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

Mimeault M, Hauke R, Mehta PP, Batra SK - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: 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.These new targeted therapies should improve the efficacy of current therapeutic treatments against aggressive cancers, and thereby preventing disease relapse and enhancing patient survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Eppley Institute of Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. mmimeault@unmc.edu

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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4401269&req=5

fig02: 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.

Mentions: The isolation of cancer progenitor cells with the stem cell-like properties from diverse solid tumour specimens and cancer cell lines also supports the fact that melanoma, skin, head and neck, thyroid, cervix, lung, liver, breast, ovary, prostate, pancreas, gastrointestinal and retinal cancers may arise from the malignant transformation of tissue-specific adult stem cells and/or their early progenies (Table 1, 2) [39, 40,47, 49, 50, 54, 59, 61, 65, 68, 70, 71, 75, 76, 80, 83–87, 96, 98–105, 189]. Particularly, the re-activation of distinct growth factor signalling including EGFR, hedgehog, Wnt/β -catenin, Notch and/or integrin pathways, which frequently occurs in cancer progenitor cells during the cancer initiation and EMT program, may lead to different cancer subtypes (Fig. 1, 2) [13, 31, 35–37, 39, 40, 42, 49, 54–57, 59–62, 64, 102, 190, 191]. For instance, the occurrence of different malignant transforming events in breast stem cells during cancer initiation and/or accumulating of distinct genetic/epigenic alterations in breast cancer progenitor cells and/or their early progenies during cancer progression may result in the formation of different breast cancer subtypes [39, 42, 47, 56, 60, 68, 75, 77, 190, 192–196]. It has been observed that the targeted expression of stabilized -catenin in the basal epithelial cells of mouse mammary epithelium resulted in an enhanced proliferation of basal-type cell-like progenitor cells possessing an abnormal differentiation potential, whose oncogenic event led to development of invasive basal-type carcinomas [192]. Based on the gene expression signatures detected in distinct breast cancers including the expression levels of cytokeratin 5/6 (CK5/6), erbB2/HER-2/Neu, estrogen receptor (ERα) and/or progesterone receptor (PR), the invasive breast cancers have been classified at least five subtypes [8, 14, 156, 197–201]. Among them, there are the basal-like (CK5/6+, ERα−, PR−, erbB2−/low, EGFR+, vimentin+ and KIT+); erbB2+ overexpressing (ERα− and PR−; luminal A (ERα+ and/or PR+ and erbB2−); luminal B (ER + and/or PR+ and erbB2+) and normal breast-cancer subtype (high expression of normal epithelium genes and low expression of luminal epithelial gene products) [8, 14, 152, 197–201]. It has been observed that the ERα -negative breast cancer subtypes including the basal-like breast cancers and erbB2-overexpressing breast cancers, which are among the most aggressive breast cancer forms diagnosed, are generally associated with a poor prognosis and survival of patients to current clinical therapies [197–200, 202, 203]. Despite the activation of estrogen-ERα signalling cascade may contribute to ERα+-epithelial cell proliferation, it has been observed that the ovariectomy had no effect on the size of the mouse mammary EGFR+ stem cell-enriched population, which did not express ERα, PR or erbB2 [204, 205]. Moreover, the mouse ERα−breast cancer cells may express a lower level of E-cadherin than the ERα+ breast cancer cells, and therefore they can display a higher migratory capacity [206]. Although further studies are essential to confirm the implication of estrogens/ERα+ cascade for the proliferation of human ER − breast cancer progenitor cells, it appears likely that the different breast cancer subtypes may respond differently to the therapies consisting to targeting ERα, erbB2 and/or EGFR [202, 203, 207]. In this matter, we are reporting the specific functional properties of cancer progenitor cells that may contribute to their resistance to current therapies.


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

Mimeault M, Hauke R, Mehta PP, Batra SK - J. Cell. Mol. Med. (2007 Sep-Oct)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401269&req=5

fig02: 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.
Mentions: The isolation of cancer progenitor cells with the stem cell-like properties from diverse solid tumour specimens and cancer cell lines also supports the fact that melanoma, skin, head and neck, thyroid, cervix, lung, liver, breast, ovary, prostate, pancreas, gastrointestinal and retinal cancers may arise from the malignant transformation of tissue-specific adult stem cells and/or their early progenies (Table 1, 2) [39, 40,47, 49, 50, 54, 59, 61, 65, 68, 70, 71, 75, 76, 80, 83–87, 96, 98–105, 189]. Particularly, the re-activation of distinct growth factor signalling including EGFR, hedgehog, Wnt/β -catenin, Notch and/or integrin pathways, which frequently occurs in cancer progenitor cells during the cancer initiation and EMT program, may lead to different cancer subtypes (Fig. 1, 2) [13, 31, 35–37, 39, 40, 42, 49, 54–57, 59–62, 64, 102, 190, 191]. For instance, the occurrence of different malignant transforming events in breast stem cells during cancer initiation and/or accumulating of distinct genetic/epigenic alterations in breast cancer progenitor cells and/or their early progenies during cancer progression may result in the formation of different breast cancer subtypes [39, 42, 47, 56, 60, 68, 75, 77, 190, 192–196]. It has been observed that the targeted expression of stabilized -catenin in the basal epithelial cells of mouse mammary epithelium resulted in an enhanced proliferation of basal-type cell-like progenitor cells possessing an abnormal differentiation potential, whose oncogenic event led to development of invasive basal-type carcinomas [192]. Based on the gene expression signatures detected in distinct breast cancers including the expression levels of cytokeratin 5/6 (CK5/6), erbB2/HER-2/Neu, estrogen receptor (ERα) and/or progesterone receptor (PR), the invasive breast cancers have been classified at least five subtypes [8, 14, 156, 197–201]. Among them, there are the basal-like (CK5/6+, ERα−, PR−, erbB2−/low, EGFR+, vimentin+ and KIT+); erbB2+ overexpressing (ERα− and PR−; luminal A (ERα+ and/or PR+ and erbB2−); luminal B (ER + and/or PR+ and erbB2+) and normal breast-cancer subtype (high expression of normal epithelium genes and low expression of luminal epithelial gene products) [8, 14, 152, 197–201]. It has been observed that the ERα -negative breast cancer subtypes including the basal-like breast cancers and erbB2-overexpressing breast cancers, which are among the most aggressive breast cancer forms diagnosed, are generally associated with a poor prognosis and survival of patients to current clinical therapies [197–200, 202, 203]. Despite the activation of estrogen-ERα signalling cascade may contribute to ERα+-epithelial cell proliferation, it has been observed that the ovariectomy had no effect on the size of the mouse mammary EGFR+ stem cell-enriched population, which did not express ERα, PR or erbB2 [204, 205]. Moreover, the mouse ERα−breast cancer cells may express a lower level of E-cadherin than the ERα+ breast cancer cells, and therefore they can display a higher migratory capacity [206]. Although further studies are essential to confirm the implication of estrogens/ERα+ cascade for the proliferation of human ER − breast cancer progenitor cells, it appears likely that the different breast cancer subtypes may respond differently to the therapies consisting to targeting ERα, erbB2 and/or EGFR [202, 203, 207]. In this matter, we are reporting the specific functional properties of cancer progenitor cells that may contribute to their resistance to current therapies.

Bottom Line: 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.These new targeted therapies should improve the efficacy of current therapeutic treatments against aggressive cancers, and thereby preventing disease relapse and enhancing patient survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Eppley Institute of Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. mmimeault@unmc.edu

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.

Show MeSH
Related in: MedlinePlus