Prostate cancer, with an estimated 1.3 million new cases and 360,000 deaths every year, affects elderly men worldwide. Prostate cancer can either develop slowly without symptoms or aggressively by quickly disseminating the disease. To move, cancer cells need to adhere to the extracellular matrix (ECM) and this is crucial for the development of metastases. Prostate cancer cells metastasize mainly to nearby organs and to the bones, where the tissue microenvironment is mainly built by collagens. The stem cell-like cells in prostate cancer are known to express high levels of integrin α2β1, a collagen receptor. Here we studied the role of integrin α2β1 in the motility, survival and signaling of prostate cancer cells. In addition, we analyzed the ECM in the prostate and also the matrix produced by prostate-derived primary fibroblasts in vitro using mass spectrometry and proteomics.

This thesis consists of work published in two separate articles and one manuscript. The first part focuses on the role of integrin α2β1 in prostate cancer cells. In the study DU145 cells were treated with the cytotoxic drug docetaxel and analyzed by flow cytometry. Cell sorting, genome editing with CRISPR/ Cas9 and RNA sequencing were also used. In addition, 3D cell culture, migration and invasion assays were used throughout the study. The second part of this thesis focuses on the ECM of the human prostate. Surgically removed prostates were used to extract ECM proteins, which were analyzed by mass spectrometry to studythe molecular composition of the matrix. Prostate tissue was also used to isolate primary fibroblasts. The fibroblasts were propagated in cell culture to study their influence on DU145 and PC3 prostate cancer cells in vitro. Using this approach we were able to study the ECM produced solely by fibroblasts or in co-culture with cancer cells. We also investigated further the effect of fibroblasts and the ECM on cancer cell motility and observed that fibroblasts induce DU145 cancer cell invasive capability and in co-culture enhance ECM synthesis and its active remodeling.

In conclusion, this thesis showed that α2β1 integrin is essential for cancer cell dissemination. In addition integrin α2β1 downregulates the proliferation of prostate cancer cells and due to this selection pressure favors the α2β1low/negative daughter cells of the stem cell like cells. The ECM is synthesized mainly by fibroblasts and the active rearrangement of the ECM is regulated by fibroblast-cancer cell crosstalk.