Gastrik Karsinomlarda Siklooksijenaz-2, Vasküler Endotelyal Büyüme Faktörü Ekspresyonu ve Anjiyogenezisle İlişkisi

Year 2016, Volume: 17 Issue: 1, 1 - 10, 01.04.2016

Özlem Ekici Çiğdem Tokyol Fatma Hüsniye Dilek Fatma Aktepe Önder Şahin Dursun Ali Şahin

Abstract

Amaç: Bu çalışmanın amacı, mide karsinomları ile bunların lenf nodu metastazlarında siklooksijenaz-2 (COX-2) ve vasküler endotelyal büyüme (growth) faktörü (VEGF) immün reaktivitelerini belirlemek, bunların anjiyogenezle ve histopatolojik prognostik parametrelerle olan ilişkisini araştırmaktır.Gereç ve Yöntemler: Otuz üç gastrik karsinom olgusunda immünhistokimyasal yöntemlerle COX-2, VEGF ekspresyonu ve CD34 ile belirlenen mikrodamar dansitesi (MVD) derecesi incelendi.Bulgular: COX-2 ile normal mukoza %96,9, karsinom grubu %87,8 oranında pozitif boyandı. Tümördeki COX-2 boyanma derecesi ile mukozadaki COX-2 boyanma derecesi arasında istatistiksel olarak anlamlı bir fark izlenmedi. Damar invazyonu pozitif olguların COX-2 ile lenf nodu boyanma derecesi anlamlı olarak daha yüksek idi (p<0,01). VEGF ile normal mukoza %100, karsinom grubu %93,9 oranında pozitif boyandı. Normal mukoza karsinom grubuna kıyasla VEGF ile anlamlı olarak daha yüksek oranda pozitiflik gösterdi (p=0,05). MVD derecesi tümöre kıyasla mukozada daha fazla idi (p<0,01). Kötü diferansiye karsinomlar, iyi ve orta derecede diferansiye karsinomlara göre anlamlı olarak daha yüksek MVD derecesine sahipti (p<0,05). Tümörde ve metastatik lenf nodlarında COX-2 ve VEGF ekspresyonu ile MVD derecesi arasında herhangi bir ilişki tespit edilmedi. COX-2, VEGF ve MVD derecesinin klinikopatolojik parametrelerle ilişkisi istatistiksel olarak anlamlı bulunmadı.Sonuç: Bu bulgulara göre gastrik karsinomlarda MVD derecesi artarken, tümör diferansiasyonu azalıyor olabilir, fakat COX-2 ve VEGF’nin gastrik karsinom gelişimindeki rolü henüz tam olarak anlaşılamamıştır. COX-2, VEGF ve MVD derecesinin gastrik karsinogenezis sürecindeki yerini tam olarak açığa kavuşturabilmek için daha geniş serilerle ileri çalışmalara gereksinim vardır

Keywords

COX-2, VEGF, anjiyogenez, mide karsinomu, immünhistokimya

Cyclooxygenase-2 and Vascular Endothelial Growth Factor Expression and Their Correlation with Angiogenesis in Gastric Carcinomas

Abstract

Objective: The aim of this study was to investigate the expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in gastric carcinomas and lymph node metastasis and their relationship with angiogenesis and prognostic histopathological parameters. Materials and Methods: COX-2 and VEGF expression and microvessel density (MVD) grade identified by antibodies against CD34 were investigated immunohistochemically in 33 patients with gastric carcinoma. Results: The expression of COX-2 was 96.9% in normal mucosa and 87.8% in gastric carcinoma. Although COX-2 expression in mucosa was higher than in carcinoma, the difference was not statistically significant. The COX-2 positivity rates in lymph nodes were significantly higher in patients with vascular invasion (p<0.01). The expression of VEGF was 100% in normal mucosa and 93.9% in gastric carcinoma. VEGF levels in mucosa were significantly higher than in carcinoma (p=0.05). MVD grade in mucosa was significantly higher than in gastric carcinoma (p<0.01). MVD values were significantly higher in poorly differentiated carcinomas than in well and moderately differentiated carcinomas (p<0.05). There was no association between COX-2 and VEGF expression and MVD grade in tumor tissues and metastatic lymph nodes. There was no correlation of clinicopathological parameters with COX-2 and VEGF expression and MVD grade. Conclusion: Our results suggest that the MVD in gastric carcinoma may correlate with tumor grade, but the precise roles of COX-2 and VEGF in gastric cancers are not yet fully understood. Further studies with large series are needed to clarify the importance of COX-2, VEGF and MVD in cancer progression.

