Reprogramming of melanoma cells by embryonic microenvironments

Abstract

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...

Chick Embryo Extract Demethylates Tumor Suppressor Genes in Osteosarcoma Cells

“…These include studies with amphibian oocyte extracts [1] or zebrafish embryo extracts [8]. Epigenetic reprogramming of metastatic melanoma cells had been previously reported when the cells are injected into chick embryos [11,27]. Here we have shown for the first time the application of extracts from chick embryos in epigenetic reprogramming of osteosarcoma cells.…”

“…Similarly, exposure to an embryonic microenvironment can also exert a profound effect by epigenetically reprogramming tumor cells [20]. For example, when metastatic melanoma cells were injected into chicken or mouse embryos, the tumorigenicity and metastatic phenotypes of tumor cells were found to be suppressed [11,27]. Amphibian oocyte extracts [1] and zebrafish embryo extracts [8] were found to repress growth and induce apoptosis of breast cancer cells and colon cancer cells, respectively.…”

Endothelial Fate and Angiogenic Properties of Human CD34 + Progenitor Cells in Zebrafish

“…In fact, apart from previous investigations showing the fate of human cancer cells in the developing zebrafish 48 and the recent demonstration of angiogenic activity of mouse and human tumor cell lines, 46 no other evidence exists that human stem cells colonize the developing zebrafish embryos and respond to specific developmental cues. In this context, our results may also have important translational implication for in utero correction of vascular defects in human embryos by injected stem cells.…”

“…48 In addition, given the relative ease of zebrafish genetic manipulation systems, xenotransplantation of human cells in zebrafish has been proposed as a reference technique to define the properties of human cancer (stem) cells. 49 Our study is in line with these emerging concepts and shows the versatility of this system to also address fundamental human developmental and cell biology questions.…”

Hooked! Modeling human disease in zebrafish

“…More recently, the zebrafish system has emerged as reliable model for tumor transplantation assays (102,103). Cancer cell lines derived from different species and tissues have been transplanted into zebrafish in order to study tumor cell reprogramming (104), migration, metastasis, and effects on vasculogenesis (102,(104)(105)(106)(107)(108). The generation of the double pigmentation mutant casper (109,110), which has a completely transparent body even in adulthood, has greatly facilitated noninvasive tracing of tumor cells using fluorescent imaging techniques (111), making zebrafish a highly attractive transplantation model.…”