SCIENTIFIC REPORT 2010 - 2011 - IOV

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MDSC are able to suppress the activation of both alloactivated and mitogen activated T lymphocytes, while ex-vivo isolated BM cells and untreated BM cells do not interfere significantly with T lymphocyte proliferation. BM-MDSC consist of a heterogeneous cell population comprising myeloid cells at various stages of differentiation, ranging from more immature cells to mature granulocytes and monocytes. We investigated which myeloid subpopulation had the highest suppressive activity and our results clearly indicate that only one fraction of BM-MDSC, containing an immature myeloid population, has the suppressive activity. This immature cell population has morphology and phenotype resembling to promyelocytes, and it is able not only to block lymphocyte proliferation, but also to affect IFN-γ production and to induce T cell apoptosis. When we investigated the relationship between T cell activation and BM-MDSC-mediated suppression, we found that the promyelocytic-like population was able to proliferate and maintain its immature phenotype when co-cultured with activated T lymphocytes; conversely, the same myeloid subset showed a diminished proliferative index and differentiated to more mature myeloid cells when co-cultured with resting T lymphocytes. In the blood of breast and colorectal cancer patients we could clearly identify an immature myeloid population resembling in vitro generated BM-MDSC. Our data suggest that circulating MDSC levels, phenotypically similar to those described in human BM experiments, are clinically relevant and: (i) increase over time in patients with progressive disease; (ii) correlate with an established prognostic marker (i.e. circulating tumor cells) in advanced breast cancer; and (iii) their persistently high or increasing levels following chemotherapy are associated with poor survival. Conclusions and future perspectives. The identification of this population with inhibitory function, and the efficient and rapid in vitro generation gives us the opportunity to use this model of expansion of human MDSC to study its expression profile and to specifically define its regulatory network of expression. In fact, the integrative analysis of micro(mi)RNA/mRNA expression profiles allows to reconstruct a network of functional interactions occurring in cells by analyzing the panel of potential regulatory relationships predicted from sequence information. Our integrative approach assumes that the final effect of a truly functional interaction between miRNA and its predicted mRNA targets can be seen as a pair of anticorrelated expression profiles. According to the increasing experimental evidence supporting the miRNA mechanism of target degradation rather than translational repression, the integration of target predictions with miRNA and gene expression profiles has been proposed to improve the detection of functional miRNA-mRNA relationships. Since miRNA tend to down-regulate target mRNA, the expression profiles of genuinely interacting pairs are expected to be anti-correlated. Integrative analysis can be performed adopting a variational Bayesian model, or by using a non heuristic methodology based on the anti-correlation between miRNA and mRNA expression profiles. rEGulaTiON Of TumOr DOrmaNCy: DiSSECTiNG ThE mOlECular paThwayS DOwNSTrEam Of NOTCh fOr ThErapEuTiC purpOSES Principal Investigators: Stefano Indraccolo, Alberto Amadori Background. Angiogenesis contributes to regulate tumor dormancy, a condition defined by the presence in the host of fully transformed yet non-tumorigenic cells. Using a model of angiogenesis-dependent dormancy of T Acute Lymphoblastic Leukemia (T-ALL) cells, it was previously found that angiogenic factors induce expression of the Notch ligand Dll4 in the vasculature. Dll4 appears to activate Notch3 signalling in T-ALL cells, an event which protects them from apoptosis and initiates progressive tumor growth. These findings - reinforced by similar observations in colorectal cancer xenografts - suggest that endothelial cells embedded in tissues undergoing angiogenesis may communicate activation signals to tumor cells, which contribute to the switching towards an aggressive phenotype. Here we wish to investigate whether novel Notch-targeted drugs could maintain tumor dormancy in pre-clinical models of cancer. Methods. Studies on T-ALL make use of a clinically relevant model of engraftment of primary human leukemia samples in NOD/SCID mice recently set-up in the lab. Specifically, the hypothesis that blockade of the Notch3-Dll4 interaction by anti- Dll4 or anti-Notch1/3 antibodies could exert therapeutic effects in T-ALL as well as solid tumors is being tested. Tumor burden is quantified by measurement of blood parameters and live imaging of the tumors. Effects of anti-Notch drugs on gene expression will be analyzed by low density arrays on RNA extracted from FACSsorted T-ALL cells. The global effects of Notch inhibition on the THE DEPARTMENTS - DEPARTMENT OF EXPERIMENTAL, LABORATORY AND TRANSLATIONAL ONCOLOGY 148
phosphokinome will be investigated by a microarray approach. Results. A correlation was seen between the Notch/Fbw7 genetic status and expression levels of Notch-related transcripts in T-ALL xenografts. Preliminary results indicate that anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing an active Notch pathway, including samples derived from poor responders or relapsed patients. Anti-Notch1-treated mice had a significant reduction in the percentage of blasts in the blood, the spleen and the BM. Moreover, we observed an increase in the levels of T-ALL cell apoptosis and a strong inhibitory effect on Notch transcriptional profile following anti-Notch1 treatment. Conclusions. These results indicate that Notch1/Fbw7 mutated T-ALL samples are suitable candidates for Notch targeted therapy and highlight the potential of measurements of Notch target genes as surrogate biomarkers of the therapeutic response. Perspectives. Upon completion, this pre-clinical study will enable us to plan a phase I clinical trial for Notch-targeted therapy of relapsed or chemotherapy-resistant T-ALL. mOlECular aNalySiS Of GaSTrOiNTESTiNal STrOmal TumOrS (GiSTS) iN CliNiCal praCTiCE Principal Investigator: Roberta Bertorelle Background. The discovery in 1998 of the pathogenic alteration of Gastrointestinal Stromal Tumor (GIST) has changed the natural history of this tumor highly resistant to conventional chemotherapy, providing a target for a molecular therapeutic approach. Mutations of KIT or PDGFRA gene, coding for class III THE DEPARTMENTS - DEPARTMENT OF EXPERIMENTAL, LABORATORY AND TRANSLATIONAL ONCOLOGY 149
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SCIENTIFIC REPORT 2010 - 2011 ISTIT
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Chief Officer Address THE INSTITUTE
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The IOV Governance The IOV is gover
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GENERAL DIRECTORATE Pier Carlo Muzz
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of Ramucirumab using a double-blind
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late (occurring after the first che
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Charles R M Bangham How does HTLV-1
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carcinoma with singular bone metast
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[as member of AIRTUM WG: Zambon P,
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in laryngeal carcinoma treated with
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european patients with central nerv
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2011 PUBLICATIONS / Non indexed in
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Index of Names A Alaibac Mauro 46,
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Analytical Index A Acute Lymphoblas
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Colophon Title: Scientific Report 2
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