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Tonia Cenci,
Maurizio Martini,
Nicola Montano,
Quintino G D'Alessandris,
Maria Laura Falchetti,
Daniela Annibali,
Mauro Savino,
Federico Bianchi, Francesco Pierconti,
Sergio Nasi,
Roberto Pallini,
Luigi Maria Larocca
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ABSTRACT: Although the c-Myc oncogene is frequently deregulated in human cancer, its involvement in the pathogenesis of glioblastoma is not clear. We conducted immunohistochemical analysis of the expression of c-Myc, polycomb ring finger oncogene (BMI1), and acetylation of the lysine 9 (H3K9Ac) of histone 3 in 48 patients with glioblastoma who underwent surgery followed by radiotherapy and temozolomide treatment. The expression of c-Myc, BMI1, and H3K9ac was correlated with clinical characteristics and outcome. We found that overexpression of c-Myc was significantly associated with that of BMI1 (P = .009), and that patients who harbored glioblastomas overexpressing c-Myc and BMI1 showed significantly longer overall survival (P < .0001 and P = .0009, respectively). Our results provide the first evidence of the prognostic value of c-Myc and associated genes in patients with glioblastoma. The favorable effect of c-Myc and BMI1 expression on survival is likely mediated by the sensitization of cancer cells to radiotherapy and temozolomide through the activation of apoptotic pathways.
American Journal of Clinical Pathology 09/2012; 138(3):390-6. · 2.60 Impact Factor
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ABSTRACT: Background: Chronic inflammation may play a role in prostate carcinogenesis. Molecular alterations of the Suppressor of Cytokine Signaling (SOCS)-3 can contribute to explain the pleiotropic role of interleukin (IL)-6 in this type of cancer. Recently, the methylation of SOCS3 gene has been demonstrated to cause the non-expression of the protein, being involved in the pathogenesis of prostate cancer (PC) and identifying a subset of aggressive tumors. We evaluated the expression of SOCS3 protein in patients (pt) with bioptically-diagnosed PC by immunohistochemical analysis, which is easier to perform, cheaper and more reproducible compared to DNA analysis. Methods: We analyzed the protein expression of SOCS3 by immunohistochemistry in 44 patients (pt) with PC diagnosed after biopsy. Slides were incubated with monoclonal antibody SOCS3 (1E4, 1.5 μg/mL; Abnova, Taiwan). The SOCS3 staining intensity was evaluated by two pathologists (FP and LML) in three different ways: positive (+), negative (-) and weak (+/-). Colonic mucosa was used as positive control. 36/44 patients underwent radical prostatectomy (RP). Results: Biopsy Gleason score (Gs) was: <7 in 8 pt, 7 in 33 pt (3 + 4 pattern in 21 pt, 4 + 3 pattern in 12 pt), >7 in 3 pt. 8/8 (100%) pt with Gs <7 and 7/33 (21%) with Gs 7 were SOCS+. 15/33 (45%) pt with Gs 7 and 3/3 (100%) pt with Gs >7 were negative. In 11/33 pt (33%) Gs 7 a weak intensity was found so they were classified as SOCS3 +/-.25/36 (69%) patients who underwent RP were SOCS3- (15 pt with Gs 7(3 + 4), 7 pt with Gs 7(4 + 3), 3 pt with Gs 8) and 11/36 (30%) SOCS3+ (8 pt with Gs 6 and 3 pt with Gs 7(3 + 4)) (Tab 2). 12/25 (48%) SOCS3- pt had an organ-confined disease (≤pT2), whereas 13/25 (52%) had an extra prostatic neoplasm (5 pT3a (one was N+), 6 pT3b, 1 pT4). All SOCS3+ patients (8/8 (100%)) had an organ-confined disease. 3/3 (100%) SOCS3+/- pt had an extra prostatic neoplasm (>pT2). Conclusions: SOCS3- pt turned out to have a more aggressive disease compared with SOCS3+. In particular, also SOCS3+/- patients seemed to have an aggressive behavior. The non-expression of SOCS3 protein may identify PC with more aggressive behavior and can be evaluated with immunohystochemical analysis, which is a relatively easy and cheap procedure in clinical practice. These results, if confirmed by a wider population and a longer follow-up, may encourage the research on the use of this molecular family as a prognostic marker and a target for therapy with demethylating agents.
