Alterations in signaling pathways of PCSCs

Alterations in the signaling pathways are probably one of the reasons why cancer stem cells gain a tumorigenic potential. Thus, disclosing the signaling pathways' expressional regulations might provide potential therapeutic targets. The WNT, JAK/STAT, NF-kB, NOTCH, and PI3K/AKT/mTOR signaling pathways were found to be the regulators of CSC biology in prostate tissue and therefore are candidate targets. The idea of inhibiting signaling that induces proliferation and survival could mean an effective therapy for PC [77].

Proteins acting in the WNT signaling pathway are usually over-expressed in PCSCs. Hence, tumorigenesis is promoted and prostaspheres which have self-renewal capacity exhibit proliferation, differentiation, and heterogeneous expression of stem cell-associated markers such as CD44, ABCG2 and CD133. When WNT inhibitors are applied the size of prostaspheres and their self-renewal ability can be reduced; plus, the CD133 and CD44 expressions are down-regulated. WNT activity also regulates the self-renewal capacity of PC cells that have stem cell-like features and inhibition of WNT signaling potentially reduces the self-renewal ability of PCSCs with an enviable therapeutic outcome [76].

The JAK/STAT signaling pathway seems to be important in PCSC biology. Than, when PCSCs expressing aldehyde dehydrogenase (ALDH+), which is involved in the formation of bone metastasis, were treated via a galiellactone- a specific STAT3 signaling inhibitor-; apop-tosis of cancerous cells could be induced [78]. Besides, in vivo targeting of STAT3 in a drug treated DU145 xenograft gave also desired results. Therefore, targeting of JAK/STAT signaling pathway components might be a promising therapeutic resulting in ALDH1A1 expres-sional down-regulation in PSCSs [78]. The importance of the NF-kB signaling pathway came up after the finding of enhanced functional signaling in purified nai've stem-like human prostatic TICs. When cells were treated with small molecular inhibitors that targeted the NF-kB

signaling pathway secondary sphere formation in vitro and tumor-initiation in vivo could be inhibited [59].

Cell fate specification, initiation of differentiation, and SC maintenance is regulated by the NOTCH signaling pathway in many tissues [79]. The over-expression of various proteins that function in the NOTCH signaling cascade has been found in a number of different tumors including PC. For example JAGGED-1, a NOTCH receptor ligand, has been found to be significantly more expressed in metastatic PC when compared with localized PC or benign prostatic tissue samples. This up-regulation also correlated with clinical features like recurrence, progression and metastasis of PC [80]. When Jagged-1 expression was down-regulated with small interfering RNAs (siRNAs) cell growth was inhibited and cell cycle arrest achieved in the S phase of cell division [81].

The PI3K/AKT/mTOR signaling pathway member PTEN was first identified as a candidate tumor suppressor gene that was frequently mutated in brain, breast, and prostate tumors [82]. Introduction of PTEN into cancer cells that lack PTEN function down-regulated cell migration and survival, and induced cell cycle arrest and apoptosis [82]. PTEN is the most mutated gene in metastatic PC that is advanced and has an aggressive tumor phenotype; and has been associated with cancer progression in 30-60% of PC cases [83]. An association between androgen-independent tumor growth and PTEN mutations has also been discovered [84]. A number of mouse models for PC suggested that PTEN might play a role in the initiation or early progression of this disease. PTEN heterozygous mice are likely to develop epithelial dysplasia and hyperplasia resembling high-grade PIN and adenocarcinoma [53, 85]. While PTEN mutations lead to a predisposition for PC in mouse models, such an association could not be shown for human yet [83, 84].

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