KOLOREKTAL KANSERDE ARTMIŞ ENDOGLİN DÜZEYİ İLE İNFLAMATUVAR TÜMÖR MİKROÇEVRE İLİŞKİSİ

Year 2025, Volume: 49 Issue: 3, 681 - 688, 19.09.2025

Gizem Ozsener , Dilsa Mızrak Kaya , Filiz Bakar Ateş

https://doi.org/10.33483/jfpau.1647572

Abstract

Amaç: Kolorektal kanser (CRC) dünyada en yaygın görülen kanserlerden biri olup, kansere bağlı ölümlerin önde gelen nedenleri arasındadır. Tümörlerin sıklıkla kronik enflamasyon ortamında geliştiği ve tümör biyopsi örneklerinde enflamatuvar hücrelerin mevcut olduğu gözlemine dayanarak, enflamasyon ve kanser arasında nedensel bir bağlantı öne sürülmüştür. Epidemiyolojik çalışmalar, kronik enflamasyonun farklı kanser türlerine zemin hazırladığını ortaya çıkarmıştır. Kronik inflamasyonun kanser gelişimini destekleyebildiğini ve tümör kaynaklı enflamasyonun kartopu etkisi yaratarak tümör progresyonunu sürdürdüğünü gösteren çok sayıda kanıt bulunmaktadır. Endoglin, vasküler endotel hücrelerinde tanımlanmış bir transmembran glikoprotein olup, endoglinin çeşitli hastalıklarda anjiyogenez ve inflamasyon gelişimi ile ilişkili olduğu gösterilmiştir. Bu çalışmada, kolorektal kanser hastalarında endoglin ile inflamatuvar mikroçevre ilişkisinin araştırılması amaçlandı.
Gereç ve Yöntem: Kolorektal kanser tanısı almış 50 hasta ile 50 sağlıklı gönüllü çalışmaya dahil edildi. Plazma örneklerinde, endoglin ve yaygın olarak bilinen enflamasyon belirteçlerinden olan sPLA2, cPLA2, NfκB, TGF-β1 düzeyleri ELISA (enzyme-linked immunosorbent assay) yöntemi ile ölçüldü. Ayrıca, endoglin ve PLA2 mRNA ekspresyon düzeyleri Real-Time PCR ile belirlendi.
Sonuç ve Tartışma: Kolorektal kanser hastalarında plazma endoglin, NfκB, TGFβ1 düzeylerinin, kontrol grubuna göre anlamlı olarak yüksek olduğu saptanırken, cPLA2 ve sPLA2 düzeylerinde gruplar arasında anlamlı bir farklılık bulunmadı. Kolorektal kanser grubuna ait plazma endoglin düzeyleri ile NFκB arasında anlamlı pozitif korelasyon saptandı. Gen ekspresyon analizi bulguları, kolorektal kanser grubunda endoglin ve PLA2 mRNA ekspresyon düzeylerinin, kontrol grubuna göre anlamlı olarak yüksek olduğunu gösterdi. Sonuç olarak, bu çalışma endoglinin kolorektal kanserdeki artışının inflamasyon gelişimi ile ilişki olabileceğini ve inflamatuvar mikroçevre ile ilişkili kötü prognozda rol oynayabileceğini göstermiştir.

Keywords

Endoglin , Kolorektal Kanser , NFκB , PLA2 , TGFβ1

Project Number

18L0237008

ELEVATED ENDOGLIN LEVELS AND THEIR LINK TO THE INFLAMMATORY TUMOR MICROENVIRONMENT IN COLORECTAL CANCER

Abstract

Objective: Colorectal cancer (CRC) is one of the most common cancers worldwide and is one of the leading causes of cancer-related deaths. The causal link between inflammation and cancer has been proposed based on the observation that tumors often develop in a chronic inflammatory environment and that inflammatory cells are present in tumor biopsy specimens. Epidemiological studies have revealed that chronic inflammation provides a basis for different types of cancer. There is a great deal of evidence to suggest that chronic inflammation can support cancer development and that tumor-induced inflammation maintains tumor progression by creating a snowball effect. Endoglin is a transmembrane glycoprotein identified in vascular endothelial cells and has been shown to be associated with angiogenesis and inflammation in various diseases. This study aimed to investigate the relationship between endoglin and the inflammatory microenvironment in colorectal cancer patients.
Material and Method: 50 patients diagnosed with colorectal cancer and 50 healthy volunteers were included in the study. In plasma samples, endoglin and commonly known inflammation markers such as sPLA2, cPLA2, NfκB, and TGFβ1 levels were measured by ELISA (enzyme-linked immunosorbent assay) method. In addition, endoglin and PLA2 mRNA expression were determined by Real-Time PCR.
Result and Discussion: In colorectal cancer patients, plasma endoglin, NfκB, TGFβ1 levels were found to be significantly higher than in the control group, while no significant difference was found between the groups in cPLA2 and sPLA2 levels. A significant positive correlation was found between plasma endoglin levels and NFκB in the colorectal cancer group. Gene expression analyses showed that endoglin and PLA2 mRNA expression levels were significantly higher in the colorectal cancer group than in the control group. In conclusion, this study showed that the increase in endoglin in colorectal cancer may be associated with the development of inflammation and may play a role in poor prognosis associated with the inflammatory microenvironment.