Urologia 07/2012;
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ABSTRACT: Dynamic contrast enhanced magnetic resonance improves prostate cancer detection. The aims of this paper are to verify whether wash-in-rate parameter (speed of contrast uptake in dynamic contrast enhanced magnetic resonance) can help to differentiate prostate cancer from non-neoplastic T2-weighted hypointense lesions within prostate gland and to assess a cut-off for prostate cancer diagnosis.
Prospective, monocentric, multi-departmental study. Thirty consecutive patients underwent T2-weighted and dynamic contrast enhanced magnetic resonance, and re-biopsy. T2-weighted hypointense lesions, >5mm in size, were noted. Lesions were assessed as cancerous (showing mass effect, or no defined margin within transitional zone) and non cancerous (no mass effect) and were compared with histopathology by 2×2 tables. Wash-in-rate of each lesion was calculated and was correlated with histopathology. Student's t-test was adopted to assess significant differences. Receiver operating characteristic (ROC) analysis was employed to identify the best cut-off for wash-in-rate in detecting prostate cancer.
At re-biopsy, cancer was proven in 43% of patients. On T2-weighted MRI, 111 hypointense lesions ≥5mm in size were found. Sensitivity, specificity and accuracy of T2-weighted MRI were 80% (±12.4 CI 95%), 74.6% (±10.1 CI 95%), and 76.5% (±7.9 CI 95%), respectively. Mean WR was 5.8±1.9/s for PCa zones and 2.96±1.44/s for non-PCa zones (p<0.00000001). At ROC analysis, the best area under curve (AUC) for wash-in-rate parameter was associated to 4.2/s threshold with 82.5% sensitivity (CI±7.07), 97.2% specificity (CI±4.99) and 91.2% accuracy (CI±5.27). Eighteen false positive lesions on T2-weighted MRI showed low wash-in-rate values suggesting non-cancer lesions, while in 5/8 false negative cases high wash-in-rate values correctly suggested prostate cancer. Nine lesions with surgically proven cancer were not included in the saturation biopsy scheme, in 2/9 cases the only site of cancer.
Wash-in-rate parameter allows to differentiate prostate cancer from non-neoplastic lesions, helping cancer detection in areas not included in the biopsy scheme.
European journal of radiology 06/2012; 81(11):3090-5. · 2.65 Impact Factor
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ABSTRACT: Chronic inflammation and subsequent tissutal alterations may play a key role in prostate carcinogenesis. In this way, molecular alterations of the suppressor of cytokine signaling 3 (SOCS3), one of the most important inhibitory molecule of inflammatory signal transduction circuitries, could contribute to explain the pleiotropic role of interleukin-6 (IL-6) in this type of cancer.
We analyzed the methylation status and mRNA expression of SOCS3 in 20 benign prostate hyperplasias (BPH) and in 51 prostate cancer specimens. We analyzed the SOCS3 methylation status using methylation-specific PCR. Hypermethylation was confirmed by sequencing after subcloning. Epigenetic silencing of this gene was also demonstrated by real-time PCR and by immunohistochemistry. Results and correlation with clinical data were statistically analyzed.
We found that the promoter of SOCS3 was methylated in 39.2% of prostate cancer. On the contrary, all BPH and normal controls had an unmethylated pattern. Real-time analysis showed that in methylated cases SOCS3 mRNA expression was reduced by three and four folds as compared to BPH and unmethylated cases, respectively. Interestingly, SOCS3 mRNA level was higher in unmethylated prostate cancer than in BPH. The immunohistochemical staining analysis for SOCS 3 confirmed mRNA results. Moreover, methylation of SOCS3 promoter significantly associated with intermediate-high grade Gleason score (P = 0.0007) and with an unfavorable clinical outcome (P = 0.0019).
Our data suggest that SOCS3 hypermethylation may be involved in the pathogenesis of prostate cancer and could identify a tumor subset with an aggressive behavior.
