Küçük hücreli dışı akciğer kanserlerinde endoglin, CD31 ve VEGFR2 ile saptanan mikrodamar yoğunluğu ve sağkalıma etkisi

Yıl 2022, Cilt: 15 Sayı: 1, 69 - 76, 01.01.2022

Hülya Çetin , Ferda Bir , Sevin Başer Öncel , Argün Kış , Yaşar Enli

https://doi.org/10.31362/patd.929791

Öz

Amaç: Gün geçtikçe artmakta olan kanser çağımızın ciddi küresel sağlık sorunudur ve akciğer kanseri tüm dünyada toplam kanser sayısı içerisinde en sık görülen kanserdir. Tümörlerin gelişiminde ve metastazında anjiogenez önemli bir rol oynamaktadır. Farklı endotel belirteçleri ile hesaplanan mikrodamar yoğunluğunun (MY) bazı tümörlerde kötü prognoz ve ileri evre ile ilişkili olduğu gösterilmiştir ve buradan hareketle metastazı öngörebileceği ileri sürülmüştür. Çalışmamızda, küçük hücreli dışı akciğer kanserlerinde (KHDAK) MY’yi immünohistokimyasal olarak endoglin, CD31 ve VEGFR2 ile tespit edip, serum endoglin seviyesi ile ilişkilendirerek sonuçlarımızı akciğer tümörlerinin progresyonu ile karşılaştırmayı amaçladık.
Gereç ve yöntem: Çalışmamızda 36 skuamöz hücreli karsinom (SHK) ve 36 adenokarsinom olmak üzere toplam 72 akciğer dokusunda anjiogenik faktörlerden endoglin (CD105), CD31, VEGFR2’nin ekspresyonu immünohistokimyasal olarak incelendi. Primer akciğer kanseri tanısı alan gönüllü 26 kişinin ve 26 sağlıklı gönüllüden alınan serumlarda endoglin seviyesi Elisa yöntemi ile tespit edildi.
Bulgular: Endoglinin aktive edilmiş endotelyal hücreleri için daha büyük bir afiniteye sahip olduğunu gözledik. Her iki tümör tipinde CD31 nonspesifik boyanma göstermiş MY daha zor tespit edilmiştir. VEGFR2 boyalı kesitlerde tümör içinde ve dışındaki damar duvarlarında yaygın pozitiflik saptandı. Serum endoglin seviyesinin KHDAK hastaları ile kontrol grubu arasında istatistiksel olarak anlamlı olmadığı tespit edildi. İmmünohistokimyasal olarak endoglin, CD31 ve VEGFR2 ekspresyonu ile sağkalım arasında istatistiksel olarak anlamlılık mevcut değildi.
Sonuç: Çalışmamız sonucunda KHDAK’de immünohistokimyasal olarak spesifik boyanan endoglinin SHK ve adenokarsinom tipli hastalarda anjiogenezin değerlendirilmesinde daha iyi bir belirteç olabileceğini düşünmekteyiz.

Anahtar Kelimeler

Küçük hücreli dışı akciğer kanseri (KHDAK), anjiogenez, endoglin, CD31, VEGFR2

Destekleyen Kurum

Pamukkale Üniversitesi, Bilimsel Araştırma Projeleri Koordinasyon Birimi

Proje Numarası

2017SABE003

Microvessel density determined by endoglin, CD31 and VEGFR2 and its effect on survival in non-small cell lung cancers

Öz

Purpose: Increasing day by day, cancer is a serious global health problem of our age and lung cancer is the most common cancer in the total number of cancers worldwide. Angiogenesis plays an important role in the development and metastasis of tumors. It has been shown that microvessel density (MY) calculated with different endothelial markers is associated with poor prognosis and advanced stage in some tumors and from there it is suggested that metastasis can be predicted. In our study, we aimed to detect MY immunohistochemically with endoglin, CD31 and VEGFR2 in non-small cell lung cancers (KHDAK), correlate it with serum endoglin level and compare our results with the progression of lung tumors.
Materials and methods: In our study, the expression of endoglin (CD105), CD31, VEGFR2 from angiogenic factors was examined immunohistochemically in a total of 72 lung tissues, 36 of which were squamous cell carcinomas (SHK) and 36 were adenocarcinomas. Endoglin level was determined by Elisa method from blood taken from 26 volunteers and 26 healthy volunteers diagnosed with primary lung cancer.
Results: We observed that endoglin has a greater affinity for activated endothelial cells. Both tumor types showed nonspecific CD31 staining, and MY was difficult to determine. On VEGFR2 stained sections, diffuse positivity was detected in the vessel walls inside and outside the tumor. It was found that the blood endoglin level was not statistically significant between the KHDAK and the control group. Immunohistochemically, there was no difference statistically significant between endoglin, CD31 and VEGFR2 expression and survival.
Conclusions: As a result of our study, we think that immunohistochemically specific stained endoglin in KHDAK may be a better marker in the evaluation of angiogenesis in patients with both SHK and adenocarcinoma types.

