Patrizia Tunici - Academia.edu (original) (raw)

Papers by Patrizia Tunici

PDF file - 32K, Effects of different compound AXIN stabilizers on TNKS1 and TNKS2.

PDF file - 98K, In vitro response of T98G cells to WNT signaling inhibition.

Genetic alterations and in vivo tumorigenicity of neurospheres

Cancer immunology, immunotherapy : CII, Jan 9, 2018

British journal of cancer, Jan 21, 2009

Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of ma... more Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of malignant tumours. Diverse genetic programs regulate CSC behaviours, and CSCs from glioblastoma patients are qualitatively distinct from each other. The intrinsic connection between the presence of CSCs and malignancy is unclear. We set out to test whether tumour stem-like cells can be identified from benign tumours. Tumour sphere cultures were derived from hormone-positive and -negative pituitary adenomas. Characterisation of tumour stem-like cells in vitro was performed using self-renewal assays, stem cell-associated marker expression analysis, differentiation, and stimulated hormone production assays. The tumour-initiating capability of these tumour stem-like cells was tested in serial brain tumour transplantation experiments using SCID mice. In this study, we isolated sphere-forming, self-renewable, and multipotent stem-like cells from pituitary adenomas, which are benign tumours. We f...

Progress in brain research, 2001

Cytotechnology, 2003

Stem cells of different origin are under careful scrutiny as potential new tools for the treatmen... more Stem cells of different origin are under careful scrutiny as potential new tools for the treatment of several neurological diseases. The major focus of these reaserches have been neurodegenerative disorders, such as Huntington Chorea or Parkinson Disease (Shihabuddin et al., 1999). More recently attention has been devoted to their use for brain repair after stroke (Savitz et al., 2002). In this review we will focus on the potential of stem cell treatments for glioblastoma multiforme (Holland, 2000), the most aggressive primary brain tumor, and globoid cell leukodystrophy (Krabbe disease), a metabolic disorder of the white matter (Berger et al., 2001). These two diseases may offer a paradigm of what the stem cell approach may offer in term of treatment, alone or in combination with other therapeutic approaches. Two kinds of stem cells will be consideredhere: neural stem cells and hematopoietic stem cells, both obtained after birth. The review will focus on experimental models, with a...

International Journal of Cancer, 2012

Cancer Research, 2012

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. The aggress... more Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. The aggressive and highly invasive phenotype of these tumors makes them among the more destructive human cancers with a median survival of less than one year. In the different GBM tumor subtypes several altered genes and multiple pathways cooperate to promote and sustain tumor growth, tumor invasion and tumor recurrence. Although Wnt pathway activation was historically linked to the presence of mutations involving key components of the network (APC, β-catenin or AXIN proteins), an increasing number of studies suggest that aberrant Wnt signaling can also be initiated by several alternative mechanisms. Autocrine signaling mediated by specific Wnt ligands has been linked to lung, breast and pancreatic tumours, but also malignant melanoma cells spreading. Wnt signals, both positive and negative, form a class of paracrine growth factors that could act to influence multiple myeloma cell growth, metastati...

Cancer Research, 2012

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the adult central ner... more Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the adult central nervous system. The highly lethal nature of this tumor partly derives from the acquisition of an invasive phenotype, which allows the tumor cells to infiltrate the surrounding brain tissues. In fact the tumor cells, leading to the recurrence of the primary neoplasm highly contribute to the lack of success in eradicating this disease. Recent evidences suggested that a rare population of stem-like cells (or tumor initiating cells) present in brain tumors may be responsible for development of highly invasive and chemoresistant recurrent tumors. It was suggested that not all the cells from a given brain tumor show the same ability to proliferate and sustain the growth. Only a relatively small fraction of those cells, termed Brain Tumor Stem-like Cells (BTSCs), possess the ability to proliferate, self-renew extensively and adapt to very different micro-environments. Further investigations have demonstrated that BTSCs also more closely mirror the phenotype and genotype of the primary tumors, in fact when used in animal models they are able to generate a tumor that recapitulates the features of the human GBMs. The absence of stem cell specific markers has posed challenges to the identification and isolation of BTSCs from the bulk tumor cells in a definitive manner. Furthermore, recent findings suggest that the Hedgehog (HH) pathway is involved in BTSCs population maintaining in GBM. We report that in a commercially available human recurrent GBM line (DBTRG-05MG) and in different patients derived GBM cells; the key components required for an active HH pathway, such as PTCH1, SMO and SHH, are present and differently expressed according to culture conditions. Cells cultured in serum containing media, have a switched-off HH pathway, while cells kept in serum free containing media supplemented with EGF and bFGF to promote the formation of floating growing neurospheres, show a functional HH signaling pathway. These GBM cells respond to the same mitogens that activate normal adult neural stem cells showing multipotent differentiation properties and expressing markers of the normal stem cells lineage, such as Nestin, SOX2, Bmi1 and Musashi1. Proliferation assays performed using GBM patient-derived neurospheres clearly showed higher sensitivity to the different SMO antagonists tested when compared to the adherent counterpart cultured in serum containing media. The effect of small molecules SMO antagonists in self-renewal assays, confirmed the implication of the HH pathway in the growth of these stem-like cells. Taken together, these data demonstrate the presence of an operational HH pathway in human GBM derived neurospheres, and the ability of those cells to be applied in a drug discovery setting as a reliable SMO antagonists phenotypic testing tool. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3363. doi:1538-7445.AM2012-3363

