Tumor-bone cellular interactions in skeletal metastases

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50 Citations (Scopus)

Abstract

Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reliably cause bone metastases, reproducing many of the clinical features seen in patients. Animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors. Local interactions stimulated by these factors drive a vicious cycle between tumor and bone that perpetuates skeletal metastases. Bone metastases can be osteolytic, osteoblastic, or mixed. Parathyroid hormone-related protein, PTHrP, is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1, ET-1. Other potential osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, stanniocalcin, N-terminal fragments of PTHrP, and adrenomedullin. Osteoblasts are the main regulators of osteoclasts, and stimulation of osteoblast proliferation can increase osteoclast formation and activity. Thus, combined expression of osteoblastic and osteolytic factors can lead to mixed metastases or to increased osteolysis. Prostate-specific antigen is a protease, which can cleave PTHrP and thus change the balance of osteolytic versus osteoblastic responses to metastatic tumor cells. Bone itself stimulates tumor by releasing insulin-like growth factors and transforming growth factor-β. Secreted 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-resorptive drugs reduce the release of active factors stored in bone, and PTHrP-neutralizing antibody, inhibitors of the RANK ligand pathway, and ET-1 receptor antagonist are in clinical trials. These adjuvant therapies act on bone cells, rather than the tumor cells. Recent gene array experiments identify additional factors, which may in the future prove to be clinically important targets.

Original languageEnglish (US)
Pages (from-to)308-318
Number of pages11
JournalJournal of Musculoskeletal Neuronal Interactions
Volume4
Issue number3
StatePublished - Sep 2004
Externally publishedYes

Fingerprint

Parathyroid Hormone-Related Protein
Neoplasm Metastasis
Bone and Bones
Neoplasms
Osteoclasts
Osteoblasts
Interleukin-11
RANK Ligand
Connective Tissue Growth Factor
Adrenomedullin
Bone Morphogenetic Proteins
Osteolysis
Platelet-Derived Growth Factor
Diphosphonates
Transforming Growth Factors
Endothelin-1
Somatomedins
Prostate-Specific Antigen
Neutralizing Antibodies
Interleukin-8

Keywords

  • Adrenomedullin
  • Bone metastasis
  • Breast
  • Cancer
  • Endothelin
  • Parathyroid hormone-related protein
  • Prostate
  • Prostate-specific antigen
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Neuroscience(all)
  • Endocrinology

Cite this

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title = "Tumor-bone cellular interactions in skeletal metastases",
abstract = "Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reliably cause bone metastases, reproducing many of the clinical features seen in patients. Animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors. Local interactions stimulated by these factors drive a vicious cycle between tumor and bone that perpetuates skeletal metastases. Bone metastases can be osteolytic, osteoblastic, or mixed. Parathyroid hormone-related protein, PTHrP, is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1, ET-1. Other potential osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, stanniocalcin, N-terminal fragments of PTHrP, and adrenomedullin. Osteoblasts are the main regulators of osteoclasts, and stimulation of osteoblast proliferation can increase osteoclast formation and activity. Thus, combined expression of osteoblastic and osteolytic factors can lead to mixed metastases or to increased osteolysis. Prostate-specific antigen is a protease, which can cleave PTHrP and thus change the balance of osteolytic versus osteoblastic responses to metastatic tumor cells. Bone itself stimulates tumor by releasing insulin-like growth factors and transforming growth factor-β. Secreted 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-resorptive drugs reduce the release of active factors stored in bone, and PTHrP-neutralizing antibody, inhibitors of the RANK ligand pathway, and ET-1 receptor antagonist are in clinical trials. These adjuvant therapies act on bone cells, rather than the tumor cells. Recent gene array experiments identify additional factors, which may in the future prove to be clinically important targets.",
keywords = "Adrenomedullin, Bone metastasis, Breast, Cancer, Endothelin, Parathyroid hormone-related protein, Prostate, Prostate-specific antigen, Transforming growth factor-β",
author = "John Chirgwin and Khalid Mohammad and Theresa Guise",
year = "2004",
month = "9",
language = "English (US)",
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pages = "308--318",
journal = "Journal of Musculoskeletal Neuronal Interactions",
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AU - Chirgwin, John

AU - Mohammad, Khalid

AU - Guise, Theresa

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N2 - Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reliably cause bone metastases, reproducing many of the clinical features seen in patients. Animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors. Local interactions stimulated by these factors drive a vicious cycle between tumor and bone that perpetuates skeletal metastases. Bone metastases can be osteolytic, osteoblastic, or mixed. Parathyroid hormone-related protein, PTHrP, is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1, ET-1. Other potential osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, stanniocalcin, N-terminal fragments of PTHrP, and adrenomedullin. Osteoblasts are the main regulators of osteoclasts, and stimulation of osteoblast proliferation can increase osteoclast formation and activity. Thus, combined expression of osteoblastic and osteolytic factors can lead to mixed metastases or to increased osteolysis. Prostate-specific antigen is a protease, which can cleave PTHrP and thus change the balance of osteolytic versus osteoblastic responses to metastatic tumor cells. Bone itself stimulates tumor by releasing insulin-like growth factors and transforming growth factor-β. Secreted 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-resorptive drugs reduce the release of active factors stored in bone, and PTHrP-neutralizing antibody, inhibitors of the RANK ligand pathway, and ET-1 receptor antagonist are in clinical trials. These adjuvant therapies act on bone cells, rather than the tumor cells. Recent gene array experiments identify additional factors, which may in the future prove to be clinically important targets.

AB - Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reliably cause bone metastases, reproducing many of the clinical features seen in patients. Animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors. Local interactions stimulated by these factors drive a vicious cycle between tumor and bone that perpetuates skeletal metastases. Bone metastases can be osteolytic, osteoblastic, or mixed. Parathyroid hormone-related protein, PTHrP, is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1, ET-1. Other potential osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, stanniocalcin, N-terminal fragments of PTHrP, and adrenomedullin. Osteoblasts are the main regulators of osteoclasts, and stimulation of osteoblast proliferation can increase osteoclast formation and activity. Thus, combined expression of osteoblastic and osteolytic factors can lead to mixed metastases or to increased osteolysis. Prostate-specific antigen is a protease, which can cleave PTHrP and thus change the balance of osteolytic versus osteoblastic responses to metastatic tumor cells. Bone itself stimulates tumor by releasing insulin-like growth factors and transforming growth factor-β. Secreted 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-resorptive drugs reduce the release of active factors stored in bone, and PTHrP-neutralizing antibody, inhibitors of the RANK ligand pathway, and ET-1 receptor antagonist are in clinical trials. These adjuvant therapies act on bone cells, rather than the tumor cells. Recent gene array experiments identify additional factors, which may in the future prove to be clinically important targets.

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KW - Prostate-specific antigen

KW - Transforming growth factor-β

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