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Abstract :
[en] ADAM28 is highly overexpressed in non-small-cell lung cancer samples. Notably through a global proteomic approach, we recently identified an upregulation of ADAM28 after induction of lung inflammation in a mouse model of asthma.
In addition to data published in the literature and to our findings about ADAM28 expression in various pathological tissues, intrinsic characteristics of this proteinase argue for considering it as a potential regulator of cellular signalling pathways leading to an inflammatory pulmonary microenvironment and to carcinogenesis. Indeed, ADAM28 possesses an active catalytic domain and interacts in a non-proteolytic manner with some integrins (α4β1) and some P-selectin ligands involved in inflammatory cell migration. Recently, ADAM28 was shown to shed pro-TNF-alpha suggesting an important role in tumour control.
This project aims to characterize molecular mechanisms involving host-derived ADAM28 in tumour development and metastatic dissemination to lung tissues.
We intend to determine the effects of ADAM28 depletion on physiological and pathological processes in ADAM28 conditional knockout mice, which have been developed in our laboratory (in collaboration with the Max Planck Institute, Munich). This unique mouse strain provides a precious tool to investigate ADAM28 implication in disease models including tumour growth and dissemination.
There is no spontaneous phenotype for ADAM28 full knockout animals, which are fertile and do not display any significant abnormality or defect.
To understand the implication of ADAM28 in lung tumour cell dissemination, ADAM28 KO mice were intravenously injected with Lewis Lung Carcinoma cells and B16K1 melanoma cells. Our results show an increased tumour development in lungs of KO mice. To explain these surprising data, the vessel structure and permeability will be observed in our KO and WT littermates. Moreover, ADAM28 is described to be associated with lymphocyte transendothelial migration and is known to be expressed by lymphocytes. Consequently, we analysed the presence of lymphocyte subtypes implicated in tumour cytotoxicity or in the regulation of immune response. We observed that CD8 positive T-cells are less expressed in the spleen of naive KO mice and in the early stages after tumour cells injection. We also observed less CD8 T-cells in the lung of KO mice at a later stage in our model of tumour dissemination. These preliminary data suggest a role of ADAM28 in maturation and function of T cells. Hence, we will investigate the antigen presentation to immune cells and the link between tumour cells, cytokines production and B and T-cells stimulation.
The role of ADAM28 derived from tumour cell as a pro-tumour factor is widely described in the literature. However, our results demonstrate an anti-tumour function of ADAM28 expressed in tumour microenvironment suggesting a dual role of ADAM28, depending on the origin of the protease. More investigations are required to explain this contradictory effect before drawing further conclusions.