Keywords

COX-2, VEGF, angiogenesis, gastric carcinoma, immunohistochemistry

References

• 1. Liu C, Crawford JM. The Gastrointestinal Tract. In: Kumar V, Abbas AK, Fausto N (eds). Robbins Pathologic Basis of Disease. 7th ed. China: Elsevier Saunders, 2005: 797-76.
• 2. Rosai J. Gastrointestinal Tract. In: Rosai J (ed). Rosai and Ackerman’s Surgical Pathology. 9th ed. Edinburgh: Mosby, 2004: 648-711.
• 3. Göçmen E, Kocaoğlu H. Mide Kanseri Epidemiyolojisi. Türkiye Klinikleri Cerrahi Dergisi 2000; 15: 161-2.
• 4. Kumar V, Abbas AK, Fausto N. Acute and Chronic Inflammation. In: Kumar V, Abbas AK, Fausto N (eds). Robbins Pathologic Basis of Disease. 7th ed. China: Elsevier Saunders, 2005: 47-86.
• 5. Kumar V, Abbas AK, Fausto N. Neoplasia. In: Kumar V, Abbas AK, Fausto N (eds). Robbins Pathologic Basis of Disease. 7th ed. China: Elsevier Saunders, 2005: 269-342.
• 6. Weidner N, Semole JP, Welch WR, Folkman J. Tumor angiogenesis and metastases correlation in invasive breast carcinoma. N Eng J Med 1991; 324: 1-8.
• 7. Bosari S, Lee AK, De Lelli S, Willey BD, Heatly GJ, Silverman ML. Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol 1992; 23: 755-61.
• 8. Kumar V, Abbas AK, Fausto N. Tissue Renewal and Repair: Regeneration, Healing, and Fibrosis. In: Kumar V, Abbas AK, Fausto N (eds). Robbins Pathologic Basis of Disease. 7th ed. China: Elsevier Saunders, 2005: 87-118.
• 9. Topak N. Kolon karsinogenezisinde siklooksijenazların rolü. Uzmanlık Tezi, Afyonkarahisar: Afyon Kocatepe Üniversitesi Tıp Fakültesi Patoloji Anabilim Dalı, 2007.
• 10. Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989; 339: 58-61.
• 11. Brooks P, Emery P, Evans JF. Interpreting the clinical signifance of the differantial inhibition of cyclooxygenase-2. Rheumatology 1999; 38: 779-88.
• 12. Buskens CJ, Sivula A, Van Rees BP, Haglund C, Offerhaus GJ, van Lanschot JJ, et al. Comparison of cyclooxygenase-2 expression in adenocarcinomas of the gastric cardia and distal oesophagus. Gut 2003; 52: 1678-83.
• 13. Bottone FG, Martinez JM, Alston-Mills B, Eling TE. Gene modulation by COX-1 and COX-2 spesific inhibitors in human colorectal carcinoma cancer cells. Carcinogenesis 2004; 25: 349- 57.
• 14. Cheng T, Cao W, Wen R, Steinberg RH, Lavail MM. Prostaglandin E2 induces vascular endothelial growth factor expression and basic fibroblast growth factor mRNA expression in cultured rat Müller cells. Invest Ophthalmol Vis Sci 1998; 39: 581-91.
• 15. Ben-Av P, Crofford LJ, Wilder RL, Hla T. Induction of vascular endothelial growth factor expression in synovial fibroblast by prostaglandin E and interleukin-1: A potential mechanism for inflamatory angiogenesis. FEBS Left 1995; 372: 83-7.
• 16. Han SL, Tang HJ, Hua YW, Ji SQ, Lin DX. Expression of COX-2 in stomach cancers and its relation to their biological features. Dig Surg 2003; 20: 107-14. 17. Lim HY, Joo HJ, Choi JH, Yi JW, Yang MS, Cho DY, et al. Increased expression of cyclooxygenase-2 protein in human gastric carcinoma. Clin Cancer Res 2000; 6: 519-25.
• 18. Fujita T, Matsui M, Takaku K, Vetake H, Ichikawa W, Taketo M, et al. Size and invasion dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas. Cancer Res 1998; 58: 4823-6.
• 19. Murata H, Kawano S, Tsuji S, Sawaoka H, Kimura Y, Shiozaki H, et al. Cyclooxygenase-2 overexpression enhances lymphatic invasion and metastasis in human gastric carcinoma. Am J Gastroenterol 1999; 94: 451-5.
• 20. Koga T, Shibahara K, Kabashima A, Sumiyoshi Y, Kimura Y, Takhashi I, et al. Overexpression of cyclooxygenase-2 and tumor angiogenesis in human gastric cancer. Hepatogastroenterology 2004; 51: 1626-30.
• 21. Tatsuguchi A, Matsui K, Shinji Y, Guids K, Tsukui T, Kishida T, et al. Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue. Hum Pathol 2004; 35: 488-95.
