Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers

Abstract

Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. This review summarizes recent advances in our understanding of the cellular origin and molecular mechanisms at the basis of cancer initiation and progression as well as the heterogeneity of cancers arising from the malignant transformation of adult stem/progenitor cells. We describe the critical functions provided by several growth factor cascades, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF) receptor (KIT), hedgehog and Wnt/beta-catenin signalling pathways that are frequently activated in cancer progenitor cells and are involved in their sustained growth, survival, invasion and drug resistance. Of therapeutic interest, we also discuss recent progress in the development of new drug combinations to treat the highly aggressive and metastatic cancers including refractory/relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas and gastrointestinal cancers which remain incurable in the clinics. The emphasis is on new therapeutic strategies consisting of molecular targeting of distinct oncogenic signalling elements activated in the cancer progenitor cells and their local microenvironment during cancer progression. These new targeted therapies should improve the efficacy of current therapeutic treatments against aggressive cancers, and thereby preventing disease relapse and enhancing patient survival.

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Scheme showing the critical functions assumed by cancer progenitor cells and the bone-marrow derived circulating cells in the development of leukaemias, sarcomas, brain tumours and various epithelial cancers. The accumulating genetic alterations in haematopoietic stem cells (HSCs) and/or lymphoid or myeloid precursors, which may lead to the development of leukaemias, are shown. Moreover, the genetic alteration in the embryonic hemangioblast or neuroectodermal stem cell-derived progeny, which may lead to their persistence in adult life and subsequent hemangioblastoma or neuroectodermal tumour formation, is also indicated. The genetic or epigenic alterations in neural stem cells (NSCs) and/or neuronal and glial cell lineage precursors, whose molecular events may result in their malignant transformation into brain tumour stem cells (BTSCs) and the generation of malignant neuronal and glial cell lineage precursors, are also shown. In addition, the implication of tissue-specific adult stem cells and reactive stromal host cells including the activated fibroblasts, immune cells and bone-marrow-derived endothelial progenitor cells (EPCs) in the tumour neovascularization is also illustrated. Abbreviations: LSC, leukaemic stem cell; MMPs, matrix metalloproteinases; MPS, mesodermal progenitor cells; MSC, mesenchymal stem cell;SDF-1, stromal cell-derived factor-1;uPA, urokinase type plasminogen-activator.

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Scheme showing the possible oncogenic cascades involved in the stimulation of sustained growth, survival, migration and drug resistance of cancer progenitor cells. The intracellular elements induced through the activation of EGF-EGFR, PDGF/PDGFR, SCF/KIT, hedgehog (SHH/PTCH/GLI), Notch and Wnt/β -catenin signalling and possible cross-talks between these cascades are shown. The changes in the expression levels of numerous target gene products, including down-regulated E-cadherin and up-regulated matrix metalloproteinases (MMPs), urokinase plasminogen activator (uPA) and vascular endothelial growth factor (VEGF), which can contribute both to the malignant transformation of cancer progenitor cells during cancer progression and angiogenesis, are also indicated. Furthermore, the effects of pharmacological agents acting as the potent inhibitors of the oncogenic cascades including the selective inhibitors of EGF-EGFR system (gefitinib and erlotinib), smoothened hedgehog signalling element (cyclopamine), Notch (γ-secretase inhibitor) as well as Wnt/β -catenin cascades (monoclonal anti-Wnt antibody ‘mAb’) on the cancer cells are also indicated. Abbreviations: APC, adenomatous polyposis coli; ABCG2/BCRP-1, brain cancer resistence protein-1; CDK, cyclin-dependent kinase; CoA, co-activators; COX-2, cyclooxygenase-2; Dsh, Dishevelled; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Fzd, Frizzled receptor, GSKβ, glycogen synthase kinaseβ; ICN, intracellular domain of Notch; Iκ Bα, inhibitor of nuclear factor- κBβ; KIT, stem cell factor receptor; LEF, lymphocyte enhancer factor;LPR, lipoprotein co-receptor;MAPKs, mitogen-activated protein kinases;MEK, extracel-lular signal-related kinase kinase;NF-κ B, nuclear factor-kB;PI₃K, phosphatidylinositol-3’kinase; PTEN, tensin homo-logue deleted on chromosome 10;PDGF, platelet-derived growth factor;PDGFR, platelet-derived growth factor-receptor; PLC-γ, phospholipase C-γ; PTCH, hedgehog-patched receptor; SCF, stem cell factor; SHH, sonic hedgehog ligand;SMO, smoothened;TCL, T-cell factor;WIF-1, Wnt-inhibitory factor-1;Wnt, Wingless ligand.