancers (Basel) 2021;13. DOI: https://doi.org/10.3390/cancers13112610
Hida K, Maishi N, Annan DA, Hida Y. Contribution of tumor endothelial cells in cancer progression. Int J Mol Sci 2018;19. DOI: https://doi.org/10.3390/ijms19051272
Stacer AC, Fenner J, Cavnar SP, et al. Endothelial CXCR7 regulates breast cancer metastasis. Oncogene 2016;35: 1716-24. DOI: https://doi.org/10.1038/onc.2015.236
Sobierajska K, Ciszewski WM, Sacewicz-Hofman I, Niewiarowska J. Endothelial cells in the tumor microenvironment. Adv Exp Med Biol 2020;1234:71-86. DOI: https://doi.org/10.1007/978-3-030-37184-5_6
Huang M, Liu T, Ma P, et al. C-met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J Clin Invest 2016;126:1801-14. DOI: https://doi.org/10.1172/JCI84876
Li B, Zhao WD, Tan ZM, et al. Involvement of rho/rock signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett 2006;580: 4252-60. DOI: https://doi.org/10.1016/j.febslet.2006.06.056
Zhang H, Yue X, Chen Z, et al. Define cancer-associated fibroblasts (CAFS) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials. Mol Cancer 2023;22:159. DOI: https://doi.org/10.1186/s12943-023-01860-5
Erdogan B, Ao M, White LM, et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J Cell Biol 2017;216:3799-816. DOI: https://doi.org/10.1083/jcb.201704053
Peinado H, Zhang H, Matei IR, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 2017;17:302-17. DOI: https://doi.org/10.1038/nrc.2017.6
Abdel Sater AH, Bouferraa Y, Amhaz G, et al. From tumor cells to endothelium and gut microbiome: a complex interaction favoring the metastasis cascade. Front Oncol 2022;12:804983. DOI: https://doi.org/10.3389/fonc.2022.804983
Zhang G, Li M, Zhou D, et al. Loss of endothelial emcn drives tumor lung metastasis through the premetastatic niche. J Transl Med 2022;20:446. DOI: https://doi.org/10.1186/s12967-022-03649-4
Carlson P, Dasgupta A, Grzelak CA, et al. Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat Cell Biol 2019;21:238-50. DOI: https://doi.org/10.1038/s41556-018-0267-0
Zeng Q, Mousa M, Nadukkandy AS, et al. Understanding tumour endothelial cell heterogeneity and function from single-cell omics. Nat Rev Cancer 2023;23:544-64. DOI: https://doi.org/10.1038/s41568-023-00591-5

Supporting Agencies

This manuscript was supported by Science Foundation Ireland (SFI) Frontiers for the Future award

How to Cite

Ünlü, B., Joshi, N., & O’Sullivan, J. M. (2024). Endothelial cell dysfunction in cancer: a not-so-innocent bystander. Bleeding, Thrombosis and Vascular Biology, 3(s1). https://doi.org/10.4081/btvb.2024.116

Similar Articles

1 2 3 > >> 

You may also start an advanced similarity search for this article.