Yeshiva University, Regina Elena Cancer Institute and Massachusetts Institute of Technology | Date: 2013-11-07
Methods and kits for diagnosis, prognosis and treatment of metastatic tumors are provided where the metastatic tumor is characterized by changes in expression of +++, ++ and/or 11a variants of Mena.
Ragazzoni Y.,Regina Elena Cancer Institute
Cell death & disease | Year: 2013
We have previously demonstrated that the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) induces apoptosis and cell cycle arrest in human leukemia cells. The aim of this study was to evaluate whether CPTH6 is able to affect autophagy. By using several human tumor cell lines with different origins we demonstrated that CPTH6 treatment induced, in a dose-dependent manner, a significant increase in autophagic features, as imaged by electron microscopy, immunoblotting analysis of membrane-bound form of microtubule-associated protein 1 light chain 3 (LC3B-II) levels and by appearance of typical LC3B-II-associated autophagosomal puncta. To gain insights into the molecular mechanisms of elevated markers of autophagy induced by CPTH6 treatment, we silenced the expression of several proteins acting at different steps of autophagy. We found that the effect of CPTH6 on autophagy developed through a noncanonical mechanism that did not require beclin-1-dependent nucleation, but involved Atg-7-mediated elongation of autophagosomal membranes. Strikingly, a combined treatment of CPTH6 with late-stage autophagy inhibitors, such as chloroquine and bafilomycin A1, demonstrates that under basal condition CPTH6 reduces autophagosome turnover through an impairment of their degradation pathway, rather than enhancing autophagosome formation, as confirmed by immunofluorescence experiments. According to these results, CPTH6-induced enhancement of autophagy substrate p62 and NBR1 protein levels confirms a blockage of autophagic cargo degradation. In addition, CPTH6 inhibited autophagosome maturation and compounds having high structural similarities with CPTH6 produced similar effects on the autophagic pathway. Finally, the evidence that CPTH6 treatment decreased α-tubulin acetylation and failed to increase autophagic markers in cells in which acetyltransferase ATAT1 expression was silenced indicates a possible role of α-tubulin acetylation in CPTH6-induced alteration in autophagy. Overall, CPTH6 could be a valuable agent for the treatment of cancer and should be further studied as a possible antineoplastic agent.
Bellacchio E.,Bambino Gesu Childrens Hospital |
Paggi M.G.,Regina Elena Cancer Institute
Journal of Cellular Physiology | Year: 2013
The retinoblastoma (RB) family consists of three genes, RB1, RBL1, and RBL2, that code for the pRb, p107, and pRb2/p130 proteins, respectively. All these factors have pivotal roles in controlling fundamental cellular mechanisms such as cell cycle, differentiation and apoptosis. The founder and the most investigated RB family protein is pRb, which is considered to be the paradigm of tumor suppressors. However, p107 and pRb2/p130 clearly display a high degree of structural and functional homology with pRb. Interestingly, these factors were first identified as physical targets of the Adenovirus E1A oncoprotein. Indeed, RB family proteins are the most important and widely investigated targets of small DNA virus oncoproteins, such as Adenovirus E1A, human papillomavirus E7 and Simian virus 40 large T antigen. By interacting with pRb and with other RB family members, these oncoproteins neutralize their growth suppressive properties, thus stimulating proliferation of the infected cells, de-differentiation, and resistance to apoptosis. All these acquired features strongly favor the rise and selection of immortalized and mutation-prone cells, leading to a higher propensity in undergoing transformation. Our present work aims to illustrate and delve into these protein-protein interactions. Considering that these viral oncoproteins are dispensable for normal cellular functions, they can create "oncogene addiction" in the infected/transformed cells. This makes the possibility to dismantle these interactions extremely attractive, thus promoting the development of highly specific smart molecules capable of targeting only the infected/transformed cells that express these viral factors. © 2012 Wiley Periodicals, Inc.
