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Croci D.O.,CONICET | Croci D.O.,University of Buenos Aires | Salatino M.,CONICET | Salatino M.,University of Buenos Aires | And 17 more authors.
Journal of Experimental Medicine | Year: 2012

Kaposi's sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus-8 (HHV-8/KS-associated herpesvirus [KSHV]) infection, is the most common AIDS-associated malignancy. Clinical management of KS has proven to be challenging because of its prevalence in immunosuppressed patients and its unique vascular and inflammatory nature that is sustained by viral and host-derived paracrine-acting factors primarily released under hypoxic conditions. We show that interactions between the regulatory lectin galectin-1 (Gal-1) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis of KS. Expression of Gal-1 is found to be a hallmark of human KS but not other vascular pathologies and is directly induced by both KSHV and hypoxia. Interestingly, hypoxia induced Gal-1 through mechanisms that are independent of hypoxia-inducible factor (HIF) 1α and HIF-2α but involved reactive oxygen species-dependent activation of the transcription factor nuclear factor κB. Targeted disruption of Gal-1-N-glycan interactions eliminated hypoxia-driven angiogenesis and suppressed tumorigenesis in vivo. Therapeutic administration of a Gal-1-specific neutralizing mAb attenuated abnormal angiogenesis and promoted tumor regression in mice bearing established KS tumors. Given the active search for HIF-independent mechanisms that serve to couple tumor hypoxia to pathological angiogenesis, our findings provide novel opportunities not only for treating KS patients but also for understanding and managing a variety of solid tumors. © 2012 Croci et al. Source

Tarantini L.,U.O. di Cardiologia | Feola M.,Riabilitazione Cardiologica Unita Scompenso Cardiaco | Albini A.,Polo Scientifico e Tecnologico | Gori S.,U.O. di Oncologia | And 3 more authors.
Giornale Italiano di Cardiologia | Year: 2012

The amplification of the HER receptor system is present in approximately 20% of breast cancers and confers a marked malignancy and a poor prognosis. Trastuzumab, a monoclonal antibody directed against the HER2 receptor, has dramatically improved the prognosis of patients with HER2+ metastatic and early breast cancer. However, the use of trastuzumab is associated with the possible development of myocardial dysfunction and heart failure. Trastuzumab-induced cardiac injury may be reversible, and a substantial proportion of patients can complete therapy. For this reason, careful monitoring of cardiac function, an aggressive treatment of hypertension and possibly the use of non-anthracycline-containing chemotherapy protocols are required during trastuzumab treatment. Owing to the selection of patients enrolled in major randomized trials, the safety profile of trastuzumab is currently unclear in elderly women, in patients at high cardiovascular risk and in those with structural heart disease on optimal treatment. Further studies are therefore needed to determine whether this highly effective therapy in breast cancer survival can be extended to such categories of patients. © 2012 Il Pensiero Scientifico Editore. Source

Albini A.,Polo Scientifico e Tecnologico | Noonan D.M.,University of Insubria
Current Opinion in Cell Biology | Year: 2010

Invasive and metastatic cells must cross basement membranes (BMs) in order to disseminate to distant sites. The 'chemoinvasion assay' using a reconstituted basement membrane, matrigel, in Boyden blind-well chambers was developed 25 years ago as a tool for invasion and metastasis research. Since then, it was adapted for investigation of how different cells types engage with and penetrate basement membrane, including research in angiogenesis, invasive cell migration, protease functions, and preclinical development of anti-invasive and anti-angiogenic agents. As novel mechanisms of metastasis and angiogenesis come to light and old paradigms are challenged, we examine how the assay can still provide innovative insights. We review established applications and variants of the matrigel invasion assay, highlight key findings derived from it and discuss future developments, including roles for accessory and cancer stem cells. © 2010 Elsevier Ltd. Source

Albini A.,Polo Scientifico e Tecnologico | Mussi V.,CBA Centro Biotecnologie Avanzate | Parodi A.,CBA Centro Biotecnologie Avanzate | Ventura A.,CBA Centro Biotecnologie Avanzate | And 12 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2010

Single-wall carbon nanotubes (SWCNTs) could be promising delivery vehicles for cancer therapy. These carriers are generally introduced intravenously, however, little is known of their interactions with endothelial cells, the cells lining vessels and mediating clearance of nanoparticles. Here we show that SWCNTs of 1 to 5 μm in length, both "pristine" and functionalized by oxidation, had limited toxicity for endothelial cells in vitro as determined by growth, migration morphogenesis, and survival assays. Endothelial cells transiently took up SWCNTs, and several lines of data indicated that they were associated with an enhanced acidic vesicle compartment within the endothelial cells. Our findings of SWCNT interactions with endothelial cells suggest these may be optimal vehicles for targeting the vasculature and potential carriers of anti-angiogenic drugs. The implications on their biological activity must be taken into account when considering the use of these nanoparticles for therapeutic delivery of drugs. From the Clinical Editor: Interactions of single walled carbon nanotubes (SWCNTs) with endothelial cells following IV administration remains unclear. Functionalized and naïve SWCNTs of 1-5 mm in length had limited toxicity to endothelial cells in vitro. Endothelial cells transiently took up SWCNTs and were associated with an enhanced acidic vesicle compartment within the cells. These findings suggest that SWCNTs may be promising vehicles for targeting the vasculature and potential carriers of anti-angiogenic drugs. © 2010 Elsevier Inc. All rights reserved. Source

Bruno A.,Polo Scientifico e Tecnologico | Bruno A.,University of Insubria | Pagani A.,Polo Scientifico e Tecnologico | Magnani E.,Polo Scientifico e Tecnologico | And 4 more authors.
Cancer Treatment and Research | Year: 2014

In addition to aberrant transformed cells, tumors are tissues that contain host components, including stromal cells, vascular cells (ECs) and their precursors, and immune cells. All these constituents interact with each other at the cellular and molecular levels, resulting in the production of an intricate and heterogeneous complex of cells and matrix defined as the tumor microenvironment. Several pathways involved in these interactions have been investigated both in pathological and physiological scenarios, and diverse molecules are currently targets of chemotherapeutic and preventive drugs. Many phytochemicals and their derivatives show the ability to inhibit tumor progression, angiogenesis, and metastasis, exerting effects on the tumor microenvironment. In this review, we will outline the principal players and mechanisms involved in the tumor microenvironment network and we will discuss some interesting compounds aimed at interrupting these interactions and blocking tumor insurgence and progression. The considerations provided will be crucial for the design of new preventive approaches to the reduction in cancer risk that need to be applied to large populations composed of apparently healthy individuals. © Springer-Verlag Berlin Heidelberg 2014 Source

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