Federico Schuster

Abstract 4717: Clinical implications for m-tyrosine, an isomer of p-tyrosine, for the treatment of aggressive prostate tumors

Clinical and experimental evidence suggest that primary tumors may exert a controlling action on its metastases. The phenomenon, by which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis, is known as concomitant tumor resistance (CR). We have previously showed in murine T-lymphoma (LB) tumors, that meta-tyrosine (m-Tyr) an isomer of tyrosine not present in normal proteins, is the main serum anti-tumoral factor responsible for CR. In this work, we assess for the first time the CR phenomenon in human prostate cancer (PCa). Athymic nude mice were inoculated with PC3 cells (primary implant) and after 14 days the animals received a second inoculation (secondary implant). Strikingly, the growth of the secondary implant was significantly reduced after 27 days, in animals carrying the primary xenograft. When phenylalanine (Phe), a protective amino acid highly present in primary tumors, and precursor of p-tyrosine, was periodically inoculated at the site of a secondary tumor implant (otherwise inhibited by CR), this secondary implant grew similarly to controls. On the contrary, when m-Tyr was inoculated at the site of a primary tumor implant or systemically, this implant did not grow. Tumor inhibition was associated with low expression of Ki-67 and STAT3. In vitro analyses demonstrate the higher inhibitory activity of the serum from tumor-bearing mice on PC3 cell proliferation, compared to serum from control animals. m-Tyr could account for most of the growth-inhibitory activity present in the serum. Furthermore, we observed an increase in the frequency of Gr1+ CD11b+ MDSCs in bone marrow, spleen and lymph nodes from tumor-bearing mice compared to control mice. This expansion correlated with a significantly higher production of reactive oxygen species and enhanced suppressor function upon CD8+ T cell proliferation. Further, in vitro studies also showed that exposure of PC3 cells to m-Tyr inhibited cell growth, induced G0/G1 cell cycle arrest, altered the expression levels of survivin, Ki67 and Hes1; impaired the NFκB/STAT3 pathway and induced autophagy; effects reversed by Phe treatment. Strikingly, m-Tyr periodic intravenous administration provoked a dramatic reduction of experimental lung metastases generated in mice bearing PC3 human tumors. Altogether, we demonstrate for the first time that RC occurs in experimental human solid tumors, that this effect is mediated by m-Tyr, a non-cytotoxic metabolite with high potential clinical implications for metastatic PCa. Citation Format: Geraldine Gueron, Nicolas Anselmino, Paula Chiarella, Emiliano Ortiz, Alejandra Paez, Jimena Giudice, Federico Schuster, Daiana Leonardi, Felipe Jaworski, Estefania Labanca, Veronica Manzano, Javier Cotignola, Roberto Meiss, Norma D′Accorso, Nora Navone, Raul Ruggiero, Elba Vazquez. Clinical implications for m-tyrosine, an isomer of p-tyrosine, for the treatment of aggressive prostate tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4717.

Trends of Social Protest in Argentina: 1989–2007

This chapter presents the results of empirical research, based on the notion of social protest: The study focus over a period of time long enough to question the transformations of social mobilisation in Argentina beyond the analysis of specific organizations or episodes of contention.

Abstract 5199: A second round for concomitant resistance in human cancer: A restraint upon metastasis