Nistico P.,Regina Elena Cancer Institute |
Bissell M.J.,Lawrence Berkeley National Laboratory |
Radisky D.C.,Mayo Clinic Cancer Center
Cold Spring Harbor Perspectives in Biology | Year: 2012
Epithelial-mesenchymal transition (EMT) is a physiological process in which epithelial cells acquire the motile and invasive characteristics of mesenchymal cells. Although EMTin embryonic development is a coordinated, organized process involving interaction between many different cells and tissue types, aspects of the EMT program can be inappropriately activated in response to microenvironmental alterations and aberrant stimuli, and this can contribute to disease conditions including tissue fibrosis and cancer progression. Here we will outline how EMT functions in normal development, how it could be activated in pathologic conditions- especially by matrix metalloproteinases-and how it may be targeted for therapeutic benefit. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.
Maugeri-Sacca M.,Regina Elena Cancer Institute |
Bartucci M.,Instituto Superiore Of Sanita |
De Maria R.,Regina Elena Cancer Institute
Cancer Treatment Reviews | Year: 2013
The checkpoint kinase 1 (Chk1) is a key component of the DNA damage response, a molecular network deputed to maintain genome integrity. Nevertheless, cancer cells aberrantly exploit these circuits to overcome chemotherapy-induced cytotoxicity. Chk1 inhibitors have been developed as a chemopotentiating strategy and different molecular mechanisms underlying the synergism with chemotherapeutics have been uncovered. The monotherapy with Chk1 inhibitors seems to be endowed with antitumor activity against cancer cells characterized by specific defects in the DNA damage machinery or characterized by elevated levels of oncogene-induced replication stress. In this biological framework Chk1 neutralization represents a synthetic lethality-based therapeutic approach. Moreover, a dual targeting of the DNA damage machinery has been proposed envisioning the association of Chk1 abrogation with poly-ADP ribose polymerase inhibitors. The spectrum of antitumor properties of Chk1 antagonists is completed by the activity against cancer stem cells, the prominent tumorigenic population that is equipped to survive stressful conditions through multiple and interconnected mechanisms. Although the clinical development of the first generation of Chk1 antagonists was hindered by off-target effects and an unfavorable pharmacokinetic profile, a new wave of early clinical trials with more selective compounds are currently being carried out. To this end, the identification of predictive biomarkers and an in-depth characterization of molecular circuits governed by Chk1 are issues that need to be addressed for sharpening the therapeutic potential of Chk1 inhibitors. © 2012 Elsevier Ltd.
Bonci D.,Regina Elena Cancer Institute
Oncogene | Year: 2015
Although the development of bone metastasis is a major detrimental event in prostate cancer, the molecular mechanisms responsible for bone homing and destruction remain largely unknown. Here we show that loss of miR-15 and miR-16 in cooperation with increased miR-21 expression promote prostate cancer spreading and bone lesions. This combination of microRNA endows bone-metastatic potential to prostate cancer cells. Concomitant loss of miR-15/miR-16 and gain of miR-21 aberrantly activate TGF-β and Hedgehog signaling, that mediate local invasion, distant bone marrow colonization and osteolysis by prostate cancer cells. These findings establish a new molecular circuitry for prostate cancer metastasis that was validated in patients' cohorts. Our data indicate a network of biomarkers and druggable pathways to improve patient treatment.Oncogene advance online publication, 15 June 2015; doi:10.1038/onc.2015.176. © 2015 Macmillan Publishers Limited
Nistico P.,Regina Elena Cancer Institute
Cold Spring Harbor perspectives in biology | Year: 2012
Epithelial-mesenchymal transition (EMT) is a physiological process in which epithelial cells acquire the motile and invasive characteristics of mesenchymal cells. Although EMT in embryonic development is a coordinated, organized process involving interaction between many different cells and tissue types, aspects of the EMT program can be inappropriately activated in response to microenvironmental alterations and aberrant stimuli, and this can contribute to disease conditions including tissue fibrosis and cancer progression. Here we will outline how EMT functions in normal development, how it could be activated in pathologic conditions-especially by matrix metalloproteinases-and how it may be targeted for therapeutic benefit.
