Advances in Experimental Medicine and Biology, 2011
We studied eight patients with active multiple myeloma (aMM, six males and two females; mean age ... more We studied eight patients with active multiple myeloma (aMM, six males and two females; mean age 62 years), nine patients in objective/complete response (rMM, three males and six females; mean age 70 years), and seven patients with monoclonal gammopathy of undetermined significance (MGUS, three males and four females; mean age 57 years). We used a laser Doppler to evaluate capillary blood flow and a transcutaneous oxymeter to measure transcutaneous oxygen partial pressure (TcpO2). Red blood cell (RBC) aggregation index (AI and t½) and elongation index (EI) were assessed using laser-assisted optical rotational cell analysis (LORCA), while the serum vascular endothelial growth factor (VEGF) levels were measured using enzyme-linked immunoabsorbant assay (ELISA). VEGF values were significantly increased (p < 0.001) in aMM vs. rMM and vs. MGUS. Also AI was increased (p < 0.05) in aMM vs. rMM and vs. MGUS and t½ was decreased (p < 0.05) in the aMM vs. rMM and MGUS groups; no variations were detected in EI. We found a significant correlation (p < 0.001) between AI/t½/EI and VEGF. Periflux tests were performed evaluating the basal values (t0), the physical stress (t1) and the heat stress (t3) followed by their respective relaxing times (t2, t4). A significant increase (p < 0.01) in t1 vs. t0 values was observed in all groups. No significant increase in aMM t3 vs. t0 was seen, while the increase was significant in rMM and MGUS (p < 0.01). We found a significant correlation (p < 0.001) between t0 blood flow and VEGF in aMM, rMM and MGUS. TcpO2 t0 values were significantly correlated to VEGF (p < 0.001) in all groups. Our data show that VEGF modifies the microcirculation in aMM and also modifies RBC. It is possible that other mechanisms could interfere with the peripheral microcirculation as we saw in t3 blood flow.
Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resis... more Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM) microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tu...
Journal of experimental & clinical cancer research : CR, Jan 2, 2018
Tumor microenvironment (TME) includes many factors such as tumor associated inflammatory cells, v... more Tumor microenvironment (TME) includes many factors such as tumor associated inflammatory cells, vessels, and lymphocytes, as well as different signaling molecules and extracellular matrix components. These aspects can be de-regulated and consequently lead to a worsening of cancer progression. In recent years an association between the scaffolding protein Na/H exchanger regulatory factor 1 (NHERF1) and tumor microenvironment changes in breast cancer (BC) has been reported. Subcellular NHERF1 localization, vascular endothelial growth factor (VEGF), its receptor VEGFR1, hypoxia inducible factor 1 alpha (HIF-1α), TWIST1 expression and microvessel density (MVD) in 183 invasive BCs were evaluated, using immunohistochemistry on tissue microarrays (TMA). Immunofluorescence was employed to explore protein interactions. Cytoplasmic NHERF1(cNHERF1) expression was directly related to cytoplasmic VEGF and VEGFR1 expression (p = 0.001 and p = 0.027 respectively), and inversely to nuclear HIF-1α (...
Lung cancer is the leading cause of cancer deaths throughout the world. The majority of patients ... more Lung cancer is the leading cause of cancer deaths throughout the world. The majority of patients are diagnosed with locally advanced or metastatic disease when surgery, the best curative option, is no longer feasible. Thus, the prognosis of lung cancer remains poor and heterogeneous and new biomarkers are needed. As the immune system plays a pivotal role in cancer, the study of tumor microenvironment, with regard to the immune component, may provide valuable information for a better comprehension of the pathogenesis and progression of the disease. Through a detailed and critical evaluation of the most recent publications on this topic, we provide evidences of the prognostic and predictive significance of immune markers in tumor and in peripheral blood of lung cancer patients: from the landscape of immune cells (macrophages, neutrophils, lymphocytes and natural killer) and their cytokines, to the analysis of immune-checkpoints (PD-L1 and CTLA4), up to the genetic and epigenetic regul...
