Maurizio Chiriva-Internati

Gamma-radiation upregulates MHC class I/II and ICAM-I molecules in multiple myeloma cell lines and primary tumors

SummaryThe γ-irradiation of normal cells causes an increased synthesis of specific proteins. However, few studies have described the effects of high doses of irradiation on the expression of cell surface antigens in tumor cells. This study analyzed the effects of high doses of γ-irradiation on the surface antigen expression of Major Histocompatability Complex (MHC) class I/II and intercellular adhesion molecule-1 (ICAM-I) in human multiple myeloma (MM) cell lines ARP-1, ARK-RS, and 10 MM primary tumors. The expression of surface antigens was evaluated by fluorescence-activated cell sorter analysis at different time points, following the exposure to high doses of γ-irradiation. Doses of 10,000 and 15,000 cGy were no0105 sufficient to totally block cell replication in both cell lines and primary tumors; cell replication was able to be inhibited completely only at 18,000 cGy. Lower doses (10,000 cGy) and lethal doses of irradiation (i.e., 15,000 and 18,000 cGy) increased the expression of all surface antigens present on the cells before irradiation. Essentially, such upregulation was shown to be dose dependent, with higher radiation doses resulting in higher antigen expression. Furthermore, when the kinetics of this upregulation were studied 3 and 6 d after irradiation, there was a constant increase in antigen expression in MM cells. These findings suggest that upregulation of costimulatory molecules, such as of MHC class I/II antigens and ICAM-1 molecules in MM patients treated by γ-radiation, can increase the immunogenicity of the tumor cells. In light of these findings, radiotherapy combined with immunotherapy might be considered in relapsing patients after receiving the standard treatment.

Geometry of human vascular system: Is it an obstacle for quantifying antiangiogenic therapies?

It is now recognized that all human natural and diseased anatomic systems are characterized by irregular shapes and very complex behaviors. In geometrical terms, tumor vascularity (which is the result of a nonlinear dynamic process called angiogenesis) is an archetypal anatomic system that irregularly fills a 3-dimensional Euclidean space. This characteristic, together with the highly variable nature of vessel shapes and surfaces, leads to considerable spatial and temporal heterogeneity in the delivery of oxygen, nutrients, and drugs, and the removal of metabolites. Although these biologic features have been well established, the quantitative analysis of neovascularity in 2-dimensional histologic sections still fails to view its architecture as a non-Euclidean geometrical object, thus allowing errors in visual interpretation and discordant results concerning the same tumor from different laboratories. We discuss here the tumor-induced vascular system as a fractal object, and what changes this new way of observing may bring to the quantification of effective antiangiogenic therapies.

Dendritic cell vaccination against ovarian cancer--tipping the Treg/TH17 balance to therapeutic advantage?

The pathology of ovarian cancer is characterized by profound immunosuppression in the tumor microenvironment. Mechanisms that contribute to the immunosuppressed state include tumor infiltration by regulatory T cells (Treg), expression of B7-H1 (PDL-1), which can promote T cell anergy and apoptosis through engagement of PD-1 expressed by effector T cells, and expression of indoleamine 2,3-dioxygenase (IDO), which can also contribute to effector T cell anergy. Expression of both B7-H1 and IDO has been associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in patients with ovarian cancer. In a remarkable counterpoint to these observations, ovarian tumor infiltration with TH17 cells correlates with markedly improved clinical outcomes. In this Future Perspectives review, we argue that dendritic cell (DC) vaccination designed to drive tumor-antigen-specific TH17 T cell responses, combined with adjuvant treatments that abrogate immunosuppressive mechanisms operative in the tumor microenvironment, offers the potential for clinical benefit in the treatment of ovarian cancer. We also discuss pharmacological approaches to modulation of MAP kinase signaling for manipulation of the functional plasticity of DC, such that they may be directed to promote TH17 responses following DC vaccination.

Combined Hepatocellular Cholangiocarcinomas; Analysis of a Large Database

Aim Combined hepatocellular cholangiocarcinoma (combined tumor) has been described as either a variant of hepatoma or a variant of cholangiocarcinoma. Prior studies evaluated fewer than 50 patients with combined tumors, precluding multivariate analyses. Posited was the notion that analysis of a large database would yield more definite answers. Methods This study used SEER (Surveillance, Epidemiology, and End Results Program of the National Cancer Institute) to analyze 282 combined tumors, 2,035 intrahepatic cholangiocarcinomas, and 19,336 hepatomas between the years 1973-2003. Multinomial logit regression calculated point estimates and 95% confidence intervals (c.i.) for relative risk (rr). Cox regression calculated point estimates and 95% confidence intervals (c.i.) for hazard ratios (ĥ). Results Men less often had cholangiocarcinomas than they had combined tumors (rr = 0.63, c.i. = 0.49-0.81). Hepatomas less often than combined tumors presented with distant spread (rr = 0.56, c.i. = 0.43-0.72). Men (rr = 1.50, c.i. = 1.17-1.93) and patients with a known Asian or Pacific birthplace (rr = 2.36, c.i. = 1.56-3.56) more often had hepatomas than they had combined tumors. Among patients not known to have an Asian/Pacific birthplace, a diagnosis of cholangiocarcinoma (ĥ = 0.72, c.i. = 0.63-0.82) or hepatoma (ĥ = 0.75, c.i. = 0.66-0.86) provided a better prognosis than did a diagnosis of combined tumor. Conclusion Combined tumors differ from hepatomas and cholangiocarcinomas in terms of distribution and survival patterns in the population; they should be considered neither cholangiocarcinomas nor hepatomas.

