Papers by Maurizio Provenzano
European Journal of Cancer, Oct 1, 2008
Arginase 2, inducible-and endothelial-nitric-oxide synthase (iNOS and eNOS), indoleamine 2,3dioxy... more Arginase 2, inducible-and endothelial-nitric-oxide synthase (iNOS and eNOS), indoleamine 2,3dioxygenase (IDO) and TGF-beta, might impair immune functions in prostate cancer (PCA) patients. However, their expression was not comparatively analysed in PCA and benign prostatic hyperplasia (BPH). We evaluated the expression of these genes in PCA and BPH tissues. Seventy-six patients (42 BPH, 34 PCA) were enrolled. Arginase 2, eNOS and iNOS gene expression was similar in BPH and PCA tissues. TGF-beta1 gene expression was higher in BPH than in PCA tissues (p=0.035). IDO gene expression was more frequently detectable (p=0.00007) and quantitatively higher (p=0.00001) in PCA tissues than in BPH. IDO protein, expressed in endothelial cells from both BPH and PCA, was detectable in tumour cells in PCA showing evidence of high specific gene expression. In these patients, IDO gene expression correlated with kynurenine/tryptophan ratio in sera. Thus high expression of IDO gene is specifically detectable in PCA.
Reviews in Medical Virology, 2015
SummarySeveral studies associating BK polyomavirus (BKPyV) and prostate cancer (PCa) suggested th... more SummarySeveral studies associating BK polyomavirus (BKPyV) and prostate cancer (PCa) suggested that this virus may exert its oncogenic activity at early stages of cancer development. The BKPyV oncogene, the large T antigen (LTag), has frequently been detected in areas of proliferative inflammatory atrophy, which is considered a precursor lesion leading to prostatic intraepithelial neoplasia and overt PCa. In a recently updated systematic review, the presence of BKPyV was significantly higher in PCa tissues than in healthy control tissues, providing an indication for a link between BKPyV infection and cancer risk. In addition, recent original investigations highlighted an association between expression of the virus and the clinical course of PCa. For example, by studying immune responses elicited against BKPyV LTag, a significant association between LTag positive cancer lesions and a peculiar regulatory profiling has been observed in PCa patients with evidence of disease recurrence a...
Polyomavirus BK large tumor antigen exerts tolerogenic signatures with immunodominant p53-binding regions in prostate cancer
Frontiers in Immunology, 2013
Frontiers in Oncology, 2020
Journal of Translational Medicine, 2015
In recent years the scientific literature in the field of the prostate carcinoma (PCa) pointed ou... more In recent years the scientific literature in the field of the prostate carcinoma (PCa) pointed out on the genetic heterogeneity and mutations occurring in this tumour, while little attention was given to the causes of PCa onset, in particular infectiuos agents. In this brief commentary, we wish to point out recent advancements done on the role of the human polyomavirus BK (BKPyV) in the development of PCa by harnessing both humoral and cellular immune responses. Altogether, these new insights suggest that BKPyV is involved in the transforming activity during the multistep process of PCa development. Although these findings do not provide evidence for a causal relationship between BKPyV and PCa development, additional investigations with novel techniques will help to make it a concrete event.
Nature Genetics, 2014
Prostate cancer is driven by a combination of genetic and/or epigenetic alterations. Epigenetic a... more Prostate cancer is driven by a combination of genetic and/or epigenetic alterations. Epigenetic alterations are frequently observed in all human cancers, yet how aberrant epigenetic signatures are established is poorly understood. Here we show that the gene encoding BAZ2A (TIP5), a factor previously implicated in epigenetic rRNA gene silencing, is overexpressed in prostate cancer and is paradoxically involved in maintaining prostate cancer cell growth, a feature specific to cancer cells. BAZ2A regulates numerous protein-coding genes and directly interacts with EZH2 to maintain epigenetic silencing at genes repressed in metastasis. BAZ2A overexpression is tightly associated with a molecular subtype displaying a CpG island methylator phenotype (CIMP). Finally, high BAZ2A levels serve as an independent predictor of biochemical recurrence in a cohort of 7,682 individuals with prostate cancer. This work identifies a new aberrant role for the epigenetic regulator BAZ2A, which can also serve as a useful marker for metastatic potential in prostate cancer.
ASHI Quarterly, 2001
Figure 3. When the known concentrations (expressed in logarithmic form, X axis) of target gene ar... more Figure 3. When the known concentrations (expressed in logarithmic form, X axis) of target gene are plotted against the corresponding cycle threshold (Ct, Y axis) obtained by qr-PCR, the result is a line representing the linear correlation between the two parameters. The ...
