Publications (76) View all
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Article: Anaplastic lymphoma kinase: a glimmer of hope in lung cancer treatment?
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ABSTRACT: Anaplastic lymphoma kinase (ALK) rearrangements (ALK-Rs) have been identified in 3-7% of all non-small-cell lung cancers (NSCLCs) and represent an important molecular target for NSCLC treatment. The authors discuss the role of ALK-Rs in the prediction of clinical-pathological features of NSCLCs and the technical problems related to their determination in specimens. The authors also describe the preclinical and clinical results derived from the use of ALK inhibitors. ALK-R is generally detected in patients with specific clinical-pathological features: never-smokers, young males, adenocarcinoma histotype and EGF receptor/KRAS wild-type. The diagnosis of ALK-R remains a challenge, implicating the need of a careful filtering of patients. NSCLC patients harboring ALK-R have shown sensitivity to ALK inhibitors even if their activity is limited at the time by the occurrence of mechanisms of resistance. The authors summarize the strategies that in the future could overcome these mechanisms of escape.Expert Review of Anti-infective Therapy 04/2013; 13(4):407-20. · 2.65 Impact Factor -
Article: MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells.
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ABSTRACT: P-glycoprotein (P-gp), traditionally linked to cancer poor prognosis and multidrug resistance, is undetectable in normal gastric mucosa and overexpressed in gastric cancer (GC). We propose that P-gp may be involved in Helicobacter pylori (Hp)-related gastric carcinogenesis by inhibiting apoptosis. Aim of the study was to evaluate the expression of P-gp in fetal stomach and in Hp-related gastric carcinogenesis, the epigenetic control of the multi-drug resistance-1 (MDR1) gene, the localization and interaction between P-gp and Bcl-x(L) and the effect of the selective silencing of P-gp on cell survival. P-gp and Bcl-xl expression was evaluated by immunohistochemistry on 28 spontaneously abortive human fetuses, 66 Hp-negative subjects, 138 Hp-positive chronic gastritis (CG) of whom 28 with intestinal metaplasia (IM) and 45 intestinal type GCs. P-gp/Bcl-x(L) colocalization was investigated by confocal immunofluorescence microscopy and protein-protein interaction by co-immunoprecipitation, in basal conditions and after stress-induced apoptosis, in GC cell lines AGS and MKN-28 and hepatocellular carcinoma cell line Hep-G2. The role of P-gp in controlling apoptosis was evaluated by knocking down its expression with a specific small interfering RNAs in stressed AGS and MKN-28 cell lines. P-gp is expressed in the gastric mucosa of all human fetuses while, it is undetectable in adult normal mucosa and re-expressed in 30/110 Hp-positive non-IM-CG, 28/28 IM-CG and 40/45 GCs. P-gp expression directly correlates with that of Bcl-x(L) and with the promoter hypomethylation of the MDR1 gene. In GC cell lines, P-gp is localized on the plasma membrane and mitochondria where it colocalizes with Bcl-x(L). Co-immunoprecipitation confirms the physical interaction between P-gp and Bcl-x(L) in AGS, MKN-28 and Hep-G2, at both basal level and after stress-induced apoptosis. The selective silencing of P-gp sensitizes GC cells to stress-induced apoptosis. P-gp behaves as an oncofetal protein that, by cross-talking with Bcl-x(L), acts as an anti-apoptotic agent in Hp-related gastric carcinogenesis.Laboratory Investigation 07/2012; 92(10):1407-18. · 3.64 Impact Factor -
Article: The nonreceptor-type tyrosine phosphatase PTPN13 is a tumor suppressor gene in non-small cell lung cancer.
