Tuscany Tumor Institute
Tuscany Tumor Institute
Kohonen-Corish M.R.,Garvan Institute of Medical Research |
Macrae F.,Royal Melbourne Hospital |
Macrae F.,Leiden University |
Genuardi M.,International Society for Gastrointestinal Hereditary Tumours InSiGHT |
And 24 more authors.
Human Mutation | Year: 2011
The Human Variome Project (HVP) has established a pilot program with the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) to compile all inherited variation affecting colon cancer susceptibility genes. An HVP-InSiGHT Workshop was held on May 10, 2010, prior to the HVP Integration and Implementation Meeting at UNESCO in Paris, to review the progress of this pilot program. A wide range of topics were covered, including issues relating to genotype-phenotype data submission to the InSiGHT Colon Cancer Gene Variant Databases (chromium.liacs.nl/LOVD2/colon-cancer/home.php). The meeting also canvassed the recent exciting developments in models to evaluate the pathogenicity of unclassified variants using in silico data, tumor pathology information, and functional assays, and made further plans for the future progress and sustainability of the pilot program. © 2011 Wiley-Liss, Inc.
Ippolito L.,University of Florence |
Marini A.,University of Sassari |
Cavallini L.,University of Florence |
Morandi A.,University of Florence |
And 9 more authors.
Oncotarget | Year: 2016
Drug resistance of cancer cells is recognized as the primary cause of failure of chemotherapeutic treatment in most human cancers. Growing evidences support the idea that deregulated cellular metabolism is linked to such resistance. Indeed, both components of the glycolytic and mitochondrial pathways are involved in altered metabolism linked to chemoresistance of several cancers. Here we investigated the drug-induced metabolic adaptations able to confer advantages to docetaxel resistant prostate cancer (PCa) cells. We found that docetaxel-resistant PC3 cells (PC3-DR) acquire a pro-invasive behavior undergoing epithelial-to-mesenchymal-transition (EMT) and a decrease of both intracellular ROS and cell growth. Metabolic analyses revealed that PC3-DR cells have a more efficient respiratory phenotype than sensitive cells, involving utilization of glucose, glutamine and lactate by the mitochondrial oxidative phosphorylation (OXPHOS). Consequently, targeting mitochondrial complex I by metformin administration, impairs proliferation and invasiveness of PC3-DR cells without effects on parental cells. Furthermore, stromal fibroblasts, which cause a "reverse Warburg" phenotype in PCa cells, reduce docetaxel toxicity in both sensitive and resistant PCa cells. However, re-expression of miR-205, a microRNA strongly down-regulated in EMT and associated to docetaxel resistance, is able to shift OXPHOS to a Warburg metabolism, thereby resulting in an elevated docetaxel toxicity in PCa cells. Taken together, these findings suggest that resistance to docetaxel induces a shift from Warburg to OXPHOS, mandatory for conferring a survival advantage to resistant cells, suggesting that impairing such metabolic reprogramming could be a successful therapeutic approach.
Fiaschi T.,Tuscany Tumor Institute |
Marini A.,Tuscany Tumor Institute |
Giannoni E.,Tuscany Tumor Institute |
Taddei M.L.,Tuscany Tumor Institute |
And 6 more authors.
Cancer Research | Year: 2012
Cancer-associated fibroblasts (CAF) engage in tumor progression by promoting the ability of cancer cells to undergo epithelial-mesenchymal transition (EMT), and also by enhancing stem cells traits and metastatic dissemination. Here we show that the reciprocal interplay between CAFs and prostate cancer cells goes beyond the engagement of EMT to include mutual metabolic reprogramming. Gene expression analysis of CAFs cultured ex vivo or human prostate fibroblasts obtained from benign prostate hyperplasia revealed that CAFs undergo Warburg metabolism and mitochondrial oxidative stress. This metabolic reprogramming toward a Warburg phenotype occurred as a result of contact with prostate cancer cells. Intercellular contact activated the stromal fibroblasts, triggering increased expression of glucose transporter GLUT1, lactate production, and extrusion of lactate by de novo expressed monocarboxylate transporter-4 (MCT4). Conversely, prostate cancer cells, upon contact with CAFs, were reprogrammed toward aerobic metabolism, with a decrease in GLUT1 expression and an increase in lactate upload via the lactate transporter MCT1. Metabolic reprogramming of both stromal and cancer cells was under strict control of the hypoxia-inducible factor 1 (HIF1), which drove redox- and SIRT3-dependent stabilization of HIF1 in normoxic conditions. Prostate cancer cells gradually became independent of glucose consumption, while developing a dependence on lactate upload to drive anabolic pathways and thereby cell growth. In agreement, pharmacologic inhibition of MCT1-mediated lactate upload dramatically affected prostate cancer cell survival and tumor outgrowth. Hence, cancer cells allocate Warburg metabolism to their corrupted CAFs, exploiting their byproducts to grow in a low glucose environment, symbiotically adapting with stromal cells to glucose availability. ©2012 AACR.
