The Experts below are selected from a list of 255 Experts worldwide ranked by ideXlab platform
David Malkin - One of the best experts on this subject based on the ideXlab platform.
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hypoxia enhances tumor stemness by increasing the invasive and Tumorigenic side population fraction
Stem Cells, 2008Co-Authors: Bikul Das, Rika Tsuchida, Gideon Koren, Sylvain Baruchel, David Malkin, Herman YegerAbstract:Although advances have been made in understanding the role of hypoxia in the stem cell niche, almost nothing is known about a potentially similar role of hypoxia in maintaining the tumor stem cell (TSC) niche. Here we show that a highly Tumorigenic fraction of side population (SP) cells is localized in the hypoxic zones of solid tumors in vivo. We first identified a highly migratory, invasive, and Tumorigenic fraction of post-hypoxic side population cells (SPm([hox]) fraction) in a diverse group of solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, and small-cell lung carcinoma. To identify the SPm((hox)) fraction, we used an "injured conditioned medium" derived from bone marrow stromal cells treated with hypoxia and oxidative stress. We found that a highly Tumorigenic SP fraction migrates to the injured conditioned medium in a Boyden chamber. We show that as few as 100 SPm((hox)) cells form rapidly growing tumors in vivo. In vitro exposure to hypoxia increases the SPm((hox)) fraction significantly. Quantitative real-time polymerase chain reaction and immunofluorescence studies showed that SPm((hox)) cells expressed Oct-4, a "stemness" gene having a potential role in TSC maintenance. In nude mice xenografts, SPm((hox)) cells were localized to the hypoxic zones, as demonstrated after quantum dot labeling. These results suggest that a highly Tumorigenic SP fraction migrates to the area of hypoxia; this migration is similar to the migration of normal bone marrow SP fraction to the area of injury/hypoxia. Furthermore, the hypoxic microenvironment may serve as a niche for the highly Tumorigenic fraction of SP cells.
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cisplatin treatment increases survival and expansion of a highly Tumorigenic side population fraction by upregulating vegf flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
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Cisplatin treatment increases survival and expansion of a highly Tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
Rika Tsuchida - One of the best experts on this subject based on the ideXlab platform.
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hypoxia enhances tumor stemness by increasing the invasive and Tumorigenic side population fraction
Stem Cells, 2008Co-Authors: Bikul Das, Rika Tsuchida, Gideon Koren, Sylvain Baruchel, David Malkin, Herman YegerAbstract:Although advances have been made in understanding the role of hypoxia in the stem cell niche, almost nothing is known about a potentially similar role of hypoxia in maintaining the tumor stem cell (TSC) niche. Here we show that a highly Tumorigenic fraction of side population (SP) cells is localized in the hypoxic zones of solid tumors in vivo. We first identified a highly migratory, invasive, and Tumorigenic fraction of post-hypoxic side population cells (SPm([hox]) fraction) in a diverse group of solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, and small-cell lung carcinoma. To identify the SPm((hox)) fraction, we used an "injured conditioned medium" derived from bone marrow stromal cells treated with hypoxia and oxidative stress. We found that a highly Tumorigenic SP fraction migrates to the injured conditioned medium in a Boyden chamber. We show that as few as 100 SPm((hox)) cells form rapidly growing tumors in vivo. In vitro exposure to hypoxia increases the SPm((hox)) fraction significantly. Quantitative real-time polymerase chain reaction and immunofluorescence studies showed that SPm((hox)) cells expressed Oct-4, a "stemness" gene having a potential role in TSC maintenance. In nude mice xenografts, SPm((hox)) cells were localized to the hypoxic zones, as demonstrated after quantum dot labeling. These results suggest that a highly Tumorigenic SP fraction migrates to the area of hypoxia; this migration is similar to the migration of normal bone marrow SP fraction to the area of injury/hypoxia. Furthermore, the hypoxic microenvironment may serve as a niche for the highly Tumorigenic fraction of SP cells.
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cisplatin treatment increases survival and expansion of a highly Tumorigenic side population fraction by upregulating vegf flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
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Cisplatin treatment increases survival and expansion of a highly Tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
Herman Yeger - One of the best experts on this subject based on the ideXlab platform.
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hypoxia enhances tumor stemness by increasing the invasive and Tumorigenic side population fraction
Stem Cells, 2008Co-Authors: Bikul Das, Rika Tsuchida, Gideon Koren, Sylvain Baruchel, David Malkin, Herman YegerAbstract:Although advances have been made in understanding the role of hypoxia in the stem cell niche, almost nothing is known about a potentially similar role of hypoxia in maintaining the tumor stem cell (TSC) niche. Here we show that a highly Tumorigenic fraction of side population (SP) cells is localized in the hypoxic zones of solid tumors in vivo. We first identified a highly migratory, invasive, and Tumorigenic fraction of post-hypoxic side population cells (SPm([hox]) fraction) in a diverse group of solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, and small-cell lung carcinoma. To identify the SPm((hox)) fraction, we used an "injured conditioned medium" derived from bone marrow stromal cells treated with hypoxia and oxidative stress. We found that a highly Tumorigenic SP fraction migrates to the injured conditioned medium in a Boyden chamber. We show that as few as 100 SPm((hox)) cells form rapidly growing tumors in vivo. In vitro exposure to hypoxia increases the SPm((hox)) fraction significantly. Quantitative real-time polymerase chain reaction and immunofluorescence studies showed that SPm((hox)) cells expressed Oct-4, a "stemness" gene having a potential role in TSC maintenance. In nude mice xenografts, SPm((hox)) cells were localized to the hypoxic zones, as demonstrated after quantum dot labeling. These results suggest that a highly Tumorigenic SP fraction migrates to the area of hypoxia; this migration is similar to the migration of normal bone marrow SP fraction to the area of injury/hypoxia. Furthermore, the hypoxic microenvironment may serve as a niche for the highly Tumorigenic fraction of SP cells.