Blood, 2005
To study natural killer (NK) cell–mediated antileukemic activity in chronic myelogenous leukemia ... more To study natural killer (NK) cell–mediated antileukemic activity in chronic myelogenous leukemia (CML), we investigated the ability of HLA-matched and mismatched CD56+ cells to inhibit granulocyte macrophage–colony-forming unit (CFU-GM) formation by leukemic CD34+ cells. In 14 HLA-identical donor-recipient pairs, donor CD56+ cells inhibited CML CFU-GM comparably to effectors from 14 HLA-mismatched unrelated individuals (mean inhibition 42% ± 9% vs 39.5% ± 7% at a 10:1 effector-to-target (E/T) ratio), suggesting that killer inhibitory receptor (KIR) incompatibility was not essential for an antileukemic effect. Both CD56+CD3- (natural killer [NK]) and CD56+CD3+(NK-T) cells inhibited CFU-GM growth of CML but not normal CD34+ cells. A mechanism for this leukemia-specific cytotoxicity was suggested by the abnormal overexpression of major histocompatibility class I chain–related gene A or gene B (MICA/B) on CML CD34 cells and their ability to bind the NK activation ligand NKG2D. However, ...
Annals of Surgery, 2013
Cancer is a heterogeneous disease in most respects, including its cellularity, different genetic ... more Cancer is a heterogeneous disease in most respects, including its cellularity, different genetic alterations, and diverse clinical behaviors. Traditional molecular analyses are reductionist, assessing only 1 or a few genes at a time, thus working with a biologic model too specific and limited to confront a process whose clinical outcome is likely to be governed by the combined influence of many genes. The potential of functional genomics is enormous, because for each experiment, thousands of relevant observations can be made simultaneously. Accordingly, DNA array, like other highthroughput technologies, might catalyze and ultimately accelerate the development of knowledge in tumor cell biology. Although in its infancy, the implementation of DNA array technology in cancer research has already provided investigators with novel data and intriguing new hypotheses on the molecular cascade leading to carcinogenesis, tumor aggressiveness, and sensitivity to antiblastic agents. Given the revolutionary implications that the use of this technology might have in the clinical management of patients with cancer, principles of DNA array-based tumor gene profiling need to be clearly understood for the data to be correctly interpreted and appreciated. In the present work, we discuss the technical features characterizing this powerful laboratory tool and review the applications so far described in the field of oncology.
Comprehensive Analysis of CD8 T Cell Immune Response Specific for Two Novel HLA-A*0201 Restriced CMV pp65 Peptides
Blood, Nov 16, 2005
In immune compromised subjects such as patients undergoing bone marrow, organ transplantation or ... more In immune compromised subjects such as patients undergoing bone marrow, organ transplantation or immunosuppressive therapies, Cytomegalovirus (CMV) infection is associated with significant morbidity until the individual’s immune system is completely reconstituted. One method of preventing CMV infection during immune suppression in transplant patients is represented by adoptive administration of CMV peptide-specific cytotoxic T lymphocytes (CTLs) from HLA-matched donors. Despite the strong immunogenicity demonstrated by specific HLA class I peptides, the peptide’s responsiveness varies among individuals. Therefore, it is important to identify additional epitopes for each HLA determinant of interest. In this study we report a comprehensive analysis of CD8 T cell-specific activity against two novel CMV pp65 HLA-A*0201 associated peptides in CMV-experienced HLA-A*0201 subjects. PBMCs from CMV seropositive HLA-A*0201 restricted healthy subjects were peptide-stimulated ex vivo and IFN-γ gene expression was analyzed by qrt-PCR. An IFN-γ ELISPOT assay was carried out on peptide-specific elicited CD8 T lymphocytes to confirm the qrt-PCR results. Tetrameric HLA/epitope complexes (tHLA) were used to track the levels of peptide-specific CD8 T cells responsiveness to cognate epitopes. In addition, in vitro peptide-specific expanded populations of CTLs were used in 51Cr release assay. Based on qrt-PCR results, four out of eight HLA-A*0201 peptides identified by computer algorithms were selected. Two are preaviously published peptides: pp65495–503 (NLVPMVATV) and pp65347–355 (ALFFFDIDL), while two are novel: pp65340–348 (RQYDPVAAL) and pp65310–318 (LMNGQQIFL). In spite the four peptides induced comparable mRNA IFN-γ transcript production, peptides pp65495–503, pp65340–348 and pp65310–318 