Germana Castelli

Germana Castelli
Istituto Superiore di Sanità | ISS · Department of Haematology, Oncology and Molecular Medicine

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59
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Introduction
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Publications

Publications (59)
Article
Introduction Lung cancer is the leading cause of cancer mortality worldwide; lung adenocarcinoma (LUAD) corresponds to about 40% of lung cancers. LUAD is a genetically heterogeneous disease and the definition of this heterogeneity is of fundamental importance for prognosis and treatment. Areas covered Based on primary literature, this review provi...
Article
Minimal or measurable residual disease (MRD) is a term that refers to the submicroscopic tumor disease persisting after therapy. Sensitive immunophenotypic and molecular techniques are used to detect the small amount of residual tumor cells, conferring a detection capacity clearly more sensitive of common cytomorphologic techniques. MRD evaluation...
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The development of molecular studies to define the somatic genetic alterations has revolutionized the diagnostic and therapeutic management of acute myeloid leukemia (AML). AML is a highly heterogenous disease that includes many molecular subtypes; each subtype is heterogeneous both for the presence of variable co-mutations and complex combinations...
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Metabolism in acute myeloid leukemia (AML) cells is dependent primarily on oxidative phosphorylation. However, in order to sustain their high proliferation rate and metabolic demand, leukemic blasts use a number of metabolic strategies, including glycolytic metabolism. Understanding whether monocarboxylate transporters MCT1 and MCT4, which remove t...
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Vitamin C (ascorbate) is an essential dietary requirement, with fundamental redox, anti-oxidant functions at physiologic concentrations. Vitamin C is a cofactor for Fe²⁺ and 2-oxoglutarate-dependent dioxygenases, englobing large families of enzymes, including also epigenetic regulators of DNA and histone methylation. Importantly, vitamin C is invol...
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Genome sequencing studies have characterized the genetic alterations of different tumor types, highlighting the diversity of the molecular processes driving tumor development. Comprehensive sequencing studies have defined molecular subtypes of colorectal cancers (CRCs) through the identification of genetic events associated with microsatellite stab...
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Acute myeloid leukemia (AML) is a heterogeneous disease generated by the acquisition of multiple genetic and epigenetic aberrations which impair the proliferation and differentiation of hematopoietic progenitors and precursors. In the last years, there has been a dramatic improvement in the understanding of the molecular alterations driving cellula...
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Renal cell cancer (RCC) involves three most recurrent sporadic types: clear-cell RCC (70–75%, CCRCC), papillary RCCC (10–15%, PRCC), and chromophobe RCC (5%, CHRCC). Hereditary cases account for about 5% of all cases of RCC and are caused by germline pathogenic variants. Herein, we review how a better understanding of the molecular biology of RCCs...
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In normal dividing tissues, cell homeostasis is maintained by rare cellular elements, the stem cells, that have the unique property of self-renewal and differentiation to generate a population of functionally mature tissue elements. Recent studies carried out in the last three decades support the existence of stem cells also in tumors, the so-calle...
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Tumor vascularization refers to the formation of new blood vessels within a tumor and is considered one of the hallmarks of cancer. Tumor vessels supply the tumor with oxygen and nutrients, required to sustain tumor growth and progression, and provide a gateway for tumor metastasis through the blood or lymphatic vasculature. Blood vessels display a...
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Breast cancer is the most commonly occurring cancer in women. There were over two-million new cases in world in 2018. It is the second leading cause of death from cancer in western countries. At the molecular level, breast cancer is a heterogeneous disease, which is characterized by high genomic instability evidenced by somatic gene mutations, copy...
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Angiogenesis is a word that refers to new blood vessel formation, and this process is of fundamental importance for physiological development and tissue homeostasis, as well as the genesis of several diseases, including tumors. Thus, studies carried out in the last years have shown that angiogenesis is essential for the growth of many solid tumors....
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The burden of cancer is increasing worldwide, with a continuous rise of the annual total cases. Although mortality rates due to cancer are declining in developed countries, the total number of cancer deaths continues to rise due to the increase in the number of aged people. Three main causes of cancer have been described, represented by environment...
