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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.

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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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fig01: 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.

Mentions: Numerous investigations have provided evidence that the genetic and/or epigenic alterations occurring in the multi-potent tissue-specific adult stem cells and/or their early progenies may lead to their malignant transformation into cancer progenitor cells also designated as cancer stem cells or cancer-initiating cells (Fig. 1 and 2) [3, 13, 37, 39–41, 47–53, 55, 57, 60, 62–65]. A small population of undifferentiated- or poorly differentiated cancer progenitor cells, which possesses the stem cell-like properties including their self-renewal ability and capacity to give rise to the bulk mass of further differentiated malignant cells, appears to represent the principal cancer cells that are responsible for leukaemia or tumour formation [13, 39, 40, 47, 59, 63, 66–76]. Accumulating genetic and/or epigenic alterations in leukaemic or tumourigenic cancer progenitor cells occurring during cancer progression, and more particularly the acquisition of a migratory phenotype by tumour cells during epithelial-mesenchymal transition (EMT) program, may also confer to them the invasive properties that are essential for their migration to distant metastatic sites [39, 40, 49, 64, 72, 73, 77–81]. This cancer progenitor cell model of carcinogenesis is notably supported by the fact that the poorly differentiated and highly-leukaemic or tumourigenic cancer progenitor cells isolated from patients'malignant tissue specimens may give rise to the bulk mass of further differentiated cancer cells ex vitro and in vivo, and thereby be responsible for leukaemia or tumour development (Fig. 1; Table 1, 2) [47, 63, 66–70, 72, 73, 75, 76]. Recent investigations have also revealed that a very small sub-population of cancer progenitor cells with stem cell-like properties may be isolated from well-established cancer cell lines and maintained under an undifferentiated or poorly differentiated state during long years in culture, and this even after multiple passages in medium containing serum [47, 59, 65–69, 72, 73, 75, 76, 82–84]. In regard with this, we describe here the recent investigations that have led to the isolation of cancer progenitor cells from numerous cancer types and the establishment of their functional properties ex vitro and in animal models in vivo.


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 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.
© Copyright Policy
Related In: Results  -  Collection

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

fig01: 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.
Mentions: Numerous investigations have provided evidence that the genetic and/or epigenic alterations occurring in the multi-potent tissue-specific adult stem cells and/or their early progenies may lead to their malignant transformation into cancer progenitor cells also designated as cancer stem cells or cancer-initiating cells (Fig. 1 and 2) [3, 13, 37, 39–41, 47–53, 55, 57, 60, 62–65]. A small population of undifferentiated- or poorly differentiated cancer progenitor cells, which possesses the stem cell-like properties including their self-renewal ability and capacity to give rise to the bulk mass of further differentiated malignant cells, appears to represent the principal cancer cells that are responsible for leukaemia or tumour formation [13, 39, 40, 47, 59, 63, 66–76]. Accumulating genetic and/or epigenic alterations in leukaemic or tumourigenic cancer progenitor cells occurring during cancer progression, and more particularly the acquisition of a migratory phenotype by tumour cells during epithelial-mesenchymal transition (EMT) program, may also confer to them the invasive properties that are essential for their migration to distant metastatic sites [39, 40, 49, 64, 72, 73, 77–81]. This cancer progenitor cell model of carcinogenesis is notably supported by the fact that the poorly differentiated and highly-leukaemic or tumourigenic cancer progenitor cells isolated from patients'malignant tissue specimens may give rise to the bulk mass of further differentiated cancer cells ex vitro and in vivo, and thereby be responsible for leukaemia or tumour development (Fig. 1; Table 1, 2) [47, 63, 66–70, 72, 73, 75, 76]. Recent investigations have also revealed that a very small sub-population of cancer progenitor cells with stem cell-like properties may be isolated from well-established cancer cell lines and maintained under an undifferentiated or poorly differentiated state during long years in culture, and this even after multiple passages in medium containing serum [47, 59, 65–69, 72, 73, 75, 76, 82–84]. In regard with this, we describe here the recent investigations that have led to the isolation of cancer progenitor cells from numerous cancer types and the establishment of their functional properties ex vitro and in animal models in vivo.

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