1. Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, Ghent, Belgium
2. ^*Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium

Correspondence: Marc Bracke, Laboratory of Experimental Cancerology; Department of Radiotherapy and Nuclear Medicine, De Pintelaan 185, Ghent University Hospital, B-9000 Ghent, Belgium. Email: brackemarc@hotmail.com

Received 24 March 2003; Accepted 6 May 2003; Published online 25 September 2003.

Abstract

In a screening for new growth factors released by melanoma cells, we found that the p185-phosphorylating capacity of a medium conditioned by a melanoma cell line was due to the secretion of heregulin, a ligand for the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Expression of heregulin, including a new isoform, and secretion of functionally active protein was found in several cell lines. Receptor activation by heregulin, either autocrine or paracrine, resulted in a potent growth stimulation of both melanocytes and melanoma cells. Heregulin receptor HER3 and coreceptor HER2 were the main receptors expressed by these cells. Nevertheless, none of the cell lines in our panel overexpressed HER2 or HER3. In contrast, loss of HER3 was found in two cell lines, whereas one cell line showed loss of functional HER2, both types of deregulations resulting in unresponsiveness to heregulin. This implies the heregulin/HER system as a possible important physiologic growth regulatory system in melanocytes in which multiple deregulations may occur during progression toward melanoma, all resulting in, or indicating, growth factor independence.