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ABSTRACT: The aim of the present work was to identify protein tyrosine phosphatases (PTPs) as novel, candidate tumor suppressor genes in lung cancer. Among the 38 PTPs in the human genome that show specificity for phosphotyrosine, we identified six PTPs by quantitative RT-PCR whose mRNA expression levels were significantly down-regulated in lung cancer-derived cell lines (ie, PTPRE, PTPRF, PTPRU, PTPRK, PTPRD, and PTPN13). After validation in primary samples of non-small cell lung cancer (NSCLC), we selected PTPN13 for further studies. The results presented here demonstrate that PTPN13 is a candidate tumor suppressor gene that is frequently inactivated in NSCLC through the loss of either mRNA and protein expression (64/87, 73%) or somatic mutation (approximately 8%). Loss of PTPN13 expression was apparently due to the loss of one or both copies of the PTPN13 locus at 4q (approximately 26% double deletion and approximately 37% single deletion) but not to promoter methylation. Finally, the manipulation of PTPN13 expression in lung cancer cells (ie, NCI-H292, A549) demonstrated that PTPN13 negatively regulates anchorage-dependent and anchorage-independent growth in vitro and restrains tumorigenicity in vivo, possibly through the control of the tyrosine phosphorylation of both EGFR and HER2. In conclusion, the expression screening of PTPs in lung cancer reported here has identified PTPN13 as a novel candidate tumor suppressor in NSCLC whose loss increases signaling from epidermal growth factor receptor and HER2 tyrosine kinase receptors.American Journal Of Pathology 03/2012; 180(3):1202-14. · 4.89 Impact Factor -
Article: Aberrant Expression of Cancer Stem Cells Marker Prominin-1 in Low-Grade Tubulobular Breast Carcinoma: A Correlative Study between qRT-PCR, Flow-Cytometric and Immunohistochemistry Analysis.
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ABSTRACT: Prominin1/CD133 has become the ideal marker for cancer stem cells (CSCs) detection in human tumors. In this study we examined the expression of this marker in several breast cancer specimens to associate CSCs percentage with risk factor for this neoplasia. We examined specimens from 12 patients using CD133 and CD44 antibodies for CSCs immunohistochemistry detection and for flow cytometry analysis. For each patient, we also performed the immunohistochemical staining to evaluate the expression of estrogen receptor, progesterone receptor, c-erbB-2, Ki67, and E-cadherin markers. A Taqman probe for CD133 was used for mRNA quantification by real-time polymerase chain reaction. Prominin-1 expression was heterogeneous in different carcinomas but was strikingly hyperexpressed in a tubulolobular variant of breast cancer. The results were confirmed by all three methods. Our data, although produced on a limited number of samples, showed an particularly high expression of stem cell marker CD133 in a breast cancer variant, generally with a good prognosis. Since CSCs detection by CD133 has been described as an important prognostic factor for several human cancers, we suggest the importance of detecting stem cell compartiments in all histotypes of breast carcinomas.Journal of breast cancer. 03/2012; 15(1):15-23. -
Article: CD133 and CD44 Cell surface markers do not identify cancer stem cells in primary human gastric tumors
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ABSTRACT: Emerging evidence suggests that tumors contain and are driven by a cellular component that displays stem cell properties, the so-called cancer stem cells (CSCs). CSCs have been identified in several solid human cancers; however, there are no data about CSCs in primary human gastric cancer (GC). By using CD133 and CD44 cell surface markers we investigated whether primary human GCs contain a cell subset expressing stem-like properties and whether this subpopulation has tumor-initiating properties in xenograft transplantation experiments. We examined tissues from 44 patients who underwent gastrectomy for primary GC. The tumorigenicity of the cells separated by flow cytometry using CD133 and CD44 surface markers was tested by subcutaneous or intraperitoneum injection in NOD/SCID and nude mice. GCs included in the study were intestinal in 34 cases and diffuse in 10 cases. All samples contained surface marker-positive cells: CD133+ mean percentage 10.6% and CD133+/CD44+ mean percentage 27.7%, irrespective of cancer phenotype or grade of differentiation. Purified CD133+ and CD133+/CD44+ cells, obtained in sufficient number only in 12 intestinal type GC cases, failed to reproduce cancer in two mice models. However, the unseparated cells produced glandular-like structures in 70% of the mice inoculated. In conclusion, although CD133+ and CD133+/CD44+ were detectable in human primary GCs, they neither expressed stem-like properties nor exhibited tumor-initiating properties in xenograft transplantation experiments. J. Cell. Physiol. 227: 2686–2693, 2012. © 2011 Wiley Periodicals, Inc.Journal of Cellular Physiology 02/2012; 227(6):2686 - 2693. · 3.87 Impact Factor
