Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction.
To confirm whether human cancer-induced stromal cells are derived from bone marrow, bone marrow (BM) cells obtained from beta-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/alpha-smooth muscle actin or H-2b/alpha-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 IIalpha-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.
Ishii
Genichiro
G
Pathology Division, National Cancer Center Research Institute East, 6-5-1, Kashiwanoha, Kashiwa-City, Chiba, Japan.
Sangai
Takafumi
T
Oda
Tatsuya
T
Aoyagi
Yasuyuki
Y
Hasebe
Takahiro
T
Kanomata
Naoki
N
Endoh
Yasushi
Y
Okumura
Chie
C
Okuhara
Yoko
Y
Magae
Junji
J
Emura
Makito
M
Ochiya
Takahiro
T
Ochiai
Atsushi
A
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002455:Cell Division; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009132:Muscles / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; C064658:RAG-1 protein; D001616:beta-Galactosidase