Maschio M.,Regina Elena Cancer Institute
Current Neuropharmacology | Year: 2012
In patients with brain tumor (BT), seizures are the onset symptom in 20-40% of patients, while a further 20-45% of patients will present them during the course of the disease. These patients present a complex therapeutic profile and require a unique and multidisciplinary approach. The choice of antiepileptic drugs is challenging for this particular patient population because brain tumor-related epilepsy (BTRE) is often drug-resistant, has a strong impact on the quality of life and weighs heavily on public health expenditures. In BT patients, the presence of epilepsy is considered the most important risk factor for long-term disability. For this reason, the problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control can significantly improve the patient's psychological and relational sphere. In these patients, new generation drugs such as gabapentin, lacosamide, levetiracetam, oxcarbazepine, pregabalin, topiramate, zonisamide are preferred because they have fewer drug interactions and cause fewer side effects. Among the recently marketed drugs, lacosamide has demonstrated promising results and should be considered a possible treatment option. Therefore, it is necessary to develop a customized treatment plan for each individual patient with BTRE. This requires a vision of patient management concerned not only with medical therapies (pharmacological, surgical, radiological, etc.) but also with emotional and psychological support for the individual as well as his or her family throughout all stages of the illness. © 2012 Bentham Science Publishers.
Spinella F.,Regina Elena Cancer Institute
Journal of molecular medicine (Berlin, Germany) | Year: 2013
Endothelin receptor B (ET(B)R) is a G-protein-coupled receptor overexpressed in melanoma, blood, and lymphatic endothelial cells. Given that aberrant signal transduction can be mediated through cross talk between receptors, here, we explore the functional relationship between ET(B)R and the vascular endothelial growth factor receptor (VEGFR)-3 system and how this cross talk might influence the aggressive behavior of melanoma cells. The expression of VEGFR-3 and its ligands, VEGF-C and VEGF-D, significantly increased after activating ET(B)R by ET-1 in primary and metastatic melanoma cell lines. These effects, similarly to those induced by hypoxia, were mediated by hypoxia-inducible factor (HIF)-1α and HIF-2α. ET-1 caused the phosphorylation of VEGFR-3, which was accompanied by the activation of the downstream signaling molecules, such as MAPK and AKT. Inhibition of c-Src activity or silencing of the scaffold protein β-arrestin-1 reduced ET-1-induced VEGFR-3 phosphorylation, demonstrating that, upon ET-1 stimulus, β-arrestin-1 is involved with c-Src in the ET(B)R-mediated VEGFR-3 transactivation. Moreover, ET-1 in combination with VEGF-C further increased VEGFR-3, MAPK, and AKT phosphorylation and markedly promoted cell migration and vasculogenic mimicry. Dual inhibition of ET(B)R and VEGFR-3 was required for the effective inhibition of these effects, as well as for VEGFR-3 phosphorylation, demonstrating that ET(B)R cross talk with VEGFR-3 enhances cell plasticity and motility. Finally, in melanoma xenografts, ET(B)R antagonist inhibited tumor growth and the activation of the VEGF-C/VEGFR-3 axis, indicating that targeting ET(B)R may improve melanoma treatment acting directly or indirectly by impairing ET(B)R cross talk with VEGFR-3.
Rosano L.,Regina Elena Cancer Institute |
Spinella F.,Regina Elena Cancer Institute |
Bagnato A.,Regina Elena Cancer Institute
Nature Reviews Cancer | Year: 2013
Activation of autocrine and paracrine signalling by endothelin 1 (ET1) binding to its receptors elicits pleiotropic effects on tumour cells and on the host microenvironment. This activation modulates cell proliferation, apoptosis, migration, epithelial-to-mesenchymal transition, chemoresistance and neovascularization, thus providing a strong rationale for targeting ET1 receptors in cancer. In this Review, we discuss the advances in our understanding of the diverse biological roles of ET1 in cancer and describe the latest preclinical and clinical progress that has been made using small-molecule antagonists of ET1 receptors that inhibit ET1-driven signalling. ©2013 Macmillan Publishers Limited. All rights reserved. © 2013 Macmillan Publishers Limited. All rights reserved.