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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.
The role of endothelial Dll4 in cancer metastasis
Publication . Dias, Liliana Mendonça da Silva; Duarte, António Freitas; Trindade, Alexandre Neto
The metastatic spread of cancer is still the major barrier to the treatment of this disease.
Cancer-mortality is mainly due to recurrence and metastasis. Although much has been
done in the field of cancer treatment, prevention and approach to metastases are still areas
not fully explored.
Over and under-expression of Dll4/Notch signaling has been demonstrated to impair tumor
growth through opposing patterns of vascular modulation in different mouse tumor models
and human cancer xenografts. Recent evidence implicates Dll4/Notch pathway in the
metastasis mechanism, but less is known about the specific role of endothelial Dll4. For this
reason, we proposed to investigate how endothelial Dll4 expression interferes with the
metastatic process. To address it we used a spontaneous metastasis mouse model based
on Lewis Lung Carcinoma (LLC) subcutaneous transplants in endothelial-specific Dll4 lossof-
function (eDll4cKO) and endothelial-specific Dll4 over-expression (D4OE) mice.
Results demonstrated that eDll4cKO is responsible for the vascular function regression that
leads to tumor growth reduction. Early steps of epithelial-to-mesenchymal transition (EMT)
and cancer stem cell selection were also inhibited by eDll4cKO, leading to a substantial
reduction of circulating tumor cells and reduction in the number and burden of macrometastases.
Intravasation and extravasation were also compromised by eDll4cKO, possibly
due to blockade of the metastatic niche.
In the case of the D4OE mice we observed that tumor growth reduction was achieved by
vessel proliferation restriction along with an improved vascular maturation, which allowed a
more efficient delivery of chemotherapy. This last effect of vessel normalization seemed to
prevent metastasis formation even though EMT markers were increased.
In conclusion, despite the opposite vascular architecture phenotypes of eDll4cKO and
D4OE, both lead to a reduction in metastasis. This is in line with the concept of Dll4 dosage
observed in the wound-healing context and represents a promising therapeutic approach in
metastasis prevention/ treatment.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/SAU-ONC/116164/2009