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Translational models of prostate cancer bone metastasis

Nature Reviews Urology volume 15, pages 403–421 (2018)Cite this article

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Abstract

Metastatic disease is the principal cause of prostate-cancer-related mortality. Our ability to accurately recapitulate the spread of prostate cancer to bone — the most common site of metastasis — is critical to the development of novel metastasis-directed therapies. Several translational models of prostate cancer bone metastasis have been developed, including animal models, cell line injection models, 3D in vitro models, bone implant models, and patient-derived xenograft models. The use of these models has led to numerous advances in elucidating the molecular mechanisms of metastasis and innovations in targeted therapy. Despite this progress, current models are limited by a failure to holistically reproduce each individual element of the metastatic cascade in prostate cancer bone metastasis. In addition, factors such as accurate recapitulation of immunobiological events and improvements in tumour heterogeneity require further consideration. Knowledge gained from historical and currently used models will improve the development of next-generation models. An introspective appraisal of current preclinical models demonstrating bone metastases is warranted to narrow research focus, improve future translational modelling, and expedite the delivery of urgently needed metastasis-directed treatments.

Key points

  • The development of novel metastasis-directed prostate cancer therapies is highly reliant on our ability to accurately reproduce the underlying mechanisms in vivo.

  • Existing models frequently employ a modular approach towards recapitulating particular aspects of disease progression.

  • Each model possesses specific advantages and limitations that are important to experimental design and outcomes.

  • Several valuable molecular and therapeutic advances have been made, despite the potential limitations of current models.

  • The aims of next-generation models should be to improve tumour heterogeneity and enable the study of disease immunobiology.

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Fig. 1: The journey of a cancer cell to bone and interactions within the bone microenvironment.
Fig. 2: The vicious cycle of bone metastasis.

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Acknowledgements

The authors’ research work was supported by the Prostate Cancer Canada's Rising Star Research Grant to H.S.L.

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Author notes

  1. These authors contributed equally: Richard B. Berish, Aymon N. Ali.

Authors and Affiliations

  1. Department of Surgery, Division of Urology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

    Richard B. Berish, Aymon N. Ali, Patrick G. Telmer & Hon S. Leong

  2. Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

    Richard B. Berish, John A. Ronald & Hon S. Leong

  3. Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

    John A. Ronald

  4. Department of Urology, Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA

    Hon S. Leong

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All authors researched data for the article, wrote the manuscript, made substantial contributions to discussions of content, and edited the manuscript before submission.

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Glossary

Intravasation

The migration of a cancer cell into a blood or lymphatic vessel from its primary site or the surrounding tissue.

Extravasation

The migration of a cancer cell out of the vasculature into a secondary site, typically bone for prostate cancer.

Metastatic cascade

The series of events describing the progression of cancer from a primary site to distant metastasis.

Cell lines

Populations of cells originally derived from living tissue but adapted to be grown in vitro indefinitely.

Patient-derived xenograft

(PDX). Tumour line derived from patient tissue that is usually maintained in vivo and retains natural tumour heterogeneity.

Epithelial-to-mesenchymal transition

(EMT). The evolution of a cancer cell into an invasive phenotype before metastasizing; often characterized based on the changes to cytoskeletal and adhesion proteins.

Dormancy

The ability of a cancer cell to remain in a latent, inactive state before the production of overt metastases.

Perivascular niche

A microenvironmental target adjacent to blood vessels that supports the long-term survival of specific cell types, including stem or progenitor cells.

Osteolytic lesions

Lesions characterized by the demineralization and destruction of bone.

Lateral tail vein

A commonly used vein on the lateral aspect of rodent tails used for the systematic inoculation of cancer cells; often produces lung metastases.

Intracardiac injections

Systematic inoculations of cancer cells by injection into the left ventricle of the heart; often used to initiate bone metastasis.

Osteoblastic lesions

Lesions characterized by the formation of mechanically weak woven bone.

Mouse prostate reconstitution

A model of prostate cancer involving the generation of a cancerous reconstituted prostate from fetal urogenital sinus tissue.

Subrenal capsule

A region surrounding the kidney where cells can be engrafted for the study of primary tumours; offers high take rate owing to high regional vascularity.

Orthotopic

A region where cells can be engrafted primarily for the study of primary tumours or local invasion; defined as being the region where the cell normally belongs, such as the prostate.

Tumour heterogeneity

A characteristic of tumours that are derived from more than one clonally expanded cell, giving them mixed populations of phenotypically different cells.

Transgenic mouse models

Spontaneous disease models generated by modifying expression of specific genes.

Bone implant models

Models that are often humanized disease models in which foreign mouse, human, or engineered bone tissue is engrafted subcutaneously into recipient mice.

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Berish, R.B., Ali, A.N., Telmer, P.G. et al. Translational models of prostate cancer bone metastasis. Nat Rev Urol 15, 403–421 (2018). https://doi.org/10.1038/s41585-018-0020-2

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