In a previous study, we reported the identification of Hemilipin, the first secreted heterodimeri... more In a previous study, we reported the identification of Hemilipin, the first secreted heterodimeric phospholipase A2 (sPLA2) from Hemiscorpius lepturus scorpion venom and demonstrated its effective inhibition of all angiogenesis key steps in vitro and in vivo. Here, we aimed to characterize a second sPLA2, Hemilipin2, from the same venom and to elucidate its antiangiogenic effect. The protein was purified by chromatography separation and analyzed by MALDI/TOF mass spectrometry. Its N terminal amino acid sequence was determined by Edman degradation method and the enzymatic activity by fatty acids release assay. Hemilipin2 antiangiogenic activity was investigated by studying its effect in vitro on adhesion, migration and capillary like tube formation of Human Umbilical Vein Endothelial Cells (HUVECs) and Human Pulmonary Artery Endothelial Cells (HPAECs); and in vivo on the chick embryo chorioallantoic membrane (CAM) assay. Data to be presented show that Hemilipin2 is heterodimeric composed by two subunits: the large one has a molecular weight of 12,866 and the small one of 2461 a.m.u. It has a strong calcium-dependent PLA2 activity and impacts angiogenesis in vitro and in vivo without showing any cytotoxic or apoptotic signs. Its chemical modification with p-Bromophenacyl Bromide abolishes the enzymatic activity without affecting the antiangiogenic effect. Furthermore, it has been proved that Hemilipin2 small subunit was able to inhibit blood vessel formation both in vitro and in vivo. These findings may serve as a starting point for the designing of a new generation of specific inhibitor of human angiogenesis at different steps.
Toxicon : official journal of the International Society on Toxinology, 2015
Phospholipases A2 (PLA2) are enzymes which specifically hydrolyze the sn-2 acyl ester bond of pho... more Phospholipases A2 (PLA2) are enzymes which specifically hydrolyze the sn-2 acyl ester bond of phospholipids producing free fatty acids and lysophospholipids. The secreted PLA2 (sPLA2) are the most common types of PLA2 purified from the snake venom, mammalian pancreatic juice and other sources. They display a variety of toxic actions and biological activities, including antitumoral and antiangiogenic effects. In this study, we report the isolation, characterization and the antiangiogenic activity of Hemilipin, a novel sPLA2 extracted from Hemiscorpius lepturus venom, the most dangerous scorpion in Iran. Hemilipin was purified by HPLC and analyzed by MALDI TOF/MS. The primary structure was determined by EDMAN degradation method and the PLA2 activity by titration of fatty acids released from the egg yolk phospholipids. Its antiangiogenic activity was studied in vitro by evaluating effects on apoptosis, Matrigel angiogenesis, migration and adhesion of human umbilical vein endothelial ce...
Purpose: To investigate the angiogenic role of the HGF/cMET pathway and its inhibition in bone ma... more Purpose: To investigate the angiogenic role of the HGF/cMET pathway and its inhibition in bone marrow (BM) endothelial cells (ECs) from patients with multiple myeloma (MM) vs those with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (controls). Experimental Design: The HGF/cMET pathway was evaluated in ECs from MM patients (MMECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, in ECs from patients with MGUS (MGECs), and in those from controls. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on the MMECs angiogenic activities were studied in vitro and in vivo. Results: MMECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein level vs MGECs and control ECs. MMECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, while treatment with anti-HGF and anti-cMET neutralizing antibodies (Abs) is able to inh...
A 61-year old man with coeliac disease and chronic lack of appetite, malabsorption and weight los... more A 61-year old man with coeliac disease and chronic lack of appetite, malabsorption and weight loss, despite the gluten-free diet, was operated because of a sub-diaphragmatic free air due to a small-bowel pneumatosis cystoides intestinalis (PCI). The jejunum showed granulomatous lesions with a honeycombed appearance of air cysts in the submucosa/subserosa. We found overexpression of peptide YY (PYY) into only the jejunum with PCI, while the expression was very weak or absent in the tissue without cysts. One year after surgery, he had no abdominal pain or PCI recurrence. The above chronic symptoms were plausibly attributable to the PYY.
