Host cyclooxygenase-2 modulates carcinoma growth - PubMed (original) (raw)

Host cyclooxygenase-2 modulates carcinoma growth

C S Williams et al. J Clin Invest. 2000 Jun.

Abstract

Cyclooxygenase-2 (COX-2; Ptgs2) acts as a tumor promoter in rodent models for colorectal cancer, but its precise role in carcinogenesis remains unclear. We evaluated the contribution of host-derived COX-1 and COX-2 in tumor growth using both genetic and pharmacological approaches. Lewis lung carcinoma (LLC) cells grow rapidly as solid tumors when implanted in C57BL/6 mice. We found that tumor growth was markedly attenuated in COX-2(-/-), but not COX-1(-/-) or wild-type mice. Treatment of wild-type C57BL/6 mice bearing LLC tumors with a selective COX-2 inhibitor also reduced tumor growth. A decrease in vascular density was observed in tumors grown in COX-2(-/-) mice when compared with those in wild-type mice. Because COX-2 is expressed in stromal fibroblasts of human and rodent colorectal carcinomas, we evaluated COX-2(-/-) mouse fibroblasts and found a 94% reduction in their ability to produce the proangiogenic factor, VEGF. Additionally, treatment of wild-type mouse fibroblasts with a selective COX-2 inhibitor reduced VEGF production by 92%.

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Figures

Figure 1

Figure 1

Host-derived COX-2 is important for LLC tumor growth. (a) A total of 2 × 106 LLC cells were implanted into COX-2+/+ (gray bars), COX-2+/– (white bars), or COX-2–/– (black bars) C57BL/6 mice; (b) a total of 2 × 106 LLC cells were implanted into COX-1+/+ (gray bars) or COX-1–/– (black bars) C57BL/6 mice. Tumor volumes were calculated from tumor measurements scored at the indicated day. Results are presented as the mean tumor volume ± SEM.

Figure 2

Figure 2

Celecoxib inhibits LLC tumor growth. A total of 2 × 106 LLC cells were implanted into C57BL/6 mice. Mice were fed either control chow (gray bars) or 1,500 mg/kg celecoxib-containing chow (black bars). Tumor volumes were calculated from tumor measurements taken at the indicated day and are represented as the average of each group ± SEM.

Figure 3

Figure 3

COX-1 and COX-2 are expressed within LLC tumors. Tumor lysates from LLC tumors grown in COX-2+/+ (wild-type), COX-2+/– (heterozygote), and COX-2–/– (null) mice were produced and 50 μg of lysate was fractionated on a 10% SDS-PAGE gel. (a) COX-2 and (b) COX-1 specific antisera were used to blot the membranes. Het, heterozygote.

Figure 4

Figure 4

COX-2 and VEGF are expressed in LLC isografts. COX-2 (upper panels, a and b, wild-type host), VEGF (middle panels, c and d, wild-type host), and VEGF (lower panels, e and f, COX-2–/– host) riboprobes were hybridized to sections from tumors grown in C57BL/6 mice with the designated genotype (×400). Control hybridizations with sense cRNA riboprobes were performed to validate the specificity of Rnase-A–resistant hybrids. WT, wild-type.

Figure 5

Figure 5

Decreased vascular density in LLC tumors when grown in COX-2–/– mice. (a) Representative photomicrographs of factor VIII–stained tumor sections from LLC tumors grown in wild-type (+/+) or _Ptgs2_–/– (–/–) mice (×200). (b) Factor VIII–positive vessel counts obtained by morphometric analysis of LLC tumors. Values represent the average number of vessels at ×200 ± the SD (Student’s t test; P = 0.04). HPF, high power field.

Figure 6

Figure 6

VEGF production in fibroblasts is regulated by COX-2. Production of VEGF by wild-type, COX-1–/–, and COX-2–/– fibroblasts was determined. Each treatment condition is listed below its respective bar graph. WT denotes wild-type mouse fibroblasts. We observed a 93% reduction in VEGF production in COX-2–/– fibroblasts when compared with wild-type fibroblasts. Additionally, treatment of wild-type fibroblasts with a selective COX-2 inhibitor (10 μM SC-58125) led to a ∼90% reduction in VEGF levels.

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