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Dive into the research topics where Patrizia Mancuso is active.

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Featured researches published by Patrizia Mancuso.


Nature Reviews Cancer | 2006

The multifaceted circulating endothelial cell in cancer: towards marker and target identification

Francesco Bertolini; Yuval Shaked; Patrizia Mancuso; Robert S. Kerbel

Increases in the number of circulating endothelial cells (CECs) and progenitors (CEPs) have been reported in various pathological conditions including cancer. Preclinical studies have shown that CEC and CEP kinetics correlate well with several standard laboratory angiogenesis assays, which cannot be used in humans. At the clinical level, evidence is emerging that CEC kinetics and viability might correlate with clinical outcomes in cancer patients who undergo anti-angiogenic treatment. Therefore, CEC and CEP measurement has potential as a surrogate marker for monitoring anti-angiogenic treatment and drug activity, and could help to determine the optimal biological dose of anti-angiogenic drugs, which are being used with increasing frequency in medical oncology.


Cancer Cell | 2008

Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents

Yuval Shaked; Erik Henke; Jeanine M.L. Roodhart; Patrizia Mancuso; Marlies H.G. Langenberg; Marco Colleoni; Laura G.M. Daenen; Shan Man; Ping Xu; Urban Emmenegger; Terence Tang; Zhenping Zhu; Larry Witte; Robert M. Strieter; Francesco Bertolini; Emile E. Voest; Robert Benezra; Robert S. Kerbel

Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1alpha and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine.


Thrombosis and Haemostasis | 2005

Circulating endothelial cells Biomarker of vascular disease

Andrew D. Blann; Alexander Woywodt; Francesco Bertolini; Todd M. Bull; Jill P. Buyon; Robert R. Clancy; Marion Haubitz; Robert P. Hebbel; Gregory Y.H. Lip; Patrizia Mancuso; José Sampol; Anna Solovey; Françoise Dignat-George

Recent research has recognised new populations of non-hematopoietic cells in the blood. One of these, circulating endothelial cells (CECs), often defined by the expression of membrane glycoprotein CD146, are rarely found in the blood in health, but raised numbers are present in a wide variety of human conditions, including inflammatory, immune, infectious, neoplastic and cardiovascular disease, and seem likely to be evidence of profound vascular insult. An additional population are endothelial progenitor cells, defined by the co-expression of endothelial and immaturity cell surface molecules and also by the ability to form colonies in vitro. Although increased numbers of CECs correlate with other markers of vascular disease, questions remain regarding the precise definition, cell biology and origin of CECs. For example, they may be damaged, necrotic or apopototic, or alive, and could possess procoagulant and/or proinflammatory properties. However, since these cells seem to be representative of in situ endothelium, their phenotype may provide useful information. Indeed, whatever their phenotype, there is growing evidence that CECs may well be a novel biomarker, the measurement of which will have utility in various clinical settings related to vascular injury. Despite this promise, progress is impeded by the diversity of methodologies used to detect these cells. Accordingly, results are sometimes inconclusive and even conflicting. Nevertheless, increased CECs predict adverse cardiovascular events in acute coronary syndromes, suggesting they may move from being simply a research index to having a role in the clinic. The objective of the present communication is to condense existing data on CECs, briefly compare them with progenitor cells, and summarise possible mechanism(s) by which they may contribute to vascular pathology.


International Journal of Cancer | 2008

Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rγ null mice generate a faster and more efficient disease compared to other NOD/scid-related strains

Alice Agliano; Ines Martin-Padura; Patrizia Mancuso; Paola Marighetti; Cristina Rabascio; Giancarlo Pruneri; Leonard D. Shultz; Francesco Bertolini

Transplantation of human acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) primary cells and cell lines in different strains of immunodeficient mice has led to preclinical models extensively used to investigate acute leukemia stem cells, biology and drug sensitivity. We studied the engraftment kinetics of AML and ALL cell lines and primary cells in 3 strains of NOD.CB17‐Prkdcscid (NOD/scid, NS)‐related mice (NOD.Cg‐PrkdcscidB2mtm1Unc/J, abbreviated NOD/scid/β2 null, NSB; and NOD.Cg‐PrkdcscidIl2rgtm1Wjll/SzJ, abbreviated NOD/scid/IL‐2Rγ null, NSG). The engraftment of human malignant cells was investigated by means of clinicopathological criteria, flow cytometry, PCR and immunohistochemistry. In NSG mice, we observed a significantly faster development of leukemia‐related symptoms and a higher percentage of leukemia cells in the blood, in the marrow and in the spleen. The leukemia‐related angiogenic switch (measured as the number of circulating endothelial cells and progenitors) was faster in NSG compared to NS and NSB mice. These models will be instrumental to studies on leukemia‐initiating stem cells, leukemia biology, preclinical treatment studies, and to obtain patient‐specific preclinical models to design and investigate patient‐tailored therapies.


