Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

Abstract

Recent gene expression profiling analyses and gain-and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC-and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.

Phospho-Akt Immunoreactivity in Prostate Cancer: Relationship to Disease Severity and Outcome, Ki67 and Phosphorylated EGFR Expression

“…In the present study we found that there was a high correlation between tumour pAkt-IR and pEGFR-IR scores, confirming the study of Koumakpayi et al [17], and consistent both with the finding of a high (54%) co-expression of EGFR and pAkt in prostate tumour cells [10] and the known signalling interrelationship between these two parameters [19]. We have additionally been able to show using partial multiple regression analyses that this correlation is not due to a “third-party” correlation with either the Gleason score or Ki67-IR.…”

Expression array analysis of the hepatocyte growth factor invasive program

“…In contrast, HGF-induction of CXCL1 is completely consistent with reports that its expression is increased in high grade PCa [42], and that its product increases PCa cell migration and invasion [43], as well as PCa metastasis and chemoresistance [44,45]. HGF-induction of CXCR4 is consistent with reports that its product promotes metastasis in PCa [46,47] and other cancers where exogenous CXCL12 is available [48]. Similar to the multifaceted role of many inflammatory cytokines in cancer, Interferon alpha receptor 1 (IFNAR1) can mediate inflammation associated with PCa progression [49], but can also enable increased infiltration of T-and NK cells so as to prevent tumor de-differentiation and progression [50], suggesting that HGF-induction of IFNAR1 will have context dependent effects on cell migration and/or tumor metastasis.…”

Hedgehog signaling inhibition by the small molecule smoothened inhibitor GDC‐0449 in the bone forming prostate cancer xenograft MDA PCa 118b

“…Thus combinatorial targeting is a rational approach and may include both direct epithelial compartment targeting with cytotoxic agents and stromal-epithelial inhibition necessary to achieve maximised benefit [22, 23]. …”