Ion Chiricuta Comprehensive Cancer Center

Cluj-Napoca, Romania

Ion Chiricuta Comprehensive Cancer Center

Cluj-Napoca, Romania
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Susman S.,Ion Chiricuta Comprehensive Cancer Center | Susman S.,University of Medicine and Pharmacy, Cluj-Napoca | Tomuleasa C.,Ion Chiricuta Comprehensive Cancer Center | Tomuleasa C.,Johns Hopkins University | And 8 more authors.
Journal of B.U.ON. | Year: 2012

Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide. The partial failure of classic therapeutic options makes scientists to doubt the efficacy of systemic treatments in targeting the essential cell populations and achieving cure as a final goal. Overgrowing data suggest that cancer is a disease closely linked to stem cells (SCs). It is well known that the first identification of cancer stem-like cells in acute myeloid leukaemia was soon followed by similar results in solid malignancies, including colorectal cancer, and the classic model for colon carcinogenesis supports the development of sudden mutations that will lead to the activation or inactivation of certain oncogenes or tumor suppressors. Thus, this process may go on for years before the first symptoms and the only cells able to withstand for many years, avoid apoptosis and have a high regenerative capacity are the progenitor cells found at the lower part of colon crypts. A more profound study of the mechanisms and molecular signalling pathways that control the basic characteristics of SCs, such as asymmetrical division or self-renewal, may help comprehend the basic mechanisms of cancer genesis and progression. This will result in the development of new therapeutic agents that may target chemoresistant cell populations and improve the therapeutic results. In the current review we point out the importance of cancer stem-like cells in colorectal oncology from a pathologist's point of view, stating the obvious correlation between histology, embryology and surgical pathology. © 2012 Zerbinis Medical Publications.


Tomuleasa C.,Ion Chiricuta Comprehensive Cancer Center | Kacso G.,Ion Chiricuta Comprehensive Cancer Center | Soritau O.,Ion Chiricuta Comprehensive Cancer Center | Susman S.,University of Medicine and Pharmacy, Cluj-Napoca | And 2 more authors.
Romanian Journal of Morphology and Embryology | Year: 2010

Similar to normal organs arising from normal stem cells, cancers can be viewed as organs composed of heterogeneous cellular populations arising from cancer cells with indefinite proliferation abilities. The continuous malignant progression is maintained by the proliferation of cancer stem cells and not the progeny that undergo limited proliferation before terminally differentiating. Effective therapy must eradicate malignant cells with unlimited clonogenic expansion within the primary tumor bulk. Thus, resolving both the specific cell of origin for prostate cancer and the interactions between the cells and the surrounding microenvironment within the cancer stem cell niche are crucial to appropriately define rational targets for therapeutic intervention and cure prostate cancer.


Petrushev B.,University of Medicine and Pharmacy, Cluj-Napoca | Tomuleasa C.,Johns Hopkins University | Tomuleasa C.,Ion Chiricuta Comprehensive Cancer Center | Soritau O.,Ion Chiricuta Comprehensive Cancer Center | And 12 more authors.
Experimental Oncology | Year: 2012

Objectives: Metformin, the most used oral antidiabetic drug for the treatment of type 2 diabetus mellitus, has proved encouraging results when used in the treatment of various types of cancer such as triple-negative breast cancer. Despite compelling evidence of a role of metformin as an anticancer drug, the mechanisms by which metformin exerts its oncostatic actions are not fully understood yet. Therefore, we tried to bring new insights by analyzing the anti-neoplastic effect of metformin for hepatocellular carcinoma- derived stem-like cells treated with conventional combination chemotherapy. Methods: Cancer stem-like cells previusly isolated from a hepatocellular carcinoma biopsy were treated with metformin, PIAF chemotherapy regimen and the combination of these two protocols. Measurements of lipid peroxidation, reduced glutathione, fluorescein diacetate and proliferation rates were determined, apart from the autophagy assay and apoptosis determination by chip flow cytometry. Results: Metformin alone and especially metformin in association with PIAF increases oxidative stress within the cells by increasing the levels of lipid peroxids as well as decreasing the levels of reduced glutathione. The MTT cell proliferation assay showed decreased prolife ration rates for the arm treated with metformin and with the combination of drugs in comparison with the control arm, proving high correlation with the oxidative stress results. The autophagy assay and determination of apoptosis by chip flow cytometry confirmed the results obtained in the previous assays. Conclusion: Metformin could be used in chemotherapy treatments to induce reactive oxygen species and increase the cytostatics effects within the tumor cell. Still, further experiments must be carried out on murine models before we can move on and use this drugs in the adjuvant setting for unresectable primary liver cancer. metformin, chemotherapy, hepatocellular carcinoma, stem-like cells. Copyright © Experimental Oncology, 2012.