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Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of dev...
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Acute Myelogenous Leukemia (AML) is a malignant disease of the hematopoietic cells, characterized by impaired differentiation and uncontrolled clonal expansion of myeloid progenitors/precursors, resulting in bone marrow failure and impaired normal hematopoiesis. AML comprises a heterogeneous group of malignancies, characterized by a combination of...
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CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in...
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Brain tumors are highly heterogeneous and have been classified by the World Health Organization in various histological and molecular subtypes. Gliomas have been classified as ranging from low-grade astrocytomas and oligodendrogliomas to high-grade astrocytomas or glioblastomas. These tumors are characterized by a peculiar pattern of genetic altera...
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Lung cancer causes the largest number of cancer-related deaths in the world. Most (85%) of lung cancers are classified as non-small-cell lung cancer (NSCLC) and small-cell lung cancer (15%) (SCLC). The 5-year survival rate for NSCLC patients remains very low (about 16% at 5 years). The two predominant NSCLC histological phenotypes are adenocarcinom...
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Colon cancer is the third most common cancer worldwide. Most colorectal cancer occurrences are sporadic, not related to genetic predisposition or family history; however, 20–30% of patients with colorectal cancer have a family history of colorectal cancer and 5% of these tumors arise in the setting of a Mendelian inheritance syndrome. In many patie...
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Four main histological subtypes of ovarian cancer exist: serous (the most frequent), endometrioid, mucinous and clear cell; in each subtype, low and high grade. The large majority of ovarian cancers are diagnosed as high-grade serous ovarian cancers (HGS-OvCas). TP53 is the most frequently mutated gene in HGS-OvCas; about 50% of these tumors displa...
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Germana Castelli, Elvira Pelosi, Ugo Testa Department of Oncology, Istituto Superiore di Sanità, Rome, Italy Abstract: Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and...
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Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are...
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Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death and is the most lethal of common malignancies with a five-year survival rate of <10%. PDAC arises from different types of non-invasive precursor lesions: intraductal papillary mucinous neoplasms, mucinous cystic neoplasms and pancreatic intraepithelial n...
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Liver cancer is the second most common cause of cancer-related death. The major forms of primary liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Both these tumors develop against a background of cirrhotic liver, non-alcoholic fatty liver disease, chronic liver damage and fibrosis. HCC is a heterogeneous d...
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Esophageal cancer (EC) is the eighth most common cancer and is the sixth leading cause of death worldwide. The incidence of histologic subtypes of EC, esophageal adenocarcinoma (EAC) and esophageal squamous carcinoma (ESCC), display considerable geographic variation. EAC arises from metaplastic Barrett's esophagus (BE) in the context of chronic inf...
Article
Vitamin C (Vit C or Ascorbate) is essential for many fundamental biochemical processes. Vit C is an essential nutrient with redox functions at normal physiologic concentrations. The main physiologic function of this vitamin is related to its capacity to act as a co-factor for a large family of enzymes, collectively known as Fe and 2-oxoglutarate-de...
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MicroRNAs (miRNAs or miRs) are a class of evolutionarily-conserved small, regulatory non-coding RNAs, 19–3 nucleotides in length, that negatively regulate protein coding gene transcripts’ expression. miR-146 (146a and 146b) and miR-155 are among the first and most studied miRs for their multiple roles in the control of the innate and adaptive immun...
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Background: A typical feature of acute myeloid leukemia (AML) consists in the blockade of the cell differentiation process. Many experimental studies have shown that some chemical compounds induce the selective differentiation of hematopoietic cell lines, thus supporting the rationale of using these agents to treat AML by forcing these cells to und...
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The use of high-dose ascorbate (ASC) for the treatment of human cancer has been attempted several decades ago and has been recently revived by several in vitro and in vivo studies in solid tumors. We tested the cytotoxic effects of ASC, alone or in combination with arsenic trioxide (ATO) in acute myeloid leukemia (AML) and acute promyelocytic leuke...
