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

Program in Cancer Biology and Epigenomics, Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2008; 105(11):4329-34. DOI: 10.1073/pnas.0800467105
Source: PubMed


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 cancer-associated 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.

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Available from: Lynne-Marie Postovit, Oct 09, 2015
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    • "Similarly, Nodal is expressed in a diversity of tumours, including melanoma, prostate, breast and testicular cancer (Hardy et al., 2010; Lawrence et al., 2011; Lonardo et al., 2011; Spiller et al., 2012; Strizzi et al., 2012; Topczewska et al., 2006), with the degree of tumour malignancy correlating with the amount of secreted Nodal (Spiller et al., 2012). In addition, the Nodal co-receptor Cripto is widely overexpressed in tumour cells from many different origins, and correlates with invasiveness and poor prognosis in melanoma, pancreatic cancer, breast cancer and testicular cancer (Lonardo et al., 2011; Postovit et al., 2008). "
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    ABSTRACT: Activin/Nodal growth factors control a broad range of biological processes, including early cell fate decisions, organogenesis and adult tissue homeostasis. Here, we provide an overview of the mechanisms by which the Activin/Nodal signalling pathway governs stem cell function in these different stages of development. We describe recent findings that associate Activin/Nodal signalling to pathological conditions, focusing on cancer stem cells in tumorigenesis and its potential as a target for therapies. Moreover, we will discuss future directions and questions that currently remain unanswered on the role of Activin/Nodal signalling in stem cell self-renewal, differentiation and proliferation. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(4):607-619. DOI:10.1242/dev.091769 · 6.46 Impact Factor
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    • "It has been shown that when the Nodal/TGF-Lefty pathway goes wrong, serious malignant transformation may occur. In malignant melanoma cells, for example, LEFTY inhibits the malignant properties of melanoma cells [19] [20], [21]. During the early differentiation of HES cells, LEFTY is expressed in a subset of cells, playing an important role in mesodermal cell differentiation [22]. "
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    ABSTRACT: Background Nodal/TGF-Lefty signaling pathway has important effects at early stages of differentiation of human embryonic stem cells in directing them to differentiate into different embryonic lineages. LEFTY, one of transforming growth factors in the Nodal/TGF-Lefty signaling pathway, plays an important role in the development of heart. The aim of this work was to find evidence on whether Lefty variations are associated with congenital heart diseases (CHD). Methods We sequenced the Lefty gene for 230 Chinese Han CHD patients and evaluated SNPs rs2295418, rs360057 and g.G169A, which are located within the translated regions of the genes. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using online software OEGE, and multiple-sequence alignments of LEFTY proteins were carried out using the Vector NTI software. Results Two heterozygous variants in Lefty1 gene, g.G169A and g.A1035C, and one heterozygous variant in Lefty2 gene, g.C925A, were identified. Statistical analyses showed that the rs2295418 (g.C925A) variant in Lefty2 gene was obviously associated with the risk of CHD (P value = 0.016<0.05). The genotype frequency of rs360057 (g.A1035C) variant in Lefty1 gene was associated with the risk of CHD (P value = 0.007<0.05), but the allele frequency was not (P value = 0.317>0.05). Conclusions The SNP rs2295418 in the Lefty2 gene is associated with CHD in Chinese Han populations.
    PLoS ONE 08/2014; 9(8):e104535. DOI:10.1371/journal.pone.0104535 · 3.23 Impact Factor
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    • "It has been shown that there is a cancer stem cell subset in a wide variety of solid tumors. Cancer stem cells (CSCs) are relatively resistant to therapy, and they are suggested to be responsible for cancer recurrence and probably metastasis in many tumor systems, including brain [5], prostate [5], pancreatic [6], and melanoma tumors [7]. CSCs represent a novel target for drug discovery for cancer; however, the mechanisms that regulate the self-renewal and multipotency of CSCs remain unclear. "
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    ABSTRACT: Colorectal cancer is one of the most common and fatal tumors. However, molecular mechanisms underlying carcinogenesis of colorectal cancer remain largely undefined. Here, we explored the expression and function of Nodal in colon cancer stem cells (CCSCs). Nodal and its receptors were present in numerous human colorectal cancer cell lines. NODAL and ALK-4 were coexpressed in human colon cancerous tissues, and NODAL, CD24, and CD44, markers for CCSCs, were expressed at higher levels in human colon cancerous tissues than adjacent noncancerous colon tissues. Human CCSCs were isolated by magnetic activated cell sorting using anti-CD24 and anti-CD44. Nodal transcript and protein were hardly detectable in CD44- or CD24-negative human colorectal cancer cell lines, whereas Nodal and its receptors were present in CCSCs. Notably, Nodal facilitated spheroid formation of human CCSCs, and phosphorylation of Smad2 and Smad3 was activated by Nodal in cells of spheres derived from human CCSCs. Collectively, these results suggest that Nodal promotes the self-renewal of human CCSCs and mediate carcinogenesis of human colorectal cancer via an autocrine manner through Smad2/3 pathway. This study provides a novel insight into molecular mechanisms controlling fate of human CCSCs and offers new targets for gene therapy of human colorectal cancer.
    02/2014; 2014:364134. DOI:10.1155/2014/364134
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