Giannoni E.,University of Florence |
Chiarugi P.,University of Florence |
Chiarugi P.,Tuscany Tumor Institute
Antioxidants and Redox Signaling | Year: 2014
Significance: Here, we review recent advances with regard to the role of Src kinase in the regulation of cytoskeleton organization, cell adhesion, and motility, focusing on redox circuitries engaging this kinase for anchorage and motility, control of cell survival to anoikis, as well as metabolic deregulation, all features belonging to the new hallmarks of cancer. Recent Advances: Several recent insights have reported that, alongside the well-known phosphorylation/dephosphorylation control, cysteine oxidation is a further mechanism of enzyme activation for both c-Src kinase and its oncogenic counterparts. Indeed, mounting evidence portrays redox regulation of Src kinase as a compulsory outcome in growth factors/cytokines signaling, integrin engagement, motility and invasiveness of tissues, receptor cross-talking at plasmamembrane, as well as during carcinogenesis and progression toward tumor malignancy or fibrotic disease. In addition, the kinase is an upstream regulator of NADPH oxidase-driven oxidants, a critical step for invadopodia formation and metastatic spread. Critical Issues: Not satisfactorily unraveled yet, the exact role of Src kinase in redox cancer biology needs to be implemented with studies that are aimed at clarifying (i) the exact hierarchy between oxidants sources, Src redox-dependent activation and the regulation of cell motility, and (ii) the actual susceptibility of invading cells to redox-based treatments, owing to the well-recognized ability of cancer cells to find new strategies to adapt to new environments. Future Directions: Once these critical issues are addressed, redox circuitries involving Src kinase should potentially be used as both biomarkers and targets for personalized therapies in the fight against cancer or fibrotic diseases. © 2014, Mary Ann Liebert, Inc. 2014.
Comito G.,University of Florence |
Giannoni E.,University of Florence |
Segura C.P.,University of Florence |
Barcellos-De-Souza P.,University of Florence |
And 6 more authors.
Oncogene | Year: 2014
Melanoma progression is typically depicted as a linear and stepwise process in which metastasis occurs relatively late in disease progression. Significant evidence suggests that in a subset of melanomas, progression is much more complex and less linear in nature. Epidemiologic and experimental observations in melanoma metastasis are reviewed here and are incorporated into a comprehensive model for melanoma metastasis, which takes into account the varied natural history of melanoma formation and progression. © 2014 Macmillan Publishers Limited All rights reserved.
Calvani M.,University of Florence |
Bianchini F.,University of Florence |
Taddei M.L.,University of Florence |
Becatti M.,University of Florence |
And 4 more authors.
Oncotarget | Year: 2016
Tumors contain a sub-population of self-renewing and expanding cells known as cancer stem cells (CSCs). Putative CSCs were isolated from human melanoma cells of a different aggressiveness, Hs294T and A375 cell lines, grown under hypoxia using "sphere-forming assay", CD133 surface expression and migration ability. We found that a cell sub-population enriched for P1 sphere-initiating ability and CD133 expression also express larger amount of VEGF-R2. Etoposide does not influence phenotype of this sub-population of melanoma cells, while a combined treatment with Etoposide and Bevacizumab significantly abolished P1 sphere-forming ability, an effect associated with apoptosis of this subset of cells. Hypoxic melanoma cells sorted for VEGF-R2/ CD133 positivity also undergo apoptosis when exposed to Etoposide and Bevacizumab. When Etoposide and Bevacizumab-treated hypoxic cells were injected intravenously into immunodeficient mice revealed a reduced capacity to induce lung colonies, which also appear with a longer latency period. Hence, our study indicates that a combined exposure to Etoposide and Bevacizumab targets melanoma cells endowed with stemlike properties and might be considered a novel approach to treat cancer-initiating cells.
Chiarugi P.,Tuscany Tumor Institute |
Filippi L.,University of Florence
OncoImmunology | Year: 2015
The achievement of malignant traits in several cancers is associated with tumor microenvironment reactivity. New evidence show that the stress hormone noradrenaline enhances melanoma microenvironment reactivity, mainly acting through β3-adrenoreceptors (β2-ARs), favoring recruitment of cancer-associated fibroblasts, M2-macrophages, bone marrow-derived precursors, These events concur in sustaining a pro-inflammatory and pro-angiogenic milieu, finally boosting melanoma malignancy. © 2015, Taylor & Francis Group, LLC.
PubMed | University of Florence and Tuscany Tumor Institute
Type: Journal Article | Journal: Oncoimmunology | Year: 2015
The achievement of malignant traits in several cancers is associated with tumor microenvironment reactivity. New evidence show that the stress hormone noradrenaline enhances melanoma microenvironment reactivity, mainly acting through 3-adrenoreceptors (
Chen A.C.,Baylor College of Medicine |
Migliaccio I.,Baylor College of Medicine |
Migliaccio I.,Tuscany Tumor Institute |
Rimawi M.,Baylor College of Medicine |
And 9 more authors.
Breast Cancer Research and Treatment | Year: 2012
We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin and eosin and with mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER, and HER2 signaling pathways was measured by immunohistochemistry and western blotting. The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam ? LT) or estrogen deprivation (ED ? LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype-a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogenregulated gene progesterone receptor. Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive. © Springer Science+Business Media, LLC. 2012⋯.