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.
Highlights
Bone metastasis of tumor cells is frequently seen in patients with cancer, with breast cancers and prostate cancers, and greatly deteriorates the quality of life in patients, leading to poor prognosis [1]
When the F10-snailþ tumor cells were implanted both subcutaneously and intravenously in C57BL/6 mice, tumor metastatic dissemination was more severely observed in various tissues such as lymph node, lung, and bone marrow, as compared with that of the mice implanted with B16-F10 tumors transduced with empty vectors, the subcutaneous tumor growth was slower than F10-mock growth as shown before [12]
This study revealed a novel mechanism, which is governed by FSTL1 produced from Snailþ tumor cells undergoing epithelial-to-mesenchymal transition (EMT)
Summary
Bone metastasis of tumor cells is frequently seen in patients with cancer, with breast cancers and prostate cancers, and greatly deteriorates the quality of life in patients, leading to poor prognosis [1]. Chemokines and its receptors are one of the representative molecules regulating bone tropism of tumor cells. CXCR4þ tumor cells are attracted by CXCL12 secreted from stromal cells in bone marrow [2], and CXCL12 maintains proliferation and survival of the tumor cells [3]. CCL2 is known as another chemokine critical for bone metastatic mechanism in various cancers [5, 6]. The excess of tumor growth in bone marrow results in disruption of skeletal integrity, and causes abnormal osteogenesis or osteolysis in patients with cancer [1]. One of the most influential molecules is RANKL, which is highly expressed in normal mesenchymal cells including osteoblasts and stromal cells, and metastatic tumor cells undergoing epithelial-to-mesenchymal transition One of the most influential molecules is RANKL, which is highly expressed in normal mesenchymal cells including osteoblasts and stromal cells, and metastatic tumor cells undergoing epithelial-to-mesenchymal transition (EMT; ref. 7)
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