Carmignani M.,University of L'Aquila | Volpe A.R.,University of L'Aquila | Aldea M.,University of Medicine and Pharmacy, Cluj-Napoca | Soritau O.,Ion Chiricuta Comprehensive Cancer Center | And 7 more authors.
Journal of biological regulators and homeostatic agents | Year: 2014

The high malignancy of glioblastoma has been recently attributed to the presence, within the tumor, of glioblastoma stem cells (GSC) poorly responsive to chemo- and radiotherapy. Here, the potential employment of metformin and arsenic trioxide (ATO) in glioblastoma therapy is discussed focusing on their effects on GSC. Metformin exerts anticancer effects by primarily blocking the pivotal LKB1/AMPK/mTOR/S6K1 pathway-dependent cell growth, induces selective lethal effects on GSC by impairing the GSC-initiating spherogenesis and inhibits the proliferation of CD133+ cells, while having a low or null effect on differentiated glioblastoma cells and normal human stem cells. Metformin and ATO induce autophagy and apoptosis in glioma cells by inhibiting and stimulating the PI3K/Akt and the mitogen-activated protein kinase pathways, respectively. Both drugs promote differentiation of GSC into non-tumorigenic cells. In this regard, metformin acts via activation of the AMPK-FOXO3 axis, whereas ATO blocks the interleukin 6-induced promotion of STAT3 phosphorylation. Blood-brain barrier, easily crossed by metformin but not by ATO, undergoes important glioblastoma-induced alterations that increase its permeability, thus allowing ATO to distribute more into the glioblastoma bulk than in the normal brain parenchyma. A prompt clinical assessment of metformin and ATO in glioblastoma patients would represent a valid attempt to improve their survival.


Tomuleasa C.,Johns Hopkins University | Tomuleasa C.,Ion Chiricuta Comprehensive Cancer Center | Tomuleasa C.,Victor Babes University of Medicine and Pharmacy Timisoara | Soritau O.,Ion Chiricuta Comprehensive Cancer Center | And 15 more authors.
Journal of Gastrointestinal and Liver Diseases | Year: 2012

Background & Aims: The aim of the current study was to evaluate in vitro the anti-tumor efficacy of gold nanoparticles (GNPs) conjugated with conventional chemotherapy drugs for the treatment of liver cancer. This approach based on gold proposes a novel platform therapy with minimal toxicity and increased efficacy profiles for the destruction of hepatic cancer cells. methods. GNPs, stabilized with a monolayer of L-aspartate and additional cytostatic drugs, were successfully used as a complex tumor-targeting drug-delivery system. The drugs (doxorubicin, cisplatin, and capecitabine) were non-covalently conjugated onto the hydrophilic assemblies of GNPs-L-Aspartate nanostructure. Transmission electron microscopy was used to characterize the morphological and structural properties of these drug-metallic nanostructures. Results. The cellular proliferation rates in the presence of the anti-cancer drugs delivered by the GNPs were found to be statistically lower than those of cells exposed to the cytostatic drugs alone, indicating that GNPs facilitated an increased susceptibility of cancer cells to cisplatin, doxorubicin, and capecitabine plus ribavirin. Conclusion. This approach could offer a new chemotherapy strategy for patients diagnosed with unresectable hepatocellular carcinoma (HCC).


PubMed | University of L'Aquila, University of Medicine and Pharmacy, Cluj-Napoca, Ion Chiricuta Comprehensive Cancer Center, Johns Hopkins University and Scientific Institute Casa Sollievo della Sofferenza
Type: Editorial | Journal: Journal of biological regulators and homeostatic agents | Year: 2014

The high malignancy of glioblastoma has been recently attributed to the presence, within the tumor, of glioblastoma stem cells (GSC) poorly responsive to chemo- and radiotherapy. Here, the potential employment of metformin and arsenic trioxide (ATO) in glioblastoma therapy is discussed focusing on their effects on GSC. Metformin exerts anticancer effects by primarily blocking the pivotal LKB1/AMPK/mTOR/S6K1 pathway-dependent cell growth, induces selective lethal effects on GSC by impairing the GSC-initiating spherogenesis and inhibits the proliferation of CD133+ cells, while having a low or null effect on differentiated glioblastoma cells and normal human stem cells. Metformin and ATO induce autophagy and apoptosis in glioma cells by inhibiting and stimulating the PI3K/Akt and the mitogen-activated protein kinase pathways, respectively. Both drugs promote differentiation of GSC into non-tumorigenic cells. In this regard, metformin acts via activation of the AMPK-FOXO3 axis, whereas ATO blocks the interleukin 6-induced promotion of STAT3 phosphorylation. Blood-brain barrier, easily crossed by metformin but not by ATO, undergoes important glioblastoma-induced alterations that increase its permeability, thus allowing ATO to distribute more into the glioblastoma bulk than in the normal brain parenchyma. A prompt clinical assessment of metformin and ATO in glioblastoma patients would represent a valid attempt to improve their survival.