Clinical Cancer Research | 2009

Validation of a Standardized Method for Enumerating Circulating Endothelial Cells and Progenitors: Flow Cytometry and Molecular and Ultrastructural Analyses

Patrizia Mancuso; Pierluigi Antoniotti; Jessica Quarna; Angelica Calleri; Cristina Rabascio; Carlo Tacchetti; Paola Braidotti; Hua Kang Wu; Amado J. Zurita; Luca Saronni; John B. Cheng; David R. Shalinsky; John V. Heymach; Francesco Bertolini

Purpose: Antigenic overlap among circulating endothelial cells (CEC) and progenitors (CEP), platelets, and other blood cells led to the need to develop a reliable standardized method for CEC and CEP quantification. These cells are emerging as promising preclinical/clinical tools to define optimal biological doses of antiangiogenic therapies and to help stratify patients in clinical trials. Experimental Design: We report the experimental validation of a novel flow cytometry method that precisely dissects CEC/CEP from platelets and other cell populations and provides information about CEC/CEP viability. Results: Sorted DNA/Syto16+CD45−CD31+CD146+ CECs, investigated by electron microscopy, were found to be bona fide endothelial cells by the presence of Weibel-Palade bodies. More than 75% of the circulating mRNAs of the endothelial-specific gene, VE-cadherin, found in the blood were present in the sorted population. CECs were 140 ± 171/mL in healthy subjects (n = 37) and 951 ± 1,876/mL in cancer patients (n = 78; P < 0.0001). The fraction of apoptotic/necrotic CECs was 77 ± 14% in healthy subjects and 43 ± 23% in cancer patients (P < 0.0001). CEPs were 181 ± 167/mL in healthy donors and 429 ± 507/mL in patients (P = 0.00019). Coefficients of variation were 4 ± 4% (intrareader), 17 ± 4% (interreader), and 17 ± 7% (variability over 0-72 h), respectively. Parallel samples were frozen by a standardized protocol. After thawing, coefficients of variation were 12 ± 8% (intrareader), 16 ± 10% (interreader), and 26 ± 16% (variability over 0-14 days of frozen storage), respectively. Conclusions: This procedure enumerates a truly endothelial cell population with limited intrareader and interreader variability. It appears possible to freeze samples for large-scale CEC enumeration during clinical trials. This approach could be enlarged to investigate other angiogenic cell populations as well.


Clinical Cancer Research | 2009

Predictive Potential of Angiogenic Growth Factors and Circulating Endothelial Cells in Breast Cancer Patients Receiving Metronomic Chemotherapy Plus Bevacizumab

Angelica Calleri; Anna Bono; Vincenzo Bagnardi; Jessica Quarna; Patrizia Mancuso; Cristina Rabascio; Silvia Dellapasqua; Elisabetta Campagnoli; Yuval Shaked; Aron Goldhirsch; Marco Colleoni; Francesco Bertolini

Purpose: The association of chemotherapy and antiangiogenic drugs has shown efficacy in clinical oncology. However, there is a need for biomarkers that allow selection of patients who are likely to benefit from such treatment and are useful for indicating best drug combination and schedule. Experimental Design: We investigated the predictive potential of six angiogenic molecules/transcripts and nine subpopulations of circulating endothelial cells (CEC) and progenitors (CEP) in 46 patients with advanced breast cancer treated with metronomic cyclophosphamide and capecitabine plus bevacizumab. Results: Median time to progression was 281 days. Baseline CECs higher than the first quartile were associated with an increased time to progression (P = 0.021). At progression, CECs were markedly reduced (P = 0.0002). In the cohort of 15 long-term responders, who progressed later than 1 year after beginning of therapy, circulating vascular endothelial growth factor (VEGF)-A levels measured after 2 months of therapy were significantly reduced, and there were significant trends toward lower levels of PDGF-BB, CEPs, and CECs. At the time of progression, angiogenic growth factors VEGF-A and basic fibroblast growth factor were significantly increased. Conclusions: Baseline CECs (likely reflecting an active vascular turnover) predicted a prolonged clinical benefit. At the time of relapse, a pattern of decreased CECs and increased angiogenic growth factors suggested a switch toward a different type of cancer vascularization. VEGF-A and basic fibroblast growth factor levels after 2 months of therapy were also useful to identify patients whose disease was likely to progress. These biomarkers are likely to be useful for treatment selection and might be incorporated in design of future studies. (Clin Cancer Res 2009;15(24):7652–7)


Advances in Experimental Medicine and Biology | 2003

Circulating Endothelial Cells as a Novel Marker of Angiogenesis

Patrizia Mancuso; Angelica Calleri; Cristina Cassi; Alberto Gobbi; Manuela Capillo; Giancarlo Pruneri; Giovanni Martinelli; Francesco Bertolini

