The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations

Abstract

Characterization of the molecular pathways that are required for the viability and maintenance of self-renewing tumor-initiating cells may ultimately lead to improved therapies for cancer. In this study, we show that a CD133 ؉ /CD44 ؉ population of cells enriched in prostate cancer progenitors (PCaPs) has tumor-initiating potential and that these progenitors can be expanded under nonadherent, serum-free, sphere-forming conditions. Cells grown under these conditions have increased in vitro clonogenic and in vivo tumorigenic potential. mRNA expression analysis of cells grown under sphere-forming conditions, compared with long-term monolayer cultures, revealed preferential activation of the PI3K/AKT signaling pathway. PI3K p110␣ and ␤-protein levels were higher in cells grown under sphere-forming conditions, and phosphatase and tensin homolog (PTEN) knockdown by shRNA led to an increase in sphere formation as well as increased clonogenic and tumorigenic potential. Similarly, shRNA knockdown of FoxO3a led to an increase in tumorigenic potential. Consistent with these results, inhibition of PI3K activity by the dual PI3K/mTOR inhibitor NVP-BEZ235 led to growth inhibition of PCaPs. Taken together, our data strongly suggest that the PTEN/PI3K/Akt pathways are critical for prostate cancer stem-like cell maintenance and that targeting PI3K signaling may be beneficial in prostate cancer treatment by eliminating prostate cancer stem-like cells.FoxO3a ͉ PI3Kinase ͉ prostate cancer progenitors

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

“…The fact that CD90 þ cell populations reduce to only about 4% in CHGA07 monolayercultured cells as compared with 21.5% in xenografted CHGA07 tumors suggests that CSCs populations undergo differentiation and progression under in vitro culturing conditions, which leads to the loss of their CSCs properties. This interesting finding may possibly offer an explanation for why researchers were only able to identify rare CSC population in established cancer cell lines (Dubrovska et al, 2009;Fukuda et Trastuzumab targets the CSC population in gastric tumors J Jiang et al that our methods to establish primary tumor models might already allow the in vivo selection of aggressive and highly tumorigenic tumor subsets during tumor establishment. Thus, the CD90 þ population potentially could be lower in clinical samples.…”

“…Previously, it has been shown that neuro-sphere formation in vitro is useful for the isolation of neural stem cells (Reynolds and Weiss, 1992). Up to date, CSCs have been isolated from several types of tumors, including breast and prostate cancers, by similar approaches (Dontu et al, 2003;Dubrovska et al, 2009).…”

“…It has been shown that multiple pathways are involved in the self-renewal and tumor progression of CSCs, including Notch, Wnt, Hedgehog and phosphatidyl-inositol-3 kinase (PI3K) etc (Taipale and Beachy, 2001;Reya and Clevers, 2005;Farnie and Clarke, 2007;Dubrovska et al, 2009;Zhao et al, 2009). The ERBB2 (HER2) gene is amplified in approximately 20-30% of human breast and gastric cancers, in which it is associated with aggressive disease and early development of metastasis (Slamon et al, 1989;Tanner et al, 2005;Yano et al, 2006).…”

Tpl2 induces castration resistant prostate cancer progression and metastasis

“…Recently, activation of the PI3K/Akt signaling pathway is associated with enhanced PC cell proliferation, invasion, metastasis, chemo-/radio-resistance, stemness and EMT, which would indicate that PI3K-targeting modalities could be a promising method to eliminate CSCs and to overcome treatment-resistance of PC. [36][37][38] In this study, we identified Tpl2 as a master regulator that controls the EMT and stemness of CRPC. Although Tpl2 protein kinase does not directly phosphorylate PI3K, PI3K is a downstream component of FAK/Akt and CXCL12/CXCR4 signaling pathways.…”

“…Survival of mice was significantly increased following Tpl2 KD [PC3-shTpl2, 84 (57-90) days; PC3-shCon, 34 (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) days; Supporting Information Fig. 2a].…”