The Prostate 02/2011; 71(3):318-25. · 3.48 Impact Factor
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ABSTRACT: Experimental data suggest that glioblastoma cells expressing the stem cell marker CD133 play a major role in radiochemoresistance and tumor aggressiveness. To date, however, there is no clinical evidence that the fraction of CD133-positive cells in glioblastoma that recurs after radiochemotherapy may be relevant for prognosis.
The authors used immunohistochemistry to assess CD133 expression in 37 paired glioblastoma samples, including 1 primary tumor sample and 1 recurrent tumor sample, after patients received adjuvant radiochemotherapy. To assess the actual composition of the CD133-positive glioblastoma cell population, fluorescence-associated cell sorting (FACS) analysis was used to sort CD133-positive/CD45-negative cells that were assayed for tumor-specific chromosomal aberrations using interphase fluorescence in situ hybridization. To rule out endothelial precursor cells, CD133-positive fractions also were assayed with anti-CD34 by FACS.
In recurrent glioblastomas, the percentage of CD133-positive cells was increased by 4.6-fold compared with the percentage in primary glioblastomas, although, in some tumors, it increased up to 10-fold and 20-fold. Unexpectedly, the increase in CD133 expression was associated significantly with longer survival after tumor recurrence. An analysis of tumor-specific chromosomal aberrations and in vivo studies revealed that the CD133-positive cell compartment of recurrent glioblastoma was composed of both cancer stem cells and nontumor neural stem cells. The latter cells represented from 20% to 60% of the CD133-positive cell population, and their relative percentage favorably affected the survival of patients with recurrent glioblastoma. Endothelial CD133-positive/CD34-positive precursors did not contribute to the CD133-positive cell population.
The authors hypothesized that, similar to the phenomenon described in glioblastoma models, neural stem/progenitor cells that are recruited by the tumor from surrounding brain may exert an antitumorigenic effect.
Cancer 01/2011; 117(1):162-74. · 4.77 Impact Factor
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Roberto Pallini MD,
Lucia Ricci-Vitiani PhD,
Nicola Montano MD,
Cristiana Mollinari PhD,
Mauro Biffoni PhD,
Tonia Cenci PhD,
Francesco Pierconti MD,
Maurizio Martini MD,
Ruggero De Maria MD,
Luigi Maria Larocca MD,
Roberto Pallini,
Lucia Ricci‐Vitiani,
Nicola Montano,
Cristiana Mollinari,
Mauro Biffoni,
Tonia Cenci, Francesco Pierconti,
Maurizio Martini,
Ruggero De Maria,
Luigi Maria Larocca
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ABSTRACT: BACKGROUND:Experimental data suggest that glioblastoma cells expressing the stem cell marker CD133 play a major role in radiochemoresistance and tumor aggressiveness. To date, however, there is no clinical evidence that the fraction of CD133-positive cells in glioblastoma that recurs after radiochemotherapy may be relevant for prognosis.METHODS:The authors used immunohistochemistry to assess CD133 expression in 37 paired glioblastoma samples, including 1 primary tumor sample and 1 recurrent tumor sample, after patients received adjuvant radiochemotherapy. To assess the actual composition of the CD133-positive glioblastoma cell population, fluorescence-associated cell sorting (FACS) analysis was used to sort CD133-positive/CD45-negative cells that were assayed for tumor-specific chromosomal aberrations using interphase fluorescence in situ hybridization. To rule out endothelial precursor cells, CD133-positive fractions also were assayed with anti-CD34 by FACS.RESULTS:In recurrent glioblastomas, the percentage of CD133-positive cells was increased by 4.6-fold compared with the percentage in primary glioblastomas, although, in some tumors, it increased up to 10-fold and 20-fold. Unexpectedly, the increase in CD133 expression was associated significantly with longer survival after tumor recurrence. An analysis of tumor-specific chromosomal aberrations and in vivo studies revealed that the CD133-positive cell compartment of recurrent glioblastoma was composed of both cancer stem cells and nontumor neural stem cells. The latter cells represented from 20% to 60% of the CD133-positive cell population, and their relative percentage favorably affected the survival of patients with recurrent glioblastoma. Endothelial CD133-positive/CD34-positive precursors did not contribute to the CD133-positive cell population.CONCLUSIONS:The authors hypothesized that, similar to the phenomenon described in glioblastoma models, neural stem/progenitor cells that are recruited by the tumor from surrounding brain may exert an antitumorigenic effect. Cancer 2011. © 2010 American Cancer Society.
