ADAMTS1 activity in the tumour microenvironment and the vascular niche: Focusing on substrates

Abstract

Past and recent studies have shown the importance of the extracellular scenario and its dynamism. The complexity itself and the response to different stimuli denotes the importance in processes as development, angiogenesis (creation of new blood-vessels from pre-existing ones), tissue regeneration, wound healing and tumour development among many others. Within the extracellular matrix (ECM), proteases are important components due to their processing and restructuration roles, thus, facilitating cell migration. Our main focus is a protease named ADAMTS1 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs 1), the first described member of this family of proteases. Its roles linked with angiogenesis are very well known but some other functions related to tumour biology still unclear.

The remodelling of the ECM by proteases has been subject of numerous studies for a long time, however major efforts are still required. Since the discovery of the cleavage by ADAMTS1 of nidogens, components of the ECM, our team has undertaken a main focus on the comprehension of the biological importance of this event.

The thesis project is concerned about the putative role of nidogen 1 and nidogen 2 in the development of tumour neo-vasculature. We have been able to detect relevant changes in both nidogen molecules in vessels of a variety of tumour models in an Adamts1- dependent manner. We observed an increased deposition of NIDOGEN 1 in tumour vessels of the Adamts1 knockout mice in comparison with wild-type animals. In some cases, such increase correlated with a delayed tumour progression and impaired vasculature. The overexpression of Nidogen 1 and Nidogen 2 in one of these tumour models (B16F1 mouse melanoma) revealed an altered capillary-like structure formation in-vitro. These results confirmed that nidogen 1, but not nidogen 2, is affecting to the development of the vascular network in this mouse melanoma model, in a similar manner as observed in the Adamts1 null mouse model. Importantly, the tumour vasculature was affected by the overexpression of both Nidogens but only in the Adamts1 null mouse tumours. Interestingly the overexpression of Nidogen 1 but not Nidogen 2 is accompanied by an increased in hypoxic tumour areas, standing the functionality of the tumour vasculature. Furthermore, the increase of both Nidogens within the vascular ECM enhances the deposition of COLLAGEN IV, thus, changing the composition of the tumour vessels.

Furthermore, the study of the Adamts1 null mouse exhibited that NIDOGEN 1 deposition is also altered in the vasculature of relevant organs such as kidney and spleen. Other significant substrates, like VERSICAN, have also been evaluated in these and other organs. While kidney and ovary were already reported to be altered in these mice, our findings in the spleen were unexpected. Hence, our latest studies are revealing a surprising implication of immune cell populations in relation with the decreased tumour growth that occurs in the absence of ADAMTS1. The Adamts1 mouse model creates a more prone immunosuppressive environment in which, tumour cells from two different models (B16F1 mouse melanoma and Lewis lung carcinoma, LLC) display different tumour developing capacities, directly correlated with the different tumour infiltration in regard to the Adamts1 background.