Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells

Abstract

Embryonic stem cells sustain a microenvironment that facilitates a balance of self-renewal and differentiation. Aggressive cancer cells, expressing a multipotent, embryonic cell-like phenotype, engage in a dynamic reciprocity with a microenvironment that promotes plasticity and tumorigenicity. However, the cancerassociated milieu lacks the appropriate regulatory mechanisms to maintain a normal cellular phenotype. Previous work from our laboratory reported that aggressive melanoma and breast carcinoma express the embryonic morphogen Nodal, which is essential for human embryonic stem cell (hESC) pluripotency. Based on the aberrant expression of this embryonic plasticity gene by tumor cells, this current study tested whether these cells could respond to regulatory cues controlling the Nodal signaling pathway, which might be sequestered within the microenvironment of hESCs, resulting in the suppression of the tumorigenic phenotype. Specifically, we discovered that metastatic tumor cells do not express the inhibitor to Nodal, Lefty, allowing them to overexpress this embryonic morphogen in an unregulated manner. However, exposure of the tumor cells to a hESC microenvironment (containing Lefty) leads to a dramatic down-regulation in their Nodal expression concomitant with a reduction in clonogenicity and tumorigenesis accompanied by an increase in apoptosis. Furthermore, this ability to suppress the tumorigenic phenotype is directly associated with the secretion of Lefty, exclusive to hESCs, because it is not detected in other stem cell types, normal cell types, or trophoblasts. The tumor-suppressive effects of the hESC microenvironment, by neutralizing the expression of Nodal in aggressive tumor cells, provide previously unexplored therapeutic modalities for cancer treatment.Lefty ͉ Nodal ͉ melanoma ͉ breast carcinoma

Expression of the embryonic morphogen Nodal in cutaneous melanocytic lesions

“…15 Furthermore, Nodal expression was detected by western blot in aggressive melanoma cell lines but not in cultured benign melanocytes. 15,17 Similar to the previous report, we detected high levels of Nodal expression in deep malignant melanomas and metastatic malignant melanomas. However, we also observed low levels of Nodal expression in some benign and dysplastic nevi, as well as isolated benign epidermal melanocytes.…”

“…The discrepancy between our observations and those of previous investigators might be due to differences in antibody sensitivity and/or the larger sample size of this study. In addition, Nodal expression has been shown to be sensitive to microenvironmental cues; 17 hence, Nodal expression patterns in cultured melanocytic cells may differ from in vivo expression. However, our results agree with the impression that Nodal expression increases with melanoma progression.…”

“…34 Conversely, Lefty and Cerberus, which do not require Cripto to mediate inhibition of Nodal signaling, are not expressed in melanoma cell lines. 17,32,35,36 Further studies are required to correlate these in vitro findings with patterns of Cripto expression in melanocytic lesions.…”

Role of Lefty in the anti tumor activity of human adult liver stem cells

“…The target protein of Lefty A, Nodal, an embryonal morphogen known to promote cell proliferation, 17 as well as Cripto, the co-receptor of Nodal, were expressed in HLSC, but not in MSC, suggesting an autocrine regulation of Lefty-Nodal pathway in HLSC similar to that described in embryonic stem cells. 2 On the other hand, HepG2 expressed Cripto and Nodal in the absence of Lefty expression, suggesting a deregulated pathway of Nodal-dependent proliferation (Figure 2c). …”

“…9 Current studies showed that the human embryonic stem cell microenvironment specifically neutralizes the embryonic morphogen Nodal in metastatic melanoma and breast carcinoma cells, reprogramming them to a less aggressive phenotype. 2 Uncovered embryonic stem cell-secreted Lefty, an inhibitor of Nodal signalling, is one of the important mediator of these phenomenona. 10 --13 Nodal is an embryonic morphogen that belongs to TGF-beta super family involved in maintenance of embryonic stem cell pluripotency.…”