Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction

Chie Kudo-Saito, Takafumi Fuwa, Kouichi Murakami, Yutaka Kawakami

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 follistatinlike 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 CD8low T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interferencemediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM+ cells and CD8low 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.

Original languageEnglish
Pages (from-to)6185-6193
Number of pages9
JournalCancer Research
Volume73
Issue number20
DOIs
Publication statusPublished - 2013 Oct 15

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Activated-Leukocyte Cell Adhesion Molecule
Neoplasm Metastasis
Bone and Bones
Neoplasms
T-Lymphocytes
Bone Neoplasms
Tropism
Bone Marrow Cells
Immunity
Glycoproteins
Quality of Life
RNA
Breast Neoplasms
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction. / Kudo-Saito, Chie; Fuwa, Takafumi; Murakami, Kouichi; Kawakami, Yutaka.

In: Cancer Research, Vol. 73, No. 20, 15.10.2013, p. 6185-6193.

Research output: Contribution to journalArticle

Kudo-Saito, C, Fuwa, T, Murakami, K & Kawakami, Y 2013, 'Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction', Cancer Research, vol. 73, no. 20, pp. 6185-6193. https://doi.org/10.1158/0008-5472.CAN-13-1364
Kudo-Saito, Chie ; Fuwa, Takafumi ; Murakami, Kouichi ; Kawakami, Yutaka. / Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction. In: Cancer Research. 2013 ; Vol. 73, No. 20. pp. 6185-6193.
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