Anahtar Kelimeler

Non-Small cell lung cancer, angiogenesis, endoglin, CD31, VEGFR2

Proje Numarası

2017SABE003

Kaynakça

• Referans1. Jain RK. Normalizing tumor vasculature with antiangiogenetic therapy. Nat Med 2001;7(9):987-989. https://doi.org/10.1038/nm0901-987
• Referans2. Shields TW. Pathology of Careinoma of The Lung. in Shields TW (ed): General Thoracic Surgery, 6th ed. Lippincott Willams&Wilkins; Philadelphia,2005;1455-1481.
• Referans3. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011;473:298–307. https://doi.org/10.1038/nature10144
• Referans4. Lima AB, Macedo LT, Sasse AD. Addition of bevacizumabto chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis. PLoS One 2011;6:e22681. https://doi: 10.1371/journal.pone.0022681. Epub 2011 Aug 2.
• Referans5. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990;82(1):4–6. https://doi.org/10.1093/jnci/82.1.4
• Referans6. Wikström P, Lissbrant IF, Stattin P, Egevad L, Bergh A. Endoglin (CD105) is expressed on immature blood vessels and is a marker for survival in prostate cancer; Prostate 2002;51(4):268-275. https://doi.org/10.1002/pros.10083
• Referans7. Brewer CA, Setterdahl JJ, Li MJ, Johnston JM, Mann JL, McAsey ME. Endoglin expression as a measure of microvessel density in cervical cancer. Obstet Gynecol 2000;96(2):224-228. https://doi.org/10.1016/S0029-7844(00)00864-4
• Referans8. Kumar S, Ghellal A, Li C, et al. Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis. Cancer Res 1999;59:856-861.
• Referans9. Tanaka F, Otake Y, Yanagihara K, et al. Evaluation of Angiogenesis in Non-small Cell Lung Cancer: Comparison between Anti-CD34 Antibody and
Anti-CD105 Antibody. Clin Cancer Res 2001;7:3410-3415.
• Referans10. Charpin-Taranger C, Dales JP, Garcia S, et al. The immunohistochemical expression of CD105 is a marker for high metastatic risk and worse prognosis in breast cancers. Bull Acad Natl Med 2003;187:1129-1145.
• Referans11. DeLisser HM, Baldwin HS, Albelda SM. Platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31): a multifunctional vascular cell adhesion molecule. Trends Cardiovasc Med 1997;7:203-210. https://doi.org/10.1016/S1050-1738(97)00049-2
• Referans12. Matsumura T, Wolff K, Petzelbauer P. Endothelial cell tube formation depends on cadherin 5 and CD31 interactions with filamentous actin. J Immunol 1997;158:3408-3416.
• Referans13. Pinter E, Barreuther M, Lu T, Imhof BA, Madri JA. Platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) tyrosine phosphorylation state changes during vasculogenesis in the murine conceptus. Am J Pathol 1997;150:1523-1530.
• Referans14. Fernández-Martín L, Marcos- Ramiro B, Bigarella CL, et all. Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion Molecule-1 regulates endothelial barrier function. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:e90–e102. https://doi.org/10.1161/ATVBAHA.112.252080
• Referans15. Prior BM, Yang HT, Terjung RL. What makes vessels grow with exercise training? J Appl Physiol (1985).2004;97:1119-1128. https://doi.org/10.1152/japplphysiol.00035.2004
• Referans16. Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology 2005;69:4–10. https://doi.org/10.1159/000088478
• Referans17. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. (Eds.), WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (4th ed.), International Agency for Research on Cancer, Lyon, France;2015.
• Referans18. Travis WD, Brambilla E, Hermelink HKM, Haris CC. Pathology and Genetics of Tumors of the Lung, Plevra, Thymus and Heart, Lyon: IARC Press; 2004.
• Referans19. Moran CA. Pulmonary adenocarcinoma: the expanding spectrum of histologic variants. Arch Pathol Lab Med 2006;130:958-62. https://doi.org/10.1043/1543-2165(2006)130[958:pateso]2.0.co;2
