Abstract
Simple SummaryProstate cancer (PCa) is the most prevalent cancer in males worldwide, and it was the fifth leading cause of cancer mortality in this group in 2020. Near 70% of advanced-stage PCa patients will undergo bone metastasis, suffering pathological complications that severely affect patients’ quality of life and probably progress in most cases to lethal PCa. Our main objective was to unveil novel molecules associated with choosing the bone as a metastatic niche. For this purpose, we generated and characterized a cell line with increased tropism to bone. Its molecular analysis has led us to identify factors with a potential role in bone metastasis that could also be used as biomarkers of disease progression. These data help us to understand the mechanisms that increase bone metastasis penetrance of PCa cells and could provide new therapeutic tools in the future for patients with worse prognoses.About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients’ quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells’ migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b’s role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa.
Highlights
Bone metastasis is a common complication of cancer and occurs in around 70% of patients with metastatic prostate cancer (PCa), PCa being the second-most commonly diagnosed cancer in men in the western world [1]
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Having in mind the “seed and soil” hypothesis described by Paget, which explained why certain cancers favored developing metastasis in specific organs [56,57], understanding the distinct organ-specific mechanisms that enable metastatic growth is of crucial importance
Summary
Bone metastasis is a common complication of cancer and occurs in around 70% of patients with metastatic prostate cancer (PCa), PCa being the second-most commonly diagnosed cancer in men in the western world [1]. ADT is only temporarily effective in most cases; PCa gradually acquires resistance to androgen deprivation and eventually becomes castration-resistant PCa (CRPC), which is often associated with tumor dissemination [2]. This type of cancer is frequently multifocal, and it is associated with a higher grade, stage, and recurrence rate [3]. Clonal selection strategies based on preclinical models that faithfully reproduce some stages of bone metastasis have been developed [6,7] These models provide us with useful tools to better understand the molecular basis underlying the orchestration of bone metastasis from initiation to development of distant dissemination and lead us to engineer solutions to improve outcomes for PCa patients
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