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The rapid advancement of next-generation sequencing techniques and the identification of molecular driver events responsible for leukemia development are opening the door to new pharmacologic-targeted agents to tailor treatment of acute myeloid leukemia (AML) in individual patients. However, the use of targeted therapies in AML has met with only mo...
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Circulating endothelial progenitor cells (EPCs) have been suggested as a precious source for generating functionally competent endothelial cells (ECs), candidate for various clinical applications. However, the paucity of these progenitor cells and the technical difficulties for their in vitro growth represent a main limitation to their use. In the...
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Studies carried out in the last years have improved the understanding of the cellular and molecular mechanisms controlling angiogenesis during adult life in normal and pathological conditions. Some of these studies have led to the identification of some progenitor cells that sustain angiogenesis through indirect, paracrine mechanisms (hematopoietic...
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The main hematopoietic stem cell (HSC) functions, i.e., self-renewal and differentiation, are finely regulated by both intrinsic mechanisms, such as transcriptional and epigenetic regulators, and extrinsic signals originated in the bone marrow microenvironment (HSC niche) or in the body (humoral mediators). The interaction between regulatory signal...
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The alpha-chain of the interleukin-3 receptor (IL-3RA or CD123) is frequently deregulated in myeloid neoplasias and its deregulation contributes to survival and proliferation of malignant cells. This review is focused to the analysis of the diseases in which CD123 is markedly overexpressed, such as blastic plasmocytoid dendritic neoplasms (BPDCN),...
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Introduction: In cancer patients, anemia is frequently observed, particularly as a consequence to chemotherapy (chemotherapy-induced anemia, CIA). CIA is treated with Red Blood Cell transfusions and erythropoiesis-stimulating agents (ESAs). However, the use of ESAs in anemic cancer patients is associated with reduced survival time and time to prog...
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The effect of high doses of intravenous (sodium) ascorbate (ASC) in the treatment of cancer has been controversial although there is growing evidence that ASC in high (pharmacologic) concentrations induces dose-dependent pro-apoptotic death of tumor cells, in vitro. Very few data are available on the role of ASC in the treatment of acute myeloid le...
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Studies of xenotransplantation of bone marrow and blood cells of AML patients have supported the existence of rare leukemic stem cells, able to initiate and maintain the leukemic process and bearing the typical leukemic abnormalities. LSCs possess self-renewal capacity and are responsible for the growth of the more differentiated leukemic progeny i...
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MicroRNAs (miRNAs) are important regulators of several cellular processes. During hematopoiesis, specific expression signatures have been reported in different blood cell lineages and stages of hematopoietic stem cell (HSC) differentiation. Here we explored the expression of miRNAs in umbilical cord blood stem (HSC) and progenitor cells (HPC) and c...
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MicroRNAs (miRs) play a key role in the pathogenesis of human malignancies and particularly in acute myeloid leukemias (AMLs) and are increasingly recognized as potential biomarkers and therapeutic targets. miR-21 is dysregulated in several types of cancers, including some hematologic malignancies, and plays a key role in carcinogenesis, disease re...
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The studies carried out during the last two decades have represented a great effort in trying to identify and define cell populations endowed with the phenotypic and functional properties of endothelial progenitors. From these studies a scenario now emerges indicating that in the blood there are very rare endothelial progenitor cells, called endoth...
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: HIV infection affects dendritic cells (DCs) number, maturation, and function although the cause remains largely unknown. Purified CD34 hematopoietic progenitor cells (HPCs) obtained from bone marrow of chronic HIV-infected patients were investigated for the differentiative capability toward mature DCs. HIV, although not in active replication, was...
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Dendritic cells (DCs) perform a basic role in the immune system by allowing the initiation of the primary T-cell-dependent immune response. Given previous indirect evidence that DC maturation and function are impaired by HIV, we have developed an in vitro culture system in order to verify the effect of HIV infection on DC function during the develo...
