The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis

Abstract

The prostate contains classes of epithelial cells with variable differentiation status that may serve as targets for tumor initiation (8-10). Androgen cycling experiments suggest that stem cell activity is present in the prostate (11). These cells are thought to reside in the basal layer of the prostate because these cells are androgen-independent and preferentially retained in castrated rodents. Stem cells in the basal layer give rise to transit-amplifying epithelial cells (TACs) that differentiate to produce terminally differentiated secretory luminal cells (12).The most common form of human prostate cancer expresses luminal cell-specific markers (cytokeratins 8 and 18 and prostate-specific antigen) but low levels of the basal cell marker (p63), suggesting that the disease originates in terminally differentiated luminal cells (12,13). Some studies suggest that the disease is derived from high-grade prostatic intraepithelial neoplasia (PIN), which is believed to arise from intermediate epithelial cells (14). Other studies demonstrate that the majority of androgen-independent tumors express genes such as bcl-2 that are characteristic of the basal͞stem cell compartment in normal prostate tissue (8). Prostate cancers may arise from stem cells that undergo aberrant proliferation and differentiation to produce a heterogeneous population of cells expressing luminal-, basal-, and intermediate cell-specific genes (14, 15).The tissue recombination procedure developed by Cunha and Lung (16) uses fragments dissected from rat or mouse urogenital sinus mesenchyme (UGSM) in combination with adult epithelial tissue to regenerate prostate-like tissues. We developed a dissociated cell system to facilitate the study of unique prostate cell subpopulations to demonstrate that a subpopulation of murine prostate cells possesses stem-like capacity for de novo tubule regeneration (17). We find that Sca-1 (stem cell antigen-1), a glycosylphosphatidylinositol-linked cell surface protein known to enrich for somatic stem cells in other tissues (18,19), can be used to enrich for prostate-regenerating cells (PRCs). Sca-1 ϩ cell fractions contain an increased percentage of cells with immature cell properties, including replication quiescence, androgen independence, and multilineage differentiation potential. Perturbations of the PTEN͞AKT signaling axis in these cells result in the initiation of prostate tumorigenesis, and cancer progression is associated with a concomitant increase in Sca-1 ϩ cells. These studies suggest that Sca-1-enriched PRCs possess multiple stem͞progenitor cell properties and can serve as targets for the initiation of prostate tumorigenesis. Materials and Methods Infection of Dissociated Prostate Cells with Lentivirus and ProstateRegeneration. ␤-Actin GFP transgenic mice were purchased from The Jackson Laboratory [C57BL͞6-TgN(ACTbEGFP)1Osb]. Dissociated prostate cells were prepared from 6-to 10-week-old C57BL͞6 and ␤-actin GFP transgenic mice as described in ref.

Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions

“…Moreover, Wu et al recently demonstrated a tumor suppressive function of MAP3K7/TAK1 in a shTAK1 prostate cancer mouse model system. 6,31 Also considering the biological role of MAP3K7 as a regulator of cell growth, differentiation and apoptosis, 7-9 the evidence for MAP3K7 representing the relevant tumor suppressor gene on 6q15 is very strong.…”

Hox genes in hematopoiesis and leukemogenesis

“…These and more recent findings (Hope et al, 2004) strongly suggest that leukemic cells exist in a hierarchical state in which only a small number of cells are able to self-renew extensively, and thus capable of initiating and maintaining the leukemic clone. This hierarchical model of leukemia in which a rare stem cell initiates and maintains disease has since been extended to a range of other tumors including multiple myeloma (Matsui et al, 2004), mammary carcinomas (Ponti et al, 2005), colon cancer (O'Brien et al, 2007), prostate cancer (Xin et al, 2005) and brain tumors (Singh et al, 2004). Such findings raise great interest in both the target cells that can give origin to LSCs and the mechanisms underlying their key properties such as self-renewal.…”

Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression

“…Mixing experiments produce only monochromatic tubules, suggesting that they are also clonally derived (Azuma et al 2005;Xin et al 2005). IHC analysis of these prostatic grafts reveals both CK5-positive basal cells in the outer layer of most tubules and CK8-positive luminal cells in the inner regions (Fig.…”

“…Since then, populations enriched for stem cell activity have been isolated from many adult tissues using various magnetic bead and FACS techniques Stingl et al 2006;Corti et al 2007). We and other investigators first identified the glycosyl phosphatidylinositol-anchored cell surface protein Sca-1 as a marker that can enrich for prostate stem cell activity, using magnetic bead sorting methods combined with in vitro and in vivo readout assays (Burger et al 2005;Xin et al 2005). …”