Investigation of the molecular and biophysical mechanisms of prostate cancer cell interactions with bone marrow-derived proteins and stem cells
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- Tez No: 402966
- Danışmanlar: DR. DENITSA DOCHEVA, DR. OLİVİER GİRES
- Tez Türü: Doktora
- Konular: Biyoloji, Biology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2016
- Dil: İngilizce
- Üniversite: Ludwig-Maximilians Universität München
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Biyoloji Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 101
Özet
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Özet (Çeviri)
Prostate cancer is one of the most commonly diagnosed cancer in males. At the early stages of cancer surgical and hormonal therapies can be useful applied. The principal problem arising from prostate cancer is its predisposition to metastasize. After some point they form hormone independent cells, which can also be highly invasive. This tendency arises from specific molecular mechanisms and interactions that together lead to metastatic invasion into bone. In order to investigate in detail on this topic, typical components of bone tissue were presented as substrates for two species of prostate carcinoma cell lines (PC3 and LNCaP). This study was conducted with a variety of complementary techniques to investigate cell adhesion. While PC3 cells turned out to instantly interact strongly with bone tissue, LNCaP cells interacted weak and in contrast to PC3 even refused proliferating in this environment. By quantitative PCR and real time PCR, β1-integrins were identified as key players for the interaction between PC3 cells and bone tissue. Therefore, a prostate cell immobilized to the force sensor was mechanically brought in a controlled short contact to a collagen type–I (Col-I) substrate or to a monolayer of a bone marrow derived mesenchymal stem cell line (SCP1). Then the cell was retracted while recording interaction forces. An antibody specifically blocking β1-integrins corroborated the hypothesis that β1-integrins play a major role in this interaction, but also showed that due to a high integrin turnover rate antibody treatment might not be the ultimate strategy to interfere with prostate carcinoma metastasis into the bone marrow. Similar findings characterized a treatment of SCP1 monolayers with collagenase. Even though all measured parameters resulting from the force measurements revealed an almost identical behavior of the PC3 cells probed on both surfaces Col-I and SCP1, the treatment with collagenase suggested the possibility of PC3 cells involving different mechanisms for the interaction to Col-I or to SCP1 respectively. Long-term assays up to days for PC3 and LNCaP adhesion, proliferation and spreading in co-culture with SCP1 uncovered a very similar picture for the cell interactions as the force measurements. AFM, furthermore, provided a direct measure of the cell elasticity (Youngs' modulus) and showed PC3 cells to be mechanically three times stiffer than LNCaP cells. Last during this project, a new evaluation method for force measurements was developed, that allowed to conclude on the connection of the adhesion molecules (integrins) to the intracellular cytoskeleton. From loading-rate vs. position probability density plots the anchorage of each individual detected unbinding event could be classified as rather membrane bound (tether) or cytoskeleton bound (jump). This method was clearly verified by treating the cells with Latrunculin-A a destructor of the actin filaments. For the interaction of prostate cell lines with bone tissue this evaluation method revealed not only that PC3 cells rather utilize cytoskeleton-supported receptors (filopodia) in contrast to LNCaP cells utilizing membrane bound receptors (tether) but also how blocking antibody treatment removed cytoskeleton-anchored receptors from participating in adhesion. Taken together, these findings might open a window for new applications to interfere with prostate carcinoma metastasis at the intracellular side of adhesion receptors by preventing cytoskeleton anchorage.
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