Cell-to-Cell Signaling Influences the Fate of Prostate Cancer Stem Cells and Their Potential to Generate More Aggressive Tumors

Luisa Salvatori,Maria Rita Nicotra,Matteo Antonio Russo,Pier Giorgio Natali,Stefania Crispi,Emanuela Morgante,Raffaele Adolfo Calogero,Francesca Caporuscio,Alessandra Verdina,Giuseppe Starace,Andrea Russo,Elisa Petrangeli,Alfredo Fusco

doi:10.1371/journal.pone.0031467

Abstract

An increasing number of malignancies has been shown to be initiated and propelled by small subpopulations of cancer stem cells (CSC). However, whether tumor aggressiveness is driven by CSC and by what extent this property may be relevant within the tumor mass is still unsettled. To address this issue, we isolated a rare tumor cell population on the basis of its CD44+CD24− phenotype from the human androgen-independent prostate carcinoma cell line DU145 and established its CSC properties. The behavior of selected CSC was investigated with respect to the bulk DU145 cells. The injection of CSC in nude mice generated highly vascularized tumors infiltrating the adjacent tissues, showing high density of neuroendocrine cells and expressing low levels of E-cadherin and β-catenin as well as high levels of vimentin. On the contrary, when a comparable number of unsorted DU145 cells were injected the resulting tumors were less aggressive. To investigate the different features of tumors in vivo, the influence of differentiated tumor cells on CSC was examined in vitro by growing CSC in the absence or presence of conditioned medium from DU145 cells. CSC grown in permissive conditions differentiated into cell populations with features similar to those of cells held in aggressive tumors generated from CSC injection. Differently, conditioned medium induced CSC to differentiate into a cell phenotype comparable to cells of scarcely aggressive tumors originated from bulk DU145 cell injection. These findings show for the first time that CSC are able to generate differentiated cells expressing either highly or scarcely aggressive phenotype, thus influencing prostate cancer progression. The fate of CSC was determined by signals released from tumor environment. Moreover, using microarray analysis we selected some molecules which could be involved in this cell-to-cell signaling, hypothesizing their potential value for prognostic or therapeutic applications.

Highlights

Prostatic adenocarcinoma (PCa) is a leading cause of death among men in the United States and Western Europe [1]
As the presence of cancer stem cells (CSC) in PCa [19] and prostate cancer cell lines [20] was recently demonstrated on the basis of the surface antigenic profile CD44+/a2b1hi/CD133+ and CD44+CD242, respectively, in the present study we aimed to evaluate the contribution of CSC to tumor progression
Isolation and characterization of CSC from DU145 prostate cancer cells DU145 cells were enriched by fluorescence-activated cell sorting (FACS) for the population expressing CD44+CD242 [20] which represented about 10% of bulk DU145 cells (Figure 1A)

Summary

Introduction

Prostatic adenocarcinoma (PCa) is a leading cause of death among men in the United States and Western Europe [1]. An increased NE cell population in PCa is thought to be associated with a more aggressive disease, whereas a low number of NE cells in tumor tissue have no specific prognostic meaning [6,8,9]. Both NE and secretory epithelial lineage are derived from a common pluripotent prostate stem cell [10]

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Conclusion