Advances in Experimental Medicine and Biology, 2011
We studied eight patients with active multiple myeloma (aMM, six males and two females; mean age ... more We studied eight patients with active multiple myeloma (aMM, six males and two females; mean age 62 years), nine patients in objective/complete response (rMM, three males and six females; mean age 70 years), and seven patients with monoclonal gammopathy of undetermined significance (MGUS, three males and four females; mean age 57 years). We used a laser Doppler to evaluate capillary blood flow and a transcutaneous oxymeter to measure transcutaneous oxygen partial pressure (TcpO2). Red blood cell (RBC) aggregation index (AI and t½) and elongation index (EI) were assessed using laser-assisted optical rotational cell analysis (LORCA), while the serum vascular endothelial growth factor (VEGF) levels were measured using enzyme-linked immunoabsorbant assay (ELISA). VEGF values were significantly increased (p < 0.001) in aMM vs. rMM and vs. MGUS. Also AI was increased (p < 0.05) in aMM vs. rMM and vs. MGUS and t½ was decreased (p < 0.05) in the aMM vs. rMM and MGUS groups; no variations were detected in EI. We found a significant correlation (p < 0.001) between AI/t½/EI and VEGF. Periflux tests were performed evaluating the basal values (t0), the physical stress (t1) and the heat stress (t3) followed by their respective relaxing times (t2, t4). A significant increase (p < 0.01) in t1 vs. t0 values was observed in all groups. No significant increase in aMM t3 vs. t0 was seen, while the increase was significant in rMM and MGUS (p < 0.01). We found a significant correlation (p < 0.001) between t0 blood flow and VEGF in aMM, rMM and MGUS. TcpO2 t0 values were significantly correlated to VEGF (p < 0.001) in all groups. Our data show that VEGF modifies the microcirculation in aMM and also modifies RBC. It is possible that other mechanisms could interfere with the peripheral microcirculation as we saw in t3 blood flow.
Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resis... more Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM) microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tu...
Journal of experimental & clinical cancer research : CR, Jan 2, 2018
Tumor microenvironment (TME) includes many factors such as tumor associated inflammatory cells, v... more Tumor microenvironment (TME) includes many factors such as tumor associated inflammatory cells, vessels, and lymphocytes, as well as different signaling molecules and extracellular matrix components. These aspects can be de-regulated and consequently lead to a worsening of cancer progression. In recent years an association between the scaffolding protein Na/H exchanger regulatory factor 1 (NHERF1) and tumor microenvironment changes in breast cancer (BC) has been reported. Subcellular NHERF1 localization, vascular endothelial growth factor (VEGF), its receptor VEGFR1, hypoxia inducible factor 1 alpha (HIF-1α), TWIST1 expression and microvessel density (MVD) in 183 invasive BCs were evaluated, using immunohistochemistry on tissue microarrays (TMA). Immunofluorescence was employed to explore protein interactions. Cytoplasmic NHERF1(cNHERF1) expression was directly related to cytoplasmic VEGF and VEGFR1 expression (p = 0.001 and p = 0.027 respectively), and inversely to nuclear HIF-1α (...
Lung cancer is the leading cause of cancer deaths throughout the world. The majority of patients ... more Lung cancer is the leading cause of cancer deaths throughout the world. The majority of patients are diagnosed with locally advanced or metastatic disease when surgery, the best curative option, is no longer feasible. Thus, the prognosis of lung cancer remains poor and heterogeneous and new biomarkers are needed. As the immune system plays a pivotal role in cancer, the study of tumor microenvironment, with regard to the immune component, may provide valuable information for a better comprehension of the pathogenesis and progression of the disease. Through a detailed and critical evaluation of the most recent publications on this topic, we provide evidences of the prognostic and predictive significance of immune markers in tumor and in peripheral blood of lung cancer patients: from the landscape of immune cells (macrophages, neutrophils, lymphocytes and natural killer) and their cytokines, to the analysis of immune-checkpoints (PD-L1 and CTLA4), up to the genetic and epigenetic regul...
