Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction.

Abstract

Bone metastasis greatly deteriorates the quality of life in patients with cancer. Although mechanisms have been widely investigated, the relationship between cancer bone metastasis and antitumor immunity in the host has been much less studied. Here, we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatin-like glycoprotein secreted by Snail(+) tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis-in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45(-)ALCAM(+) cells derived from bone marrow. CD45(-)ALCAM(+) cells induced bone metastasis de novo, but they also generated CD8(low) T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interference-mediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM(+) cells and CD8(low) T cells. These effects were accompanied by heightened antitumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM(+) cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in patients with cancer.

• Authors: Chie Kudo-Saito, Takafumi Fuwa, Kouichi Murakami, Yutaka Kawakami
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 20 Pg. 6185-93 (Oct 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23966294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Follistatin-Related Proteins
• Fstl1 protein, mouse
• Snail Family Transcription Factors
• Transcription Factors

Topics

• Animals
• Bone Marrow Cells (pathology)
• Bone Neoplasms (immunology, prevention & control, secondary)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Female
• Flow Cytometry
• Follistatin-Related Proteins (antagonists & inhibitors, immunology)
• Humans
• Melanoma, Experimental (immunology, prevention & control, secondary)
• Mesenchymal Stem Cells (pathology)
• Mice
• Mice, Inbred C57BL
• Molecular Targeted Therapy
• Snail Family Transcription Factors
• Transcription Factors (biosynthesis)
• Transfection