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| Author(s): |
Leonardo Luís Artico
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2019-02-20 |
| Examining board members: |
José Andrés Yunes;
Carmen Veríssima Ferreira;
Priscila Pini Zenatti
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| Advisor: | José Andrés Yunes |
| Abstract | |
Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, corresponding to about 30% of all cases of cancer and 80% of all leukemia in patients of less than 15 years old. Despite the improvement on the therapy of ALL, this disease is still the most common cause of cancer-related death in young people around the world. In the last decade, some studies have shown that high expression of IGFBP7 would be related to a worse prognosis in ALL patients. We have previously shown that ALL cells are the main source of IGFBP7 in the leukemia microenvironment, where it exerts a paracrine effect on bone marrow stromal cells, reflecting resistance to primary therapy by patients. Here we show that IGFBP7 exerts also an autocrine effect on ALL cells (cell lines and primary cells). We observed that the positive effects of INS/IGF on ALL cell lines viability were significantly enhanced by recombinant IGFBP7, promoting PI3k/Akt/mTOR pathway activation. However, IGFBP7 silencing impairs this effect, boosting the p53 pathway activation in the silenced cells. Furthermore, we illustrate that IGFBP7 knockdown sensitizes ALL cells to cytostatic actions mediated by Dexamethasone and confirmed that IGFBP7 promotes chemo-therapeutic resistance to glucocorticoids in ALL. Our data further demonstrates that IGFBP7 neutralization with monoclonal antibody is detrimental to the in vitro and in vivo leukemia viability. Finally, we have shown that association of anti-IGFBP7 antibody plus Dexamethasone dramatically reduces the ALL cellular viability, revealing the importance of IGFBP7 in leukemia progression (AU) | |
| FAPESP's process: | 17/03239-5 - IGFBP7 and dexamethasone resistance in acute lymphoblastic leukemia |
| Grantee: | Leonardo Luís Artico |
| Support Opportunities: | Scholarships in Brazil - Master |