Bioscience Reports, 2010

Pancreatic cancer stem-like cells are described by membrane expression of CD24, CD44 and ESA (epi... more Pancreatic cancer stem-like cells are described by membrane expression of CD24, CD44 and ESA (epithelial-specific antigen) and their capacity to grow as spheres in a serum-free medium containing well-defined growth factors. The capacity of a panel of four pancreatic cancer cell lines (PANC-1, CFPAC-1, PancTu-1 and PSN-1) to form spheres was tested. All cell lines with the exception of PancTu-1 developed spheres. Phenotypically, the sphere-growing cells showed an increased in vitro invasion capability. Both gene and protein expressions of markers of metastases [CXCR4 (CXC chemokine receptor 4), OPN (osteopontin) and CD44v6] and components of active hedgehog pathway signalling were assessed. Spheres clearly demonstrated increased expression of the above-mentioned markers when compared with their adherent counterpart. With the aim of identifying a minimum set of markers able to separate cells that have the capacity to form spheres from those incapable of forming spheres, a PCA (princip...

Biochimica et Biophysica Acta (BBA) - General Subjects, 1999

Frontiers in Pharmacology, 2018

DNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicit... more DNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicity and the immune recognition of neoplastic cells. This immunomodulatory activity of DHAs is linked to their ability to induce or to up-regulate on neoplastic cells the expression of a variety of immune molecules that play a crucial role in host-tumor immune interactions. To further investigate the clinical potential of diverse epigenetic compounds when combined with immunotherapeutic strategies, we have now compared the tumor immunomodulatory properties of the first generation DHAs, azacytidine (AZA) and decitabine (DAC) and of the next generation DHA, guadecitabine. To this end, human melanoma and hematological cancer cells were treated in vitro with 1 µM guadecitabine, DAC or AZA and then studied by molecular and flow cytometry analyses for changes in their baseline expression of selected immune molecules involved in different mechanism(s) of immune recognition. Results demonstrated a stronger DNA hypomethylating activity of guadecitabine and DAC, compared to AZA that associated with stronger immunomodulatory activities. Indeed, the mRNA expression of cancer testis antigens, immune-checkpoint blocking molecules, immunostimulatory cytokines, involved in NK and T cell signaling and recruiting, and of genes involved in interferon pathway was higher after guadecitabine and DAC compared to AZA treatment. Moreover, a stronger up-regulation of the constitutive expression of HLA class I antigens and of Intercellular Adhesion Molecule-1 was observed with guadecitabine and DAC compared to AZA. Guadecitabine and DAC seem to represent the optimal combination partners to improve the therapeutic efficacy of immunotherapeutic agents in combination/sequencing clinical studies.

Cancer immunology, immunotherapy : CII, Jan 20, 2017

Immunotherapy • Cancer vaccines • Checkpoint blockade agents • Targeted therapies • NIBIT Abbrevi... more Immunotherapy • Cancer vaccines • Checkpoint blockade agents • Targeted therapies • NIBIT Abbreviations ACT Adoptive cell therapy ADCC Antibody-dependent cell-mediated cytotoxicity AML Acute myeloid leukemia BED Biologically effective dose BM Brain metastases BRAFi BRAF inhibitor ccRCC Clear-cell renal cell carcinoma CIK Cytokine-induced killer CLL Chronic lymphocytic leukemia CRC Colorectal cancer CTA Cancer testis antigen DCR Disease control rate GITR Glucocorticoid-induced TNFR-related protein This meeting report is a summary of presentations from the Fourteenth Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT) on Cancer Bio-Immunotherapy, published together with a series of Focussed Research Reviews based on lectures given at the conference.