In a previous study, we reported the identification of Hemilipin, the first secreted heterodimeri... more In a previous study, we reported the identification of Hemilipin, the first secreted heterodimeric phospholipase A2 (sPLA2) from Hemiscorpius lepturus scorpion venom and demonstrated its effective inhibition of all angiogenesis key steps in vitro and in vivo. Here, we aimed to characterize a second sPLA2, Hemilipin2, from the same venom and to elucidate its antiangiogenic effect. The protein was purified by chromatography separation and analyzed by MALDI/TOF mass spectrometry. Its N terminal amino acid sequence was determined by Edman degradation method and the enzymatic activity by fatty acids release assay. Hemilipin2 antiangiogenic activity was investigated by studying its effect in vitro on adhesion, migration and capillary like tube formation of Human Umbilical Vein Endothelial Cells (HUVECs) and Human Pulmonary Artery Endothelial Cells (HPAECs); and in vivo on the chick embryo chorioallantoic membrane (CAM) assay. Data to be presented show that Hemilipin2 is heterodimeric composed by two subunits: the large one has a molecular weight of 12,866 and the small one of 2461 a.m.u. It has a strong calcium-dependent PLA2 activity and impacts angiogenesis in vitro and in vivo without showing any cytotoxic or apoptotic signs. Its chemical modification with p-Bromophenacyl Bromide abolishes the enzymatic activity without affecting the antiangiogenic effect. Furthermore, it has been proved that Hemilipin2 small subunit was able to inhibit blood vessel formation both in vitro and in vivo. These findings may serve as a starting point for the designing of a new generation of specific inhibitor of human angiogenesis at different steps.
Toxicon : official journal of the International Society on Toxinology, 2015
Phospholipases A2 (PLA2) are enzymes which specifically hydrolyze the sn-2 acyl ester bond of pho... more Phospholipases A2 (PLA2) are enzymes which specifically hydrolyze the sn-2 acyl ester bond of phospholipids producing free fatty acids and lysophospholipids. The secreted PLA2 (sPLA2) are the most common types of PLA2 purified from the snake venom, mammalian pancreatic juice and other sources. They display a variety of toxic actions and biological activities, including antitumoral and antiangiogenic effects. In this study, we report the isolation, characterization and the antiangiogenic activity of Hemilipin, a novel sPLA2 extracted from Hemiscorpius lepturus venom, the most dangerous scorpion in Iran. Hemilipin was purified by HPLC and analyzed by MALDI TOF/MS. The primary structure was determined by EDMAN degradation method and the PLA2 activity by titration of fatty acids released from the egg yolk phospholipids. Its antiangiogenic activity was studied in vitro by evaluating effects on apoptosis, Matrigel angiogenesis, migration and adhesion of human umbilical vein endothelial ce...
Purpose: To investigate the angiogenic role of the HGF/cMET pathway and its inhibition in bone ma... more Purpose: To investigate the angiogenic role of the HGF/cMET pathway and its inhibition in bone marrow (BM) endothelial cells (ECs) from patients with multiple myeloma (MM) vs those with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (controls). Experimental Design: The HGF/cMET pathway was evaluated in ECs from MM patients (MMECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, in ECs from patients with MGUS (MGECs), and in those from controls. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on the MMECs angiogenic activities were studied in vitro and in vivo. Results: MMECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein level vs MGECs and control ECs. MMECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, while treatment with anti-HGF and anti-cMET neutralizing antibodies (Abs) is able to inh...
A 61-year old man with coeliac disease and chronic lack of appetite, malabsorption and weight los... more A 61-year old man with coeliac disease and chronic lack of appetite, malabsorption and weight loss, despite the gluten-free diet, was operated because of a sub-diaphragmatic free air due to a small-bowel pneumatosis cystoides intestinalis (PCI). The jejunum showed granulomatous lesions with a honeycombed appearance of air cysts in the submucosa/subserosa. We found overexpression of peptide YY (PYY) into only the jejunum with PCI, while the expression was very weak or absent in the tissue without cysts. One year after surgery, he had no abdominal pain or PCI recurrence. The above chronic symptoms were plausibly attributable to the PYY.
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Papers by Ivana Catacchio