Targeting CD133 improves chemotherapeutic efficacy of recurrent pediatric pilocytic astrocytoma following prolonged chemotherapy

Guifa Xi, Yuping Derek Li, Gordan Grahovac, Veena Rajaram, Nitin Wadhwani, Tatiana Pundy, Barbara Mania-Farnell, Charles David James, Tadanori Tomita

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system neoplasms. In the majority of cases these tumors are benign and receive favorable prognosis following gross total surgical resection. In patients with progressive or symptomatic tumors, aggressive surgical resection is generally not feasible, thus radiation or chemotherapy are accepted initial or adjuvant interventions. Due to serious long-lasting side-effects, radiation is limited in young children; therefore, chemotherapy is widely practiced as an adjuvant treatment for these patients. However, chemotherapy can promote the emergence of multidrug resistant tumor cells that are more malignant than those of the original tumor. CD133, a putative stem cell marker in normal tissue and malignant brain tumors, enhances multidrug resistant gene 1 (MDR1) expression following chemotherapy in adult malignant glioblastomas. This study examines the relationship between CD133 and MDR1 in pediatric PAs exposed to chemotherapy, with the goal of identifying therapeutic targets that manifest as a result of chemotherapy. Methods: Slides were obtained for 15 recurrent PAs, seven of which had received chemotherapy prior to surgical treatment for the recurrent tumor. These samples, as well as primary tumor tissue slides from the same patients were used to investigate CD133 and MDR1 expression via immunofluorescence. Archived frozen tissue samples from the same patients were used to examine CD133, MDR1 and PI3K-Akt-NF-ΚB signaling mediators, via western blot. Two drug resistant pediatric PA cell lines Res186 and Res199 were also used to evaluate the role of CD133 on cell response to cytotoxic therapy. Results: CD133 and MDR1 were co-expressed and their expression was elevated in recurrent PAs from patients that had received chemotherapy, compared to patients that had not received chemotherapy. PI3K-Akt-NF-ΚB signaling mediator expression was also elevated in recurrent, chemotherapy-treated PA. Suppressing CD133 expression with siCD133 decreased levels of PI3K-Akt-NF-ΚB signaling mediators and MDR1, while increasing cell chemosensitivity, as indicated by quantification of apoptotic cells following chemotherapy. Conclusions: CD133 contributes to multidrug resistance by regulating MDR1 levels via the PI3K-Akt-NF-ΚB signal pathway not only in adult glioblastomas, but also in pediatric PAs. Targeting CD133, adjuvant to conventional chemotherapy may improve outcomes for children with recurrent PA.

Original languageEnglish (US)
Article number21
JournalMolecular Cancer
Volume16
Issue number1
DOIs
StatePublished - Jan 31 2017

Fingerprint

Astrocytoma
Pediatrics
Drug Therapy
Phosphatidylinositol 3-Kinases
Neoplasms
Genes
Glioblastoma
Gene Expression
Central Nervous System Neoplasms
Radiation Effects
Multiple Drug Resistance
Therapeutics
Brain Neoplasms
Fluorescent Antibody Technique
Signal Transduction
Stem Cells
Western Blotting
Radiation

Keywords

  • CD133
  • Chemotherapy
  • MDR1
  • Pediatric pilocytic astrocytoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

Targeting CD133 improves chemotherapeutic efficacy of recurrent pediatric pilocytic astrocytoma following prolonged chemotherapy. / Xi, Guifa; Li, Yuping Derek; Grahovac, Gordan; Rajaram, Veena; Wadhwani, Nitin; Pundy, Tatiana; Mania-Farnell, Barbara; James, Charles David; Tomita, Tadanori.

In: Molecular Cancer, Vol. 16, No. 1, 21, 31.01.2017.

Research output: Contribution to journalArticle

Xi, Guifa ; Li, Yuping Derek ; Grahovac, Gordan ; Rajaram, Veena ; Wadhwani, Nitin ; Pundy, Tatiana ; Mania-Farnell, Barbara ; James, Charles David ; Tomita, Tadanori. / Targeting CD133 improves chemotherapeutic efficacy of recurrent pediatric pilocytic astrocytoma following prolonged chemotherapy. In: Molecular Cancer. 2017 ; Vol. 16, No. 1.
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abstract = "Background: Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system neoplasms. In the majority of cases these tumors are benign and receive favorable prognosis following gross total surgical resection. In patients with progressive or symptomatic tumors, aggressive surgical resection is generally not feasible, thus radiation or chemotherapy are accepted initial or adjuvant interventions. Due to serious long-lasting side-effects, radiation is limited in young children; therefore, chemotherapy is widely practiced as an adjuvant treatment for these patients. However, chemotherapy can promote the emergence of multidrug resistant tumor cells that are more malignant than those of the original tumor. CD133, a putative stem cell marker in normal tissue and malignant brain tumors, enhances multidrug resistant gene 1 (MDR1) expression following chemotherapy in adult malignant glioblastomas. This study examines the relationship between CD133 and MDR1 in pediatric PAs exposed to chemotherapy, with the goal of identifying therapeutic targets that manifest as a result of chemotherapy. Methods: Slides were obtained for 15 recurrent PAs, seven of which had received chemotherapy prior to surgical treatment for the recurrent tumor. These samples, as well as primary tumor tissue slides from the same patients were used to investigate CD133 and MDR1 expression via immunofluorescence. Archived frozen tissue samples from the same patients were used to examine CD133, MDR1 and PI3K-Akt-NF-ΚB signaling mediators, via western blot. Two drug resistant pediatric PA cell lines Res186 and Res199 were also used to evaluate the role of CD133 on cell response to cytotoxic therapy. Results: CD133 and MDR1 were co-expressed and their expression was elevated in recurrent PAs from patients that had received chemotherapy, compared to patients that had not received chemotherapy. PI3K-Akt-NF-ΚB signaling mediator expression was also elevated in recurrent, chemotherapy-treated PA. Suppressing CD133 expression with siCD133 decreased levels of PI3K-Akt-NF-ΚB signaling mediators and MDR1, while increasing cell chemosensitivity, as indicated by quantification of apoptotic cells following chemotherapy. Conclusions: CD133 contributes to multidrug resistance by regulating MDR1 levels via the PI3K-Akt-NF-ΚB signal pathway not only in adult glioblastomas, but also in pediatric PAs. Targeting CD133, adjuvant to conventional chemotherapy may improve outcomes for children with recurrent PA.",
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AU - Xi, Guifa

