Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation

Abstract

Cancer stem cells (CSC) are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, e.g., PROMININ-1 (PROM1, CD133)1. What remains unclear is whether CSC are the direct progeny of mutated stem cells, or more mature cells that reacquire stem cell properties during tumor formation. Answering this important question will require knowledge of whether normal stem cells are susceptible to cancer causing mutations; however, this has proved difficult to test since the identity of most adult tissue stem cells is not known. Here, using an inducible-Cre-nuclear(n)LacZ reporter allele knocked into the Prom1 locus (Prom1C-L), we show that Prom1 is expressed in a variety of developing and adult tissues. Lineage-tracing studies of adult Prom1+/C-L mice containing the Rosa26YFP reporter allele showed that Prom1+ cells are located at the base of crypts in the small intestine, co-express Lgr52, generate the entire intestinal epithelium, and are therefore likely to be the small intestinal stem cell. Prom1 was reported recently to mark CSC of human intestinal tumors that arise frequently as a consequence of aberrant Wingless (WNT) signaling3-5. Activation of endogenous Wnt signaling in Prom1+/C-L mice containing a Cre-dependent mutant allele of Beta-catenin (Ctnnb1lox(ex3)) resulted first in a gross disruption of crypt architecture and a disproportionate expansion of Prom1+ cells at the crypt base. Lineage-tracing demonstrated that the progeny of these cells replaced the mucosa of the entire small intestine with neoplastic tissue that was characterized by focal high-grade intraepithelial neoplasia and crypt adenoma formation. Although all neoplastic cells arose from Prom1+ cells in these mice, only 7% of tumor cells retained Prom1 expression. Our data indicate that Prom1 marks stem cells in the adult small intestine, which are susceptible to transformation into tumors retaining a fraction of mutant-Prom1+ tumor cells.

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…In parallel, the Ire1-dependent expansion of the ISC compartment increases the stochastic chance for genotoxic damage in these cells of origin of intestinal cancer (Barker et al, 2009;Zhu et al, 2009;Medema and Vermeulen, 2011;Schepers et al, 2012). Indeed, the Ire1 dependence of increased tumorigenesis in Xbp1 /(IEC) ;Apc min mice critically implies a fundamental role of ER stress sensing as a facilitator of CRC.…”

“…APC-associated CRC can be modeled in Apc mutant mice (Moser et al, 1990). Such a model has enabled the determination that ISCs are the cells of origin in CRC (Barker et al, 2009;Zhu et al, 2009;Schepers et al, 2012). The expansion of ISCs in Xbp1 /(IEC) mice, and the desire to delineate the specific tumor-promoting role of Xbp1 deficiency specifically in IECs, prompted us to Epithelial Xbp1 suppresses tumor formation in Apc min/+ mice Inflammatory signaling is an important contributor to CAC but also to sporadic and familial CRC (Rakoff-Nahoum and Medzhitov, 2007; Lee et al, 2010), with overlapping and distinct inflammatory pathways being involved (Salcedo et al, 2010).…”

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

“…Although cancer stem cell or stem cell-like cancer cell terminology is imperfect due to its distinct differences from normal stem cell, but it does capture the shared characteristics with normal stem cells especially somatic stem cells. In this review, we used "cancer stem cell" (CSC) terminology, which does not implicate that the cellof-origin of cancer stem cells has to be normal stem cell or progenitor, although several recent studies have demonstrated that normal tissue stem cells can be transformed to be cancer stem cells (Barker et al, 2009;Zhu et al, 2009). Cancer stem cells in malignant gliomas that were called glioma stem cells or GBM stem cells (GSCs) have been identified and characterized by several groups including our group (Hemmati et al, 2003;Galli et al, 2004;Singh et al, 2004;Bao et al, 2006aBao et al, , b, 2008Lee et al, 2006;Li et al, 2009).…”

Challenges in cancer research and multifaceted approaches for cancer biomarker quest

“…Cancer stem cells are remarkably similar to normal stem cells in respect to their ability to self-renew and be multipotent [11][12][13], but until now it was not clear whether cancer stem cells are the direct progeny of mutated stem cells or more mature cells that re-acquire stem cell characteristics during tumor formation. Using an inducible Cre, nuclear LacZ reporter allele knocked into the Prominin1 locus (Prom1(C-L), Zhu et al [14] showed that Prom1(+) enterocyte precursor cells located at the base of crypts in the small intestine represent small intestinal stem cell. Furthermore, lineage-tracing studies of adult Prom1(+/C-L) mice after activation of endogenous Wnt signalling pathway demonstrated disruption of crypt architecture with neoplastic transformation and importantly only progeny of Prom1(+) cells retaining Prom1 dependent reporter gene expression marked the fraction of cells that are susceptible to neoplastic transformation.…”