Measurement of tumor angiogenesis to predict and/or to assess the efficacy of antiangiogenic therapies is mainly based on the evaluation of microvessel density (MVD). We developed a novel flow cytometry procedure to measure circulating endothelial cells (CECs) and circulating endothelial cells progenitors (CECPs) in either preclinical and clinical studies. Preclinical studies were performed on an animal model of human lymphoma. A trend toward higher CECs values was observed on day 7 and 14 after transplant, and differences vs controls were highly significant on day 21 (p = 0.0061). A strong correlation was found between CECs and tumor volume (r = 0.942, p = 0.004) and between CECs and tumor-generated VEGF (r = 0.669, p = 0.02). In mice given cyclophosphamide, most of circulating apoptotic cells were hematopoietic and not endothelial. Conversely, in mice given endostatin, all of the increase in apoptotic cells was in the endothelial cell compartment. In a parallel study, we looked for CECs in the peripheral blood of 20 healthy controls and 76 newly diagnosed cancer patients by means of four-color flow cytometry. In breast cancer (n = 46) and lymphoma (n = 30) patients, both resting and activated CECs were increased by 5 fold (P < 0.0008 vs control). CECs significantly correlated with plasma levels of VCAM-1 and VEGF. Resting and activated CECs were similar to healthy controls in 7 lymphoma patients achieving complete remission after chemotherapy, and activated CECs were found to decrease in 13 breast cancer patients evaluated before and 24h after quadrantectomy. In conclusion, our findings indicate a close relation between CEC increase and tumor progression, and support CECs evaluation as a clinically relevant, non invasive angiogenesis marker. Furthermore, this assay offers insight into anti-angiogenic activity of different drugs.


Cancer Research | 2011

Targeting Activin Receptor-Like Kinase 1 Inhibits Angiogenesis and Tumorigenesis through a Mechanism of Action Complementary to Anti-VEGF Therapies

Dana Hu-Lowe; Enhong Chen; Lianglin Zhang; Katherine D. Watson; Patrizia Mancuso; Patrick B. Lappin; Grant Raymond Wickman; Jeffrey H. Chen; Jianying Wang; Xin Jiang; Karin Kristina Amundson; Ronald Simon; Andreas Erbersdobler; Simon Bergqvist; Zheng Feng; Terri Swanson; Brett H. Simmons; John Lippincott; Gerald Fries Casperson; Wendy J. Levin; Corrado Gallo Stampino; David R. Shalinsky; Katherine W. Ferrara; Walter Fiedler; Francesco Bertolini

Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin(+) perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.


Cancer Research | 2004

Assessing Tumor Angiogenesis Increased Circulating VE-Cadherin RNA in Patients with Cancer Indicates Viability of Circulating Endothelial Cells

Cristina Rabascio; Elisabetta Muratori; Patrizia Mancuso; Angelica Calleri; Valentina Raia; Thomas J. Foutz; Saverio Cinieri; Giulia Veronesi; Giancarlo Pruneri; P. Lampertico; M. Iavarone; Giovanni Martinelli; Aron Goldhirsch; Francesco Bertolini

No markers are currently available to indicate the angiogenic profile of a specific malignant disease nor to predict response to antiangiogenic therapies. Nevertheless, many different antiangiogenic drugs are presently being tested in many clinical trials, with an obvious scarcity of useful endpoints for treatment outcome beside survival. By means of a quantitative reverse transcription-PCR approach, we measured VE-cadherin (VE-C), Tie-2, vascular endothelial growth factor receptor 2 and CD133 RNA in the blood of 14 healthy controls, 3 pregnant women, and 84 newly diagnosed (or relapsed) cancer patients. Circulating VE-C RNA was increased in pregnant women and cancer patients (P = 0.0002). VE-C RNA was particularly increased in patients affected by hematological malignancies and decreased to normal values in patients achieving complete remission. Conversely, circulating RNA levels of other endothelial or progenitor cell-specific markers Tie-2, vascular endothelial growth factor receptor 2, and CD133 were not significantly increased in either pregnant women or cancer patients. Comparison of various surrogate angiogenesis markers indicated a switch toward increased plasma vascular endothelial growth factor (VEGF) levels, viable circulating endothelial cells, and circulating VE-C RNA levels in patients affected by hematological malignancies. Taken together, our data indicate that the quantitative evaluation of circulating VE-C RNA is a specific and highly promising tool with which to investigate the angiogenic phenotype of cancer patients.


Experimental Hematology | 2000

The thin red line: angiogenesis in normal and malignant hematopoiesis

Francesco Bertolini; Patrizia Mancuso; Alberto Gobbi; Giancarlo Pruneri

This review describes the current knowledge about cell subsets involved in vasculogenesis (i.e., differentiation of endothelial cells from mesodermal precursors) and angiogenesis (i.e., blood vessel generation from pre-existing vessels), together with recent findings about angiogenesis and antiangiogenic therapies in hematopoietic malignancies such as leukemia, lymphoma, myeloma, and myelodysplastic syndromes.

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Francesco Bertolini

European Institute of Oncology

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Angelica Calleri

European Institute of Oncology

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Giovanni Martinelli

European Institute of Oncology

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Cristina Rabascio

European Institute of Oncology

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Valentina Labanca

European Institute of Oncology

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Chiara Corsini

European Institute of Oncology

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Ines Martin-Padura

European Institute of Oncology

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Stefania Orecchioni

European Institute of Oncology

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Yuval Shaked

European Institute of Oncology

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