induced a consistent and sustained IFN-γ protein release and specific killing, while the pp65347–355 failed to induce IFN-γ protein secretion and killing activity (if we exclude a positive IFN-γ protein release after 2-week in vitro induction in one of the donors tested). Comparative assays carried on the functional activity of the three peptides pp65495–503, pp65340–348 and pp65310–318 revealed no intrinsic differences in term of IFN-γ protein release and cytotoxic activity save for the CTL affinity to the HLA-A*0201/epitope complexes (pp65495–503 ~2.6% in nearly 100% of donors vs pp65340–348 ~0.67% or pp65310–318 ~0.77% in nearly one third of the donors after 2-week in vitro induction). The tHLA binding results could be possibly ascribed to differencies in the peptide avidity and stability for the HLA class I. Taken together, these results lead to the conclusion that different peptides can induce a variable levels of immune responses ranging between mere cytokine gene expression and effective cytotoxic activity. In addition, the two novel peptides selected here broaden the panel of potential reagents useful for adoptive immune therapy. Thus, in anticipation of a specific epitope-targeted immune intervention, the three HLA-A*0201 peptides described could be used in combination for adoptive transfer of epitope-specific T cells or epitope-specific vaccination.
Cancer testis antigen expression and immune responses by prostate cancer patients: Implications for prognosis and immunotherapy
Journal of Clinical Oncology, May 20, 2009
e16101 Background: Prostate cancer (PC) is the most frequent malignancy in men and it continues t... more e16101 Background: Prostate cancer (PC) is the most frequent malignancy in men and it continues to be one of the most common fatal cancers. Treatment options in advanced castration-resistant prostate cancer (CRPC) are limited. Cancer testis (CT) antigens are expressed in a variety of human cancers, but not in normal tissues except for MHC deficient spermatogonia, and represent promising targets for immunotherapy. Little is known about CT antigen expression in relation to disease progression. The aim of this study was to investigate which CT antigens are expressed and immunogenic and hence represent promising targets for patients with prostate cancer and correlate these findings with clinicopathological characteristics. Methods: To determine the expression of 6 CT antigens in prostate cancer immunohistochemistry was performed on tissue micro arrays. We investigated 6 CT antigens (NY-ESO.1, MAGE-C1, MAGE-C2, GAGE, MAGE-A1 and MAGE-A4) in benign hyperplasia (n=45), early (n=388) and late stage (n=71) prostate cancer. To determine the occurrence of spontaneous antibodies against cancer testis antigens, ELISA and Western blot was performed for NY-ESO-1, MAGE-C1 and MAGE-C2 with sera from prostate cancer patients. Results: CT antigens are increasingly expressed in late stage prostate cancers. As an exception we found MAGE-C2 to be expressed early in the course of disease, frequently inducing MAGE-C2 specific antibodies. In later stage metastatic prostate cancer patients NY-ESO-1 is more often expressed, inducing NY-ESO-1 specific antibodies. Conclusions: Cancer testis (CT) antigens are prognostic markers, frequently inducing immune responses and may be suitable for immunotherapeutic intervention in patients with prostate cancer. No significant financial relationships to disclose.
Indoleamine 2,3-dioxygenase (IDO) expression and malignant transformation in prostate cancer
Journal of Clinical Oncology, May 20, 2008
Cancers, 2022
PCa screening is based on the measurements of the serum prostate specific antigen (PSA) to select... more PCa screening is based on the measurements of the serum prostate specific antigen (PSA) to select men with higher risks for tumors and, thus, eligible for prostate biopsy. However, PSA testing has a low specificity, leading to unnecessary biopsies in 50–75% of cases. Therefore, more specific screening opportunities are needed to reduce the number of biopsies performed on healthy men and patients with indolent tumors. Urine samples from 45 patients with elevated PSA were collected prior to prostate biopsy, a mass spectrometry (MS) screening was performed to identify novel biomarkers and the best candidates were validated by ELISA. The urine quantification of PEDF, HPX, CD99, CANX, FCER2, HRNR, and KRT13 showed superior performance compared to PSA. Additionally, the combination of two biomarkers and patient age resulted in an AUC of 0.8196 (PSA = 0.6020) and 0.7801 (PSA = 0.5690) in detecting healthy men and high-grade PCa, respectively. In this study, we identified and validated nove...
