INTEBLOCK · Blocking a6 integrin cleavage as a therapeutic target for prostate cancer bone metastases
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-04-01 → 2008-03-31
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
Prostate cancer affects people all over the world. The most frequent site of prostate cancer metastasis is the bone and once it has metastasised it is incurable and extremely painful. The goal of this proposal is to develop new therapeutic tools for palliative care for bone metastases. Our model states that the high levels of uPA in the bone induce cleavage of the a6 integrin in prostate cancer cells, leading to the activation of other integrins (such as a2, a3 and av) to allow for migration and homing on the bone matrix. In this proposal, we will investigate whether the a6 integrin cleavage by uPA controls cell adhesion by integrins other than the a6 integrin, a process referred to as integrin switching".In addition, we will investigate whether the a6 integrin cleavage by uPA controls migration through focal adhesion signalling. First, we will test the hypothesis that blocking the cleavage of the a6 integrin will reduce osteoblast conditioned media (OBCM) induced adhesion of prostate cancer cells on b one matrix. We will test this by using a peptide and an antibody designed to prevent a6 integrin cleavage and we will also perform transfections of an uncleavable a6 integrin mutant in the PC3 prostate cancer cell line. We will evaluate changes in adhesio n on different substrates (collagen, vitronectin and osteopontin) using cell adhesion assays. Second, we will test the hypothesis that blocking the cleavage (using a peptide, an antibody and transfections) of the a6 integrin will reduce the phosphorylation levels of FAK, Pax and p130CAS upon OBCM stimulation.Third, using the peptide, the antibody and the transfections in the PC3 cell line, we will investigate the role of the a6 integrin cleavage by uPA in cell migration and invasion upon OBCM stimulation . Migration will be measured using the Cell Sedimentation Manifold (CSM), and the scratch assay, and invasion using the Boyden chamber method."
Original text from CORDIS.
Participants
- UNIVERISTY OF CYPRUS · NICOSIACoordinatorCity levelCyprus
Links
Data: CORDIS, © European Union