| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Cancer-stromal interaction is well known to play important roles during cancer progression. 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 (BMD-VE) and BM-derived myofibroblasts (BMD-MF) 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-positi
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ve 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. Furthermore, to assess the effect of the difference in cancer cell types on the recruitment of BMD-VE and BMD-MF,10 kinds of human cancer cell line were implanted into the subctaneous tissue of immunodeficient mice transplanted with bone marrow of double-mutant mice (RAG-1-/- b-gal Tg or RAG-1-/- GFP Tg). The recruitment frequency of BMD-VE (%BMD-VE) and BMD-MF (%BMD-MF), and tumor-associated parameters : tumor volume(TV), microvessel density(MVD), and stromal proportion (%St) were measured. The correlation among them was analyzed. Although %BMD-VE and %BMD-MF varied (from 0 to 21.6%,0 to 29.6%, respectively) depending on the cancer cell line, both parameters significantly correlated with %St (P<0.005). Furthermore %BMD-VE and %BMD-MF also significantly correlated (P<0.005). In order to assess the effect of tumor growth sites on the recruitment of the cells of interest, a human pancreatic cancer cell line, Capan-1,was transplanted into 5 different sites : subcutaneous tissue, peritoneum, liver, spleen, and lung. Tumors in the subcutaneous tissue and peritoneum induced desmoplastic stroma (%St=22.7%,19.5%, respectively) and contained BMD-VE (%BMD-VE=21.6%,16.5% respectively) and BMD-MF (%BMD-MF=29.6%,24.5%, respectively), but weak stromal induction without recruitment of BMD-VE or -MF was observed in the tumors of the liver, spleen and lung (%St=9.7%,9.1%,5.4%, respectively). These results indicate that recruitment of BMD-VE and -MF is required for stromal formation during cancer progression, and that the cancer microenvironment is important in the recruitment of BMD-VE and -MF. Less
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