Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction
| Autor: | Kouichi Murakami, Yutaka Kawakami, Takafumi Fuwa, Chie Kudo-Saito |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Follistatin-Related Proteins Population Melanoma Experimental Bone Marrow Cells Bone Neoplasms CD8-Positive T-Lymphocytes Transfection Mice Immune system Cell Line Tumor medicine Animals Humans Molecular Targeted Therapy education ALCAM education.field_of_study business.industry Melanoma Mesenchymal stem cell Bone metastasis Cancer Mesenchymal Stem Cells Flow Cytometry medicine.disease Mice Inbred C57BL medicine.anatomical_structure Oncology Female Snail Family Transcription Factors Bone marrow business Transcription Factors |
| Zdroj: | Cancer Research. 73:6185-6193 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-13-1364 |
| Popis: | 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 CD8low 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 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. Cancer Res; 73(20); 6185–93. ©2013 AACR. |
| Databáze: | OpenAIRE |
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