Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases

Su Young Kim, Chih Hung Lee, Brieanne V. Midura, Choh Yeung, Arnulfo Mendoza, Sung Hyeok Hong, Ling Ren, Donald Wong, Walter Korz, Ahmed Merzouk, Hassan Salari, Hong Zhang, Sam T. Hwang, Chand Khanna, Lee J. Helman

Research output: Contribution to journalArticle

Abstract

Metastasis continues to be the leading cause of mortality for patients with cancer. High expression of the chemokine receptor CXCR4 correlates with poor prognosis in many cancers, including osteosarcoma and melanoma. CXCL12, the ligand for CXCR4, is expressed at high levels in the lung and lymph node, which are the primary sites to which these tumors metastasize respectively. These findings suggest that therapy aimed at disruption of this specific receptor/ligand complex may lead to a decrease in metastases. CTCE-9908, a small peptide CXCR4 antagonist was utilized in two murine metastasis models to test this hypothesis. Treatment of osteosarcoma cells in vitro with CTCE-9908 led to the following changes: decreased adhesion, decreased migration, decreased invasion, and decreased growth rate. Following tail vein injection of osteosarcoma cells, mice that were treated with CTCE-9908 had a 50% reduction in the number of gross metastatic lung nodules and a marked decrease in micro-metastatic disease. Similar findings were observed following injection of melanoma cells and treatment with CTCE-9908. However, these results could only be consistently reproduced when the cells were pre-treated with the inhibitor. A novel ex vivo luciferase assay showed decreased numbers of cells in the lung immediately after injection into mice, when treated with CTCE-9908, suggesting the importance of interactions between the receptor and the ligand. Our findings show that inhibition of the CXCR4/CXCL12 pathway decreases metastatic disease in two murine tumor models and expands on previous reports to describe potential mechanisms of action.

Original languageEnglish (US)
Pages (from-to)201-211
Number of pages11
JournalClinical and Experimental Metastasis
Volume25
Issue number3
DOIs
StatePublished - May 2008
Externally publishedYes

Fingerprint

Chemokine CXCL12
Neoplasm Metastasis
Osteosarcoma
Lung
Ligands
Injections
Melanoma
Neoplasms
Chemokine Receptors
Luciferases
Action Potentials
Tail
Veins
Therapeutics
Cell Count
Lymph Nodes
CTCE-9908
Peptides
Mortality
Growth

Keywords

  • Chemokines
  • CXCR4 inhibition
  • Melanoma
  • Osteosarcoma
  • Pulmonary metastasis

ASJC Scopus subject areas

  • Cancer Research

Cite this

Kim, S. Y., Lee, C. H., Midura, B. V., Yeung, C., Mendoza, A., Hong, S. H., ... Helman, L. J. (2008). Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clinical and Experimental Metastasis, 25(3), 201-211. https://doi.org/10.1007/s10585-007-9133-3

Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. / Kim, Su Young; Lee, Chih Hung; Midura, Brieanne V.; Yeung, Choh; Mendoza, Arnulfo; Hong, Sung Hyeok; Ren, Ling; Wong, Donald; Korz, Walter; Merzouk, Ahmed; Salari, Hassan; Zhang, Hong; Hwang, Sam T.; Khanna, Chand; Helman, Lee J.

In: Clinical and Experimental Metastasis, Vol. 25, No. 3, 05.2008, p. 201-211.

Research output: Contribution to journalArticle

Kim, SY, Lee, CH, Midura, BV, Yeung, C, Mendoza, A, Hong, SH, Ren, L, Wong, D, Korz, W, Merzouk, A, Salari, H, Zhang, H, Hwang, ST, Khanna, C & Helman, LJ 2008, 'Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases', Clinical and Experimental Metastasis, vol. 25, no. 3, pp. 201-211. https://doi.org/10.1007/s10585-007-9133-3
Kim, Su Young ; Lee, Chih Hung ; Midura, Brieanne V. ; Yeung, Choh ; Mendoza, Arnulfo ; Hong, Sung Hyeok ; Ren, Ling ; Wong, Donald ; Korz, Walter ; Merzouk, Ahmed ; Salari, Hassan ; Zhang, Hong ; Hwang, Sam T. ; Khanna, Chand ; Helman, Lee J. / Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. In: Clinical and Experimental Metastasis. 2008 ; Vol. 25, No. 3. pp. 201-211.
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abstract = "Metastasis continues to be the leading cause of mortality for patients with cancer. High expression of the chemokine receptor CXCR4 correlates with poor prognosis in many cancers, including osteosarcoma and melanoma. CXCL12, the ligand for CXCR4, is expressed at high levels in the lung and lymph node, which are the primary sites to which these tumors metastasize respectively. These findings suggest that therapy aimed at disruption of this specific receptor/ligand complex may lead to a decrease in metastases. CTCE-9908, a small peptide CXCR4 antagonist was utilized in two murine metastasis models to test this hypothesis. Treatment of osteosarcoma cells in vitro with CTCE-9908 led to the following changes: decreased adhesion, decreased migration, decreased invasion, and decreased growth rate. Following tail vein injection of osteosarcoma cells, mice that were treated with CTCE-9908 had a 50{\%} reduction in the number of gross metastatic lung nodules and a marked decrease in micro-metastatic disease. Similar findings were observed following injection of melanoma cells and treatment with CTCE-9908. However, these results could only be consistently reproduced when the cells were pre-treated with the inhibitor. A novel ex vivo luciferase assay showed decreased numbers of cells in the lung immediately after injection into mice, when treated with CTCE-9908, suggesting the importance of interactions between the receptor and the ligand. Our findings show that inhibition of the CXCR4/CXCL12 pathway decreases metastatic disease in two murine tumor models and expands on previous reports to describe potential mechanisms of action.",
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