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cisplatin treatment increases survival and expansion of a highly Tumorigenic side population fraction by upregulating vegf flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
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Cisplatin treatment increases survival and expansion of a highly Tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
Bikul Das - One of the best experts on this subject based on the ideXlab platform.
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hypoxia enhances tumor stemness by increasing the invasive and Tumorigenic side population fraction
Stem Cells, 2008Co-Authors: Bikul Das, Rika Tsuchida, Gideon Koren, Sylvain Baruchel, David Malkin, Herman YegerAbstract:Although advances have been made in understanding the role of hypoxia in the stem cell niche, almost nothing is known about a potentially similar role of hypoxia in maintaining the tumor stem cell (TSC) niche. Here we show that a highly Tumorigenic fraction of side population (SP) cells is localized in the hypoxic zones of solid tumors in vivo. We first identified a highly migratory, invasive, and Tumorigenic fraction of post-hypoxic side population cells (SPm([hox]) fraction) in a diverse group of solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, and small-cell lung carcinoma. To identify the SPm((hox)) fraction, we used an "injured conditioned medium" derived from bone marrow stromal cells treated with hypoxia and oxidative stress. We found that a highly Tumorigenic SP fraction migrates to the injured conditioned medium in a Boyden chamber. We show that as few as 100 SPm((hox)) cells form rapidly growing tumors in vivo. In vitro exposure to hypoxia increases the SPm((hox)) fraction significantly. Quantitative real-time polymerase chain reaction and immunofluorescence studies showed that SPm((hox)) cells expressed Oct-4, a "stemness" gene having a potential role in TSC maintenance. In nude mice xenografts, SPm((hox)) cells were localized to the hypoxic zones, as demonstrated after quantum dot labeling. These results suggest that a highly Tumorigenic SP fraction migrates to the area of hypoxia; this migration is similar to the migration of normal bone marrow SP fraction to the area of injury/hypoxia. Furthermore, the hypoxic microenvironment may serve as a niche for the highly Tumorigenic fraction of SP cells.
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cisplatin treatment increases survival and expansion of a highly Tumorigenic side population fraction by upregulating vegf flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
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Cisplatin treatment increases survival and expansion of a highly Tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
Sylvain Baruchel - One of the best experts on this subject based on the ideXlab platform.
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hypoxia enhances tumor stemness by increasing the invasive and Tumorigenic side population fraction
Stem Cells, 2008Co-Authors: Bikul Das, Rika Tsuchida, Gideon Koren, Sylvain Baruchel, David Malkin, Herman YegerAbstract:Although advances have been made in understanding the role of hypoxia in the stem cell niche, almost nothing is known about a potentially similar role of hypoxia in maintaining the tumor stem cell (TSC) niche. Here we show that a highly Tumorigenic fraction of side population (SP) cells is localized in the hypoxic zones of solid tumors in vivo. We first identified a highly migratory, invasive, and Tumorigenic fraction of post-hypoxic side population cells (SPm([hox]) fraction) in a diverse group of solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, and small-cell lung carcinoma. To identify the SPm((hox)) fraction, we used an "injured conditioned medium" derived from bone marrow stromal cells treated with hypoxia and oxidative stress. We found that a highly Tumorigenic SP fraction migrates to the injured conditioned medium in a Boyden chamber. We show that as few as 100 SPm((hox)) cells form rapidly growing tumors in vivo. In vitro exposure to hypoxia increases the SPm((hox)) fraction significantly. Quantitative real-time polymerase chain reaction and immunofluorescence studies showed that SPm((hox)) cells expressed Oct-4, a "stemness" gene having a potential role in TSC maintenance. In nude mice xenografts, SPm((hox)) cells were localized to the hypoxic zones, as demonstrated after quantum dot labeling. These results suggest that a highly Tumorigenic SP fraction migrates to the area of hypoxia; this migration is similar to the migration of normal bone marrow SP fraction to the area of injury/hypoxia. Furthermore, the hypoxic microenvironment may serve as a niche for the highly Tumorigenic fraction of SP cells.
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cisplatin treatment increases survival and expansion of a highly Tumorigenic side population fraction by upregulating vegf flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.
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Cisplatin treatment increases survival and expansion of a highly Tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling
Oncogene, 2008Co-Authors: Rika Tsuchida, Bikul Das, Herman Yeger, Gideon Koren, Masabumi Shibuya, Paul S. Thorner, Sylvain Baruchel, David MalkinAbstract:The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly Tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-Tumorigenic osteosarcoma SP fraction to a highly Tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of Tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly Tumorigenic SP fraction.