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In recent years, the reversion of the cancer phenotype of human melanoma cells in developing zebrafish and chick embryos has been reported. The aim of this review is to revise these and other related contributions regarding the regulation of embryonic cancer and to provide a framework with which to understand results from our laboratory on the interactions of human melanoma cells with post-implanted mouse embryos cultured in vitro. To this end, we used the A375 human melanoma cell line transfected with the green fluorescent protein (GFP) gene. Labeled cells were transplanted onto the surface of the developing visceral endoderm of 7.5 dpc mouse embryos. Subsequently, we cultured the transplanted embryos for three days and monitored the movements of GFP labeled human melanoma cells by confocal microscopy. Our results show that ectopic melanoma cells internalize and migrate inside the embryo body in a way reminiscent of neural crest cells. The absence of localized tumor growth after 72 hours of in vitro embryo co-culture suggests that malignant phenotype inhibiting factors are active at the gastrulating stage and during early organogenesis. These results complement previous reports of growth regulation of B16 mouse melanoma cells by 10 dpc mouse embryonic skin (Gerschenson et al., 1986). Further research is required to elucidate the final fate of melanoma cells in mammalian embryos and the details of the signaling pathways underlying tumor growth regulation. Understanding the regulation of melanoma cells by young embryos could represent a starting point for a developmental theory of the pathogenesis of melanoma, and for future developments of more physiologically-based anticancer therapies for this and indeed, other types of aggressive tumor. KEY WORDS: cancer stem cell, cancer microenvironment, melanoma reprogramming, melanoma regulation, embryonic control of cancer, stem cell reprogrammingIn the last decades, our knowledge about tumor pathogenesis has been growing in a constant manner. Even though many oncogenes and tumor suppressor genes have been identified, it is broadly accepted that they are not enough for governing tumor behavior and that the crosstalk between tumor cells and their microenvironment plays a critical role in cancer progression. Indeed, many studies have demonstrated that the malignant phenotype can be reverted by changes in the environmental conditions without altering the tumor cell genotype (Brinster, 1974;Postovit et al., 2007). The epigenetic reprogramming of malignant cells by embryonic environments has been suggested to be due to common regulatory signals shared by embryonic and tumor stem cells (Abbott et al., 2008). Supporting this proposal, several factors, Int. J. Dev. Biol. 53: 1563-1568 (2009) including members of the Wingless (Wnt), Notch and Transforming Growth Factor Beta (TGF-beta) superfamilies, have been recently identified as common molecular messengers involved in the interaction of both malignant tumor cells and embryonic stem cells with their respective micr...

Background information. The execution phase of apoptosis is characterized by extensive blebbing of the plasma membrane, which usually results in secondary lysis in vitro. To analyse the permeability of cellular membranes during this process, we induced apoptosis in human melanoma A375 cells that had been transfected with fluorescently tagged proteins which were targeted to different subcellular locations.Results. The dual treatment of resveratrol and butyrate produced a synergistic induction of apoptosis by blocking different phases of the cell cycle. Changes in the plasma membrane, nuclear envelope and nucleoli were monitored by time-lapse confocal microscopy. Fluorescently labelled proteins were not mis-localized from their original locations in any of the cells undergoing blebbing for several hours. Thus the maintenance of karyophilic and nucleolar proteins within the nucleus during the blebbing stage and the accessibility of vital selective chromatin dyes confirmed a functional preservation of the nuclear compartment until the final necrotic blister. The translocation of phosphatidylserine to the outer leaflet of the plasma membrane was not detected during the blebbing period. Conclusion.These results show that the functional integrity of the nuclear envelope and plasma membrane may be conserved until the end of the execution phase of apoptosis.

This study has been funded by the Basque Government, Dept. of Health grant 2007111063 and Dept. of Industry (Saiotek) grant S-PC11UN008. Jairo Perez-Sanz was the recipient of a grant from Fundación Jesús de Gangoiti Barrera. The authors have no conflicts of interest to declare.