Molecular mechanisms of tumor-bone interactions in osteolytic metastases

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Abstract

In patients with advanced disease, several cancer types frequently metastasize to the skeleton, where they cause bone destruction. Osteolytic metastases are incurable and cause pain, hypercalcemia, fracture, and nerve compression syndromes. It was proposed over a century ago that certain cancers, such as that of the breast, preferentially metastasize to the favorable microenvironment provided by bone. Bone matrix is a rich store of immobilized growth factors that are released during bone resorption. Histological analysis of osteolytic bone metastases indicates that the bone destruction is mediated by the osteoclast rather than directly by the tumor cells. These observations suggest a vicious cycle driving the formation of osteolytic metastases: tumor cells secrete factors stimulating osteoclasts through adjacent bone marrow stromal cells; osteoclastic resorption in turn releases growth factors from the bone matrix; finally, locally released growth factors activate the tumor cells. This vicious cycle model has now been confirmed at the molecular level. In particular, transforming growth factor β (TGFβ) is abundant in bone matrix and released as a consequence of osteoclastic bone resorption. Bone-derived TGFβ plays an integral role in promoting the development and progression of osteolytic bone metastases by inducing tumor production of parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption. In breast cancer cells TGFβ appears to stimulate PTHrP secretion by a posttranscriptional mechanism through both Smad and p38 mitogen activated protein (MAP) kinase signaling pathways. Osteolytic metastases can be suppressed in vivo by inhibition of bone resorption, blockade of TGFβ signaling in tumor cells, and by neutralization of PTHrP. Other factors released from bone matrix may also act on tumor cells in bone, which in turn may produce other factors that stimulate bone resorption, following the vicious cycle paradigm established for TGFβ and PTHrP. An understanding at the molecular level of the mechanisms of osteolytic metastasis will result in more effective therapies for this devastating complication of cancer.

Original languageEnglish (US)
Pages (from-to)159-178
Number of pages20
JournalCritical Reviews in Eukaryotic Gene Expression
Volume10
Issue number2
StatePublished - Nov 23 2000

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Keywords

  • Bone metastasis
  • Breast cancer
  • Osteolysis
  • PTHrP
  • TGF-β

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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