Molecular mechanisms of cancer metastases to bone

John M. Chirgwin, Theresa A. Guise

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations

Abstract

Purpose of review: Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reproducibly cause bone metastases resembling those seen in patients with cancers of the breast or prostate. These animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors, which alter the phenotype of the metastatic tumor cells. Local tumor-bone interactions mediated by these factors drive a vicious cycle that perpetuates skeletal metastases. Recent findings: Bone metastases can be osteolytic or osteoblastic, and animal models have defined some of the factors responsible for each type. Parathyroid hormone-related protein is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Recent data demonstrate that osteoblastic metastases can be caused by tumor-secreted endothelin-1. Other candidate osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, and adrenomedullin. In turn, bone can stimulate tumor cells by releasing insulin-like growth factors and transforming growth factor-β. Summary: These various factors transmit the interactions between tumor and bone. They provide novel targets for therapeutic interactions to break the vicious cycle of bone metastases. Clinically approved bisphosphonate anti-resorptives reduce the release of active factors stored in bone. An antibody, which neutralizes parathyroid hormone-related protein, and an endothelin-1 receptor antagonist are in clinical trials. These adjuvant therapies act on bone cells, rather than on the tumor cells. Recent gene array experiments identify additional factors, which may be clinically important targets in the future.

Original languageEnglish (US)
Pages (from-to)317-321
Number of pages5
JournalCurrent Opinion in Orthopaedics
Volume14
Issue number5
DOIs
StatePublished - Oct 1 2003
Externally publishedYes

Keywords

  • Adrenomedullin
  • Bisphosphonate
  • Breast cancer
  • Endothelin-1
  • Osteoblastic metastasis
  • Osteolytic metastasis
  • Osteoprotegerin
  • Parathyroid hormone-related protein
  • Prostate cancer
  • RANK ligand

ASJC Scopus subject areas

  • Surgery

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