To the editor:

After reading the article by Topczewska et al.1 implicating the role of the embryonic morphogen Nodal in melanoma pathogenesis, which I found to be extremely interesting, I was struck by the lack of scientific and historical perspective displayed by the authors. In particular, there is no mention or citation within their article of the possible expression of Cripto-1 in melanomas and its potential interactions with Nodal. Cripto-1 is an essential co-receptor for Nodal and is critical for Nodal's ability to function in a biological context through a Smad2/3 and FoxH1 signaling pathway. Nearly 20 years of research have demonstrated an important and essential role for Nodal in conjunction with Cripto-1 in early vertebrate development. In addition, the expression of Cripto-1 has been documented in a number of different types of human carcinomas, thereby exemplifying the importance of an early embryonic gene in the development of cancer where Cripto-1 may function to regulate epithelial-mesenchymal transition and tumor cell invasiveness2,3. Finally, there is evidence that Cripto can function through a Nodal-independent pathway via glypican-1 and src and that Nodal can function through a Cripto-1–independent signaling pathway during early development where it can act as a bone morphogenetic protein (BMP) antagonist. A more detailed examination as to the mechanism by which Nodal can regulate melanoma tumorigenesis and invasiveness is warranted.