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

Abstract

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.

• Authors: Genichiro Ishii, Takafumi Sangai, Tatsuya Oda, Yasuyuki Aoyagi, Takahiro Hasebe, Naoki Kanomata, Yasushi Endoh, Chie Okumura, Yoko Okuhara, Junji Magae, Makito Emura, Takahiro Ochiya, Atsushi Ochiai
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 309 Issue 1 Pg. 232-40 (Sep 12 2003) ISSN: 0006-291X [Print] United States
• PMID: 12943687 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Homeodomain Proteins
• RAG-1 protein
• beta-Galactosidase

Topics

• Animals
• Bone Marrow Cells (cytology)
• Cell Division
• Cells, Cultured
• Dose-Response Relationship, Drug
• Female
• Fibroblasts (cytology, metabolism)
• Homeodomain Proteins (genetics)
• Humans
• Immunohistochemistry
• Mice
• Mice, Inbred C57BL
• Mice, SCID
• Mice, Transgenic
• Microscopy, Fluorescence
• Muscles (metabolism)
• Neoplasm Transplantation
• Neoplasms (metabolism)
• Stromal Cells (cytology)
• Time Factors
• Tumor Cells, Cultured
• beta-Galactosidase (genetics, metabolism)