Frontiers in Immunology, 2020
Prostate cancer (PCa) is a slow-growing tumor representing one of the major causes of all new can... more Prostate cancer (PCa) is a slow-growing tumor representing one of the major causes of all new cancer cases and cancer mortality in men worldwide. Although screening methods for PCa have substantially improved, the outcome for patients with advanced PCa remains poor. The elucidation of the molecular mechanism that drives the progression from a slow-growing, organ-confined tumor to a highly invasive and castration-resistant PCa (CRPC) is therefore important. We have already proved the diagnostic potential of indoleamine-2,3-dioxygenase (IDO) when detected in urine of individuals at risk of developing PCa. The aim of this study was to implement IDO as a prognostic marker for PCa patients undergoing surgical treatment. We have thus conducted an observational study by collecting 100 urine samples from patients undergoing radical prostatectomy as first treatment of choice. To test the integrity of our investigation, scale dilution cells of an established PC3 cell line were added to urine of healthy donors and used for gene expression analysis by a TaqMan assay on the catalytic part of IDO mRNA. Our data show that the quantification of IDO mRNA in urine of patients has a very promising ability to identify patients at high risk of cancer advancement, as defined by Gleason score. Our goal is to lay the groundwork to develop a superior test for PCa. The data generated are thus necessary (i) to strengthen the IDO-based diagnostic/prognostic test and (ii) to provide patients and clinicians with an affordable and easy screening test.
Frontiers in Immunology, 2018
Inflammation has been suggested to play an important role in onset and progression of prostate ca... more Inflammation has been suggested to play an important role in onset and progression of prostate cancer (PCa). Histological analysis of prostatectomy specimens has revealed focal inflammation in early stage lesions of this malignancy. We addressed the role of inflammatory stimuli in the release of PCa-specific, tumor-derived soluble factors (PCa-TDSFs) already reported to be mediators of PCa morbidity, such as indoleamine 2,3-dioxygenase (IDO) and interleukin (IL)-6. Inflammation-driven production and functions of PCa-TDFSs were tested "in vitro" by stimulating established cell lines (CA-HPV-10 and PC3) with IFN-γ or TNF-α. Expression of genes encoding IDO, IL-6, IFN-γ, TNF-α, and their receptors was investigated in tumor tissues of PCa patients undergoing radical prostatectomy, in comparison with benign prostatic hyperplasia (BPH) specimens. IFN-γ and TNF-α-treatment resulted in the induction of IDO and IL-6 gene expression and release in established cell lines, suggesting that the elicitation of PCa-TDSFs by these cytokines might contribute to progression of cancer into an untreatable phenotype. An analysis based on timing of biochemical recurrence revealed the prognostic value of IDO but not IL-6 gene expression in predicting recurrence-free survival in patients (RFS) with PCa. In addition, a urine-based mRNA biomarker study revealed the diagnostic potential of IDO gene expression in urines of men at risk of PCa development.
Chemotherapy: Open Access, 2015
Prostate cancer (PCa) is a slow-growing, organ-confined tumor usually accompanied with a favorabl... more Prostate cancer (PCa) is a slow-growing, organ-confined tumor usually accompanied with a favorable overall prognosis. Current standard-of-care chemotherapy, and recently immunotherapies, for patients suffering from this disease may prolong overall survival and improve quality of life, but they do not prevent tumor recurrence and thus are not curative. Underlying reasons are not completely understood. Recent investigations support a possible carcinogenic activity of the human BK polyomavirus (BKPyV) in the prostate. In this commentary, we envisage the development of BKPyV-related therapeutic strategies to be beneficial for individuals at risk of developing PCa.
Medical science monitor : international medical journal of experimental and clinical research, Jan 4, 2015
BACKGROUND To investigate stromal variables including angiogenesis, lymphangiogenesis, and matrix... more BACKGROUND To investigate stromal variables including angiogenesis, lymphangiogenesis, and matrix metalloproteinase (MMP) in the serum of patients with urothelial carcinoma of the bladder (UCB) and to evaluate their association with histopathological characteristics and clinical outcome. MATERIAL AND METHODS Protein levels of vascular endothelial growth factors-A, -C, -D (VEGF-A/-C/-D), their receptors- VEGF-R2 and -R3 (VEGF-R2/-R3), and matrix metalloproteinases 2, -3, and -7 (MMP-2, MMP-3, MMP-7) were quantified in the blood serum samples of 71 patients with UCB before radical cystectomy (RC). Samples of patients with non-invasive UCB or no history of UCB were investigated as controls (n=20). Protein levels in the serum were measured using a flow cytometric cytokine assay. RESULTS A positive association for VEGF-D (p<0.001) and an inverse association for MMP-2 (p=0.017) were observed in patients with positive lymph node (LN) status at the time of RC. VEGF-A (p<0.001), VEGF-C...
