Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction

• Published in: Biochemical and biophysical research communications Vol. 309; no. 1; pp. 232 - 240
• Main Authors: Ishii, Genichiro, Sangai, Takafumi, Oda, Tatsuya, Aoyagi, Yasuyuki, Hasebe, Takahiro, Kanomata, Naoki, Endoh, Yasushi, Okumura, Chie, Okuhara, Yoko, Magae, Junji, Emura, Makito, Ochiya, Takahiro, Ochiai, Atsushi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.09.2003
• Subjects: Animals; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Bone Marrow Cells - cytology; Bone-marrow-derived; Cancer-induced stroma; Cell Division; Cells, Cultured; Desmoplastic reaction; Dose-Response Relationship, Drug; Female; Fibroblasts - cytology; Fibroblasts - metabolism; Homeodomain Proteins - genetics; Humans; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, SCID; Mice, Transgenic; Microscopy, Fluorescence; Muscles - metabolism; Myofibroblast; Neoplasm Transplantation; Neoplasms - metabolism; Stromal Cells - cytology; Time Factors; Tumor Cells, Cultured; α-Smooth muscle actin; Desmoplastic reaction; Bone-marrow-derived; Myofibroblast; Cancer-induced stroma; α-Smooth muscle actin
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(03)01544-4

To confirm whether human cancer-induced stromal cells are derived from bone marrow, bone marrow (BM) cells obtained from β-galactosidase transgenic and recombination activating gene 1 (RAG-1) deficient double-mutant mice (H-2b) were transplanted into sublethally irradiated severe combined immunodeficient (SCID) mice (H-2d). The human pancreatic cancer cell line Capan-1 was subcutaneously xenotransplanted into SCID recipients and stromal formation was analyzed on day 14 and on day 28. Immunohistochemical and immunofluorescence studies revealed that BM-derived endothelial cells (X-gal/CD31 or H-2b/CD31 double-positive cells) and myofibroblasts (X-gal/α-smooth muscle actin or H-2b/α-smooth muscle actin double-positive cells) were present within and around the cancer nests. On day 14, the frequencies of BM-derived endothelial cells and BM-derived myofibroblasts were 25.3 ± 4.4% and 12.7 ± 9.6%, respectively. On day 28, the frequency of BM-derived endothelial cells was 26.7 ± 9.7%, which was similar to the value on day 14. However, the frequency of BM-derived myofibroblasts was significantly higher (39.8 ± 17.1%) on day 28 than on day 14 ( P<0.05). The topoisomerase IIα-positive ratio was 2.2 ± 1.2% for the H-2b-positive myofibroblasts, as opposed to only 0.3 ± 0.4% for the H-2b-negative myofibroblasts, significant proliferative activity was observed in the BM-derived myofibroblasts ( P<0.05). Our results indicate that BM-derived myofibroblasts become a major component of cancer-induced stromal cells in the later stage of tumor development.