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Mechanisms of bone metastasis in prostate cancer: clinical implications

https://doi.org/10.1016/j.beem.2008.01.011Get rights and content

Prostate cancer shows a strong predilection to spread to the bones. Once prostate tumour cells are engrafted in the skeleton, curative therapy is no longer possible and palliative treatment becomes the only option. Herein, we review the multifactorial mechanisms and complex cellular interactions that take place inside the bone metastatic microenvironment. Emphasis is given to the detection and treatment of the micrometastatic stage of prostate cancer, as well as our recent attempts to target the bone metastasis microenvironment-related survival factors using an anti-survival factor manipulation which can increase the efficacy of anticancer therapies such as androgen ablation therapy and chemotherapy in advanced prostate cancer.

Section snippets

Systematic spread of the tumour cells: the dynamic journey to the bones

The development of bone metastasis is a multi-step process consisting of the following sequence of events: (1) tumour growth, detachment of cancer cells, and invasion of the prostate stroma; (2) neoangiogenesis; (3) escape from the prostate by intravasation; (4) survival in the circulation; (5) chemoattraction and arrest (docking and locking) in the bone marrow endothelial vessel wall; (6) extravasation; and (7) establishment of the metastatic microenvironment (osteoblastic metastasis) via the

Colonizing the bone: the orchestration of an osteoclastic bone resorption

The osseous tissue is composed of two biologically distinct structures: the dense, mineralized cortical or compact bone (approximately 85% of the total bone mass) and the spongy, more metabolically active cancellous or trabecular bone (approximately 15% of the total bone mass) which makes up the bulk of the interior of most bones, including the vertebral bodies and pelvis. The external layer of the trabecular bone contains the multicellular red bone marrow, where the production of osteoblasts

Sheltering inside the bone marrow: domination of the osteoblastic lesions

The bone matrix and its cellular constituents (i.e. osteoblast-like cells; osteocytes and lining cells) are major direct or indirect sources of growth factors such as insulin-like growth factor 1 (IGF-1), TGF-β1, bone morphogenic proteins (BMPs), basic fibroblast growth factor (bFGF), IL-6, endothelin-1 (ET-1) and PTHrP that are also produced by metastatic prostate cancer cells and act as survival factors on prostate cancer cells.43, 44, 45, 46 These mitogens are both autocrine/paracrine

Arresting bone metastasis in its tracks: detection and treatment of the micrometastatic stage of prostate cancer

The use of prostate-specific antigen (PSA) as a pre-screening test has contributed to earlier detection of prostate cancer.52, 53 Patients that initially present with localized cancer (confined to the prostate gland) can be treated by potentially curative therapies such as radical prostatectomy or radiation therapy (either external-beam radiotherapy or sealed-source radiotherapy, also known as brachytherapy). Although the majority of patients present with clinically localized disease, a

Targeting bone metastasis microenvironment survival factors: the development of anti-survival factor manipulation

Following the micrometastatic phase, the tumour establishes permanent and fruitful cell–cell interactions with local bone cells (i.e. osteocytes, osteoblasts, osteoclasts). This is the process that transforms the micrometastatic loci to an eventual site of clinically evident metastasis (macrometastasis stage) (Figure 2). As described above, factors secreted in the local bone microenvironment support the metastatic prostate cancer cells to escape apoptosis and to optimize their survival. This

Summary

Prostate cancer exhibits a strong preference to form metastatic lesions in the bone marrow. Once bone metastasis is established, the cancer can no longer be cured and the only currently available options are palliative treatments that may improve survival and quality of life. The metastatic process is selective for cells that have survived the dynamic journey to the bone. Those cells that survive will extravasate into the bone marrow and produce osseous lesions. The prostate cancer cells usurp

Acknowledgements

Space limitations preclude the present article from being a comprehensive review, and this unfortunately limits appropriate recognition of many colleagues worldwide who have contributed immeasurably to the development of this field, as well as the numerous new drugs and therapeutic modalities that are currently under research and development.

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