The endothelin axis in cancer: the promise and the challenges of molecularly targeted therapyThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.

Abstract

The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and 2 G protein-coupled receptor subtypes, ET AR and ET BR, promotes growth and progression of a variety of tumors, such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, lung, bladder, endometrial carcinoma, Kaposi's sarcoma, brain tumors, and melanoma. Acting on selective receptors, ET-1 regulates mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptors, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion, and metastatic dissemination. At the molecular level, endothelin receptor antagonists, besides providing ideal tools for dissecting the ET axis, have demonstrated their potential in developing novel therapeutic strategies. Emerging experimental and clinical data demonstrate that interfering with endothelin receptors provides an opportunity for the development of rational combinatorial approaches using endothelin receptor antagonists in combination with chemotherapy or molecularly targeted therapy.

Endothelin B receptor expression correlates with tumour angiogenesis and prognosis in oesophageal squamous cell carcinoma

“…Furthermore, the ET axis has also been shown to have significant roles in a variety of human malignancies including ovarian, prostate, cervical, breast, colorectal, lung cancers, and melanoma (Nelson et al , 2003). Endothelin axis has been revealed to regulate tumour growth and metastasis via various mechanisms including cell proliferation, angiogenesis, antiapoptotic activity, and immune modulation (Spinella et al , 2002; Nelson et al , 2003; Wulfing et al , 2004; Herrmann et al , 2006; Bagnato et al , 2008; Buckanovich et al , 2008). Whilst upregulation of ET-1 expression has been consistently reported in various malignancies, the different expressions and functions of its receptors ETAR and ETBR have been shown in distinct tumours.…”

“…Thus, each receptor has unique roles and its function may be dependent on cancer cell type. Furthermore, selective antagonists for each receptor as well as dual ETAR/ETBR antagonist have been widely investigated, and some of them were evaluated in clinical trials (Bagnato et al , 2008). …”

Aspects of the endothelin system in colorectal cancer

“…Endothelin-1, which is produced by stromal and tumor cells, acts through different signaling pathways by EDNRA activation (AKT, MAPK, PKC, EGFR), and leads to stimulation of angiogenesis (by HIF-1a, VEGF, Cox-1/-2, PGE2), anti-apoptotic effects (AKT, NFKB), cell migration and adhesion (integrins, ILK, FAK, cadherins / catenins, connexins), increased invasion and expression of MMP and uPA (55). Endothelin-1 can stimulate fibroblast growth more by interacting with EDNRA, migration more by EDNRB, and fibroblast contraction by both of them.…”

Endothelin-1/Endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis

“…A recent study has also shown that elevated concentrations of ET-1 in plasma are associated with higher mortality in patients with certain malignancies [3]. ET-1 mediates cellular processes through its cell surface receptor by facilitating various signaling pathways including ILK, Akt, MAPK, Gαq/PKC, Src, EGFR, and GSK in an autocrine or paracrine fashion [2, 4, 5]. These pathways have been shown to regulate gene expression associated with cancer cell proliferation, adhesion, migration, invasion, angiogenesis and anti-apoptosis [6, 7].…”