• 22. Uefuji K, Ichikura T, Mochizuki H, Shinomiya N. Expression of cyclooxygenase-2 protein in gastric adenocarcinoma. J Surg Oncol 1998; 69: 168-72.
• 23. Gudis K, Sakamato C. The role of cyclooxygenase in gastric mucosal protection. Dig Dis Sci 2005; 50: 16-23.
• 24. Sung JJ, Leung WK, Go MY, To KF. Cyclooxygenase-2 expression in helicobacter pylori-associated premalignant and malignant gastric lesions. Am J Pathol 2000; 157: 729-35.
• 25. Tatsuguchi A, Sakamato C, Wada K, Akamatsu T, Miyake K, Futagami S, Kishida T, Fukuda Y, Yamanaka N, Kobatashi N. Localisation of cyclooxygenase 2 in Helicobacter pylori related gastritis and gastric ulcer tissues in humans. Gut 2000; 46: 782-9.
• 26. Brown LF, Guidi AJ, Schnitt SJ. Vascular permeability factor/ vascular endothelial growth factor and vascular stroma formation in neoplasia: Insight from in situ hybridisation studies. J Histochem Cytochem 1998; 46: 569-75.
• 27. Niki T, Iba S, Tokunou M, Yamada T, Matsuno Y, Hirohashi S. Expression of vascular endothelial growth factors A,B,C and D and their relationship to lymph node status in lung adenocarcinoma. Clin Cancer Res 2000; 6: 2431-9.
• 28. George ML, Tutton MG, Jansen F, Arnaout A, Abulafi AM, Eccles SA. VEGF-A, VEGF-C and VEGF-D in colorectal cancer progression. Neoplasia 2001; 3: 420-7.
• 29. Berse B, Brown LF, Water L, Dvorak HF, Senger DR. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages and tumors. Mol Biol Cell 1992; 3: 211-20.
• 30. Ballie R, Carlile J, Pendleton N, Schor AM. Prognostic value of vascular endothelial growth factor expression in non-small cell lung cancer. J Clin Pathol 2001; 54: 116-20.
• 31. Perrella G, Brusini P, Spelat R, Hossain P, Hopkinson A, Dua HS. Expression of haematopoetic stem cell markers CD133 and CD34 on human corneal keratocytes. Br J Ophtalmol 2007; 91: 94-9.
• 32. Kumar S, Ghellal A, Li C, Byrne G, Haboubi N, Wang JM, et al. Breast carcinoma: Vascular density determined using CD105 antibody correlates with tumor prognosis. Cancer Res 1999; 59: 856-61.
• 33. Ding S, Li C, Lin S, Yang Y, LiuD, Han Y, et al. Comparative evaluation of microvessel density determined by CD34 or CD105 in benign and malignant gastric lesions. Hum Pathol 2006; 37: 861-6.
• 34. Valente G, Mamo C, Bena A, Btechn EP, Cavaliere BS, Comino A, Palestro G, Isidoro C, Beatrice F. Prognostic significance of microvessel density and vascular endothelial growth factor expression in sinonasal carcinomas. Hum Pathol 2006; 37: 391-400.
• 35. Shi H, Xu JM, Hu NZ, Xie H. Prognostic significance of expression of Cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma. World J Gastroenterol 2003; 9: 1421-6.
• 36. Li XH, Chang XM, Song ZJ, He SX. Correlation between expression of cyclooxygenase-2 and angiogenesis in human adenocarcinoma. World J Gastroenterol 2003; 9: 674-7.
• 37. Kawabe A, Shimada Y, Uchida S, Maeda M, Yamaski S, Kato M, et al. Expression of cyclooxygenase-2 in primary and remnant gastric carcinoma: Comparing it with p53 accumulation, helicobacter pylori infection and vascular endothelial growth factor expression. J Surg Oncol 2002; 80: 79-88.
• 38. Yano T, Tanikawa S, Fujie T, Masutani M, Horie T. Vascular endothelial growth factor expression and neovascularisation in non-small cell lung cancer. Eur J Cancer 2000; 36: 601-9.
• 39. Tanaka F, Otake Y, Yanagihara K, Kawano Y, Miyahara R, Li M, Yamada T, Hanaoka N, Inui K, Wada H. Evaluation of angiogenesis in non-small cell lung cancer: Comparison between anti-CD34 antibody and anti-CD105 antibody. Clin Cancer Res 2001; 7: 3410-5.
• 40. Chandrachud LM, Pendelton N, Chisholm D, Horan MA, Schor AM. Relationship between vascularity, age and survival in non-smallcell lung cancer. Br J Cancer 1997; 76: 1367-75.