자궁경부암에서의 COX-2와 VEGF 발현에 관한 연구
Correlation of the Expression of COX-2 and VEGF in Cervical SquamousCell Carcinomas
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목적 : 자궁 경부암을 포함하여 여러 악성 종양에서 cyclooxygenase-2 (COX-2)의 과발현이 종양형성의 단계에 관련 있다고 보고되고 있다. COX는 prostaglandin형성에 관여하는 효소인데 두 가지 이성체가 알려져 있다. 평소에는 정상조직에서는 거의 발현되지 않는 혈관신생과 관련하여 종양형성에 관여하는 COX-2의 과발현의 유발은 조직의 저산소증에 의해 조절되는 것으로 알려져 있으며, 이런 저산소증은 vascular endothelial growth factor (VEGF)의 발현을 유발한다고 한다. 이에 저자들은 자궁경부암중 침윤성암 25예, 미세침윤성암 7예, 그리고 상피내암종 9예의 조직에서 COX-2 및 VEGF의 과발현과 미세혈관밀도의 상관관계를 알아보고자 하였다. 연구 방법 : 1999년 1월부터 2001년 12월까지 경희대학교 산부인과에서 자궁경부암으로 진단받은 41예와 정상자궁경부 조직 4예를 대상으로 COX-2 단클론성 항체와 Rabbit anti-human VEGF 항체를 이용하여 면역조직 화학 염색을 시행하였다. 또한 factor VIII 항체를 이용하여 미세혈관밀도를 측정하였다. COX-2와 VEGF의 면역조직화학적 염색결과는 면역반응의 염색 강도와 염색된 세포의 수에 따라 음성 (0), 약양성 (light staining, 1), 중간양성 (moderate staining, 2), 강양성 (heavy staining, 3)으로 반정량적 판독을 하였다. 결과 : COX-2 면역반응은 상피세포 기저막과 암 침윤부위가 특히 강하게 발현되는 것을 볼 수 있었다. 그리고 상피내암종, 미세침윤성 자궁경부암, 침윤성 자궁경부암으로 갈수록 강양성의 반응도가 증가하는 것을 관찰할 수 있었고 (p=0.006), VEGF 면역반응 역시 암이 진행할수록 양성의 빈도가 증가하는 경향을 확인하였다 (p=0.079). 이들 COX-2 면역반응과 VEGF 면역반응은 상관관계가 있는 것으로 확인되었다 (rs=0.686, p<0.01). 또한 이들의 면역반응은 미세혈관 밀도와 상관관계를 보이는 것으로 관찰되었다. 결론 : COX-2와 VEGF의 발현이 자궁경부 종양의 발생초기 단계에 중요한 상호역할을 하는 것으로 사료된다.
Abstract
Objective : The purpose of this study was to know the potential of growth, invasion and metastasis of uterine cervical cancer associated with neovascularization and to investigate whether the enhanced COX-2 (Cyclooxygenase-2) and VEGF (Vascular Endothelial Growth Factor) expression is showed through CIS to invasive cervical cancer and to examine that COX-2 and VEGF expressions are associated with prognostically worse pathological variables and had a direct correlation with tumor MVD (microvessel density). Methods : From January 1999 to December 2001, 45 paraffin-embedded cervical specimens were obtained by surgical resection in the Kyung Hee University Medical Center. The study group included 25 cases in invasive squamous carcinomas, 7 cases in microinvasive carcinoma, 9 cases in carcinoma in situ, 4 cases in the benign uterine diseases. All tissues were subjected to immunohistochemical staining for COX-2, VEGF and microvessel density (MVD), and immunostaining was scored using a four-point scale with (0) indicating no expression, (1) light staining, (2) moderate staining, (3) heavy staining. Results : As the cervical tumorigenesis progressed, there was a significant increase of MVC (microvessel count) and COX-2 expression. There is a significant correlation between COX-2 and VEGF expression (rs=0.686, p<0.01) in cervical neoplasms. There was no correlation between COX-2, VEGF expression and clinicopathologic factors in cervical caner. Conclusion : These findings provide evidence that the expression of COX-2 and VEGF is involved in the promotion of angiogenesis in cervical neoplasms and plays an important role in early invasion.