Keywords

Colorectal cancer , Endoglin , NFκB , PLA2 , TGFβ1

Project Number

18L0237008

References

• 1. Siegel, R.L., Giaquinto, A.N., Jemal, A. (2024). Cancer statistics, 2024. CA: A Cancer Journal for Clinicians, 74(2), 203. [CrossRef]
• 2. Rustgi, A.K. (2007). The genetics of hereditary colon cancer. Genes & Development, 21, 2525-2538. [CrossRef]
• 3. Westbrook, A.M., Szakmary, A., Schiestl, R.H. (2010). Mechanisms of intestinal inflammation and development of associated cancers: lessons learned from mouse models. Mutation Research, 705, 40-59. [CrossRef]
• 4. Beatty, J. (2014). Viral causes of feline lymphoma: Retroviruses and beyond. The Veterinary Journal, 201, 174-180. [CrossRef]
• 5. Francescone, R., Hou, V., Grivennikov, S.I. (2015). Cytokines IBD, and colitis-associated cancer. Inflammatory Bowel Disease, 21, 409-418. [CrossRef]
• 6. Calle, E.E., Kaaks, R. (2004). Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nature Reviews Cancer, 4, 579-591. [CrossRef]
• 7. Cohen, A.J., Pope, C.A. (1995). Lung cancer and air pollution. Environmental Health Perspectives, 103, 219-224. [CrossRef]
• 8. Wong, S.H., Hamel, L., Chevalier, S., Philip, A. (2000). Endoglin expression on human microvascular endothelial cells association with betaglycan and formation of higher order complexes with TGF-beta signalling receptors. European Journal of Biochemistry, 267, 5550-5560. [CrossRef]
• 9. Wikström, P., Lissbrant, I.F., Stattin, P., Egevad, L., Bergh, A. (2002). Endoglin (CD105) is expressed on immature blood vessels and is a marker for survival in prostate cancer. Prostate, 51, 268-275. [CrossRef]
• 10. González Muñoz, T., Amaral, A.T., Puerto-Camacho, P., Peinado, H., de Álava, E. (2021). Endoglin in the Spotlight to Treat Cancer. International Journal of Molecular Sciences, 22(6), 3186. [CrossRef]
• 11. Ollauri-Ibáñez, C., Núñez-Gómez, E., Egido-Turrión, C., Silva-Sousa, L., Díaz-Rodríguez, E., Rodríguez-Barbero, A., López-Novoa, J.M., Pericacho, M. (2020). Continuous endoglin (CD105) overexpression disrupts angiogenesis and facilitates tumor cell metastasis. Angiogenesis, 23, 231-247. [CrossRef]
• 12. Xi, Y., Xu, P. (2021). Global colorectal cancer burden in 2020 and projections to 2040. Translational Oncology, 14(10), 101174. [CrossRef]
• 13. Mantovani, A., Allavena, P., Sica, A., Balkwill, F. (2008). Cancer-related inflammation. Nature, 454, 436-444.
• 14. Dallas, N.A., Samuel, S., Xia, L., Fan, F., Gray, M.J., Lim, S.J., Ellis, L.M. (2008). Endoglin (CD105): A marker of tumor vasculature and potential target for therapy. Clinical Cancer Research, 14, 1931-1937. [CrossRef]
• 15. Paauwe, M., ten Dijke, P., Hawinkels, L.J. (2013). Endoglin for tumor imaging and targeted cancer therapy. Expert Opinion on Therapeutic Targets, 17, 421-435. [CrossRef]
• 16. She, X., Matsuno, F., Harada, N., Tsai, H., Seon, B.K. (2004). Synergy between anti-endoglin (CD105) monoclonalantibodies and TGF-beta in suppression of growth of human endothelial cells. International Journal of Cancer, 108(2), 251-257. [CrossRef]
• 17. Li, C., Guo, B., Wilson, P.B., Stewart, A., Byrne, G., Bundred, N., Kumar, S. (2000). Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer. International Journal of Cancer, 89, 122-126. [CrossRef]
• 18. Takahashi, N., Kawanishi-Tabata, R., Haba, A., Tabata, M., Haruta, Y., Tsai, H., Seon, B.K. (2001). Association of serum endoglin with metastasis in patients with colorectal, breast, and other solid tumors, and suppressive effect of chemotherapy on the serum endoglin. Clinical Cancer Research, 7(3), 524-532.
• 19. Marioni, G., D'Alessandro, E., Giacomelli, L., Staffieri, A. (2010). CD105 is a marker of tumour vasculature and a potential target for the treatment of head and neck squamous cell carcinoma. Journal of Oral Pathology and Medicine, 39(5), 361-367. [CrossRef]