Cancer 12/2010; 117(1):162 - 174. · 4.77 Impact Factor
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ABSTRACT: A retroperitoneal metastasis from malignant melanoma is an uncommon event and mostly secondary to a primary lesion of the posterior trunk. We report on a 38-year-old patient with malignant melanoma of the anterior trunk who presented a symptomatic metastatic mass of the left renal hilum not originating from the retroperitoneal lymph nodes of the renal hilum, surrounding and infiltrating the renal pelvis, treated with left nephrectomy, complete mass excision and regional lymph node dissection. The patient later developed also brain metastases and is now undergoing immunotherapy.
Archivio italiano di urologia, andrologia: organo ufficiale [di] Società italiana di ecografia urologica e nefrologica / Associazione ricerche in urologia 06/2010; 82(2):119-21.
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Alessia Calzolari,
Luigi Maria Larocca,
Silvia Deaglio,
Veronica Finisguerra,
Alessandra Boe,
Carla Raggi,
Lucia Ricci-Vitani, Francesco Pierconti,
Fabio Malavasi,
Ruggero De Maria,
Ugo Testa,
Roberto Pallini
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ABSTRACT: Under physiological conditions, transferrin receptor 2 (TfR2) is expressed in the liver and its balance is related to the cell cycle rather than to intracellular iron levels. We recently showed that TfR2 is highly expressed in glioblastoma cell lines. Here, we demonstrate that, in these cells, TfR2 appears to localize in lipid rafts, induces extracellular signal-regulated kinase 1/2 phosphorylation after transferrin binding, and contributes to cell proliferation, as shown by RNA silencing experiments. In vitro hypoxic conditions induce a significant TfR2 up-regulation, suggesting a role in tumor angiogenesis. As assessed by immunohistochemistry, the level of TfR2 expression in astrocytic tumors is related to histologic grade, with the highest expression observed in glioblastomas. The level of TfR2 expression represents a favorable prognostic factor, which is associated with the higher sensitivity to temozolomide of TfR2-positive tumor cells in vitro. The endothelial cells of glioblastoma vasculature also stain for TfR2, whereas those of the normal brain vessels do not. Importantly, TfR2 is expressed by the subpopulation of glioblastoma cells with properties of cancer-initiating cells. TfR2-positive glioblastoma cells retain their TfR2 expression on xenografting in immunodeficient mice. In conclusion, our observations demonstrate that TfR2 is a neoantigen for astrocytomas that seems attractive for developing target therapies.
Translational oncology 04/2010; 3(2):123-34. · 3.40 Impact Factor
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ABSTRACT: An important pathogenetic mechanism in Hodgkin lymphoma (HL) is the interaction between the neoplastic and reactive cells mediated by a complex network of cytokines with activation of cytokine signal transduction (STAT) pathways. We studied the prognostic impact of the phosphorylation status of STAT5 in HL. By using immunohistochemical analysis, we found phosphorylated STAT5 (pSTAT5) in 35 (38%) of 93 lymph node biopsy specimens of patients with HL. The detection of pSTAT5 in Hodgkin and Reed-Sternberg (HRS) cells in classical HL (cHL) was not associated with any clinical and biologic features evaluated, including Epstein-Barr virus status. The primary end point for analysis of clinical outcome was freedom from treatment failure (FFTF). At a median follow-up of 5 years, pSTAT5+ patients with cHL had a better FFTF than pSTAT5-patients (77% vs 56%; P = .03), which translated into a reduced risk for failure for pSTAT5+ patients with a hazard ratio of 0.2 (95% confidence interval, 0.06-0.73; P = .015). Our data suggest that the phosphorylation status of STAT5 of HRS cells in cHL could be a prognostic marker in HL.
