Ties of stemness may even bring about a more aggressive tumor phenotype [814]. CR-1 is an example of a gene which has been shown to play a role in regular stem cells and during EMT, and has also been located to be expressed within a CSC subpopulation contributing to early cancer progression [85, 86]. Inside the embryo, Cr-1 is detected at high levels through gastrulation, when epiblastic cells undergo EMT, facilitating their migration via the primitive streak and eventually giving rise towards the mesoderm and endoderm [30]. CR-1 has also been shown to promote EMT, migration, invasion and branching morphogenesis in vitro in mouse mammary epithelial cells and in vivo in mammary gland hyperplasias and in tumors derived from MMTV-CR-1 transgenic mice [879]. Furthermore, NMuMG mouseSemin Cancer Biol. Author manuscript; accessible in PMC 2015 December 01.Klauzinska et al.Pagemammary epithelial cells that overexpress the transcription Metabotropic Glutamate Receptors Proteins Gene ID element Msx2 undergo morphological and molecular modifications which can be usually related with EMT. Interestingly, a rise in Cr-1 expression was detected in NMuMG Msx2-transfected cells suggesting that Cr-1 may possibly market EMT in these cells [90]. Additionally, CR-1 is involved in tumor epithelial cell plasticity and may be an essential EMT regulator in conjunction with Snail, Slug, Twist, and Six1 [91]. Within this context, CR-1 can substantially boost Snail expression in mammary epithelial cells [87]. Noteworthy, CR-1 is enriched in a subpopulation of cancer cells with stem-like characteristics. Current proof has demonstrated the presence of two distinct subpopulations of cells possessing high and low levels of CR-1 expression in human embryonal carcinoma (EC) cells [92],, pluripotent stem cells derived from germ cell teratocarcinomas. Interestingly, each subpopulations behaved differently displaying distinct gene expression profiles and differences in vitro and in vivo with respect to oncogenic competency. The EC cell fraction containing higher levels of CR-1 formed tumor spheres inside a serum-free suspension culture with an efficiency substantially greater than the CR-1 low-expressing EC cells. Furthermore, when injected subcutaneously into nude mice, the CR-1 high-expressing EC cells had been able to generate tumors that had been bigger in size and with a shorter tumor latency period compared with tumors derived from CR-1 low-expressing cells [92]. In the identical context, elements on the Nodal/CR-1 signaling pathway had been located to be overexpressed in pancreatic stem cells which regulated self-renewal and in vivo tumorigenicity [93]. Blocking the Alk4/7 receptor reversed the chemoresistance of the pancreatic CSCs. Additionally, CR-1 has also been CD1c Proteins Accession identified inside a CSC population of hormone-responsive and refractory human prostate tumor cell lines getting distinct patterns of androgen metabolism, supporting a prospective function for this population in prostate oncogenesis and tumor progression [94]. Moreover, a smaller subpopulation of CR-1 expressing cells was isolated from metastatic melanoma cells and was identified as a marker for CSCs in melanoma [86]. Ultimately, a recent report described 3 signaling pathways namely canonical Wnt, non-canonical Wnt and TGF-, which induce an EMT program and subsequently function in an autocrine manner to maintain the mesenchymal stem cell state [95]. Remarkably, CR-1, collectively with other TGF- and Wnt members of the family and proangiogenic factors, was amongst the reported secreted proteins present inside the culture medium of.