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Embryologic and genetic evidence suggest a common origin of haematopoietic and endothelial lineages. In the murine embryo, recent studies indicate the presence of haemogenic endothelium and of a common haemato-endothelial precursor, the haemangioblast. Conversely, so far, little evidence supports the presence of haemogenic endothelium and haemangio...
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The tyrosine kinase Tie-2 and its ligands Angiopoietins (Angs) transduce critical signals for angiogenesis in endothelial cells. This receptor and Ang-1 are coexpressed in hematopoietic stem cells and in a subset of megakaryocytes, though a possible role of angiopoietins in megakaryocytic differentiation/proliferation remains to be demonstrated. To...
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Cord blood (CB) is a rich source of hematopoietic stem cells (HSCs) and for this reason CB transplantation has been used successfully for the treatment of some malignant and nonmalignant diseases. However, this technique is limited by the relatively low number of HSCs present in each CB unit and by the delayed engraftment of platelets and neutrophi...
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FMS-related tyrosine kinase 3 (FLT3) mutations are found in 30% of cases of acute myeloid leukaemia (AML). In addition, recent studies have lead to the identification of about 10-15% of AML patients displaying high expression of FLT3, not associated with mutations of the receptor (FLT3 Wild-type High, FLT3WTH). These AMLs, as well as those displayi...
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The human hemoglobin switch (HbF-->HbA) takes place in the peri/post-natal period. In adult life, however, the residual HbF (<1%) may be partially reactivated by chemical inducers and/or cytokines such as the kit ligand (KL). MicroRNAs (miRs) play a pivotal role in normal hematopoiesis: downmodulation of miR-221/222 stimulates human erythropoietic...
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It is generally conceded that selective combinations of transcription factors determine hematopoietic lineage commitment and differentiation. Here we show that in normal human hematopoiesis the transcription factor nuclear factor I-A (NFI-A) exhibits a marked lineage-specific expression pattern: it is upmodulated in the erythroid (E) lineage while...
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The promyelocytic leukemia zinc-finger protein (PLZF) is a transcription factor and c-kit is a receptor tyrosine kinase associated with human disease, particularly in hematopoietic cells. MicroRNAs (miRs) are post-transcriptional regulators of gene expression, and c-kit has been described as a target of miRs-221 and -222 in erythropoiesis. In the p...
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MicroRNAs are small non-coding RNAs that regulate gene expression through mRNA degradation or translational inhibition. MicroRNAs are emerging as key regulators of normal hematopoiesis and hematologic malignancies. Several miRNAs are differentially expressed during hematopoiesis and their specific expression regulates key functional proteins involv...
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Mesenchymal stromal cells (MSCs) represent a bone marrow (BM) population, classically defined by five functional properties: extensive proliferation, ability to differentiate into osteoblasts, chondrocytes, adipocytes, and stromal cells-supporting hematopoiesis. However, research progress in this area has been hampered by lack of suitable markers a...
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We have developed a new culture system whereby human hematopoietic progenitors purified from adult peripheral blood extensively proliferate and gradually differentiate into >95% pure monocytic (Mo) cells. At all developmental stages treatment with interleukin (IL)-4+granulocyte-macrophage colony-stimulating factor or IL-4+c-Kit-ligand+FLT-3 ligand...
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Transgenic mice with cardiac-specific overexpression of active Akt (TG) not only exhibit hypertrophy but also show enhanced left ventricular (LV) function. In 3–4-month-old TG, heart/body weight was increased by 60% and LV ejection fraction was elevated (84 ± 2%, p < 0.01) compared with nontransgenic littermates (wild type (WT)) (73 ± 1%). An incre...
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The expression/function of vascular endothelial growth factor (VEGF) receptors (VEGFR1/Flt1 and VEGFR2/KDR/Flk1) in hematopoiesis is under scrutiny. We have investigated the expression of Flt1 and kinase domain receptor (KDR) on hematopoietic precursors, as evaluated in liquid culture of CD34(+) hematopoietic progenitor cells (HPCs) induced to unil...

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