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Concomitant tumor resistance (CR) is the phenomenon according to which a tumor-bearing host inhibits the growth of secondary tumor implants. Ehrlich first described it in 1906, but this phenomenon remained forgotten for about 60 years. After its renascence, some groups have demonstrated that both immunogenic and non-immunogenic tumors can induce CR in different animal models. Metastases could be considered as secondary tumor implants developed spontaneously during the primary tumor growth, thus CR could be relevant for cancer progression. Clinical and experimental evidence suggest that the removal of human and murine tumors might be followed by an abrupt increase in metastatic growth, hence the primary tumor could exert a controlling action on its metastases. In previous papers we demonstrated that, in mice, two temporally separate peaks of CR can be detected during murine T-lymphoma (LB) primary tumor growth. The second peak of CR is mediated by most large-sized immunogenic and non-immunogenic tumors and is associated with the anti-tumor and anti-metastatic serum factor meta-tyrosine (m-tyr), an isomer of tyrosine not present in normal proteins. Based on this background, in this work we assessed whether CR was also occurring in human tumor experimental models. Athymic nude mice were inoculated s.c. in the right flank, with the human prostate cancer cell line PC3 (1 × 106, primary implant). After 14 days the animals received a second inoculation of PC3 cells in the left flank (1 × 106, secondary implant). The control group only received the secondary implant. The growth of the secondary implant was significantly reduced (92%; P<0.05) at 27 days, in animals carrying the primary implant. Moreover, m-tyr was detected in the serum of mice bearing the RC phenomenon. The tumor growth inhibition was recapitulated in animals inoculated with the primary tumors and injected with m-tyr. Strikingly the RC phenomenon was reversed when secondary implants were injected with phenylalanine, a protective amino acid highly present in primary tumors. In vitro results also showed that exposure of PC3 cells to m-tyr inhibited cell growth and a G0/G1 cell cycle arrest, which was concomitant with alterations in the mRNA expression levels of survivin (apoptosis inhibitor), Ki67 (proliferation marker), Hes1 (transcription factor involved in Notch pathway) and STAT3 (prostate cancer survival factor) (P<0.01). We have further validated the RC phenomenon in two other human cancer models: anaplastic carcinoma of the lung (CALU-6), and nasopharyngeal carcinoma (KB), exhibiting also high levels of m-tyr in serum from nu/nu mice bearing CALU-6 or KB tumors. Altogether, we showcase for the first time that CR is triggered in human solid tumors, that this phenomenon is mediated by m-tyr and provide the molecular mechanisms that drive this process. These results offer an alternative therapeutic avenue in the management of metastatic cancers. Citation Format: Geraldine Gueron, Nicolas Anselmino, Damian Manchuca, Emiliano G. Ortiz, Maria Noelia Carabelos, Federico Schuster, Paula Chiarella, Alejandra Paez, Felipe M. Jaworski, Javier Cotignola, Roberto Meiss, Raul Ruggiero, Elba S. Vazquez. A second round for concomitant resistance in human cancer: A restraint upon metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5199. doi:10.1158/1538-7445.AM2015-5199

Abstract LB-43: Unveiling the molecular significance of HO-1 and muskelin interaction: two masterminds behind the morphology and the adhesive behavior of prostate cancer cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Prostate Cancer (PCa) is the second leading cause of cancer death in American men. The inflammatory tumor microenvironment is a fertile niche that releases reactive oxygen species, which accelerates the malignant transformation and appears as a fine tuner of the adhesive behavior of cells. Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, represents an essential event in cellular responses to pro-oxidative and pro-inflammatory insults. As we previously reported that HO-1 over-expression impaired tumor growth and angiogenesis in vivo we sought to assess whether HO-1 could regulate the adhesive properties and the morphology of PCa cells. A bioinformatics enrichment analysis using Metacore, GeneMANIA and DAVID was performed; rendering a significant association of the HO-1 regulated genes with several proteins located in the extracellular space and cell membrane; compartments highly correlated with the adhesive behavior of cells. In an effort to understand the molecular mechanisms underlying HO-1s role in cell morphology regulation we used a proteomics approach to identify HO-1 partners. We performed GST-pull-down assays using lysates from PC3 cells transfected with either GST-tagged HO-1 or the empty vector, and the isolated proteins were subjected to MALDI-TOF/TOF analyses. Our results showed that HO-1 interacts with Muskelin, a nucleocytoplasmic mediator of cellular morphology and adhesiveness. Up-regulation of Muskelin under HO-1 induction in PCa cells was confirmed by confocal microscopy. A high degree of nuclear overlay between HO-1 and Muskelin signals was observed when cells were exposed to hemin, a potent specific inducer of HO-1 or genetically manipulated to over-express HO-1, compared to controls. Interestingly after HO-1 induction, both protein exhibit similar sub-cellular dynamics, relocating from the cell membrane, towards the cell nuclei. Altogether, we have shown for the first time that HO-1 binds and up-regulates Muskelin, a specific factor involved in shaping cellular morphology and adhesive properties, favoring a less aggressive phenotype and further supporting the anti-tumoral function of HO-1in PCa. Citation Format: Geraldine Gueron, Jimena Giudice, Alejandra Paez, Pia Valacco, Noelia Carabelos, Federico Schuster, Javier Cotignola, Felipe Jaworski, Daiana Leonardi, Maria Binaghi, Marcelo Marti, Nora Navone, Elba Vazquez. Unveiling the molecular significance of HO-1 and muskelin interaction: two masterminds behind the morphology and the adhesive behavior of prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-43. doi:10.1158/1538-7445.AM2014-LB-43