Trends in Endocrinology & Metabolism
ReviewsEndothelins as Autocrine Regulators of Tumor Cell Growth
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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)
- et al.
Growth regulatory properties of endothelins
Peptides
(1993) - et al.
Endothelin-1 expression by human hepatocellular carcinoma
Biochem Biophys Res Commun
(1995) - et al.
Decreased ETB receptor expression in human metastatic melanoma cells
Biochem Biophys Res Commun
(1996) - et al.
Autocrine growth factors and tumorigenic transformation
Immunol Today
(1990) - et al.
Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1
J Biol Chem
(1993) - et al.
Human melanoma cells express functional endothelin-1 receptors
Biochem Biophys Res Commun
(1994) - et al.
Focal adhesion kinase (p125FAK): a point of convergence in the action of neuropeptides, integrins, and oncogenes
Cell
(1992) - et al.
Autocrine actions of endothelin-1 as a growth factor in human ovarian carcinoma cells
Clin Cancer Res
(1995) - et al.
Activation of mitogenic signaling by endothelin-1 in ovarian carcinoma cells
Cancer Res
(1997) - et al.
Endothelin messenger RNA and receptors are differentially expressed in cultured human breast epithelial and stromal cells
J Clin Invest
(1990)
Editorial: malignant transformation of ovarian epithelium
J Natl Cancer Inst
Role of transactivation of the EGF receptor in signaling by G-protein-coupled receptors
Nature
Endothelin-1 promotes steroidogenesis and stimulates protooncogene expression in transformed murine Leydig cell
Endocrinology
Autoradiographic localization of endothelin-1 binding sites in human colonic cancer tissue
J Pathol
Production and secretion of endothelin by hepatocellular carcinoma
J Clin Endocrinol Metab
Endothelin-1 is an autocrine/paracrine regulator of porcine granulosa cells
J Endocrinol Invest
The role of endothelin-1 in regulating human granulosa cell proliferation and steroidogenesis in vitro
J Clin Endocrinol Metab
Production of endothelin in human cancer cell lines
Cancer Res
Stimulation of anchorage-independent cell growth by endothelin in NRK 49F cells
Cancer Res
Endothelins stimulate c-fos and nerve growth factor expression in astrocytes and astrocytoma
J Neurochem
Endothelin expression in normal human anterior pituitaries and pituitary adenomas
J Clin Endocrinol Metab
Presence of endothelin-1 in the normal and pathological human thyroid
Endocrinol Invest
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