Molecular mediators of skeletal metastasis from prostate cancer

Qingxin Liu

doi:10.17918/00009767

Skeletal metastasis caused by prostate adenocarcinoma is the major cause of morbidity and mortality associated with this form of tumor. It is widely accepted that prostate cancer cells colonize the skeleton and progress into macroscopic tumors only if their phenotype is compatible with the bone microenvironment in which they first lodge. Thus, malignant cells with the highest propensity to develop into clinically overt metastases depend largely on their ability to mobilize stromal cells and utilize factors within the newly invaded microenvironment. For this to occur, prostate cancer cells must be able to express specific genes and encoded proteins to mediate the interaction with stromal cells to maintain the growth and survival in the bone. Previous evidence has demonstrated that bone-metastatic potential of prostate cancer cells is correlated with the level of platelet-derived growth factor receptor a (PDGFR[alpha]) expression. In our pre-clinical animal model, which allows the identification of disseminated cancer cells, from their arrival to the skeleton via the hematogenous route to the successive stages of growth into macroscopic bone lesions. Targeting PDGFR[alpha] signaling in human prostate cancer cells using a monoclonal antibody against PDGFR[alpha] in vivo reduced skeletal metastases By employing the same pre-clinical animal model, the research presented here sought to determine the temporal effects of PDGFR[alpha] during the metastatic process. The expression of PDGFR[alpha] under control of a doxycycline inducible vector was introduced in low-bone metastatic prostate cancer cells and their bone metastatic potential in vivo was assessed. In these experiments, it was discovered that the expression of PDGFR[alpha] was essential for maintaining survival of disseminated cancer cells. Furthermore, by using mutational analysis of PDGFR[alpha], it was shown that kinase activity was required for its pro-metastatic effects. In light of the previous findings, the next experiments presented in this dissertation were devoted to identification of bone-metastatic genes and their encoded products that would be responsible for bone tropism of prostate cancer cells. In theses experiments, several human prostate cancer cell lines were subjected to microarray gene-expression analysis. Among these cell lines, some express high levels of PDGFR[alpha] and develop into large, lethal metastases in mice, and others, after reaching the bone, either remain at a disseminated tumor cell stage or produce small foci that eventually fail to survive. The microarray results showed that expression of PDGFR[alpha] in selected human bone metastatic prostate cancer cells up-regulated a set of seven genes and confers bone- metastatic potential. By performing further comparative genomic analyses and validation of malignant phenotypes in vivo, final analysis showed that Interleukin-1 r3, Chemokine C-X-C ligand 6 (CXCL6), and peptidase inhibitor 3 (PI3) were uniformly upregulated in all PDGFR[alpha]-dependent bone metastatic cells. Among these genes, the pro-metastatic function of IL-1[beta] is the focus of this dissertation. It was found that the levels of IL-1[beta] expression in prostate cancer cells positively influence their bone metastatic potential in our pre-clinical animal model. This pro-metastatic function of IL-1[beta] may be a consequence of its ability to up-regulate cyclooxygenase-2 (COX-2) expression in bone marrow mesenchymal stem cells, which would reciprocate with growth factors and secretion of other cytokines which make the marrow with more hospitable to DTCs. This notion is supported by the results of in vivo cell-cooperation experiments in which cells that lack independent bone metastatic behavior were capable of forming skeletal metastases when co-injected with bone metastatic prostate cancer cells. In conclusion, these findings strongly implicate PDGFR[alpha]-regulated gene products (e.g. IL-1[beta] in the bone tropism of prostate cancer. This growing body of evidence provides molecular targets for curative therapies directed against metastatic prostate cancer, which is currently an incurable disease.

Molecular mediators of skeletal metastasis from prostate cancer

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Molecular mediators of skeletal metastasis from prostate cancer

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