• Referans20. Bozkurt B, Selçuk ZT, Fırat P, Kalyoncu AF, Artvinli M. 1972-2002 döneminde Hacettepe Üniversitesi Tıp Fakültesi Hastanesinde akciğer kanseri tanısı konulan hastaların histolojik ve epidemiyolojik değerlendirilmesi. Toraks Dergisi 2004;5:148-153.
• Referans21. Sulu E, Damadoğlu E, Nergiz S, ve ark. Primer akciğer kanserinde tümör tipi ve cinsiyet dağılımı değişiyormu? 2004 yılı sonuçlarının daha önceki yıllar ile karşılaştırılması. Tüberküloz ve Toraks Dergisi 2007;55:59-63.
• Referans22. Bochner BH, Cote RJ, Weidner N, et al. Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst 1995;87:1603–1612. https://doi.org/10.1093/jnci/87.21.1603
• Referans23. Mineo TC, Ambrogi V, Baldi A, et al. Prognostic impact of VEGF, CD31, CD34, and CD105 expression and tumour vessel invasion after radical surgery for IB–IIA non-small cell lung cancer. J Clin Pathol 2004;57:591–597. http://dx.doi.org/10.1136/jcp.2003.013508
• Referans24. Ciocâlteu A, Săftoiu A, Pirici D, et all. Tumor neoangiogenesis detection by confocal laser endomicroscopy and anti-CD105 antibody: Pilot study. World J Gastrointest Oncol 2015;7:361-368. https://doi.org/10.4251/wjgo.v7.i11.361
• Referans25. Mitselou A, Galani V, Skoufi U, Arvanitis DL, Lampri E, Ioachim E. Syndecan-1, Epithelial-Mesenchymal Transition Markers (E-cadherin/β-catenin) and Neoangiogenesis-related Proteins (PCAM-1 and Endoglin) in Colorectal Cancer. Anticancer Res 2016;36(5):2271-80.
• Referans26. Moghaddam NA, Mahsuni P, Taheri D. Evaluation of Endoglin as an Angiogenesis Marker in Glioblastoma. Iran J Pathol 2015;10:89-96.
• Referans27. Tanno S, Ohsaki Y, Nakanishi K, Toyoshima E, Kikuchi K. Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3. Lung Cancer 2004;46:11-19. https://doi.org/10.1016/j.lungcan.2004.03.006
• Referans28. Wu W, Onn A, Isobe T, et al. Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade. Mol Cancer Ther 2007;6:471-483. https://doi.org/10.1158/1535-7163.mct-06-0416
• Referans29. Bonnesen B, Pappot H, Holmstav J, Skov BG. Vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 expression in non-small cell lung cancer patients:Relation to prognosis. Lung Cancer 2009;66:314-318. https://doi.org/10.1016/j.lungcan.2009.02.013
• Referans30. Pajares MJ, Agorreta J, Larrayoz M, et al. Expression of tumor-derived vascular endothelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung. J Clin Oncol 2012;30:1129-1136. https://doi.org/10.1200/jco.2011.37.4231
• Referans31. Holzer TR, Fulford AD, Nedderman DM, et al. Tumor cell expression of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in patients with squamous cell carcinoma of the lung. PLoS One 2013;8:e80292. https://doi.org/10.1371/journal.pone.0080292
• Referans32. Seto T, Higashiyama M, Funai H, et al. Prognostic value of expression of vascular endothelial growth factor and its flt-1and KDR receptors in stage I non-small-cell lung cancer. Lung Cancer 2006;53:91-96. https://doi.org/10.1016/j.lungcan.2006.02.009
• Referans33. Carrillo de Santa Pau E, Arias FC, Caso Peláez E, et al. Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer. Cancer 2009;115:1701-1712. https://doi.org/10.1002/cncr.24193
• Referans34. Smith NR, Baker D, James NH, et al. Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res 2010;16:3548-3561. https://doi.org/10.1158/1078-0432.ccr-09-2797
• Referans35. Devery AM, Wadekar R, Bokobza SM, Weber AM, Jiang Y and Ryan AJ. Vascular endothelial growth factor directly stimulates tumour cell proliferation in non-small cell lung cancer. Int J Oncol 2015;47:849-856. https://doi.org/10.3892/ijo.2015.3082
• Referans36. Szubert S, Moszynski R, Michalak S, Nowicki M, Sajdak S, Szpurek D. The associations between serum VEGF, bFGF and endoglin levels with microvessel density and expression of proangiogenic factors in malignant and benign ovarian tumors. Microvasc Res 2016;107 91-96. https://doi.org/10.1016/j.mvr.2016.06.002