Investigation on the effect of Dll4Fc anti-angiogenic tumour therapy on metastatic dissemination

Financiador

Organização

Publicações

The role of Jagged1 in adult angiogenesis and in solid tumor development

Publication . Pedrosa, Ana Rita Ponce Álvares de Águeda; Duarte, António Freitas; Trindade, Alexandre Neto

Jagged1 (Jag1) is a Notch signaling ligand, which has been described as essential for developmental angiogenesis and to play an important role in several aspects of tumor biology. However the underlying mechanism related to Jagged1/Notch signaling still remain incompletely understood. Therefore this thesis analyzed Jagged1 driven Notch signaling enrolment in adult angiogenesis settings, and in tumor development. To address the role of endothelial Jag1 in physiological and tumoral angiogenesis, endothelial-specific Jag1 mutants driven angiogenic phenotypes were assessed in skin wound healing and in transplanted tumors and prostatic autochthonous tumor growth, respectively. An extensive transcription and expression analysis of Notch signaling members in the tumorigenic development of the mouse prostate was also performed to identify ectopically expressed Notch members. Lastly, the therapeutic potential of an Anti-Jagged1/2 antibody in mouse prostate cancer was evaluated. Altogether, results presented here demonstrate that Jagged1 is a pro-angiogenic ligand due to its ability to antagonize Dll4/Notch1 mediated signaling. It also has a pro-maturation function by both endothelial Notch4 and perivascular Notch3 mediated signaling. Both these functions contribute to accelerated wound healing and tumor growth, by inducing a more functional vasculature. Moreover, we have identified a new angiocrine function for endothelial Jagged1, mediated through Notch3/Hey1 activation in tumor cells. Finally, we have demonstrated that either by mediated endothelial-specific angiocrine function or by tumor cells mediated Jagged1 ectopic expression, this ligand regulated tumor cell proliferation, apoptosis, de-differentiation, epithelial-to-mesenchymal transition and cancer stem-like cells proliferation and survival. Ultimately, we have demonstrated that blocking Jagged-mediated Notch signaling inhibited development and progression of mouse prostate cancer and therefore constitutes a promising therapeutic approach in prostate cancer treatment.

2016-01-12Tese de doutoramento

Acesso aberto

Ver mais

Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

3599-PPCDT

Número da atribuição

PTDC/SAU-ONC/121742/2010