The adeno-associated virus major regulatory protein Rep78-c-Jun-DNA motif complex modulates AP-1 activity

Multiple epidemiologic studies show that adeno-associated virus (AAV) is negatively associated with cervical cancer (CX CA), a cancer which is positively associated with human papillomavirus (HPV) infection. Mechanisms for this correlation may be by Rep78s (AAVs major regulatory protein) ability to bind the HPV-16 p97 promoter DNA and inhibit transcription, to bind and interfere with the functions of the E7 oncoprotein of HPV-16, and to bind a variety of HPV-important cellular transcription factors such as Sp1 and TBP. c-Jun is another important cellular factor intimately linked to the HPV life cycle, as well as keratinocyte differentiation and skin development. Skin is the natural host tissue for both HPV and AAV. In this article it is demonstrated that Rep78 directly interacts with c-Jun, both in vitro and in vivo, as analyzed by Western blot, yeast two-hybrid cDNA, and electrophoretic mobility shift-supershift assay (EMSA supershift). Addition of anti-Rep78 antibodies inhibited the EMSA supershift. Investigating the biological implications of this interaction, Rep78 inhibited the c-Jun-dependent c-jun promoter in transient and stable chloramphenicol acetyl-transferase (CAT) assays. Rep78 also inhibited c-Jun-augmented c-jun promoter as well as the HPV-16 p97 promoter activity (also c-Jun regulated) in in vitro transcription assays in T47D nuclear extracts. Finally, the Rep78-c-Jun interaction mapped to the amino-half of Rep78. The ability of Rep78 to interact with c-Jun and down-regulate AP-1-dependent transcription suggests one more mechanism by which AAV may modulate the HPV life cycle and the carcinogenesis process.

Senescent Remodeling of the Innate and Adaptive Immune System in the Elderly Men with Prostate Cancer

Despite years of intensive investigation that has been made in understanding prostate cancer, it remains a major cause of death in men worldwide. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer in the elderly men is becoming a disease of increasing significance. Aging is a progressive degenerative process strictly integrated with inflammation. Several theories have been proposed that attempt to define the role of chronic inflammation in aging including redox stress, mitochondrial damage, immunosenescence, and epigenetic modifications. Here, we review the innate and adaptive immune systems and their senescent remodeling in elderly men with prostate cancer.

Comment on 'Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area'

Comment on ‘Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area’

Abstract C29: Combination of SP17 with CA125 serologic measurement for detection of ovarian cancer

Ovarian cancer (OC) is a serious healthy issue for women worldwide, ranking second for mortality rates among gynecological malignancies. CA125 (MUC16) is the only available biomarker to monitor disease and treatment response in OC but it suffers from poor performance for diagnostic purposes. As a consequence, increasing efforts are being made for the identification of novel tumor biomarkers to improve CA125 test specificity and sensitivity. More than 30 serum biomarkers have been studied alone or in combination with CA125. We have previously shown that SP17, a member of the cancer/testis antigen (CTA) family, is a potential biomarker that allows for the discrimination of the normal ovary from OC cells and for the tracking of OC disease in a xenograft mouse model. Here we hypothesized that SP17 serum levels could be exploited as a diagnostic test to detect early lesions of OC and to discriminate between malignant and benign lesions. We analyzed SP17 expression in primary ovarian tissues from ovarian cancer patients, benign ovarian lesions and healthy subjects through RT-PCR and immunohistochemistry. SP17 and CA125 levels were measured in the sera of the same subjects by ELISA. We found that SP17 expression was restricted to OC cells at the transcriptional and translational levels, and that the measurement of SP17 concentration in the serum afforded accurate discrimination between subjects with different prognoses allowing for predicting overall survival time. SP17 assay alone was superior to CA125 in discriminating between ovarian cancer and benign ovarian tumors: combining SP17 and CA125 assays, we obtained 96% sensitivity, 89% specificity and 97% PPV. SP17 is a novel serum biomarker for ovarian cancer. SP17 serum measurement in combination with CA125 affords improved positive predictive value for diagnostic purposes. Citation Format: Maurizio Chiriva-Internati, Leonardo Mirandola, Yuefei Yu, Marjorie R. Jenkins, Everardo Cobos, Jose A. Figueroa, Hans W. Nijman, W. Martin Kast. Combination of SP17 with CA125 serologic measurement for detection of ovarian cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C29.