European Journal of Pharmaceutical Sciences, 2016

Preclinical imaging modalities represent an essential tool to develop a modern and translational ... more Preclinical imaging modalities represent an essential tool to develop a modern and translational biomedical research. To date, Optical Imaging (OI) and Magnetic Resonance Imaging (MRI) are used principally in separate studies for molecular imaging studies. We decided to combine OI and MRI together through the development of a lentiviral vector to monitor the Wnt pathway response to Lithium Chloride (LiCl) treatment. The construct was stably infected in glioblastoma cells and, after intracranial transplantation in mice, serial MRI and OI imaging sessions were performed to detect human ferritin heavy chain protein (hFTH) and firefly luciferase enzyme (FLuc) respectively. The system allowed also ex vivo analysis using a constitutive fluorescence protein expression. In mice, LiCl administration has shown significantly increment of luminescence signal and a lower signal of T2 values (P b 0.05), recorded noninvasively with OI and a 7 Tesla MRI scanner. This study indicates that OI and MRI can be performed in a single in vivo experiment, providing an in vivo proof-of-concept for drug discovery projects in preclinical phase.

European Journal of Medicinal Chemistry, 2015

Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initi... more Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.

Methods in molecular biology (Clifton, N.J.), 2009

The identification of a subpopulation of brain tumor cells with potent tumorigenic capacity stren... more The identification of a subpopulation of brain tumor cells with potent tumorigenic capacity strengthens the cancer stem cell hypothesis of the origin of the tumors that has recently attracted the attention of many researchers. Reports have been published on the identification of tumor cells with stem cells characteristics in different types of tumors (acute myelogenic leukemia, breast cancer, prostate cancer, bone sarcomas, liver cancer, and melanomas). We and other groups have previously reported the isolation of cancer stem cells from adult glioblastoma multiforme. These cells express stem cell markers, and when differentiated they express glial and neuronal markers. In vivo they give a tumor that recapitulates the characteristics of the tumor in the patient. More recently we have isolated tumor stem-like cells also from benign tumors like pituitary adenomas. Cells derived from pituitary adenomas are able to grow as floating aggregates resembling the neurospheres (typical of norma...

Molecular cancer, Jan 2, 2006

Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been id... more Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally...

PDF file - 32K, Effects of different compound AXIN stabilizers on TNKS1 and TNKS2.

PDF file - 98K, In vitro response of T98G cells to WNT signaling inhibition.

Genetic alterations and in vivo tumorigenicity of neurospheres

Cancer immunology, immunotherapy : CII, Jan 9, 2018

British journal of cancer, Jan 21, 2009

Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of ma... more Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of malignant tumours. Diverse genetic programs regulate CSC behaviours, and CSCs from glioblastoma patients are qualitatively distinct from each other. The intrinsic connection between the presence of CSCs and malignancy is unclear. We set out to test whether tumour stem-like cells can be identified from benign tumours. Tumour sphere cultures were derived from hormone-positive and -negative pituitary adenomas. Characterisation of tumour stem-like cells in vitro was performed using self-renewal assays, stem cell-associated marker expression analysis, differentiation, and stimulated hormone production assays. The tumour-initiating capability of these tumour stem-like cells was tested in serial brain tumour transplantation experiments using SCID mice. In this study, we isolated sphere-forming, self-renewable, and multipotent stem-like cells from pituitary adenomas, which are benign tumours. We f...

Progress in brain research, 2001

Cytotechnology, 2003

Stem cells of different origin are under careful scrutiny as potential new tools for the treatmen... more Stem cells of different origin are under careful scrutiny as potential new tools for the treatment of several neurological diseases. The major focus of these reaserches have been neurodegenerative disorders, such as Huntington Chorea or Parkinson Disease (Shihabuddin et al., 1999). More recently attention has been devoted to their use for brain repair after stroke (Savitz et al., 2002). In this review we will focus on the potential of stem cell treatments for glioblastoma multiforme (Holland, 2000), the most aggressive primary brain tumor, and globoid cell leukodystrophy (Krabbe disease), a metabolic disorder of the white matter (Berger et al., 2001). These two diseases may offer a paradigm of what the stem cell approach may offer in term of treatment, alone or in combination with other therapeutic approaches. Two kinds of stem cells will be consideredhere: neural stem cells and hematopoietic stem cells, both obtained after birth. The review will focus on experimental models, with a...

