BBB seminar: Taina Pihlajaniemi
Cell-matrix dialogue involving evolutionarily conserved collagens and endostatin
Department of Medical Biochemistry and Molecular Biology, University of Oulu, Finland
The extracellular matrix (ECM) plays a crucial role in controlling cell differentiation and function in multicellular animals. Cells receive survival and positional information from the ECM and it is now evident that ECM biology permeates all aspects of cellular function. Collagens, constituting the most abundant of the families of ECM proteins, play a dominant structural role in maintaining the integrity of tissues. However, compelling evidence shows that collagens can also serve as a reservoir for growth factors and modulate cell signalling critical for tissue morphogenesis and homeostasis. The crucial functions of collagens are clearly illustrated by a wide spectrum of inherited and sporadic diseases found in humans. Collagens XV and XVIII are structurally related basement membrane-associated proteoglycans, their highest degree of homology involving the C-terminal endostatin domain, which is able to inhibit angiogenesis and endothelial cell proliferation. Collagen XVIII contains additionally a cysteine-rich frizzled (Fz) domain, which may be involved in Wnt signalling and inhibition of tolloid proteinases.
Our recent work indicates that the endostatin collagens have much more complex developmental and physiological roles than understood until now. These collagens occur in tissues in association with most basement membranes (BMs). We have proposed a model for collagen XVIII in the tightening of BMs. Moreover, our data suggest that collagen XV is needed in the structural integrity of the BM-fibrillar matrix interphase.
Endostatin is one of the strongest known inhibitors of angiogenesis and tumour growth in experimental models, while little is known about the roles of its collagen XV homologue restin and the precursor collagens in these processes. Most studies on the antiangiogenic and antitumour effects of endostatin have used implanted tumours in mice and substantial doses of recombinant endostatin. In the light of the possible tumour suppressor role of collagen XV, we have analysed the growth of various transplantable tumours as well as tumour neovascularisation in Col15a1 -/- and Col18a1 -/- mice and in mice lacking both collagens that show compound effects at least in the eye. Injected tumour cells typically produce endogenous collagens XV and XVIII. This hampers the analysis of the lack of these collagens on tumour growth. We therefore believe that chemical carcinogenesis models provide better possibilities for evaluating the roles of collagens XV and XVIII in malignant processes. We have recently set up a 7,12-dimethyl-benz( a )anthracene-12- O -tetradecanoylphorbol-13-acetate-based protocol for the development of carcinogen-induced skin tumours and tumour angiogenesis using as the first model a mouse line overexpressing endostatin in their epidermal basal cells. Results from these experiments will be discussed
Host: Helge Wiig, Department of Biomedicine