AU - Li, Yuping Derek

AU - Grahovac, Gordan

AU - Rajaram, Veena

AU - Wadhwani, Nitin

AU - Pundy, Tatiana

AU - Mania-Farnell, Barbara

AU - James, Charles David

AU - Tomita, Tadanori

PY - 2017/1/31

Y1 - 2017/1/31

N2 - Background: Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system neoplasms. In the majority of cases these tumors are benign and receive favorable prognosis following gross total surgical resection. In patients with progressive or symptomatic tumors, aggressive surgical resection is generally not feasible, thus radiation or chemotherapy are accepted initial or adjuvant interventions. Due to serious long-lasting side-effects, radiation is limited in young children; therefore, chemotherapy is widely practiced as an adjuvant treatment for these patients. However, chemotherapy can promote the emergence of multidrug resistant tumor cells that are more malignant than those of the original tumor. CD133, a putative stem cell marker in normal tissue and malignant brain tumors, enhances multidrug resistant gene 1 (MDR1) expression following chemotherapy in adult malignant glioblastomas. This study examines the relationship between CD133 and MDR1 in pediatric PAs exposed to chemotherapy, with the goal of identifying therapeutic targets that manifest as a result of chemotherapy. Methods: Slides were obtained for 15 recurrent PAs, seven of which had received chemotherapy prior to surgical treatment for the recurrent tumor. These samples, as well as primary tumor tissue slides from the same patients were used to investigate CD133 and MDR1 expression via immunofluorescence. Archived frozen tissue samples from the same patients were used to examine CD133, MDR1 and PI3K-Akt-NF-ΚB signaling mediators, via western blot. Two drug resistant pediatric PA cell lines Res186 and Res199 were also used to evaluate the role of CD133 on cell response to cytotoxic therapy. Results: CD133 and MDR1 were co-expressed and their expression was elevated in recurrent PAs from patients that had received chemotherapy, compared to patients that had not received chemotherapy. PI3K-Akt-NF-ΚB signaling mediator expression was also elevated in recurrent, chemotherapy-treated PA. Suppressing CD133 expression with siCD133 decreased levels of PI3K-Akt-NF-ΚB signaling mediators and MDR1, while increasing cell chemosensitivity, as indicated by quantification of apoptotic cells following chemotherapy. Conclusions: CD133 contributes to multidrug resistance by regulating MDR1 levels via the PI3K-Akt-NF-ΚB signal pathway not only in adult glioblastomas, but also in pediatric PAs. Targeting CD133, adjuvant to conventional chemotherapy may improve outcomes for children with recurrent PA.

AB - Background: Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system neoplasms. In the majority of cases these tumors are benign and receive favorable prognosis following gross total surgical resection. In patients with progressive or symptomatic tumors, aggressive surgical resection is generally not feasible, thus radiation or chemotherapy are accepted initial or adjuvant interventions. Due to serious long-lasting side-effects, radiation is limited in young children; therefore, chemotherapy is widely practiced as an adjuvant treatment for these patients. However, chemotherapy can promote the emergence of multidrug resistant tumor cells that are more malignant than those of the original tumor. CD133, a putative stem cell marker in normal tissue and malignant brain tumors, enhances multidrug resistant gene 1 (MDR1) expression following chemotherapy in adult malignant glioblastomas. This study examines the relationship between CD133 and MDR1 in pediatric PAs exposed to chemotherapy, with the goal of identifying therapeutic targets that manifest as a result of chemotherapy. Methods: Slides were obtained for 15 recurrent PAs, seven of which had received chemotherapy prior to surgical treatment for the recurrent tumor. These samples, as well as primary tumor tissue slides from the same patients were used to investigate CD133 and MDR1 expression via immunofluorescence. Archived frozen tissue samples from the same patients were used to examine CD133, MDR1 and PI3K-Akt-NF-ΚB signaling mediators, via western blot. Two drug resistant pediatric PA cell lines Res186 and Res199 were also used to evaluate the role of CD133 on cell response to cytotoxic therapy. Results: CD133 and MDR1 were co-expressed and their expression was elevated in recurrent PAs from patients that had received chemotherapy, compared to patients that had not received chemotherapy. PI3K-Akt-NF-ΚB signaling mediator expression was also elevated in recurrent, chemotherapy-treated PA. Suppressing CD133 expression with siCD133 decreased levels of PI3K-Akt-NF-ΚB signaling mediators and MDR1, while increasing cell chemosensitivity, as indicated by quantification of apoptotic cells following chemotherapy. Conclusions: CD133 contributes to multidrug resistance by regulating MDR1 levels via the PI3K-Akt-NF-ΚB signal pathway not only in adult glioblastomas, but also in pediatric PAs. Targeting CD133, adjuvant to conventional chemotherapy may improve outcomes for children with recurrent PA.

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KW - Chemotherapy

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