International Journal of Cancer, 2012

Cancer Research, 2012

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. The aggress... more Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. The aggressive and highly invasive phenotype of these tumors makes them among the more destructive human cancers with a median survival of less than one year. In the different GBM tumor subtypes several altered genes and multiple pathways cooperate to promote and sustain tumor growth, tumor invasion and tumor recurrence. Although Wnt pathway activation was historically linked to the presence of mutations involving key components of the network (APC, β-catenin or AXIN proteins), an increasing number of studies suggest that aberrant Wnt signaling can also be initiated by several alternative mechanisms. Autocrine signaling mediated by specific Wnt ligands has been linked to lung, breast and pancreatic tumours, but also malignant melanoma cells spreading. Wnt signals, both positive and negative, form a class of paracrine growth factors that could act to influence multiple myeloma cell growth, metastati...

Cancer Research, 2012

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the adult central ner... more Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the adult central nervous system. The highly lethal nature of this tumor partly derives from the acquisition of an invasive phenotype, which allows the tumor cells to infiltrate the surrounding brain tissues. In fact the tumor cells, leading to the recurrence of the primary neoplasm highly contribute to the lack of success in eradicating this disease. Recent evidences suggested that a rare population of stem-like cells (or tumor initiating cells) present in brain tumors may be responsible for development of highly invasive and chemoresistant recurrent tumors. It was suggested that not all the cells from a given brain tumor show the same ability to proliferate and sustain the growth. Only a relatively small fraction of those cells, termed Brain Tumor Stem-like Cells (BTSCs), possess the ability to proliferate, self-renew extensively and adapt to very different micro-environments. Further investigations have demonstrated that BTSCs also more closely mirror the phenotype and genotype of the primary tumors, in fact when used in animal models they are able to generate a tumor that recapitulates the features of the human GBMs. The absence of stem cell specific markers has posed challenges to the identification and isolation of BTSCs from the bulk tumor cells in a definitive manner. Furthermore, recent findings suggest that the Hedgehog (HH) pathway is involved in BTSCs population maintaining in GBM. We report that in a commercially available human recurrent GBM line (DBTRG-05MG) and in different patients derived GBM cells; the key components required for an active HH pathway, such as PTCH1, SMO and SHH, are present and differently expressed according to culture conditions. Cells cultured in serum containing media, have a switched-off HH pathway, while cells kept in serum free containing media supplemented with EGF and bFGF to promote the formation of floating growing neurospheres, show a functional HH signaling pathway. These GBM cells respond to the same mitogens that activate normal adult neural stem cells showing multipotent differentiation properties and expressing markers of the normal stem cells lineage, such as Nestin, SOX2, Bmi1 and Musashi1. Proliferation assays performed using GBM patient-derived neurospheres clearly showed higher sensitivity to the different SMO antagonists tested when compared to the adherent counterpart cultured in serum containing media. The effect of small molecules SMO antagonists in self-renewal assays, confirmed the implication of the HH pathway in the growth of these stem-like cells. Taken together, these data demonstrate the presence of an operational HH pathway in human GBM derived neurospheres, and the ability of those cells to be applied in a drug discovery setting as a reliable SMO antagonists phenotypic testing tool. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3363. doi:1538-7445.AM2012-3363

Bioscience Reports, 2010

Pancreatic cancer stem-like cells are described by membrane expression of CD24, CD44 and ESA (epi... more Pancreatic cancer stem-like cells are described by membrane expression of CD24, CD44 and ESA (epithelial-specific antigen) and their capacity to grow as spheres in a serum-free medium containing well-defined growth factors. The capacity of a panel of four pancreatic cancer cell lines (PANC-1, CFPAC-1, PancTu-1 and PSN-1) to form spheres was tested. All cell lines with the exception of PancTu-1 developed spheres. Phenotypically, the sphere-growing cells showed an increased in vitro invasion capability. Both gene and protein expressions of markers of metastases [CXCR4 (CXC chemokine receptor 4), OPN (osteopontin) and CD44v6] and components of active hedgehog pathway signalling were assessed. Spheres clearly demonstrated increased expression of the above-mentioned markers when compared with their adherent counterpart. With the aim of identifying a minimum set of markers able to separate cells that have the capacity to form spheres from those incapable of forming spheres, a PCA (princip...