American Journal of Clinical Pathology 04/2008; 129(3):472-7. · 2.60 Impact Factor
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Maria Laura Falchetti,
Maria Patrizia Mongiardi,
Paolo Fiorenzo,
Giovanna Petrucci, Francesco Pierconti,
Igea D'Agnano,
Giorgio D'Alessandris,
Giulio Alessandri,
Maurizio Gelati,
Lucia Ricci-Vitiani,
Giulio Maira,
Luigi Maria Larocca,
Andrea Levi,
Roberto Pallini
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ABSTRACT: Tumor angiogenesis is a complex process that involves a series of interactions between tumor cells and endothelial cells (ECs). In vitro, glioblastoma multiforme (GBM) cells are known to induce an increase in proliferation, migration and tube formation by the ECs. We have previously shown that in human GBM specimens the proliferating ECs of the tumor vasculature express the catalytic component of telomerase, hTERT, and that telomerase can be upregulated in human ECs by exposing these cells to GBM in vitro. Here, we developed a controlled in vivo assay of tumor angiogenesis in which primary human umbilical vascular endothelial cells (HUVECs) were subcutaneously grafted with or without human GBM cells in immunocompromised mice as Matrigel implants. We found that primary HUVECs did not survive in Matrigel implants, and that telomerase upregulation had little effect on HUVEC survival. In the presence of GBM cells, however, the grafted HUVECs not only survived in Matrigel implants but developed tubule structures that integrated with murine microvessels. Telomerase upregulation in HUVECs enhanced such effect. More importantly, inhibition of telomerase in HUVECs completely abolished tubule formation and greatly reduced survival of these cells in the tumor xenografts. Our data demonstrate that telomerase upregulation by the ECs is a key requisite for GBM tumor angiogenesis.
International Journal of Cancer 04/2008; 122(6):1236-42. · 5.44 Impact Factor
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Luca Miele, Francesco Pierconti,
Alessandra Forgione,
Vittoria Vero,
Giovanni Cammarota,
Francesco Molinari,
Gabriele Masselli,
Esmeralda Capristo,
Maurizio Martini,
Luigi M Larocca,
Ignazio M Civello,
Giovanni Gasbarrini,
Antonio Grieco
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ABSTRACT: Celiac disease is characterized by intestinal inflammation and mucosal atrophy that improves on a gluten-free diet. Delayed diagnosis can result in diet-refractory disease known as refractory sprue, which is linked to other disorders (intestinal lymphoma, ulcerative jejunoileitis, mesenteric lymph-node cavitation, collagenous sprue, malignancy) and carries a poor prognosis. Here we report the case of a young woman diagnosed with Marsh stage 3C celiac disease with intestinal occlusion due to intra-abdominal cystic lymphangioma mimicking mesenteric lymph-node cavitation, and hyposplenism. Despite a number of prognostically negative features, the disease has been managed successfully for the past 2 years with a gluten-free diet. The pathogenesis, prognosis and therapeutic implications are discussed.
European Journal of Gastroenterology & Hepatology 12/2007; 19(11):1026-30. · 1.76 Impact Factor
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Digestive Diseases and Sciences 06/2007; 52(5):1360-3. · 2.12 Impact Factor
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Neurology 06/2007; 68(18):1541-2. · 8.31 Impact Factor
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ABSTRACT: The aim of this study was to determine the occurrence of polymorphic variants of EBV BamHI fragment Z (BZLF1) promoter zone Zp in tumor and non-tumor-associated EBV. We characterized the Zp region in type A and type B EBV, infecting AIDS-related non-Hodgkin's lymphomas (AIDS-NHL) and non-malignant lymphoid tissues derived from HIV-positive patients and from healthy individuals.
The Zp region was directly sequenced in 133 EBV-positive DNA samples: 63 AIDS-NHL (32 systemic AIDS-NHL and 31 AIDS-primary central nervous system lymphoma [AIDS-PCNSL]), 30 lymphoid tissues derived from HIV-positive individuals and 40 lymphoid samples derived from healthy individuals. The chi square test was used to assess for statistically significant differences among proportions, and a two-tailed P value </=0.05 was chosen as statistically significant.
We found three polymorphic Zp variants: Zp-P, considered to be the prototype sequence; Zp-V3, that differs from Zp-P for three nucleotide substitutions; and a new variant, Zp-PV, that differs from Zp-P for a single nucleotide substitution. Zp-V3 was significantly associated with AIDS-PCNSL (P<0.001) and with systemic AIDS-NHL (P=0.007), in particular with AIDS-related immunoblastic lymphoma (P<0.001). Moreover, in malignant samples, this variant was also significantly associated with type B EBV (P<0.001). Finally, the new identified Zp-PV variant was isolated in 7 AIDS-PCNSL.
The frequency of polymorphisms in the regulatory zone of BZLF1 is different between malignant and non-malignant samples in AIDS patients and may identify EBV subtypes with different transforming activities, including those associated to the pathogenesis of B cell lymphoma.
The Journal of infection 03/2007; 54(3):298-306. · 4.13 Impact Factor
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ABSTRACT: Permanent cell cultures are invaluable tools for understanding the biological characteristics of tumors. In the present study the authors report on the establishment of permanent human cell lines from three cases of aggressive chordomas of the clival region. All of the parental tumors showed telomerase activity. Cultured chordoma cells had a doubling time of 5 to 7 days and grew as a monolayer of cells that retained both the immunophenotype and the p53 status of the parental tumor. In vitro, chordoma cells overexpressed telomerase, supporting the hypothesis that this enzyme is required for the immortalization process.
Journal of Neurosurgery 10/2006; 105(3):482-4. · 2.96 Impact Factor
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ABSTRACT: Telomerase is a specialized DNA polymerase that is required to replicate the ends of linear chromosomes, the telomeres. The majority of human cancers express high levels of telomerase activity that is permissive for tumor growth because it provides cells with an extended proliferative potential. Additionally, telomerase exerts cell growth promoting functions and favors cell survival. Human glioblastoma multiforme (GBM) cells express high level of telomerase activity owing to the overexpression of human telomerase reverse transcriptase (hTERT), the limiting subunit of the enzyme. Here we used retroviral mediated RNA interference to dampen down telomerase activity in two distinct human GBM cell lines, U87MG and TB10. Substantial decrease of hTERT mRNA and telomerase activity had only minimal effects on telomere length maintenance, cell growth and survival in vitro. On the contrary, development of tumors upon subcutaneously grafting of U87MG and TB10 cells and intracranial implantation of U87MG cells in nude athymic mice was strongly reduced by telomerase inhibition.
Neurological Research 08/2006; 28(5):532-7. · 1.52 Impact Factor
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ABSTRACT: Telomerase is highly expressed in advanced stages of most cancers where it allows the clonal expansion of transformed cells by counteracting telomere erosion. Telomerase may also contribute to tumor progression through still undefined cell growth-promoting functions. Here, we inhibited telomerase activity in 2 human glioblastoma (GBM) cell lines, TB10 and U87MG, by targeting the catalytic subunit, hTERT, via stable RNA interference (RNAi). Although the reduction in telomerase activity had no effect on GBM cell growth in vitro, the development of tumors in subcutaneously and intracranially grafted nude mice was significantly inhibited by antitelomerase RNAi. The in vivo effect was observed within a relatively small number of population doublings, suggesting that telomerase inhibition may hinder cancer cell growth in vivo prior to a substantial shortening of telomere length. Tumor xenografts that arose from telomerase-inhibited GBM cells also showed a less-malignant phenotype due both to the absence of massive necrosis and to reduced angiogenesis. © 2005 Wiley-Liss, Inc.
International Journal of Cancer 12/2005; 118(9):2158 - 2167. · 5.44 Impact Factor
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ABSTRACT: Angiogenesis is essential for the growth of solid tumors. We have observed previously that the vascular endothelial cells of astrocytic brain tumors express human telomerase reverse transcriptase (hTERT) mRNA, suggesting a role for telomerase in the angiogenesis of these neoplasms. Here, we used an in vitro model to demonstrate that the telomerase machinery might be trans-activated in primary endothelial cells by glioblastoma tumor cells. We found that glioblastoma cells in vitro do induce hTERT mRNA and hTERT protein expression, as well as telomerase enzyme activity in the endothelial cells, and that this phenomenon is mediated by diffusible factor(s). These results provide strong evidence of the involvement of telomerase in tumor angiogenesis and will stimulate research on antitelomerase drugs for treatment of malignant brain gliomas.
Cancer Research 08/2003; 63(13):3750-4. · 7.86 Impact Factor
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ABSTRACT: Chordomas of the skull base are generally regarded as slow-growing tumors; however, approximately 20% of these lesions have been shown to recur as early as 1 year postsurgery. The classic pathological paradigms are poor predictors of outcome, and additional markers are needed to identify patients at risk for early tumor recurrence. In this study the authors describe such a marker.
In a series of 26 patients with chordomas of the skull base, the authors investigated the relationship between the biological behavior of the tumor, which was determined according to the interval for its recurrence and volume doubling time, and several pathological and molecular features, which included the histological variant, proliferative activity, mutation of p53 protein, expression of human telomerase reverse transcriptase (hTERT) messenger (m)RNA, loss of heterozygosity (LOH), and microsatellite instability. The major finding in this study was that hTERT mRNA expression in chordoma cells identifies those tumors that exhibit unusually fast rates of growth. The expression of hTERT mRNA was frequently associated with mutation of p53 protein, indicating that telomerase dysfunction combines with abnormal p53 function to initiate the unrestrained clonal expansion of the tumor cells. In cases in which the tumor was partially removed, mutation of p53 protein and expression of hTERT mRNA predicted increased doubling time for residual tumor as well as the probability of tumor recurrence. Cell proliferation, as investigated using the Ki-67 method, was significantly related to the tumor doubling time; however, the authors found that the pattern of cell proliferation was not homogeneous throughout the chordoma tissue, and that the proliferative index might change by a factor as high as 8 among different regions of the same tumor. The LOH and microsatellite instability do not seem to affect the prognosis of skull base chordomas.
Reactivation of telomerase in chordomas is a reliable predictor of outcome. The ability to predict the biological behavior of chordomas might have immediate implications in the management of this disease in patients who undergo surgery.
Journal of Neurosurgery 05/2003; 98(4):812-22. · 2.96 Impact Factor
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Annunziata Gloghini,
Gianluca Gaidano,
Luigi M Larocca, Francesco Pierconti,
Antonella Cingolani,
Luigino Dal Maso,
Daniela Capello,
Silvia Franceschi,
Umberto Tirelli,
Massimo Libra,
Huifeng Niu,
Riccardo Dalla-Favera,
Antonino Carbone
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ABSTRACT: Knowledge of the role of cell-cycle regulators in the pathogenesis of acquired immune deficiency syndrome-related non-Hodgkin's lymphomas (AIDS-NHLs) is scarce. Here we analyzed 86 systemic AIDS-NHLs and 20 AIDS-primary central nervous system lymphomas for expression of p27(Kip1), a negative regulator of cell-cycle progression belonging to the Kip family of cyclin-dependent kinase inhibitors. In parallel, we investigated the relationship between p27(Kip1), the lymphoma proliferation index, Epstein-Barr virus status, expression of cellular cyclin D3 and cyclin D1, and B-cell differentiation stage. We report that AIDS-immunoblastic lymphomas (AIDS-IBLs), either systemic or primarily localized to the central nervous system, consistently express p27(Kip1) protein (19 of 24 and 10 of 14, respectively) despite the high proliferative rate of the lymphoma clone, suggesting a failure of p27(Kip1) to inhibit the cell cycle in AIDS-IBL. Conversely, the remaining systemic AIDS-NHLs and AIDS-primary central nervous system lymphomas preferentially fail to express p27(Kip1). Expression of p27(Kip1) in Epstein-Barr virus-positive AIDS-NHLs generally associates with latent membrane protein 1 (LMP1) expression and is related to a late stage of B-cell differentiation, characterized by the BCL-6-/MUM1+/syn-1+/- phenotypic profile, whereas it seems to be unrelated to the expression of cellular cyclins. In B cells in vitro, induction of LMP-1 expression under the control of inducible promoters up-regulates expression of p27(Kip1), thus providing a putative mechanistic explanation for the association between LMP1 and p27(Kip1) observed in vivo. Overall, these data show that AIDS-IBL pathogenesis is characterized by loss of the inverse relationship between p27(Kip1) positivity and tumor growth fraction that is otherwise generally observed in normal lymphoid tissues and in most other types of NHLs.
American Journal Of Pathology 08/2002; 161(1):163-71. · 4.89 Impact Factor
