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.

Figure 1

Molecular oncogenic events associated with PC initiation and progression to a locally invasive disease stage and bone metastasis and novel targeting therapies. The scheme shows the PC initiation through the accumulation of genetic and epigenetic alterations in prostate-resident adult stem cells resulting in their malignant transformation into tumorigenic PC stem/progenitor cells also designated as PC-initiating cells. The transformation of tumorigenic PC stem/progenitor cells into migrating PC stem/progenitor cells, which may be induced through the sustained activation of distinct growth factor signaling pathways during the EMT program and PC progression, is also shown. Furthermore, the possible invasion of certain tumorigenic and migrating PC stem/progenitor cells in the activated stroma, which may lead to their dissemination through the peripheral circulation at distant sites including bones along chemoattractant ligand gradient systems such as SDF-1/CXCR4, is illustrated. The activation of metastasis-initiating cells under specific microenvironmental conditions prevalent at bone induced via the release of diverse paracrine growth factors and cytokines by fibroblasts and bone cells, and that is associated with the formation of secondary tumor formation at bone, is also illustrated. The release of growth factors and cytokines such as SHH, TGF-α, TGF-β and MIC-1 by PC cells that can induce in a paracrine manner the differentiation of either osteoblast or osteoclast precursors into osteoblasts or osteoclasts, thereby causing the osteoblastic lesion (new bone formation) or osteolytic lesion (bone destruction) in certain cases, is also indicated. In addition, the molecular targeting of distinct gene products deregulated in PC- and metastasis-initiating cells, which might constitute a potential strategy to improve current treatments, eradicate the total PC cell mass and prevent disease relapse, is also indicated.

Figure 2

Frequent oncogenic pathways involved in the malignant transformation of PC stem/progenitor cells and their progenies during PC progression and metastases. The activation of the EGFR, sonic hedgehog SHH/PTCH/GLI, Wnt/β-catenin, HA/CD44, TGFβ/TGFβR, ECM component/β1-integrin and SDF-1/CXCR4 signaling pathways, which may contribute to the sustained growth, survival and migration of PC stem/progenitor cells and their progenies and possible interactions between these signaling cascades, are shown. The activation of the downstream signaling elements including PI3K/Akt, mitogen-activated protein kinases, NF-κB and focal adhesion kinase (FAK), which in turn contribute to the upregulation of the expression of different target genes involved in the malignant transformation of PC stem/progenitor cells and their progenies during the EMT process and treatment resistance, are indicated. More specifically, the inhibition of p21^CIP1 and p27^KIPI inhibitors of cyclin-dependent kinases induced through these growth factor cascades may cooperate to promote the cell cycle progression and growth of PC cells, while the enhanced expression of antiapoptotic factors such as Bcl-2, Bcl-xL and inhibitor of apoptosis protein (IAP) and phosphorylation of Bad may promote their survival. In addition, the potential stimulation of HIFs via the activation of mTOR and under hypoxic conditions, which may contribute to the enhanced glycolysis and acquisition of a more malignant behavior and chemoresistance of PC cells and tumor angiogenesis, is also illustrated.

Figure 3

Novel therapeutic strategies against aggressive, invasive and metastatic PC cancers by targeting distinct growth factor signaling cascades and drug resistance–associated molecules in prostatic cancer stem/progenitor cells and their progenies. The possible antiproliferative, antiinvasive and/or apoptotic effects induced by a specific inhibitor of tyrosine kinase activity of EGFR (gefitinib and erlotinib), receptor tyrosine kinase (RTK) activity, smoothened (SMO) hedgehog signaling element (cyclopamine and GDC-0449), Notch (γ-secretase inhibitor) and Wnt/β-catenin (sFRP2) as well as TGFβR antagonist or CXCR4 antagonist (AM3100) and monoclonal antibody (mAb) directed against SHH ligand, CD44, Wnt ligand or CXCR4 are indicated. Moreover, the inhibitory effect induced by different pharmacological agents on the downstream signaling effectors induced through these growth factor cascades and under hypoxic conditions such as PI3K/Akt/mTOR, NF-κB and HIFs as well as an inhibitor of glycolytic metabolism (2-DG) and 2-DG–induced autophagy (metformin) is also indicated. In addition, the potent inhibitory effect mediated by a specific inhibitor of EGFR or hedgehog on ABCG2-multidrug efflux pump and whose event may lead to the intracellular accumulation of chemotherapeutic drugs is also illustrated.