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Ciardiello C.,Cedars Sinai Medical Center | Ciardiello C.,Experimental Pharmacology Unit | Cavallini L.,Cedars Sinai Medical Center | Cavallini L.,University of Florence | And 8 more authors.
International Journal of Molecular Sciences | Year: 2016

Extracellular Vesicles (EVs) have received considerable attention in recent years, both as mediators of intercellular communication pathways that lead to tumor progression, and as potential sources for discovery of novel cancer biomarkers. For many years, research on EVs has mainly investigated either the mechanism of biogenesis and cargo selection and incorporation, or the methods of EV isolation from available body fluids for biomarker discovery. Recent studies have highlighted the existence of different populations of cancer-derived EVs, with distinct molecular cargo, thus pointing to the possibility that the various EV populations might play diverse roles in cancer and that this does not happen randomly. However, data attributing cancer specific intercellular functions to given populations of EVs are still limited. A deeper functional, biochemical and molecular characterization of the various EV classes might identify more selective clinical markers, and significantly advance our knowledge of the pathogenesis and disease progression of many cancer types. © 2016 by the authors; licensee MDPI, Basel, Switzerland.

Masuelli L.,University of Rome La Sapienza | Budillon A.,Experimental Pharmacology Unit | Marzocchella L.,University of Rome Tor Vergata | Mrozek M..-A.,University of Rome La Sapienza | And 10 more authors.
Journal of Cellular Physiology | Year: 2012

The presence of lymph node metastases is one of the most important prognostic indicators in head and neck squamous cell carcinomas (HNSCCs). An alteration of the E-cadherin-catenins complex and EGFR is essential for the invasiveness of cancer cells. Caveolin-1, the major structural protein of the caveolae, represents a scaffolding molecule for several signaling proteins including EGFR. Although caveolin-1 has been shown to play a role in inducing the invasive phenotype of cancer cells, its role appears to be cell-type specific and for some tumors it has not been defined yet. In this study we used 57 HNSCC specimens to investigate whether the abnormal expression of caveolin-1 was associated with the derangement of the E-cadherin-catenins complex and with the overexpression of ErbB receptors. We demonstrate that in HNSCCs caveolin-1 overexpression is associated with the simultaneous abnormal expression of at least one member of the E-cadherin/α-β catenins complex and multiple ErbB receptors as well as with lymph node metastases. We also demonstrate that chronic stimulation of a human hypopharyngeal carcinoma cell line (FaDu) with EGF induced the internalization of β-catenin and caveolin-1 and their co-localization with EGFR. Moreover, EGF treatment induced an increased physical interaction between EGFR/β-catenin/caveolin-1 and between E-cadherin/β-catenin/caveolin-1. These molecular events were associated with an increased directional motility of FaDu cells in vitro. These findings may provide new insight into the biology of HNSCC progression and help to identify subgroups of primary HNSCCs with a more aggressive behavior. © 2011 Wiley Periodicals, Inc.

Guerra A.,University of Salerno | Fugazzola L.,University of Milan | Marotta V.,University of Salerno | Cirillo M.,University of Salerno | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: BRAFV600E is considered a negative prognostic marker in papillary thyroid carcinoma (PTC), but unexplained conflicting results are present in the literature. In light of the new finding that most PTC consist of a mixture of tumor cells with wild-type and mutant BRAF, we examined the associations between the percentage of BRAFV600E alleles and both the clinicopathological parameters at time of diagnosis and the disease outcome in a large series of PTCs. Study Design: Tumors from 168 patients with PTC were genotyped for BRAFV600E using BigDye Terminator sequencing and pyrosequencing, and the clinical parameters were analyzed. The associations between clinicopathological characteristics, including disease recurrence at follow-up (median 5.1 yr) and the percentage of mutant BRAF alleles were assessed. Results: The observed prevalence of BRAFV600E was higher when using pyrosequencing then when using BigDye Terminator sequencing (53.6 vs. 36.9%). In the PTC positive for BRAFV600E, the percentage of mutant alleles ranged from 5.1 to 44.7% of the total BRAF alleles, with a median of 20.6%. The presence or the percentage of BRAFV600E alleles did not correlate significantly with sex, multicentricity, lymph node metastasis, or tumor stage. The percentage of BRAFV600E alleles directly correlated with age at diagnosis and tumor volume (R2 = 0.223, P = 0.039, and R2 = 0.166, P < 0.001, respectively). The percentage of BRAF V600E alleles (P = 0.014), tumor volume (P = 0.012), and lymph node metastasis (P = 0.008) predicted the disease outcome. The odds ratio of recurrence for PTC with BRAFV600E alleles of 30% or greater, compared with that for PTC with BRAFV600E alleles of less than 30%, was 5.31 (P = 0.002). Conclusions: A high percentage of BRAFV600E alleles defines a PTC molecular subtype and predicts a poorer disease outcome. The analysis of BRAF mutations by pyrosequencing is useful to refine the risk stratification of patients with PTC. Copyright © 2012 by The Endocrine Society.