• 20. Zhang, T., Ma, C., Zhang, Z., Zhang, H., Hu, H. (2021). NF-κB signaling in inflammation and cancer. MedComm, 2(4), 618-653. [CrossRef]
• 21. Yamaguchi, M., Okamura, S., Yamaji, T., Iwasaki, M., Tsugane, S., Shetty, V., Koizumi, T. (2019). Plasma cytokine levels and the presence of colorectal cancer. PLoS One, 14(3), e0213602. [CrossRef]
• 22. Guo, Q., Jin, Y., Chen, X., Ye, X., Shen, X., Lin, M., Zeng, C., Zhou, T., Zhang, J. (2024). NF-κB in biology and targeted therapy: New insights and translational implications. Signal Transduction and Targeting Therapy, 9, 53. [CrossRef]
• 23. Slattery, M.L., Fitzpatrick, F.A. (2009). Convergence of hormones, inflammation, and energy-related factors: a novel pathway of cancer etiology. Cancer Prevention Research, 2(11), 922-930. [CrossRef]
• 24. Hoesel, B., Schmid, J.A. (2013). The complexity of NF-κB signaling in inflammation and cancer. Molecular Cancer, 12, 86. [CrossRef]
• 25. Buckhaults, P., Rago, C., St Croix, B., Romans, K.E., Saha, S., Zhang, L., Vogelstein, B., Kinzler, K.W. (2001). Secreted and cell surface genes expressed in benign and malignant colorectal tumors. Cancer Research, 61(19), 6996-7001.
• 26. Friedman, E., Gold, L.I., Klimstra, D., Zeng, Z.S., Winawer, S., Cohen, A. (1995). High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer. Cancer Epidemiology, Biomarkers and Prevention. 4(5),549-554.
• 27. Itatani, Y., Kawada, K., Sakai, Y. (2019). Transforming Growth Factor-β Signaling Pathway in Colorectal Cancer and Its Tumor Microenvironment. International Journal of Molecular Sciences, 20(23), 5822. [CrossRef]
• 28. Kimawaha, P., Jusakul, A., Junsawang, P., Loilome, W., Khuntikeo, N., Techasen, A. (2020). Circulating TGF-β1 as the potential epithelial mesenchymal transition-biomarker for diagnosis of cholangiocarcinoma. Journal of Gastrointestinal Oncology, 11(2), 304-318. [CrossRef]
• 29. Divella, R., Daniele, A., Savino, E., Palma, F., Bellizzi, A., Giotta, F., Simone, G., Lioce, M., Quaranta, M., Paradiso, A., Mazzocca, A. (2013). Circulating levels of transforming growth factor-βeta (TGF-β) and chemokine (C-X-C motif) ligand-1 (CXCL1) as predictors of distant seeding of circulating tumor cells in patients with metastatic breast cancer. Anticancer Research, 33(4), 1491-1497.
• 30. Kelly, A., Houston, S.A., Sherwood, E., Casulli, J., Travis, M.A. (2017). Regulation of Innate and Adaptive Immunity by TGFβ. Advances in Immunology, 134, 137-233. [CrossRef]
• 31. Bennett, A., Civier, A., Hensby, C.N., Melhuish, P.B., Stamford, I.F. (1987). Measurement of arachidonate and its metabolites extracted from human normal and malignant gastrointestinal tissues. Gut, 28, 315-318. [CrossRef]
• 32. Soydan, A.S., Tavares, I.A., Weech, P.K., Temblay, N.M., Bennett, A. (1996). High molecular weight phospholipase A2 and fatty acids in human colon tumours and associated normal tissue. European Journal of Cancer, 32A(10), 1781-1787. [CrossRef]
• 33. Panel, V., Boëlle, P.Y., Ayala-Sanmartin, J., Jouniaux, A.M., Hamelin, R., Masliah, J., Trugnan, G., Fléjou, J.F., Wendum, D. (2006). Cytoplasmic phospholipase A2 expression in human colon adenocarcinoma is correlated with cyclooxygenase-2 expression and contributes to prostaglandin E2 production. Cancer Letters, 243, 255-263. [CrossRef]
• 34. Wendum, D., Svrcek, M., Rigau, V., Boëlle, P.Y., Sebbagh, N., Parc, R., Masliah, J., Trugnan, G., Fléjou, J.F. (2003). COX-2, inflammatory secreted PLA2, and cytoplasmic PLA2 protein expression in small bowel adenocarcinomas compared with colorectal adenocarcinomas. Modern Pathology, 16(2), 130-136. [CrossRef]
• 35. Yoo, Y.S., Lim, S.C., Kim, K.J. (2011). Prognostic significance of cytosolic phospholipase A2 expression in patients with colorectal cancer. Journal of the Korean Surgical Society, 80(6), 397-403. [CrossRef]