Reviews
Endothelins as Autocrine Regulators of Tumor Cell Growth

https://doi.org/10.1016/S1043-2760(98)00094-0Get rights and content

Abstract

Endothelin 1 (ET-1) is produced by several types of human cancer cells and has been proposed to participate in tumor development or progression by exerting autocrine or paracrine actions on neoplastic cells and their surrounding stromal cells. Recently, an ET-1-mediated autocrine loop has been implicated in the growth of ovarian tumor cells. The co-expression of ET-1 and ETA receptors, with consequent activation of growth signaling pathways in human ovarian carcinoma cells, constitutes a mechanism for the autocrine regulation of tumor cell growth. Such findings also provide a basis for further investigation of the role of tyrosine phosphorylation in ET-1-regulated growth responses in ovarian tumor cells. The overexpression of ET-1 and its receptor in cancer cells may serve as a tumor marker, and could provide potential targets for therapy.

Section snippets

Role of Endothelin in Tumor Cell Growth

Neoplastic cells frequently produce bioactive substances, including hormones, cytokines, and growth factors, that influence not only their cells of origin but also the surrounding normal tissues and remote target organs. Such tumor products are thus capable of exerting autocrine, paracrine and endocrine actions. ET-1 appears to act predominantly as a paracrine mediator, as ET-1-producing cells are adjacent to ET-1 receptor-expressing cells in several neoplastic tissues.

ET-1 is produced in

ET-1 as an Autocrine Regulator of Tumor Growth

There is increasing experimental evidence (Table 1) in support of the proposal that the autocrine actions of growth factors produced by transformed cells might be important determinants of local and metastatic tumor growth (Sporn and Roberts, 1985Lang and Burgess, 1990). Early evidence for such an action of ET-1 on tumor cell growth was described by Shichiri et al. (1991)in epithelial carcinoma cell lines derived from the human cervix (HeLa) and larynx (Hep-2). Both cell types expressed ET

ET-1 as an Autocrine Growth Factor in Ovarian Carcinoma Cells

Recent studies on ovarian cancer have focused on factors that regulate the growth of malignant ovarian epithelium (Bast et al., 1992). Significant amounts of ET-1 mRNA are present in the ovary of several species. In the rat ovary, ETs are produced and act via ETB receptors to cause short-term stimulation but subsequent inhibition of gonadotropin-induced progesterone secretion (Kamada et al., 1993). In the human ovary, ET-1 has been detected in follicular fluid, and ET-1, ETA and ETB receptor

Conclusions and Perspectives

The above findings have demonstrated the biological relevance of the ET-1 autocrine loop in the development and maintenance of a variety of neoplasms. It is likely that the molecular mechanisms that underlie this activity are of multiple types. First, the presence of ET-1 in malignant but not normal ovarian tissue might indicate that ET-1 plays a role in tumor pathogenesis, and might represent a new prognostic factor in some malignancies. In addition to such increased production of autocrine

Acknowledgements

This work was supported by the Associazione Italiana Ricerca sul Cancro and Ministero della Sanità. We thank Drs Raffaele Tecce and Valeria Di Castro for their contributions to studies on ovarian cancer cells, and Dr Pier Giorgio Natali for helpful discussions.

References (45)

  • RC Bast et al.

    Editorial: malignant transformation of ovarian epithelium

    J Natl Cancer Inst

    (1992)
  • H Daub et al.

    Role of transactivation of the EGF receptor in signaling by G-protein-coupled receptors

    Nature

    (1996)
  • A Ergul et al.

    Endothelin-1 promotes steroidogenesis and stimulates protooncogene expression in transformed murine Leydig cell

    Endocrinology

    (1993)
  • H Inagaki et al.

    Autoradiographic localization of endothelin-1 binding sites in human colonic cancer tissue

    J Pathol

    (1992)
  • M Ishibashi et al.

    Production and secretion of endothelin by hepatocellular carcinoma

    J Clin Endocrinol Metab

    (1993)
  • S Kamada et al.

    Endothelin-1 is an autocrine/paracrine regulator of porcine granulosa cells

    J Endocrinol Invest

    (1993)
  • S Kamada et al.

    The role of endothelin-1 in regulating human granulosa cell proliferation and steroidogenesis in vitro

    J Clin Endocrinol Metab

    (1995)
  • M Kusuhara et al.

    Production of endothelin in human cancer cell lines

    Cancer Res

    (1990)
  • M Kusuhara et al.

    Stimulation of anchorage-independent cell growth by endothelin in NRK 49F cells

    Cancer Res

    (1992)
  • RG Ladenheim et al.

    Endothelins stimulate c-fos and nerve growth factor expression in astrocytes and astrocytoma

    J Neurochem

    (1993)
  • M Lange et al.

    Endothelin expression in normal human anterior pituitaries and pituitary adenomas

    J Clin Endocrinol Metab

    (1994)
  • M Lenziardi et al.

    Presence of endothelin-1 in the normal and pathological human thyroid

    Endocrinol Invest

    (1995)
  • Cited by (83)

    • Therapeutic potential of endothelin inhibitors in canine hemangiosarcoma

      2016, Life Sciences
      Citation Excerpt :

      The discovery of new therapeutic approaches that are aimed at novel molecular targets is imperative in veterinary medicine. Endothelin-1 (ET-1) is expressed in human tumors and is involved in a wide range of tumor-related processes, such as cell proliferation, inhibition of apoptosis, matrix remodeling, bone deposition and metastasis [4,5]. Endothelin type B receptor (ETB) antagonists inhibit cell growth and induce cell death in human melanoma cells in vitro [6].

    • Elevated expression of urotensin II and its receptor in diethylnitrosamine-mediated precancerous lesions in rat liver

      2011, Peptides
      Citation Excerpt :

      Although the precancerous stage of HCC is well-defined, the underlying molecular mechanisms leading to hepatocarcinogenesis remain largely unclear. Some vasoactive peptides are known to be produced and secreted by tumor cells and act as a paracrine growth stimulator [1]. Urotensin II (UII) is a cyclic somatostatin-like neuropeptide originally isolated from fish urophysis in 1985 [2].

    • Endothelin-Biology and disease

      2010, Cellular Signalling
    View all citing articles on Scopus
    View full text