Endothelin and the Tumor Microenvironment: a Finger in Every Pie

Overview

Journal Clin Sci (Lond)

Specialties Biochemistry
General Medicine
Science

Date 2024 May 24

PMID 38785410

Authors

Philipp F Arndt

Kati Turkowski

Michael J Cekay

Bastian Eul

Friedrich Grimminger

Rajkumar Savai

Affiliations

Soon will be listed here.

Abstract

The tumor microenvironment (TME) plays a central role in the development of cancer. Within this complex milieu, the endothelin (ET) system plays a key role by triggering epithelial-to-mesenchymal transition, causing degradation of the extracellular matrix and modulating hypoxia response, cell proliferation, composition, and activation. These multiple effects of the ET system on cancer progression have prompted numerous preclinical studies targeting the ET system with promising results, leading to considerable optimism for subsequent clinical trials. However, these clinical trials have not lived up to the high expectations; in fact, the clinical trials have failed to demonstrate any substantiated benefit of targeting the ET system in cancer patients. This review discusses the major and recent advances of the ET system with respect to TME and comments on past and ongoing clinical trials of the ET system.

Citing Articles

The endothelin-1-driven tumor-stroma feed-forward loops in high-grade serous ovarian cancer.

Tocci P, Roman C, Sestito R, Caprara V, Sacconi A, Molineris I Clin Sci (Lond). 2024; 138(14):851-862.

PMID: 38884602 PMC: 11230866. DOI: 10.1042/CS20240346.

References

Sugita Y, Terasaki M, Nakashima S, Ohshima K, Morioka M, Abe H . Perivascular microenvironment in primary central nervous system lymphomas: the role of chemokines and the endothelin B receptor. Brain Tumor Pathol. 2014; 32(1):41-8. DOI: 10.1007/s10014-014-0206-0. View

Hu X, Liu H, Li C . MiRNA-19b-3p downregulates the endothelin B receptor in gastric cancer cells to prevent angiogenesis and proliferation. Acta Biochim Pol. 2023; 70(2):363-370. DOI: 10.18388/abp.2020_6595. View

Lara Jr P, Ely B, Quinn D, Mack P, Tangen C, Gertz E . Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421. J Natl Cancer Inst. 2014; 106(4):dju013. PMC: 3982883. DOI: 10.1093/jnci/dju013. View

Semenza G . Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3(10):721-32. DOI: 10.1038/nrc1187. View

Kajiyama H, Shibata K, Terauchi M, Morita T, Ino K, Mizutani S . Neutral endopeptidase 24.11/CD10 suppresses progressive potential in ovarian carcinoma in vitro and in vivo. Clin Cancer Res. 2005; 11(5):1798-808. DOI: 10.1158/1078-0432.CCR-04-2395. View

Freitas J, Lopez J, Llorian C, Boroni M, Kos L . The immunosuppressive role of Edn3 overexpression in the melanoma microenvironment. Pigment Cell Melanoma Res. 2021; 34(6):1084-1093. DOI: 10.1111/pcmr.13002. View

Wculek S, Cueto F, Mujal A, Melero I, Krummel M, Sancho D . Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2019; 20(1):7-24. DOI: 10.1038/s41577-019-0210-z. View

Bagnato A, Rosano L, Spinella F, Di Castro V, Tecce R, Natali P . Endothelin B receptor blockade inhibits dynamics of cell interactions and communications in melanoma cell progression. Cancer Res. 2004; 64(4):1436-43. DOI: 10.1158/0008-5472.can-03-2344. View

Davenport A, Hyndman K, Dhaun N, Southan C, Kohan D, Pollock J . Endothelin. Pharmacol Rev. 2016; 68(2):357-418. PMC: 4815360. DOI: 10.1124/pr.115.011833. View

10.

James N, Caty A, Payne H, Borre M, Zonnenberg B, Beuzeboc P . Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a.... BJU Int. 2010; 106(7):966-73. DOI: 10.1111/j.1464-410X.2010.09638.x. View

11.

Tzeng H, Tang C, Tsai C, Chiu C, Wu M, Yen Y . ET-1 Promotes Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells via the microRNA-489-3p /TWIST Axis. Onco Targets Ther. 2021; 14:5005-5018. PMC: 8502871. DOI: 10.2147/OTT.S294312. View

12.

Rosano L, Di Castro V, Spinella F, Tortora G, Nicotra M, Natali P . Combined targeting of endothelin A receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity. Cancer Res. 2007; 67(13):6351-9. DOI: 10.1158/0008-5472.CAN-07-0883. View

13.

Berger Y, Dehmlow H, Blum-Kaelin D, Kitas E, Loffler B, Aebi J . Endothelin-converting enzyme-1 inhibition and growth of human glioblastoma cells. J Med Chem. 2005; 48(2):483-98. DOI: 10.1021/jm040857x. View

14.

Sandhu S, McNeil C, LoRusso P, Patel M, Kabbarah O, Li C . Phase I study of the anti-endothelin B receptor antibody-drug conjugate DEDN6526A in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma. Invest New Drugs. 2019; 38(3):844-854. DOI: 10.1007/s10637-019-00832-1. View

15.

Spinella F, Caprara V, Garrafa E, Di Castro V, Rosano L, Natali P . Endothelin axis induces metalloproteinase activation and invasiveness in human lymphatic endothelial cells. Can J Physiol Pharmacol. 2010; 88(8):782-7. DOI: 10.1139/Y10-050. View

16.

Hinsley E, Hunt S, Hunter K, Whawell S, Lambert D . Endothelin-1 stimulates motility of head and neck squamous carcinoma cells by promoting stromal-epithelial interactions. Int J Cancer. 2011; 130(1):40-7. DOI: 10.1002/ijc.25968. View

17.

Rosano L, Spinella F, Di Castro V, Dedhar S, Nicotra M, Natali P . Integrin-linked kinase functions as a downstream mediator of endothelin-1 to promote invasive behavior in ovarian carcinoma. Mol Cancer Ther. 2006; 5(4):833-42. DOI: 10.1158/1535-7163.MCT-05-0523. View

18.

Nelson J, Hedican S, George D, Reddi A, Piantadosi S, Eisenberger M . Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med. 1995; 1(9):944-9. DOI: 10.1038/nm0995-944. View

19.

Wang Z, Wang K, Yu X, Chen M, Du Y . Comprehensive analysis of expression signature and immune microenvironment signature of biomarker Endothelin Receptor Type A in stomach adenocarcinoma. J Cancer. 2022; 13(7):2086-2104. PMC: 9066206. DOI: 10.7150/jca.68673. View

20.

Kageyama Y, Koshiji M, To K, Tian Y, Ratcliffe P, Huang L . Leu-574 of human HIF-1alpha is a molecular determinant of prolyl hydroxylation. FASEB J. 2004; 18(9):1028-30. DOI: 10.1096/fj.03-1233fje. View