참고문헌 (43)
- Weidner N, "The relationship of tumor angiogenesis and metastasis with emphasis on invasive breast cancer. In: Advances in pathology", 5, pp.101~122 (1992), Mosby-Year Book
- Folkman J, "Tumor angiogenesis", 43, pp.175~203 (1985)
- Connolly DT, "Vascular permeability factor. a unique regulator of blood vessel function", 47, pp.219~223 (1991)
- Folkman J, "Angiogensis in vitro", 288, pp.551~556 (1980)
- Ishikawa F, "Identification of angiogenic activity and the cloning and expression of platelet derived endothelial cell growth factor", 288, pp.557~562 (1989)
- Tischer E, "Vascular endothelial growth factor: a new member of the platelet- derived growth factor gene family", 165, pp.1198~1206 (1989)
- Semple JP, "Angiogenesis and metastasis-Correlation in invasive breast carcinoma", 324, pp.1~8 (1991)
- Crafe P, "Enhancement of tumor growth and vascular density by fransfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells", 87, pp.213~219 (1995)
- Marme D, "Tumor angiogenesis:the pivotal role of vascular endothelial growth factor", 14, pp.166~174 (1996)
- Cottreau C, "Possible role of ovarian epithelial inflammation in ovarian cancer", 91, pp.1459~1467 (1999)
- Viinikka LU, "Increased synthesis of prostacyclin and thromboxane in human ovarian malignancy", 48, pp.2396~2398 (1988)
- Zakim D, "Inhibition if cyclooxygenase:an novel approach to cancer prevention", 216, pp.201~210 (1997)
- Zingg HH, "Regulation of COX-2 gene expression in rat uterus in vivo and in vitro", 52, pp.463~481 (1996)
- Liu XH, "NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and downregulates bcl-2 expression in LNCaP cells", 10, pp.4245~4249 (1998)
- Manos MM, "Prevalence of HPV in cervical cancer:a world-wide perspective", 87, pp.796~802 (1995)
- errington CS, "HPV and cervical neoplasia. II. Interaction of HPV with other factors", 48, pp.1~6 (1995)
- Folkman J, "Angiogenic factor", 235, pp.442~447 (1987)
- Denekamp J, "Vascular as a target for tumor therapy", 4, pp.28~38 (1984)
- Hochberg M, "Self-regulation of growth in three demensions", 138, pp.745~753 (1973)
- Greenberg ER, "Reduced risk of large-bowel adenomas among aspirin users", 85, pp.912~916 (1993)
- Egan KM, "Aspirin and the risk of colorectal cancer in women", 333, pp.609~614 (1995)
- Taketo MM, "Cyclooxygenase-2 inhibitors in tumorigenesis (part II)", 90, pp.1609~1620 (1998)
- Dannenberg AJ, "Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis", 56, pp.2556~2560 (1996)
- Oshima M, "Suppression of intestinal polyposis in ApcΔ716 knickout mice by inhibition of cyclooxygenase-2", 87, pp.803~809 (1996)
- Coffey RJ, "Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas", 107, pp.1183~1188 (1994)
- Honkanen N, "Expression of cyclooxygenase-2 in human gastric carcinoma", 57, pp.1276~1280 (1997)
- Sarbia M, "cyclooxygenase-2 expression in human esophageal carcinoma", 59, pp.198~204 (1999)
- Dannenberg AJ, "Cyclooxygenase-2 expression in up-regulated in human pancreatic cancer", 59, pp.987~990 (1999)
- Scollard D, "Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer", 90, pp.455~460 (1998)
- Gaffney DK, "Elevated COX-2 expression in cervical carcinoma: reduced cause- specific survival and pelvic control", 24(5), pp.443~446 (2001)
- Kulkarni S, "Cyclooxygenase-2 is overexpressed in human cervical cancer", 7(2), pp.429~434 (2001)
- 손우석, "자궁경부암에서 Cyclooxygenase-2의 발현과 혈관신생", 45, pp.399~403 (2002)
- Kawano S, "Cyclooxygenase regulates angiogenesis induced by colon cancer cells", 93, pp.705~716 (1998)
- Sawaoka H, "Cyclooxygenase inhibitors suppress angiogenesis and reduced tumor growth in vivo", 79, pp.1469~1477 (1999)
- Williams CS, "Host cyclooxygenase-2 modulates carcinoma growth", 105, pp.1589~1594 (2000)
- Gately S, "The contribution of cyclooxygenase-2 to tumor angiogenesis", 19, pp.19~27 (2000)
- Galli SJ, "Tumor cells secrete a vascular permeability factor which promotes ascites fluid accumulation", 219, pp.983~985 (1983)
- Bauer T, "Hypoxic sitmulation of vascular endothelial growth factor expression in vitro and vivo", 71, pp.374~379 (1994)
- Mohanraj D, "Vascular permeability factor gene expression in normal and neoplastic human ovaries", 54, pp.276~280 (1994)
- Hoshina S, "Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer", 85(10), pp.1045~1049 (1994)
- Gaffney DK, "Epidermal growth factor receptor(EGFR) and vascular endothelial growth factor(VEGF) negatively affect overall survival in carcinoma of the cervix treated with radiotherapy", 56(4), pp.922~928 (2003)
- 이선경, "자궁경부암에서 혈관 내피 성장인자 및 VEGF mRNA의 발현에 대한 연구", 45, pp.89~96 (2002)
- Seo SS, "Expression of cyclooxygenase-1 and -2 associated with expression of VEGF in primary cervical cancer and at metastatic lymph nodes", 90(1), pp.83~90 (2003)