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Ishii, G. et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem. Biophys. Res. Commun. 309, 232-240

Hannover Medical School, Hanover, Lower Saxony, Germany
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 09/2003; 309(1):232-40. DOI: 10.1016/S0006-291X(03)01544-4
Source: PubMed

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.

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    • "In the context of cancer, Quante et al. found that approximately 20% of the myofibroblasts in an inflammation-induced gastric cancer model were bone-marrow derived (29). In a pancreatic cancer model, BMCs contributed with up to 40% to the α-SMA-positive CAF population (28). However, in a breast cancer model studying systemic signaling, myofibroblasts in tumors growing at a distant site were derived from local sources but not from BMCs (25), indicating tissue type or cancer model-specific differences. "
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    • "Although some data indicate that the stromal compartment, when microdissected from human breast tumors, exhibits genetic alterations, the proportion of such alterations in fibroblasts remains rare suggesting that EMT cannot be the main origin for myofibroblasts [57]. Recent data from human breast cancers and animal models established that myofibroblasts can derive from bone marrow derived cells, such as fibrocytes or mesenchymal stem cells [58] [59] [60] [61] [62] [63]. Moreover , various mesenchymal cell types, including endothelial cells, pericytes or pre-adipocytes can also be converted into myofibroblasts in breast carcinomas [56] [64] [65]. "
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    • "While the origin of CAFs is not fully defined, they are thought to arise from several sources. Depending on the exact type of cancer, up to 40% of CAFs can be derived from bone marrow precursor cells (Ishii et al. 2003, Direkze et al. 2004) that are attracted to the site of the neoplastic growth from the circulation and populate the growing tumour. CAFs may also originate from epithelial cancer cells that have undergone epithelial-to-mesenchymal transition (Petersen et al. 2003). "
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