PC3 prostate tumor-initiating cells with molecular profile FAM65Bhigh/MFI2low/LEF1low increase tumor angiogenesis

Abstract

BackgroundCancer stem-like cells are proposed to sustain solid tumors by virtue of their capacity for self-renewal and differentiation to cells that comprise the bulk of the tumor, and have been identified for a variety of cancers based on characteristic clonal morphologies and patterns of marker gene expression.MethodsSingle cell cloning and spheroid culture studies were used to identify a population of cancer stem-like cells in the androgen-independent human prostate cancer cell line PC3.ResultsWe demonstrate that, under standard culture conditions, ~10% of PC3 cells form holoclones with cancer stem cell characteristics. These holoclones display high self-renewal capability in spheroid formation assays under low attachment and serum-free culture conditions, retain their holoclone morphology when passaged at high cell density, exhibit moderate drug resistance, and show high tumorigenicity in scid immunodeficient mice. PC3 holoclones readily form spheres, and PC3-derived spheres yield a high percentage of holoclones, further supporting their cancer stem cell-like nature. We identified one gene, FAM65B, whose expression is consistently up regulated in PC3 holoclones compared to paraclones, the major cell morphology in the parental PC3 cell population, and two genes, MFI2 and LEF1, that are consistently down regulated. This molecular profile, FAM65Bhigh/MFI2low/LEF1low, also characterizes spheres generated from parental PC3 cells. The PC3 holoclones did not show significant enriched expression of the putative prostate cancer stem cell markers CD44 and integrin α2β1. PC3 tumors seeded with holoclones showed dramatic down regulation of FAM65B and dramatic up regulation of MFI2 and LEF1, and unexpectedly, a marked increase in tumor vascularity compared to parental PC3 tumors, suggesting a role of cancer stem cells in tumor angiogenesis.ConclusionsThese findings support the proposal that PC3 tumors are sustained by a small number of tumor-initiating cells with stem-like characteristics, including strong self-renewal and pro-angiogenic capability and marked by the expression pattern FAM65Bhigh/MFI2low/LEF1low. These markers may serve as targets for therapies designed to eliminate cancer stem cell populations associated with aggressive, androgen-independent prostate tumors such as PC3.

Anticancer Properties of Teucrium persicum in PC-3 Prostate Cancer Cells

“…T persicum extract induced an epithelial-like phenotype in PC-3 cells together with cell membrane localization of E-Cadherin and β-Catenin proteins ( Figure 5 and Figure 6). PC-3 prostate cancer cells have a mesenchymal phenotype and are very invasive and produce tumors in laboratory animals (Zhou et al, 2009;Kandouz et al, 2010;Zhang and Waxman, 2010;Tai et al, 2011). Our results showed that in these cells, both E-Cadherin and β-Catenin proteins were cytoplasmic and cells having either protein at the cell membrane were extremely rare (Figures 5 and 6).…”

BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence

“…2d,e). Previous studies demonstrated that the PC3 cell line retains a small fraction of cells (~1%) that can initiate serially transplantable tumors 32,33 and can be distinguished by their ability to form holoclones, which are small, dense colonies with a high capacity for self-renewal 34,35 . Remarkably, unlike control knockdown cells, PC3 cells stably depleted of BAZ2A were unable to form holoclones and meroclones (an intermediate phenotype of holoclones) and generated only paraclones, which retain no self-renewal capacity ( Fig.…”

The Potential Target Therapy of Prostate Cancer Stem Cells

“…It has also been shown that holoclone-forming cells, cells whose progeny forms almost exclusively growing colonies, in prostate cancer specimens with the highest clonogenic potential were associated with stem cell phenotypes . More, the presence of large holoclones was also consistently observed in prostate cancer cell protaspheres (Li et al, 2008;Zhang & Waxman, 2010), suggesting that spheres with stem cell-like features have a higher proliferative potential. Indeed, protaspheres were capable of forming new generations of protaspheres and retained proliferative capacity as well as clonogenic potential after serial passages (Guzman-Ramirez et al, 2009).…”