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.
Highlights
Prostate cancer (PC) is among the most commonly diagnosed malignancies and is the second leading cause of cancerrelated deaths in men [1,2,3,4,5,6]
These recent advances in the last few years on establishment of the molecular mechanisms at the basis of prostate carcinogenesis and metastases have revealed that the alterations of a specific subset of gene products may occur in PC- and metastasis-initiating cells endowed with stem cell–like properties versus their progenies during PC etiopathogenesis and transition to locally invasive, metastatic and recurrent disease stages
It appears that the intrinsic properties of highly tumorigenic and migrating PC stem/progenitor cells and their acquisition of more malignant and multidrug resistance phenotypes during PC progression may contribute to their persistence at primary and secondary neoplasms, tumor regrowth and disease relapse after treatment initiation
Summary
Prostate cancer (PC) is among the most commonly diagnosed malignancies and is the second leading cause of cancerrelated deaths in men [1,2,3,4,5,6]. Progenitor cells during disease progression, including a migratory ability during the epithelial-mesenchymal transition (EMT) program, may lead to their invasion, dissemination through the peripheral circulation and metastases at distant sites, including bones, treatment resistance and disease relapse (Figure 1) [5,13, 46,47,50,51,52,56,57,58,59,60,63,64,65,67,68,72,73,74,75,76,77,78] In this matter, we review the most recent advancements on the establishment of the cellular origin of PCs and key signal transduction elements that can cooperate for the acquisition of more malignant phenotypes by PC stem/progenitor cells and their progenies during prostate carcinogenesis, metastases at bones and other distant sites and treatment resistance. REVIEW ARTICLE with a high risk of disease recurrence or relapse after treatment initiation
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