Clinicopathologic significance of high CD133 expression in colorectal carcinomas

Öz

Background: To investigate the prognostic significance of CD133 expression in colorectal carcinomas (CRC). Material and Method: CD133 expression was investigated immunohistochemically on the paraffin blocks of 70 sporadic colorectal carcinoma cases which were diagnosed at the department of pathology in Suleyman Demirel University. Low positivity was defined as positive immunoreactivity in < 50% of neoplastic glands, and high positivity was defined as positive immunoreactivity in ≥ 50% of neoplastic glands. Furthermore, the relation of CD133 immunohistochemical expression with pathologic parameters and survival rates were investigated. Results: CD133 expression was detected in 82.9% of the examined cases and high CD133 expression was significantly associated with poorer disease free survival (p=0.004). CD133 expression was significantly higher in tumors located in rectosigmoidal region (p=0.005) and showed a significant negative correlation with histologic grade (p=0.020). Conclusion: In the present study none of the poorly differentiated tumors showed high CD133 positivity probably due to the lack of luminal areas in poorly differentiated areas of the tumor, which is in consistence with the previously published data. Our results indicate that immunohistochemical CD133 expression, which correlates with poorer disease free survival, may be an independent prognostic marker in colorectal carcinoma. The findings of this study support the cancer stem cell model, and reveal the clinical importance of CD133 in CRC cases and present a strong association between high CD133 expression and disease-free survival

Anahtar Kelimeler

• CD133
• colon cancer
• immunohistochemistry
• prognosis

Kolorektal kanserlerde yüksek CD133 ekspresyonunun klinikopatolojik önemi

Öz

Amaç: Kolorektal karsinomlarda (CRC) CD133 ekspresyonunun prognostik öneminin
belirlenmesi hedeflendi. Materyal ve Metot: Süleyman Demirel Üniversitesi Patoloji
Anabilim Dalı’nda tanı almış sporadik kolorektal kanserli 70 olguya ait CD133
ekspresyonları, parafin bloklarda immunohistokimyasal olarak araştırıldı. Neoplazik
bezlerin % 50’sinden azında boyanma düşük pozitif; % 50 ve daha fazlasında boyanma
yüksek pozitif imünoreaktivite olarak değerlendirildi. Ayrıca, patolojik parametreler ve
sağ kalım oranları ile CD133 immünhistokimyasal ekspresyon düzeyleri arasındaki ilişki
araştırıldı. Bulgular: CD133 ekspresyonu incelenen olguların % 82.9’unda tespit edildi ve
yüksek CD133 düzeyi anlamlı (p = 0.004) derecede kötü hastalıksız sağkalım ile ilişkili
bulundu. CD133 ifadesi rektosigmoid bölgede bulunan tümörlerde anlamlı (p = 0.005)
derecede yüksekti ve histolojik grade ile anlamlı (p = 0.020) negatif korelasyon gösterdi.
Sonuç: Daha önceden yayınlanmış verilerle uyumlu olarak muhtemelen tümörün kötü
diferansiye alanlarındaki luminal bölgelerin eksikliğine bağlı olarak bu çalışmadaki kötü
diferensiye tümörlerde yüksek CD133 pozitifliği belirlenmedi. Sonuçlarımız kötü hastalıksız
sağkalım ile korelasyon gösteren immünohistokimyasal CD133 ekspresyonunun kolorektal
karsinoma için bağımsız bir prognostik belirleyici (markır) olabileceğini göstermektedir.
Bu çalışmanın bulguları, kanser kök hücre modelini desteklemekte ve CRC olgularında
CD133’ün klinik önemini ve yüksek CD133 ekspresyonu ile hastalıksız sağkalım arasında
güçlü bir ilişki olduğunu ortaya koymaktadır.

Anahtar Kelimeler

• CD133
• kolon kanseri
• immünohistokimya
• prognoz

Kaynakça

1. Lodewick TM, de Jong MC, van Dam RM, Bemelmans MHA, Neumann UP, Damink SWMO, et al. Effects of postoperative morbidity on long-term outcome following surgery for colorectal liver metastases. World J Surg 2015; 39(2): 478-86.
2. Naqvi S, Nazir SF. Screening for colorectal cancer. In: Khan JS, editor. Colorectal cancer - surgery, diagnostics and treatment, InTech; 2014. p. 3-22.
3. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med, 2006; 355: 1253-61.
4. Horst D, Scheel SK, Liebmann S, Neumann J, Maatz S, Kirchner T, et al. The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer. J Pathol 2009; 219: 427-34.
5. Kojima M, Ishii G, Atsumi N, Fujii S, Saito N, Ochiai A. Immunohistochemical detection of CD133 expression in colorectal cancer: A clinicopathoplogic study. Cancer Sci 2008; 99: 1578-83.
6. Shmelkov SV, St Clair R, Lyden D, Rafii S. AC133/ CD133/Prominin-1. Int J Biochem Cell Biol 2005; 37: 715-9.
7. O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445: 106- 10.
8. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445: 111-5.

9. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 2007; 1:389-402.
10. Rich JN, Bao S. Chemotherapy and cancer stem cells. Cell Stem Cell 2007; 1:353-5.
11. Li CY, Li BX, Liang Y, Peng RQ, Ding Y, Xu DZ, et al. Higher percentage of CD133+ cells is associated with poor prognosis in colon carcinoma patients with stage IIIB. J Transl Med 2009; 7:56-63.
12. Hamilton SR, Rubio CA, Vogelstein B. Carcinoma of the colon and rectum. In: Hamilton SR, Aaltonen LA, editors. World Health Organization classification of tumours. Tumours of the digestive system, Lyon: IARC Press; 2000. P. 101-119.
13. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, et al. AJCC Cancer Staging Manual, New York: Springer-Verlag, 2002.
14. Horst D, Kriegl L, Engel J, Kirchner T, Jung A. CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br J Cancer 2008; 99:1285-1289.
15. Vaz MA, Martinez JC, Devesa JM, Trill JD, Abraira V, Riquelme A, et al. Prognostic value of stem cell quantification in stage II colon cancer. Plos One 2014; 9(2): e88480.
16. El-Khattouti A, Sheehan NT, Monico J, Drummond HA, Haikel Y, Brodel R, et al. CD133(+) melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: Significance for melanoma treatment. Cancer Lett 2015; 357(1): 83- 104.
17. Wang Q, Chen ZG, Du CZ, Wang HW, Yan L, Gu J. Cancer stem cell marker CD133+ tumour cells and clinical outcome in rectal cancer. Histopathology 2009; 55: 284-293.
18. Mia-Jan K, Jung SY, Kim IY, Oh SS, Choi E, Chang SJ, et al. CD133 expression is not an independent prognostic factor in Stage II and III colorectal cancer but may predict the better outcome in patients with adjuvant therapy. BMC Cancer 2013; 13: 166-175.
19. Zhang NH, Li J, Li Y, Zhang XT, Liao WT, Zhang JY, et al. Coexpression of CXCR4 and CD133 proteins is associated with poor prognosis in stage II–III colon cancer patients. Exp Ther Med 2012; 3: 973-982.
20. Oliver JA, Ortiz R, Melguizo C, Álvarez PJ, Gómez- Millán J, Prados J. Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma. BMC Cancer 2014; 14: 511.
21. Singh T, Amirtham U, Satheesh CT, Lakshmaiah KC, Suresh TM, Govind Babu K, et al. Floor-of-mouth metastasis in colorectal cancer. Ann Saudi Med 2011; 31(1): 87–89.
22. Yuge R, Kitadai Y, Shinagawa K, Onoyama M, Tanaka S, Yasui W, et al. mTOR and PDGF pathway blockade inhibits liver metastasis of colorectal cancer by modulating the tumor microenvironment. Am J Pathol 2015; 185(2): 399-408.
23. Li L, Cole J, Margolin DA. Cancer stem cell and stromal microenvironment. Ochsner J 2013; 13: 109-118.
24. Li J, Guo H, Guan XD, Cai CN, Yang LK, Li YC, et al. The impact of laparoscopic converted to open colectomy on short-term and oncologic outcomes for colon cancer. J Gastrointest Surg 2015; 19: 335-343.
25. Vaiopoulos AG, Kostakis ID, Koutsilieris M, Papavassiliou AG. Colorectal cancer stem cells. Stem Cells 2012; 30: 363-371.
26. Anderson EC, Hessman C, Levin TG, Monroe MM, Wong MH. The role of colorectal cancer stem cells in metastatic disease and therapeutic response. Cancers (Basel) 2011; 1: 319-339.
27. Huh JW, Park YS, Lee JH, Kim HR, Shin MG, Kim YJ. CD133 mRNA expression and microsatellite instability in colorectal carcinoma. J Surg Oncol 2010; 102: 765-770