PubMed | Ion Chiricuta Comprehensive Cancer Center
Type: Journal Article | Journal: Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie | Year: 2010

Similar to normal organs arising from normal stem cells, cancers can be viewed as organs composed of heterogeneous cellular populations arising from cancer cells with indefinite proliferation abilities. The continuous malignant progression is maintained by the proliferation of cancer stem cells and not the progeny that undergo limited proliferation before terminally differentiating. Effective therapy must eradicate malignant cells with unlimited clonogenic expansion within the primary tumor bulk. Thus, resolving both the specific cell of origin for prostate cancer and the interactions between the cells and the surrounding microenvironment within the cancer stem cell niche are crucial to appropriately define rational targets for therapeutic intervention and cure prostate cancer.


PubMed | Ion Chiricuta Comprehensive Cancer Center
Type: Journal Article | Journal: Journal of B.U.ON. : official journal of the Balkan Union of Oncology | Year: 2010

The purpose of this study was to challenge current knowledge on the potential therapeutic advantages of stem cells in radiotherapy by developing an in vitro model of the healthy tissue surrounding or replacing the widely resected tumor. After radical surgery, the start of radiotherapy is often delayed due to wound healing process, with potential loss of the opportunity for treating microscopic disease instead of macroscopic early recurrence. Hyperfractionated radiotherapy, contrary to the standard one, can extend the limits of radical surgery and shorten the gap before the onset of postoperative radiotherapy, with potential improvement in local control.By using both mesenchymal stem cells and pre-differentiated osteoblasts, cultured in proper pro-osteogenic media after cell irradiation, we investigated both the differences in the response to DNA damage between lineages undergoing differentiation in culture and the intensity of the mineralization process.Ionizing radiation stimulated stem cell proliferation and differentiation at 0.5 Gy and 1 Gy, thus confirming in vitro the clinical results of hyperfractionated irradiation randomized trials in head and neck cancers -HNCs-.To our knowledge, this study is the first to investigate the biophysics of low dose gamma irradiation on stem cell culture, focusing on the potential applications in radiation oncology. For advanced oral cavity and oropharyngeal cancers, as radical surgery often implies major bone resection, the use of mesenchymal stem cells as bone reconstruction vectors might shorten the onset of adjuvant hyperfractionated radiotherapy which enhances the mineralization process. As postoperative radiotherapy has recently being revisited for osteosarcoma, this scenario could impact also on bone reconstruction process in this pathology.


PubMed | Ion Chiricuta Comprehensive Cancer Center
Type: Journal Article | Journal: Journal of B.U.ON. : official journal of the Balkan Union of Oncology | Year: 2010

Brain tumors are the leading cause of cancer mortality in children and remain incurable despite advances in surgery and adjuvant therapies. The failure of malignant gliomas to respond to conventional treatment reflects the unique biology of these tumors, linked to a small population of stem-like precursors. This study describes the characteristics of stem cells isolated from glioblastoma multiforme (GM) and gives insight into the mechanism of brain tumorigenesis.Tumor stem-like precursors were identified from primary human GM-derived cell culture using immunocytochemistry and reverse transcription polymerase chain reaction (RT-PCR). Cells were cultured in vitro in stem cell medium supplemented with growth factors and then the capacity of the surviving stem-like precursors to form tumor spheres and to continue to proliferate after chemoradiotherapy were tested.The tumor cells expressed the cellular markers CD133, CD105, CD90, Nanog, Oct 3/4, CXCR4, nestin, glial fibrillary acidic protein (GFAP), neurofilament protein (NF) and human glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Cells also displayed a high proliferative potential despite chemotherapy and irradiation and also had the ability to form spheroids in suspension.High grade gliomas contain stem-like precursors, which exhibit neural stem cell properties with tumorigenicity, establishing a novel developmental paradigm in the study of brain carcinogenesis and providing a powerful tool to develop patient-tailored therapy for this devastating disease.


PubMed | Ion Chiricuta Comprehensive Cancer Center
Type: Journal Article | Journal: Journal of B.U.ON. : official journal of the Balkan Union of Oncology | Year: 2012

Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide. The partial failure of classic therapeutic options makes scientists to doubt the efficacy of systemic treatments in targeting the essential cell populations and achieving cure as a final goal. Overgrowing data suggest that cancer is a disease closely linked to stem cells (SCs). It is well known that the first identification of cancer stem-like cells in acute myeloid leukaemia was soon followed by similar results in solid malignancies, including colorectal cancer, and the classic model for colon carcinogenesis supports the development of sudden mutations that will lead to the activation or inactivation of certain oncogenes or tumor suppressors. Thus, this process may go on for years before the first symptoms and the only cells able to withstand for many years, avoid apoptosis and have a high regenerative capacity are the progenitor cells found at the lower part of colon crypts. A more profound study of the mechanisms and molecular signalling pathways that control the basic characteristics of SCs, such as asymmetrical division or self-renewal, may help comprehend the basic mechanisms of cancer genesis and progression. This will result in the development of new therapeutic agents that may target chemoresistant cell populations and improve the therapeutic results. In the current review we point out the importance of cancer stem-like cells in colorectal oncology from a pathologists point of view, stating the obvious correlation between histology, embryology and surgical pathology.

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