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Blocking a6 integrin cleavage as a therapeutic target for prostate cancer bone metastases

Final Activity Report Summary - INTEBLOCK (Blocking a6 integrin cleavage as a therapeutic target for prostate cancer bone metastases)

We have previously shown that the a6 integrin can be cleaved by uPA to produce a smaller form of the a6 integrin called a6p. This variant remains on the cell surface while the amino-terminal fragment of the a6 integrin (ligand binding region) remains in the extracellular matrix (a6N). The a6p integrin is present in prostate cancer tissue but not in normal prostate.

The work of this proposal had several goals. Our first goal was to develop the reagents necessary for the experiments. These reagents included the production of an integrin a6 cleavage blocking peptide and a blocking antibody, and also cells transfected with the uncleavable a6 integrin. Once we developed the necessary reagents we completed the objectives of the project which were to determine whether blocking the a6 integrin cleavage would inhibit integrin mediated adhesion, focal adhesion signalling and migration and invasion. Our results indicated that the a6 integrin cleavage is important during integrin mediated adhesion, FAK signalling, and migration and invasion.

While conducting our experiments, we established additional objectives which were to investigate whether the a6 integrin cleavage occurs during normal development and during carcinogenesis. Specifically, our studies aimed to determine the role of the a6 integrin cleavage during Xenopus development and also to investigate whether the a6 integrin is cleaved during mouse carcinogenesis. Our results showed that the a6 integrin cleavage is spatially and temporally regulated during Xenopus embryonic development, and also occurs at high levels during mouse skin carcinogenesis.

Overall, not only we have completed the objectives of our proposal, but we went much further to perform animal studies both in mice and Xenopus and also started experiments in bone cancer cell lines. Our work resulted in the publication of our results in scientific journals and the presentation of our work in scientific conferences. It also generated new lines of research which can help understand the process of carcinogenesis and help fight cancer. Also, new research tools have been generated which will be valuable for future experiments and they could also lead to the development of potential diagnostic and therapeutic tools.