Biochimica et Biophysica Acta (BBA) - General Subjects, 1999

Frontiers in Pharmacology, 2018

DNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicit... more DNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicity and the immune recognition of neoplastic cells. This immunomodulatory activity of DHAs is linked to their ability to induce or to up-regulate on neoplastic cells the expression of a variety of immune molecules that play a crucial role in host-tumor immune interactions. To further investigate the clinical potential of diverse epigenetic compounds when combined with immunotherapeutic strategies, we have now compared the tumor immunomodulatory properties of the first generation DHAs, azacytidine (AZA) and decitabine (DAC) and of the next generation DHA, guadecitabine. To this end, human melanoma and hematological cancer cells were treated in vitro with 1 µM guadecitabine, DAC or AZA and then studied by molecular and flow cytometry analyses for changes in their baseline expression of selected immune molecules involved in different mechanism(s) of immune recognition. Results demonstrated a stronger DNA hypomethylating activity of guadecitabine and DAC, compared to AZA that associated with stronger immunomodulatory activities. Indeed, the mRNA expression of cancer testis antigens, immune-checkpoint blocking molecules, immunostimulatory cytokines, involved in NK and T cell signaling and recruiting, and of genes involved in interferon pathway was higher after guadecitabine and DAC compared to AZA treatment. Moreover, a stronger up-regulation of the constitutive expression of HLA class I antigens and of Intercellular Adhesion Molecule-1 was observed with guadecitabine and DAC compared to AZA. Guadecitabine and DAC seem to represent the optimal combination partners to improve the therapeutic efficacy of immunotherapeutic agents in combination/sequencing clinical studies.

Cancer immunology, immunotherapy : CII, Jan 20, 2017

Immunotherapy • Cancer vaccines • Checkpoint blockade agents • Targeted therapies • NIBIT Abbrevi... more Immunotherapy • Cancer vaccines • Checkpoint blockade agents • Targeted therapies • NIBIT Abbreviations ACT Adoptive cell therapy ADCC Antibody-dependent cell-mediated cytotoxicity AML Acute myeloid leukemia BED Biologically effective dose BM Brain metastases BRAFi BRAF inhibitor ccRCC Clear-cell renal cell carcinoma CIK Cytokine-induced killer CLL Chronic lymphocytic leukemia CRC Colorectal cancer CTA Cancer testis antigen DCR Disease control rate GITR Glucocorticoid-induced TNFR-related protein This meeting report is a summary of presentations from the Fourteenth Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT) on Cancer Bio-Immunotherapy, published together with a series of Focussed Research Reviews based on lectures given at the conference.

European Journal of Pharmaceutical Sciences, 2016

Preclinical imaging modalities represent an essential tool to develop a modern and translational ... more Preclinical imaging modalities represent an essential tool to develop a modern and translational biomedical research. To date, Optical Imaging (OI) and Magnetic Resonance Imaging (MRI) are used principally in separate studies for molecular imaging studies. We decided to combine OI and MRI together through the development of a lentiviral vector to monitor the Wnt pathway response to Lithium Chloride (LiCl) treatment. The construct was stably infected in glioblastoma cells and, after intracranial transplantation in mice, serial MRI and OI imaging sessions were performed to detect human ferritin heavy chain protein (hFTH) and firefly luciferase enzyme (FLuc) respectively. The system allowed also ex vivo analysis using a constitutive fluorescence protein expression. In mice, LiCl administration has shown significantly increment of luminescence signal and a lower signal of T2 values (P b 0.05), recorded noninvasively with OI and a 7 Tesla MRI scanner. This study indicates that OI and MRI can be performed in a single in vivo experiment, providing an in vivo proof-of-concept for drug discovery projects in preclinical phase.

European Journal of Medicinal Chemistry, 2015

Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initi... more Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.

Methods in molecular biology (Clifton, N.J.), 2009

The identification of a subpopulation of brain tumor cells with potent tumorigenic capacity stren... more The identification of a subpopulation of brain tumor cells with potent tumorigenic capacity strengthens the cancer stem cell hypothesis of the origin of the tumors that has recently attracted the attention of many researchers. Reports have been published on the identification of tumor cells with stem cells characteristics in different types of tumors (acute myelogenic leukemia, breast cancer, prostate cancer, bone sarcomas, liver cancer, and melanomas). We and other groups have previously reported the isolation of cancer stem cells from adult glioblastoma multiforme. These cells express stem cell markers, and when differentiated they express glial and neuronal markers. In vivo they give a tumor that recapitulates the characteristics of the tumor in the patient. More recently we have isolated tumor stem-like cells also from benign tumors like pituitary adenomas. Cells derived from pituitary adenomas are able to grow as floating aggregates resembling the neurospheres (typical of norma...

Molecular cancer, Jan 2, 2006

Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been id... more Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally...