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Francesco Pezzella

Publications and source records attributed to Francesco Pezzella.

13 recordsLinked to original sources
PubMed2006

Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors.

BACKGROUND & AIMS: Prediction of biological behavior in pancreatic endocrine tumors (PET) is difficult on histologic criteria alone. The aim of this study was to characterize PET gene expression by complementary DNA (cDNA) microarray and identify specific differences in gene-expression profiles between nonmetastatic and metastatic tumors. METHODS: We studied 24 well-differentiated PETs corresponding to 12 benign tumors and to 12 carcinomas with metastasis. Total RNAs were extracted followed by microarray hybridization, imaging scan procedure, and statistical anaylsis. PET tissue arrays were constructed from 129 archival tumors for immunohistochemical validation of microarray data. RESULTS: A total of 123 transcripts were found to separate nonmetastatic from metastatic PETs (ie, 72 up-regulated and 51 down-regulated genes in malignant tumors). Some of these genes were involved in pathways related to (1) angiogenesis and remodeling (CD34, cadherin-5, E-selectin, semaphorin E, and fibrillin), (2) signal transduction through tyrosine kinases (tyrosine kinase-2, platelet-derived growth factor-Rbeta, MKK4, and discoidin domain receptor-1), (3) calcium-dependent cell signaling (transient receptor potential cation channel-1, calcium channel voltage-dependent beta2, neurocalcin delta, and GABA-A receptor gamma2), and (4) response to drug (MDR1 and carcinoembryonic antigen-related cell adhesion molecule 6). By using tissue arrays, we confirmed the differential expression of CD34 (P = .0008), E-selectin (P = .003), MKK4 (P = .0001), and MDR1 (P = .0003) in metastatic vs nonmetastatic PETs. CONCLUSIONS: This study provides insight into tumorigenic pathways in PET. Some of the genes identified are potentially new molecular markers for the detection and treatment of these tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Surveillance for the detection of early lung cancer in patients with bronchial dysplasia.

BACKGROUND: The natural history of bronchial preinvasive lesions and the risk of developing lung cancer in patients with these lesions are not clear. Previous studies have treated severe dysplasia and carcinoma in situ (CIS) on the assumption that most will progress to invasive carcinoma. AIMS: To define the natural history of preinvasive lesions and assess lung cancer risk in patients with these lesions. HYPOTHESIS: Most preinvasive lesions will not progress to invasive carcinoma but patients with these lesions will be at high risk. METHODS: A cohort of patients with preinvasive lesions underwent fluorescence bronchoscopy every 4-12 months and computed tomography of the chest annually. The main end point was the development of invasive carcinoma. RESULTS: 22 patients with 53 lesions were followed up for 12-85 months. 11 cancers were diagnosed in 9 patients. Of the 36 high-grade lesions (severe dysplasia and CIS), 6 progressed to invasive cancers. 5 separate cancers developed at remote sites in patients with high-grade lesions. All cancers were N0M0 and curative treatment was given to 8 of the 9 patients. The cumulative risk of developing lung cancer in a patient with a high-grade lesion was 33% and 54% at 1 and 2 years, respectively. Of the 17 low-grade lesions, none progressed to invasive carcinoma. CONCLUSIONS: Although the risk of malignant progression of individual preinvasive lesions is relatively small, patients with high-grade lesions are at high risk of lung cancer. Surveillance facilitated early detection and treatment with curative intent in most patients.

Aged↗
PubMed2006

Phosphorylated KDR can be located in the nucleus of neoplastic cells.

KDR (kinase insert domain receptor) phosphorylation induces several effects which lead eventually to cell proliferation and survival. The precise mechanisms by which KDR, once it is activated, communicates with the nucleus are starting to be understood but have not yet been completely unravelled. Two in vitro studies on animal cell lines reported in the literature have demonstrated that, following stimulation with VEGF, KDR is actually translocated within the nucleus. Our aim was to investigate whether this translocation occurs in human cells both in vitro and in vivo. Using laser scanning confocal microscopy, a variable nuclear localization of phosphorylated and total KDR in cell lines and tumour samples was found. In human neoplastic cell lines, hypoxic stimulation greatly increased the nuclear amount of total KDR but less so that of the phosphorylated form. Only after hypoxia and VEGF stimulation there was a comparably increased expression of phosphorylated and total KDR observed in the nuclei of these cells. We conclude that neoplastic cells show a variable expression of total and phosphorylated KDR in the nucleus. The precise functional meaning of nuclear location remains to be established.

Cell Hypoxia↗
PubMed2005

Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer.

Angiogenesis is regarded as essential for tumour growth. However, we have demonstrated that some other aggressive non-small-cell lung carcinomas (n-SCLC) do not have angiogenesis. In this study, using cDNA microarray analysis, we demonstrate that angiogenic and nonangiogenic tumour types can be distinguished by their gene expression profiles. Tissue samples from 42 n-SCLC patients were obtained with consent. In all, 12 tumours were nonangiogenic and 30 angiogenic. The two groups were matched by age, sex, smoking and tumour stage. Total RNAs were extracted followed by microarray hybridization and image scan procedure. Data were analysed using GeneSpring 5.1 software. A total of 62 genes were found to be able to separate angiogenic from nonangiogenic tumours. Nonangiogenic tumours have higher levels of genes concerned with mitochondrial metabolism, mRNA transcription, protein synthesis and the cell cycle. Angiogenic tumours have higher levels of genes coding for membrane vesicles, integrins, remodelling, angiogenesis and apoptosis. These results further support our first finding that nonangiogenic lung tumours are fast-growing tumours filling the alveoli in the absence of vascular remodelling. We raise the hypothesis that in nonangiogenic tumours, hypoxia leads to a higher activation of the mitochondrial respiratory chain, which allows tumour growth without triggering angiogenesis.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Somatic genetic changes accompanying lung tumor development.

Carcinomas are believed to develop by incremental steps of increasingly abnormal morphology driven by accumulating somatic genetic changes. This process is often difficult to study, as the early stages are undetectable. We used fluorescence bronchoscopy, which enhances detection of preinvasive bronchial lesions, and have obtained sequential biopsies of carcinoma in situ (CIS) from a patient with no detectable tumor and from a squamous cell carcinoma that developed 19 months after presentation at the site of one of the previous CIS lesions. Biopsies of preinvasive CIS, which follow-up showed had different pathologic outcomes, and tumor were microdissected to obtain enriched cell populations and DNA prepared from them. Molecular characteristics of these biopsies were compared by loss of heterozygosity analysis, TP53 mutation analysis, and comparative genomic hybridization. Although all lesions examined had the same TP53 mutation and almost identical allelotypes, differences were observed. Loss in 5q21 and amplification of 3q25-26 were associated with the lesion that progressed and the subsequent carcinoma. Allele loss at 4p16 was detected in the tumor but not in any of the CIS lesions, suggesting it was a late event associated with tumor invasion. Amplification at 4q12 was specifically observed in the tumor and in the CIS at the site of eventual tumor formation. Although these findings may be unique to this one patient, the successful demonstration of sequential genetic changes raises the possibility that this approach, unencumbered by interpatient variability between lesions, will greatly facilitate the identification of molecular events driving the invasive process

Adult↗
PubMed2005

Angiogenin is up-regulated in the nucleus and cytoplasm in human primary breast carcinoma and is associated with markers of hypoxia but not survival.

Angiogenin, a 14.2 kD polypeptide that was originally noted for its angiogenic activity, is now increasingly recognized to have a multiplicity of biological roles in both physiological and pathological conditions. In breast cancer, there are conflicting studies questioning the role of angiogenin. Here, the pattern of expression of angiogenin during the transition from normal breast tissue to ductal carcinoma in situ and invasive carcinoma is reported together with the correlates between the level of angiogenin in 239 invasive carcinomas and standard clinicopathological parameters, hypoxia-inducible factor (HIF)-1 alpha and the HIF-1 alpha target gene DEC-1. This study shows that angiogenin expression is up-regulated in the cytoplasmic and nuclear compartments in in situ carcinoma and invasive carcinoma compared with normal breast tissue and that angiogenin expression in invasive carcinomas is significantly positively associated with high tumour grade (p = 0.03), positive oestrogen receptor (ER) status (p = 0.01), HIF-1 alpha (p = 0.001) and DEC 1 (p = 0.001), but not with patient age (p = 0.8), tumour size (p = 0.25), lymph node status (p = 0.69), epidermal growth factor receptor (p = 0.56) or microvessel density (p = 0.32). No difference in relapse-free (p = 0.26) or overall (p = 0.63) survival was observed in patients stratified by angiogenin expression. This study suggests that angiogenin may be important in breast cancer progression and that, through its relationship with ER, it may be a target for tamoxifen.

Biomarkers, Tumor↗
PubMed2005

Expression and cellular localization of vascular endothelial growth factor A and its receptors in acute and chronic leukemias: an immunohistochemical study.

We aimed to study the expression of phosphorylated vascular endothelial growth factor receptor 2 (pVEGFR-2), a membrane-bound tyrosine kinase receptor to vascular endothelial growth factor, in 76 cases of leukemia and nonneoplastic myeloproliferative disease and in 8 reactive bone marrows. The microvessel density (MVD) and the expression of both pVEGFR-2 and its ligand, VEGFA, were evaluated in these cases. We used archival cases and immunohistochemistry with a monoclonal antibody generated by us to the autophosphorylation sites in the cytoplasmic tail of VEGFR-2 and von Willebrand factor antibody to evaluate MVD. Our results demonstrate increased expression of this phosphorylated receptor in the neoplastic cells in acute myeloid and lymphoblastic leukemias. This correlated with increased MVD and VEGFA expression by the neoplastic cells. Interestingly, there was nuclear relocation of this receptor in these diseases. This raises the possibility that pVEGFR-2 may be involved in the transcriptional regulation of these leukemias. Small molecule inhibitors to this receptor may therefore be a useful adjunct in the therapy for these diseases.

Adult↗
PubMed2005

Expression of TRAIL and TRAIL receptors in normal and malignant tissues.

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, is a member of the TNF family of proteins. Tumour cells were initially found to have increased sensitivity to TRAIL compared with normal cells, raising hopes that TRAIL would prove useful as an anti-tumor agent. The production of reliable monoclonal antibodies against TRAIL and its receptors that can stain fixed specimens will allow a thorough analysis of their expression on normal and malignant tissues. Here we report the generation of monoclonal antibodies against TRAIL and its four membrane-bound receptors (TR1-4), which have been used to stain a range of normal and malignant cells, as routinely fixed specimens. Low levels of TRAIL expression were found to be limited mostly to smooth muscle in lung and spleen as well as glial cells in the cerebellum and follicular cells in the thyroid. Expression of the TRAIL decoy receptors (TR3 and 4) was not as widespread as indicated by Northern blotting, suggesting that they may be less important for the control of TRAIL cytotoxicity than previously thought. TR1 and TR2 expression increases significantly in a number of malignant tissues, but in some common malignancies their expression was low, or patchy, which may limit the therapeutic role of TRAIL. Taken together, we have a panel of monoclonal antibodies that will allow a better assessment of the normal role of TRAIL and allow assessment of biopsy material, possibly allowing the identification of tumors that may be amenable to TRAIL therapy.

Antibodies, Monoclonal↗
PubMed2004

Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray.

PURPOSE: Spiral computed tomography (CT) can detect lung cancer at an early stage, but the malignant potential is unknown. The question is, as follows: do these small lesions have the same lethal potential as do symptomatic tumors? EXPERIMENTAL DESIGN: We used a cDNA microarray platform and compared the gene expression profile of spiral CT-detected lung carcinomas with a matched case-control population of patients presenting with symptomatic lung cancer. RESULTS: CT-detected and symptomatic tumors have shown a comparable gene expression profile. Correspondence analysis has demonstrated that nine genes were differentially expressed, although with a high variability across the samples that prevented distinguishing the two groups of tumors. Analysis of these nine genes has suggested that early-detected tumors have higher levels of retinoic acid production and higher expression levels of caveolin 2, matrix Gla, and cystatin A, which are already known to be lost during tumor progression. CONCLUSIONS: All of the tumors observed are histologically malignant according to the WHO Classification. Early lung cancers that are detected by screening have a gene expression pattern similar to, but not identical to, that of symptomatic lung carcinomas.

Aged↗
PubMed2003

Arylamine N-acetyltransferase-1 is highly expressed in breast cancers and conveys enhanced growth and resistance to etoposide in vitro.

Comparative two-dimensional proteome analysis was used to identify proteins differentially expressed in multiple clinical normal and breast cancer tissues. One protein, the expression of which was elevated in invasive ductal and lobular breast carcinomas when compared with normal breast tissue, was arylamine N-acetyltransferase-1 (NAT-1), a Phase II drug-metabolizing enzyme. NAT-1 overexpression in clinical breast cancers was confirmed at the mRNA level and immunohistochemical analysis of NAT-1 in 108 breast cancer donors demonstrated a strong association of NAT-1 staining with estrogen receptor-positive tumors. Analysis of the effect of active NAT-1 overexpression in a normal luminal epithelial-derived cell line demonstrated enhanced growth properties and etoposide resistance relative to control cells. Thus, NAT-1 may not only play a role in the development of cancers through enhanced mutagenesis but may also contribute to the resistance of some cancers to cytotoxic drugs.

Arylamine N-Acetyltransferase↗
PubMed2002

Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer.

Tumor-associated macrophages (TAMs) produce angiogenic factors and in breast cancer are associated with high vascular grade and poor survival. TAMs preferentially migrate to hypoxic areas within tumors and strongly express hypoxia-inducible factor (HIF)-2 alpha. This study examined whether HIF-2 alpha was involved in TAM angiogenic activation by correlating its expression with tumor microvessel density as a marker of angiogenesis, and other tumor variables, in a series of human primary invasive breast carcinomas. A correlation was found between high TAM HIF-2 alpha and high tumor vascularity (P < 0.0001), as well as high tumor grade (P = 0.007). The relation of HIF-2 alpha expression to a recently described oxygen-dependent pathway of angiogenesis was also studied, and an inverse relationship was found between TAM HIF-2 alpha and tumor thymidine phosphorylase expression (P = 0.02). These results suggest that TAM HIF-2 signaling may be a useful target for future antiangiogenic strategies but show that tumors use both oxygen-dependent and oxygen deficiency-regulated pathways for angiogenesis. Thus, combined blockade of pathways and careful assessment of these pathways in trials are necessary.

Adult↗
PubMed2002

Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival.

PURPOSE: Tumor hypoxia is known to be associated with resistance to chemotherapy, radiotherapy, and poorer survival. Recently, it is shown that hypoxia induces the expression of hypoxia-inducible factor-1alpha and 2alpha (HIF-1alpha and HIF-2alpha), which then up-regulates the expression of downstream genes such as carbonic anhydrase IX (CA IX) and vascular endothelial growth factor (VEGF). EXPERIMENTAL DESIGN: We examined the expression of HIF-1alpha, HIF-2alpha, CA IX, and VEGF by immunohistochemistry in nasopharyngeal carcinoma (NPC) biopsies from 90 consecutive patients recruited between 1994 and 1997 in a randomized controlled trial of chemoradiation in locally advanced NPC and investigated their relationship with survival. RESULTS: HIF-1alpha was expressed in 52 of 90 (58%), HIF-2alpha in 6 of 89 (7%), CA IX in 51 of 90 (57%), and VEGF in 54 of 90 (60%) of tumors. Tumor HIF-1alpha expression correlated significantly with that of CA IX (P = 0.008) and VEGF (P = 0.003). High tumor HIF-1alpha expression was associated with a trend for poor overall survival (P = 0.06). Tumors with a positive hypoxic profile (defined as high expression of both HIF-1alpha and CA9) were associated with worse progression-free survival (P = 0.04). Tumors with both hypoxic and angiogenic profile (defined as high VEGF expression) were associated with a worse progression-free survival (P = 0.0095). CONCLUSION: Overexpression of HIF-1alpha, CA IX, and VEGF is common in NPC, which is probably related to hypoxia up-regulated expression involving a HIF-dependent pathway, and is associated with poor prognosis. Targeting the hypoxia pathway may be useful in the treatment of NPC.

Adult↗