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Murine models based on acute myeloid leukemia-initiating stem cells xenografting

World Journal of Stem Cells 2018年第6期10卷 57-65页

作者： Cristina Mambet Mihaela Chivu-Economescu Lilia Matei laura georgiana necula Denisa laura Dragu Coralia Bleotu Carmen Cristina Diaconu Cellular and Molecular Pathology Department Stefan S. Nicolau Institute of Virology Nicolae Cajal Institute Titu Maiorescu University

Acute myeloid leukemia(AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells(LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to in-troduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models.

关键词： Acute myeloid leukemia Leukemia-initiating stem cells Antigen markers Murine models Xenografts

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Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics

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World Journal of Gastroenterology 2014年第31期20卷 10790-10801页

作者： Cristiana Pistol Tanase Ana Iulia Neagu laura georgiana necula Cristina Mambet Ana-Maria Enciu Bogdan Calenic Maria Linda Cruceru Radu Albulescu Department of Biochemistry-Proteomics Victor Babes National Institute of Pathology Stefan S Nicolau Institute of Virology Carol Davila University of Medicine and Pharmacy National Institute for Chemical Pharmaceutical Research and Development

Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells(CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.

关键词： Cancer stem cells Pancreatic cancer Cancer stem ce

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New therapeutic options opened by the molecular classification of gastric cancer

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World Journal of Gastroenterology 2018年第18期24卷 1942-1961页

作者： Mihaela Chivu-Economescu Lilia Matei laura G necula Denisa L Dragu Coralia Bleotu Carmen C Diaconu Department of Cellular and Molecular Pathology Stefan S. Nicolau Institute of Virology Nicolae Cajal Institute Titu Maiorescu University

Gastric cancer(GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC.

关键词： Gastric cancer Molecular classification Immunotherapy Targeted therapy Clinical trials

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Gastrointestinal cancer stem cells as targets for innovative immunotherapy

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World Journal of Gastroenterology 2020年第14期26卷 1580-1593页

作者： Mihaela Chivu-Economescu laura G necula Lilia Matei Denisa laura Dragu Ana I Neagu Irina Alexiu Coralia Bleotu Carmen Cristina Diaconu Department of Cellular and Molecular Pathology Stefan S.Nicolau Institute of VirologyBucharest 030304Romania Nicolae Cajal Institute Titu Maiorescu UniversityBucharest 040441Romania

The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized.Gastrointestinal cancer stem cells(GCSCs)are considered to be responsible for tumor initiation,growth,resistance to cytotoxic therapies,recurrence and metastasis due to their unique properties.These properties make the current therapeutic trials against GCSCs ineffective.Moreover,recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system.Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy.This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells,instead of aiming physically destruction of cancer cells through radio-or chemotherapy.New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens,using innate immune cells like the natural killer and T cells,T-cell chimeric antigen receptor technology,dendritic cell vaccine,or immune checkpoint inhibitors.In this respect,better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.

关键词： Immunotherapy Gastrointestinal cancer Cancer stem cells CAR-T Dendritic cells vaccines Immune checkpoints inhibitors

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Recent advances in gastric cancer early diagnosis

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World Journal of Gastroenterology 2019年第17期25卷 2029-2044页

作者： laura necula Lilia Matei Denisa Dragu Ana I Neagu Cristina Mambet Saviana Nedeianu Coralia Bleotu Carmen C Diaconu Mihaela Chivu-Economescu Department of Cellular and Molecular Pathology Stefan S.Nicolau Institute of Virology Faculty of Medicine Titu Maiorescu University

Gastric cancer(GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva,stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.

关键词： Biomarkers Gastric cancer Early diagnosis Genetic and epigenetic alterations Circulating molecules

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High plasma levels of COL10A1 are associated with advanced tumor stage in gastric cancer patients

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World Journal of Gastroenterology 2020年第22期26卷 3024-3033页

作者： laura necula Lilia Matei Denisa Dragu Ioana Pitica Ana Iulia Neagu Coralia Bleotu Simona Dima Irinel Popescu Carmen C Diaconu Mihaela Chivu-Economescu Department of Cellular and Molecular Pathology Stefan S.Nicolau Institute of VirologyBucharest 030304Romania Titu Maiorescu University Faculty of MedicineBucharest 040441Romania Fundeni Clinical Institute Bucharest 022328Romania

BACKGROUND Gastric cancer(GC)remains an aggressive malignancy with a high rate of mortality,being the third leading cause of cancer-related death.More than one million newly diagnosed cases and 782685 deaths due to GC were reported in 2018.GC is characterized by limited effective treatment options and the lack of consistent biomarkers for the diagnosis and prognosis of these patients.The discovery of new biomarkers useful in the early diagnosis of GC is mandatory.AIM To evaluate the potential of COL10A1 as a circulating biomarker for the diagnosis and prognosis of gastric adenocarcinoma patients.METHODS Plasma and tissue obtained from 49 patients with gastric adenocarcinoma have been used in exploring the expression of COL10A1.Real-time PCR and western blot techniques were used to evaluate COL10A1 level in gastric tumor tissue compared to normal adjacent tissue.The circulating level of COL10A1 was also evaluated by ELISA in plasma of gastric adenocarcinoma patients.Survival analysis was made in order to evaluate the potential of COL10A1 as a biomarker for the diagnosis and prognosis of gastric adenocarcinoma patients.RESULTS Our results showed a significant increase in COL10A1 gene expression and protein levels in gastric tumor tissue compared to adjacent normal tissue(P<0.05).COL10A1 seems to show an elevated expression from the beginning of carcinogenesis,in the early stages,and its increased level remains elevated during cancer progression.A significant increase of COL10A1 plasma level in gastric adenocarcinoma patients was also identified.Moreover,increased COL10A1 plasma level was associated with poor survival of the patients.Plasma COL10A1 performed a diagnostic value in GC with area under the receiver operating characteristic curve(AUC)of 0.9171(P=0.0002),sensitivity of 87.76%,and specificity of 100.0%.Furthermore,this study demonstrated the potential role of plasma COL10A1 in the early detection of GC,as in the early stage,we obtained an AUC of 0.8789(P=0.0030),sensitivity of 81.25%,and specificity of 100

关键词： Gastric cancer COL10A1 Circulating biomarkers Early diagnosis Poor prognosis Tumor stage

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Therapies targeting cancer stem cells: Current trends and future challenges

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World Journal of Stem Cells 2015年第9期7卷 1185-1201页

作者： Denisa L Dragu laura G necula Coralia Bleotu Carmen C Diaconu Mihaela Chivu-Economescu Cellular and Molecular Department Stefan S. Nicolau Institute of Virology Nicolae Cajal Institute Titu Maiorescu University Biochemistry-Proteomics Department Victor Babes National Institute of Pathology

Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells(CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a longlasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of mi RNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers.

关键词： Cancer stem cells Targeted therapy Anticancer drug

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