Oncotarget, Jan 31, 2015
Infectious agents, including the BK polyomavirus (BKPyV), have been proposed as important inflamm... more Infectious agents, including the BK polyomavirus (BKPyV), have been proposed as important inflammatory pathogens in prostate cancer. Here, we evaluated whether the preoperative antibody response to BKPyV large T antigen (LTag) and viral capsid protein 1 (VP1) was associated with the risk of biochemical recurrence in 226 patients undergoing radical prostatectomy for primary prostate cancer. Essentially, the multivariate Cox regression analysis revealed that preoperative seropositivity to BKPyV LTag significantly reduced the risk of biochemical recurrence, independently of established predictors of biochemical recurrence such as tumor stage, Gleason score and surgical margin status. The predictive accuracy of the regression model was denotatively increased by the inclusion of the BKPyV LTag serostatus. In contrast, the VP1 serostatus was of no prognostic value. Finally, the BKPyV LTag serostatus was associated with a peculiar cytokine gene expression profile upon assessment of the cel...
PLoS ONE, 2011
The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In mo... more The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In most cases, no CT antigen is found in normal tissues, except in testis, making them ideal targets for cancer immunotherapy. A comprehensive analysis of CT antigen expression has not yet been reported in prostate cancer. MAGE-C2/CT-10 is a novel CT antigen. The objective of this study was to analyze extent and prognostic significance of MAGE-C2/CT10 protein expression in prostate cancer. 348 prostate carcinomas from consecutive radical prostatectomies, 29 castration-refractory prostate cancer, 46 metastases, and 45 benign hyperplasias were immunohistochemically analyzed for MAGE-C2/CT10 expression using tissue microarrays. Nuclear MAGE-C2/CT10 expression was identified in only 3.3% primary prostate carcinomas. MAGE-C2/CT10 protein expression was significantly more frequent in metastatic (16.3% positivity) and castration-resistant prostate cancer (17% positivity; p,0.001). Nuclear MAGE-C2/CT10 expression was identified as predictor of biochemical recurrence after radical prostatectomy (p = 0.015), which was independent of preoperative PSA, Gleason score, tumor stage, and surgical margin status in multivariate analysis (p,0.05). MAGE-C2/CT10 expression in prostate cancer correlates with the degree of malignancy and indicates a higher risk for biochemical recurrence after radical prostatectomy. Further, the results suggest MAGE-C2/CT10 as a potential target for adjuvant and palliative immunotherapy in patients with prostate cancer.
Journal of Urology, 2013
PURPOSE: Myoblasts are capable of forming muscle fibers after transplantation and are therefore e... more PURPOSE: Myoblasts are capable of forming muscle fibers after transplantation and are therefore envisioned as a treatment for urinary incontinence after radical prostatectomy. However, the safety of this treatment and the interaction of myoblasts with remaining neighboring cancerare unknown. We investigated the interactions between myoblasts and prostate carcinoma cellsin vitro and in vivo. MATERIALS AND METHODS: Myoblasts isolated fromrectus abdominis were used in a series of coculture experiments with prostate cancer cells and subcutaneously co-injected in vivo. Cell proliferation, cell cycle arrest and apoptosis of cancers in co-culture with myoblasts were assessed. Tumor volume and metastasis formation were evaluated in a mouse model. Tissue specific markers were assessed by immunohistochemistry, FACS analyses, Western blot and RT-qPCR. RESULTS: In this study we have demonstrated that myoblasts, in proximity to tumor, provide paracrine TNF to their microenvironment, decreasing tumor growth of all prostate cancer cell lines examined. Co-culture experiments showed induction of cell cycle arrest, tumor death by apoptosis and increased differentiation of myoblasts. This effect was largely blocked by TNF inhibition. The same outcome was demonstrated in a mouse model, where co-injected human myoblasts also inhibited tumor growth and metastasis formation of all prostate cancer cell lines evaluated. CONCLUSIONS: Myoblasts restrict prostate cancer growth and limit metastasis formation by paracrine TNF secretion in vitro and in vivo.
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Papers by Maurizio Provenzano