Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells

Anne T. Mancino, Vicki Klimberg, Matsuo Yamamoto, Stavros C. Manolagas, Etsuko Abe

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Background. Breast cancer metastasis to bone causes resorption of the mineralized matrix by osteoclasts. Macrophage colony stimulating factor (M-CSF) and receptor activator of the NF-κB ligand (RANKL) are produced by stromal cells and are essential for osteoclast formation. The human breast cancer cell line, MDA-MB-231, reliably forms bone metastases in a murine model and stimulates osteoclast formation in culture. We hypothesized that MDA-MB-231 stimulates osteoclast formation through secretion of M-CSF and/or RANKL. Materials and methods. We cocultured MDA-MB-231 and a bone marrow derived cell line, UAMS-33, and evaluated the expression of M-CSF and RANKL mRNA. Osteoclast formation was assessed using these cells added to hematopoietic cell cultures. Results. MDA-MB-231 exhibited constitutive expression of M-CSF mRNA. As expected, addition of recombinant M-CSF (30 ng/ml) and RANKL (30 ng/ml) to hematopoietic osteoclast precursors supported osteoclast formation, while the addition of soluble RANKL alone or MDA-231 without added RANKL did not. Notably, coculture of MDA-231 with hematopoietic cells and added soluble RANKL stimulated significant osteoclast formation, indicating that MDA-231 served as an effective source for M-CSF. MDA-231 did not express RANKL. However, when cocultured with the murine bone marrow stromal cell line UAMS-33, RANKL expression was significantly increased in the latter cells. MDA-231 also stimulated osteoclast formation in coculture with UAMS-33 and hematopoietic cells. Conclusions. We conclude that MDA-MB-231 increases osteoclast formation by secreting adequate amounts of M-CSF protein and enhancing the expression of RANKL by stromal support cells. The ability to stimulate osteoclasts may explain the ability to metastasize to bone.

Original languageEnglish (US)
Pages (from-to)18-24
Number of pages7
JournalJournal of Surgical Research
Volume100
Issue number1
DOIs
StatePublished - 2001
Externally publishedYes

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Macrophage Colony-Stimulating Factor
Osteoclasts
Stromal Cells
Osteogenesis
Breast Neoplasms
Coculture Techniques
Cell Line
Macrophage Colony-Stimulating Factor Receptors
Neoplasm Metastasis
Bone and Bones
Messenger RNA
Bone Resorption
Mesenchymal Stromal Cells
Bone Marrow Cells
Cell Culture Techniques
Ligands

Keywords

  • Bone metastasis
  • Breast cancer
  • M-CSF
  • MDA-MB-231
  • Osteoclastogenesis
  • RANKL

ASJC Scopus subject areas

  • Surgery

Cite this

Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. / Mancino, Anne T.; Klimberg, Vicki; Yamamoto, Matsuo; Manolagas, Stavros C.; Abe, Etsuko.

In: Journal of Surgical Research, Vol. 100, No. 1, 2001, p. 18-24.

Research output: Contribution to journalArticle

Mancino, Anne T. ; Klimberg, Vicki ; Yamamoto, Matsuo ; Manolagas, Stavros C. ; Abe, Etsuko. / Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. In: Journal of Surgical Research. 2001 ; Vol. 100, No. 1. pp. 18-24.
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T1 - Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells

AU - Mancino, Anne T.

AU - Klimberg, Vicki

AU - Yamamoto, Matsuo

AU - Manolagas, Stavros C.

AU - Abe, Etsuko

PY - 2001

Y1 - 2001

N2 - Background. Breast cancer metastasis to bone causes resorption of the mineralized matrix by osteoclasts. Macrophage colony stimulating factor (M-CSF) and receptor activator of the NF-κB ligand (RANKL) are produced by stromal cells and are essential for osteoclast formation. The human breast cancer cell line, MDA-MB-231, reliably forms bone metastases in a murine model and stimulates osteoclast formation in culture. We hypothesized that MDA-MB-231 stimulates osteoclast formation through secretion of M-CSF and/or RANKL. Materials and methods. We cocultured MDA-MB-231 and a bone marrow derived cell line, UAMS-33, and evaluated the expression of M-CSF and RANKL mRNA. Osteoclast formation was assessed using these cells added to hematopoietic cell cultures. Results. MDA-MB-231 exhibited constitutive expression of M-CSF mRNA. As expected, addition of recombinant M-CSF (30 ng/ml) and RANKL (30 ng/ml) to hematopoietic osteoclast precursors supported osteoclast formation, while the addition of soluble RANKL alone or MDA-231 without added RANKL did not. Notably, coculture of MDA-231 with hematopoietic cells and added soluble RANKL stimulated significant osteoclast formation, indicating that MDA-231 served as an effective source for M-CSF. MDA-231 did not express RANKL. However, when cocultured with the murine bone marrow stromal cell line UAMS-33, RANKL expression was significantly increased in the latter cells. MDA-231 also stimulated osteoclast formation in coculture with UAMS-33 and hematopoietic cells. Conclusions. We conclude that MDA-MB-231 increases osteoclast formation by secreting adequate amounts of M-CSF protein and enhancing the expression of RANKL by stromal support cells. The ability to stimulate osteoclasts may explain the ability to metastasize to bone.

AB - Background. Breast cancer metastasis to bone causes resorption of the mineralized matrix by osteoclasts. Macrophage colony stimulating factor (M-CSF) and receptor activator of the NF-κB ligand (RANKL) are produced by stromal cells and are essential for osteoclast formation. The human breast cancer cell line, MDA-MB-231, reliably forms bone metastases in a murine model and stimulates osteoclast formation in culture. We hypothesized that MDA-MB-231 stimulates osteoclast formation through secretion of M-CSF and/or RANKL. Materials and methods. We cocultured MDA-MB-231 and a bone marrow derived cell line, UAMS-33, and evaluated the expression of M-CSF and RANKL mRNA. Osteoclast formation was assessed using these cells added to hematopoietic cell cultures. Results. MDA-MB-231 exhibited constitutive expression of M-CSF mRNA. As expected, addition of recombinant M-CSF (30 ng/ml) and RANKL (30 ng/ml) to hematopoietic osteoclast precursors supported osteoclast formation, while the addition of soluble RANKL alone or MDA-231 without added RANKL did not. Notably, coculture of MDA-231 with hematopoietic cells and added soluble RANKL stimulated significant osteoclast formation, indicating that MDA-231 served as an effective source for M-CSF. MDA-231 did not express RANKL. However, when cocultured with the murine bone marrow stromal cell line UAMS-33, RANKL expression was significantly increased in the latter cells. MDA-231 also stimulated osteoclast formation in coculture with UAMS-33 and hematopoietic cells. Conclusions. We conclude that MDA-MB-231 increases osteoclast formation by secreting adequate amounts of M-CSF protein and enhancing the expression of RANKL by stromal support cells. The ability to stimulate osteoclasts may explain the ability to metastasize to bone.

KW - Bone metastasis

KW - Breast cancer

KW - M-CSF

KW - MDA-MB-231

KW - Osteoclastogenesis

KW - RANKL

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