Prominin1 marks intestinal stem cells that are susceptible to neoplastic transformation

By Liqin Zhu, P. Gibson, D. Currle, Y. Tong, R. Richardson, I. Bayazitov, H. Poppleton, Stanislav S Zakharenko, D. Ellison, Richard J. Gilbertson. Nature, 2008

710 citations recorded by the source corpus.

Cancer stem cells are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, for example, prominin 1 (PROM1, also called CD133). What remains unclear is whether cancer stem cells are the direct progeny of mutated stem cells or more mature cells that reacquire stem cell properties during tumour formation. Answering this question will require knowledge of whether normal stem cells are susceptible to cancer-causing mutations; however, this has proved difficult to test because the identity of most adult tissue stem cells is not known. Here, using an inducible Cre, nuclear 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 Rosa26-YFP reporter allele showed that Prom1+ cells are located at the base of crypts in the small intestine, co-express Lgr5 (ref. 2), generate the entire intestinal epithelium, and are therefore the small intestinal stem cell. Prom1 was reported recently to mark cancer stem cells of human intestinal tumours that arise frequently as a consequence of aberrant wingless (Wnt) signalling. Activation of endogenous Wnt signalling in Prom1+/C-L mice containing a Cre-dependent mutant allele of β-catenin (Ctnnb1lox(ex3)) resulted 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 tumour cells retained Prom1 expression. Our data indicate that Prom1 marks stem cells in the adult small intestine that are susceptible to transformation into tumours retaining a fraction of mutant Prom1+ tumour cells.

Subfields: Genetics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/57231e2694d46d9ea1a905f84fa17e80fbd1a38b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Hugo J. G. Snippert
2. Hans Clevers
3. Jane E. Visvader
4. R. Nusse
5. Pengfei Lu

In Molecular Biology

1. Hans Clevers
2. Jane E. Visvader
3. Hugo J. G. Snippert
4. T. Schatton
5. M. Frank
6. N. Frank
7. R. Nusse
8. Zena Werb

In Oncology

1. Hans Clevers
2. Hugo J. G. Snippert
3. Jane E. Visvader
4. T. Schatton
5. M. Frank
6. N. Frank
7. Zena Werb
8. C. Blanpain

Citations in the corpus

• SSEA-1 Is an Enrichment Marker for Tumor-Initiating Cells in Human Glioblastoma (2009, background): “…data are applicable to the human and whether mRNA expression correlates with immunopositivity of CD133 antibodies that recognize glycosylationdependent epitopes remain unanswered questions (Coskun et al., 2008; Mirzadeh et al., 2008; Shmelkov et al., 2008; Uchida et al., 2000; Zhu et al., 2009).”
• The intestinal crypt, a prototype stem cell compartment. (2013, background): “Musashi-1 (Potten et al., 2003) and Prominin1/CD133 (Zhu et al., 2009) also mark Lgr5 stem cells, but their expression may extend into the lower TA compartment (Itzkovitz et al., 2012; Muñoz et al., 2012; Snippert et al., 2009).”
• The therapeutic promise of the cancer stem cell concept. (2010, background): “Based on the demonstrated utility and feasibility of the genetic lineage tracking approach for CSC identification in human malignant melanoma and the success of similar cell fate tracking techniques as part of CSC identification strategies in human breast and brain cancer (47) as well as in models o”
• Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. (2010, neutral): “Similar data were obtained using a CD133-based lineage tracing strategy (Zhu et al., 2009).”
• Tracking adult stem cells (2011, background): “Lineage tracings initiated in PROM1 + cells indicated the presence of long-lived, multilineage clones”
• Cells of origin in cancer (2011, background): “This target cell is also marked by CD133 (also known as PROM1 or prominin 1”