Avallone A.,Gastrointestinal Medical Oncology Unit | Gennaro E.D.,Experimental Pharmacology Unit | Silvestro L.,Gastrointestinal Medical Oncology Unit | Iaffaioli V.R.,Gastrointestinal Medical Oncology Unit | Budillon A.,Experimental Pharmacology Unit
Expert Opinion on Drug Safety | Year: 2014

Introduction: 5-fluorouracil continues to be the cornerstone of treatment for colorectal cancer. Although fluoropyrimidines are generally considered as well-Tolerated drugs, severe toxicities can be a major clinical problem, and the recommended prolonged infusion of 5-fluorouracil provokes discomfort in patients. Raltitrexed (Tomudex), a quinazoline analogue of folinic acid, is a selective and direct thymidylate synthase (TS) inhibitor with a convenient 3-weekly schedule of administration. Areas covered: In this review, through critical insight into the mechanism of action and main clinical experiences, the authors suggest the necessity to reconsider raltitrexed as a valuable anticancer drug and as a suitable option for colorectal cancer. The authors highlight its emerging therapeutic role in clinical practice for patients with fluoropyrimidine-induced cardiotoxicity or a significant history of cardiac disease. Expert opinion: This review discusses if TS could still be a relevant target for colorectal cancer in the era of molecular therapy and if raltitrexed should still be considered a drug with a life-Threatening toxicity. Furthermore, this review discusses the principal combination clinical experiences of raltitrexed and its emerging therapeutic role in clinical practice as a suitable option for colorectal cancer patients with fluoropyrimidine-induced cardiotoxicity or a significant history of cardiac disease. © Informa UK, Ltd.

Guerra A.,University of Salerno | Sapio M.R.,University of Salerno | Marotta V.,University of Naples Federico II | Campanile E.,University of Salerno | And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: BRAFV600E is considered a primary event, a negative prognostic marker, and a site for pharmacological intervention in papillary thyroid carcinoma (PTC). We asked whether BRAFV600Ecan occur as a subclonal event in PTC and whether this and other oncogenes can coexist in the same tumor. Study Design: We determined by pyrosequencing the percentage of mutant BRAF, NRAS, and KRAS alleles in a series of conventional PTC. We also analyzed the BRAF mutation status in PTC cell clones in culture. Results: BRAFV600E alleles were present in 41 of 72 PTC (56.9%) in the range 44.7 to 5.1% of total BRAF alleles. In four PTC samples, mutant BRAF alleles were about 50%, being therefore compatible with a clonal heterozygous mutation. In 27 PTC samples, BRAFV600E alleles were in the range of 25 to 5.1%. This finding was confirmed after exclusion of the presence of a large contamination by lymphoreticular cells and by the analysis of PTC cells selected by laser capture. Analysis of clones derived from a single cell confirmed the presence of two distinct PTC populations with wild-type or mutated BRAF. Simultaneous subclonal BRAF and KRAS mutations were demonstrated in two PTC. Conclusions: These data demonstrate that clonal BRAFV600E is a rare occurrence in PTC, although frequently this cancer consists of a mixture of tumor cells with wild-type and mutant BRAF. These results suggest that BRAF mutation in PTC is a later subclonal event, its intratumoral heterogeneity may hamper the efficacy of targeted pharmacotherapy, and its association with a more aggressive disease should be reevaluated. Copyright © 2012 by The Endocrine Society.

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