Presence of Human Circulating Progenitor Cells for Cancer Stromal Fibroblasts in the Blood of Lung Cancer Patients

Authors

  • Genichiro Ishii,

    1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
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  • Ta-Kashi Ito,

    1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
    2. Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan
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  • Kazuhiko Aoyagi,

    1. Genetics Division, National Cancer Center Research Institute, Tokyo, Japan
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  • Hiroshi Fujimoto,

    1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
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  • Haruki Chiba,

    1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
    2. Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan
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  • Takahiro Hasebe,

    1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
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  • Satoshi Fujii,

    1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
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  • Kanji Nagai,

    1. Thoracic Oncology Divisions, National Cancer Center Hospital East, Chiba, Japan
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  • Hiroki Sasaki,

    1. Genetics Division, National Cancer Center Research Institute, Tokyo, Japan
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  • Atsushi Ochiai M.D., Ph.D.

    Corresponding author
    1. Pathology Division, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
    2. Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan
    • Pathology Division, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, 6-5-1 Kashiwanoha, Kashiwa-City, Chiba 277-8577, Japan. Telephone: 81-4-7134-6855; Fax: 81-4-7134-6865
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Abstract

Recent animal data have suggested that cancer-induced stroma consists of blood-borne fibroblasts as well as tissue-derived fibroblasts. In this study, mononuclear cells isolated from the pulmonary vein blood of lungs resected from lung cancer patients were cultured to confirm the presence of blood-borne fibroblast. In 34% (16 of 47) of the cases, spindle cells with fibroblast morphology proliferated in a disarrayed fashion and were positive for vimentin and collagen type I but negative for both specific myogenic and endothelial markers. The cDNA profiles of blood-borne fibroblasts, tissue-derived (lung) fibroblasts, human vascular smooth muscle cells (HSMCs), and umbilical vein endothelial cells (HUVECs) were clustered with a hierarchical classification algorithm. The profiles of the blood-borne fibroblasts were clearly isolated from those of the tissue-derived fibroblasts, HSMCs, and HUVECs. When carboxyfluorescein succinyl ester (CFSE)-labeled human mononuclear cells from the blood of lung cancer patients were transferred into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with a human lung cancer xenograft, CFSE-labeled fibroblasts were found around the cancer nests. We investigated the several clinicopathological factors of blood-borne fibroblast-positive patients. The blood-borne fibroblast-positive cases had a significantly larger central fibrotic area in primary lung cancer than in the negative cases (123 ± 29 vs. 59 ± 13 mm2; p = .02). Our results indicated that the blood in the vicinity of human lung cancer contains fibroblast progenitor cells that have the capacity to migrate into the cancer stroma and differentiate into fibroblasts having biological characteristics different from those of tissue-derived fibroblasts.

Disclosure of potential conflicts of interest is found at the end of this article.

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