Studies of Mesenchymal Progenitor Cells and Tumour Growth, Integrins and Matrix Metalloproteinases

Sammanfattning: In this thesis we characterize the effect of mesenchymal progenitor cells (MPCs) on tumour growth, and show that MPCs can have inhibitory effects on tumour development. We developed a method to subcutaneously transplant tumour cells, cultured in vitro in a pre-formed gelatin matrix, that made it possible to study the early phases of tumour development. Using this method we inoculated rats with gelatine matrices containing MPCs mixed with colon carcinoma cells. We found that, in the presence of MPCs, the early tumour development was inhibited and we could demonstrate an altered pattern of infiltrating cells. This inhibitory effect was confirmed and further studied using intra-hepatic and retro-peritoneal co-injections of colon carcinoma cells and MPCs. Supporting this finding we demonstate, using a glioma tumour model, that subcutaneous or intra-cranial co-injections of MPCs and tumour cells, results in retarded tumour growth. Furthermore, we show an inhibitory effect from MPCs on the proliferation of both tumour cells and SEA stimulated lymphocytes in vitro. We also studied the interaction between the collagen-binding integrins ?10?1 and ?11?1 and the collagen degrading enzyme matrix metalloproteinase-13 (MMP-13). Using the ?10 and ?11 I-domains, as well as solubilised integrins we found that proMMP-13, but not proMMP-9, bound in a cation independent manner and that the binding was abrogated when the pro-enzyme was activated. We also found that pre-incubation of the ?10 and ?11 I-domains with a triple helical collagen peptide increased the capacity of the integrins to bind proMMP-13. Taken together, this implicates the collagen-binding integrins ?10?1 and ?11?1 as important targets in the control of MMP activity in pathological conditions such as tumour invasion and metastasis and cartilage degeneration in arthritic disease.