Abstract
Bone metastasis is the major deleterious event in prostate cancer (PCa). TMPRSS2-ERG fusion is one of the most common chromosomic rearrangements in PCa. However, its implication in bone metastasis development is still unclear. Since bone metastasis starts with the tropism of cancer cells to bone through specific migratory and invasive processes involving osteomimetic capabilities, it is crucial to better our understanding of the influence of TMPRSS2-ERG expression in the mechanisms underlying the bone tropism properties of PCa cells. We developed bioluminescent cell lines expressing the TMPRSS2-ERG fusion in order to assess its role in tumor growth and bone metastasis appearance in a mouse model. First, we showed that the TMPRSS2-ERG fusion increases cell migration and subcutaneous tumor size. Second, using intracardiac injection experiments in mice, we showed that the expression of TMPRSS2-ERG fusion increases the number of metastases in bone. Moreover, TMPRSS2-ERG affects the pattern of metastatic spread by increasing the incidence of tumors in hind limbs and spine, which are two of the most frequent sites of human PCa metastases. Finally, transcriptome analysis highlighted a series of genes regulated by the fusion and involved in the metastatic process. Altogether, our work indicates that TMPRSS2-ERG increases bone tropism of PCa cells and metastasis development.
Highlights
Prostate cancer (PCa) is one of the most commonly diagnosed disease and the second cause of cancerrelated deaths affecting men in Western world [1]
Since bone metastasis starts with the tropism of cancer cells to bone through specific migratory and invasive processes involving osteomimetic capabilities, it is crucial to better our understanding of the influence of TMPRSS2-ERG expression in the mechanisms underlying the bone tropism properties of prostate cancer (PCa) cells
In order to assess the role of TMPRSS2-ERG fusion in PCa development, we generated cell lines stably overexpressing the fusion using retroviral translocation from luciferase expressing cells PC3M-luc
Summary
Prostate cancer (PCa) is one of the most commonly diagnosed disease and the second cause of cancerrelated deaths affecting men in Western world [1]. Bone metastases affect more than 80% of advanced stage PCa patients and constitute the major injurious events [2] with severe pain, nerve compression and pathologic fracture. Metastatic prostate cancer cells acquire a bone celllike phenotype by a process called osteomimicry, which allows their survival and their proliferation in the bone marrow microenvironment [3, 4]. At this stage, the tightlycontrolled balance between osteoblastic bone formation and osteoclastic bone resorption is aberrantly modified, thereby altering bone metabolism [5,6,7]. A major challenge for PCa treatment is to identify factors controlling tumor growth and metastases
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