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: 9.81). 04/2008; 105(11):4329-34. DOI: 10.1073/pnas.0800467105
Source: PubMed

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 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, Aug 10, 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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    • "Most recently, our group showed that microenvironmentally induced changes in the expression patterns of specific T-cell specific, HMG-box (LEF/TCF) transcription factors may be important for the phenotype switching mechanism (Eichhoff et al., 2011). That the microenvironment is involved in phenotype switching is corroborated by the results of other groups who have explored its influence on melanoma gene expression and metastatic potential (Folberg et al., 2006; Postovit et al., 2008; Seftor et al., 2006). Several laboratories have considered the phenotype switching model and reported data supporting a relationship between factors expressed in a phenotype-specific manner and disease progression (Alexaki et al., 2010; Almanzar et al., 2009; Carreira et al., 2006; O'Connell et al., 2009; Orgaz et al., 2009). "
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    • "Pioneering studies in human melanoma showed that Nodal is secreted from aggressive melanoma cells and that blockade of Nodal signaling inhibited melanoma cell invasiveness , colony forming ability and tumorigenicity [12]. Nodal expression and tumorigenicity were also reduced in melanoma and breast cancer cell lines when they were grown in an embryonic microenvironment containing the Nodal antagonist Lefty [13]. Nodal was subsequently found to be expressed in cancerous but not normal prostate specimens and its overexpression in prostate cancer cell lines enhanced anchorage independent growth while inhibiting AR signaling and down regulating the expression of androgen-responsive genes [106]. "
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