title: 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 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.
authors.affiliation: Program in Cancer Biology and Epigenomics, Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614, USA.
authors.forename: Lynne-Marie
authors.initials: LM
authors.lastname: Postovit
authors.forename: Naira V
authors.initials: NV
authors.lastname: Margaryan
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Seftor
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Kirschmann
authors.forename: Alina
authors.initials: A
authors.lastname: Lipavsky
authors.forename: William W
authors.initials: WW
authors.lastname: Wheaton
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Abbott
authors.forename: Richard E B
authors.initials: RE
authors.lastname: Seftor
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
mesh_terms: D018929:Cell Culture Techniques; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D055457:Nodal Protein; D010641:Phenotype; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014410:Tumor Stem Cell Assay
chemical_list: C526007:NODAL protein, human; D055457:Nodal Protein; D016212:Transforming Growth Factor beta