The Endothelin Axis: A Novel Target for Pharmacotherapy of Female Malignancies

Abstract

The endothelin axis (ET axis), comprising the three peptides endothelin (ET)-1, -2, -3 and their receptors ET(A)R and ET(B)R, is expressed in various cells and tissues. The biologically active ET-1 is formed by endothelin-converting enzyme (ECE) from inactive big-ET-1. ET-1 has emerged as an important peptide in a host of biological functions, including development, cellular proliferation, apoptosis and angiogenesis, thereby playing an important physiological and pathophysiological role. As these effects are mediated by ET(A)R, activation of ET(B)R prevents apoptosis, inhibits ECE expression and mediates the clearance of ET-1. Emerging data indicate that the ET axis is involved in tumourigenesis and tumour progression of various cancers. Expression of the ET axis has been demonstrated in a wide range of human tumours. Since most data have been reported for female malignancies, this review will focus on the role of the ET axis in cancers of the ovary, the cervix and the breast. In ovarian cancer, activation of ET(A)R by ET-1 is a key mechanism in the cellular signalling network promoting cancer growth and progression. Similar effects have been shown for cervical and endometrial cancer. In breast cancer, ET-1 via ET(A)R promotes proliferation and invasion, mediates bone metastases and predicts unfavourable response to chemotherapy. The outstanding role of ET-1 and ET(A)R in carcinogenesis and tumour progression has led to an extensive search for interfering agents, resulting in the development of selective ET(A)R antagonists on the one hand and inhibitors of the endothelin-converting enzyme (ECE) on the other. Targeting the ET axis via ET(A)R or ECE blockade seems to be a promising approach in the treatment of female malignancies.

Expression of endothelin 2 and localized clear cell renal cell carcinoma

“…Post frozen robust multiarray analysis normalization [23], the average fold change of metastatic expression relative to patient-matched primary expression was 0.54 (p=0.007) for the probeset (206758_at) that mapped to ET-2. As such, therapeutics targeted at ET-2 could be studied further as a potential novel method for ccRCC chemoprevention (particularly in high risk individuals) as well as a neoadjuvant treatment for patients undergoing surgical excision of a clinically localized ccRCC tumor [24, 25]. Moreover, given that ET-2 encodes a secretory protein [5, 26], circulating levels of the ET-2 protein could also be explored as a marker of early disease in high risk populations as well.…”

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.

“…Increased expression of the endothelin axis has been documented in invasive ductal carcinoma (IDC) of the breast compared with that in the healthy breast or in noninvasive ductal carcinoma in situ. Elevated expression of ET-1 is more common in IDCs of larger size and high histologic grade and in the presence of lymphovascular invasion, as well as in the serum of breast cancer patients with lymph node metastases (Smollich and Wulfing 2007).…”

“…ECE-1 is overexpressed in breast carcinoma and its expression is associated with an unfavourable outcome . The expression of ET-1 and its receptors increase during the progression of breast carcinomas, correlating with the malignant potential (Smollich and Wulfing 2007). Moreover, elevated expression of members of the ET family, in particular the ET A R, is associated with reduced disease-free survival and overall survival.…”

Endothelin

“…Other cardiovascular-related diseases have shown promising clinical indications. Furthermore, exciting new results from basic science studies have associated endothelin antagonist therapy to many other cancer-related diseases, including targets for pharmacotherapy of female malignancies [105]. Without doubt, a detailed understanding of the molecular mechanisms of endothelin is a crucial step in identifying new effective therapies for other diseases.…”