Advertisement

Journal of Gastrointestinal Cancer

, Volume 50, Issue 4, pp 824–837 | Cite as

The Prognostic Value of Cancer Stem Cell Markers (Notch1, ALDH1, and CD44) in Primary Colorectal Carcinoma

  • Salem Y. MohamedEmail author
  • Randa Mohamed Kaf
  • Mona Mostafa Ahmed
  • Amira Elwan
  • Hassan R Ashour
  • Amr Ibrahim
Original Research

Abstract

Background

Cancer stem cells proved to have a vital role in cell migration, invasion, metastasis, and treatment resistance of colorectal cancer (CRC) that subsequently lead to poor clinical outcomes. These stem cells may be a novel therapeutic target for the management of CRC progression. Signals of the Notch-1 pathway are responsible for acquisition of stem cell characters. ALDH1 and CD44 are usually detected in stem cells in colorectal cancer.

Aim

The aims of this work are to evaluate the immunohistochemical expression of cancer stem cell markers ALDH1, Notch1, and CD44 in colorectal cancer and investigate their correlation with clinicopathological characters and patient survival.

Methods

Paraffin-embedded specimens of 70 patients with primary colorectal carcinoma were analyzed for Notch 1, ALDH1, and CD44 expressions by immunohistochemistry.

Results

Notch1 was mainly located in the cytoplasm of CRC tissues, rarely expressed in adjacent normal tissues. A highly statistically significant relationship was found between grading, lymphovascular invasion, the degree of lymphocytic infiltration, peritumoral budding, lymph node ratio, lymph node metastasis, and Notch1 expression (p < 0.001). There was a highly statistically significant relationship found between AJCC stage and Notch1 expression (p < 0.001). CD44 was mainly located in the cell membrane of CRC tissues. A highly statistically significant relationship was found between grading (p = 0.006), lymphovascular invasion, the degree of lymphocytic infiltration, peritumoral budding, lymph node metastasis, lymph node ratio, and CD44 expression (p < 0.001). There was a highly statistically significant relationship found between AJCC stage and CD44 expression (p < 0.001). ALDH1 was detected in the cytoplasm of the CRC tissue. A highly statistically significant relationship was found between grading, lymphovascular invasion, the degree of lymphocytic infiltration, peritumoral budding, lymph node metastasis, lymph node ratio, and ALDH1 expression (p < 0.001). There was a highly statistically significant relationship found between AJCC stage and ALDH1 expression (p < 0.001). There is a highly statistically significant direct correlation between Notch1, CD44 expression, and ALDH1 expression (p < 0.001).

Conclusions

There is a substantial correlation between Notch 1, ALDH1, and CD44 as cancer stem cell markers and lymph node metastasis, advanced stage and tumor recurrence in colorectal carcinoma.

Conclusion

Expression of stem cell markers ALDH1, Notch1, and CD44 correlates with poor prognosis in a CRC and represents an independent prognostic factor. They are associated with a feature of epithelial-mesenchymal transition evidenced by their association with high tumor burden.

Keywords

Primary colorectal carcinoma Notch1 ALDH1 CD44 CSCs 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Boman B, Wicha M. Cancer stem cells: a step toward the cure. J Clin Oncol. 2008;26(17):2795–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Chang B, Liu G, Xue F, Rosen D, Xiao L, Wang X, et al. ALDH1 expression correlates with favorable prognosis in ovarian cancers. Mod Pathol. 2009;9(22):817–23.CrossRefGoogle Scholar
  3. 3.
    Chen J, Xia Q, Jiang B, Chang W, Yuan W, Ma Z, et al. Prognostic value of cancer stem cell marker ALDH1 expression in colorectal cancer: a systematic review and meta-analysis. PLoS One. 2015a;10(12):e0145164.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Chen L, Jiang B, Wang Z, Liu M, Yang H, Xing J. Combined preoperative CEA and CD44v6 improves prognostic value in patients with stage I and stage II colorectal cancer. Clin Transl Oncol. 2015b;16(3):285–92.CrossRefGoogle Scholar
  5. 5.
    Chu D, Zhang Z, Zhou Y, Wang W, Li Y, Zhang H, et al. Notch1 and Notch2 have opposite prognostic effects on patients. With colorectal cancer. Ann Oncol. 2011;22(11):2440–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Dalerba P, Dylla S, Park I, Liu R, Wang X, Cho R, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci. 2007;104(24):10158–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Edge S, Compton C. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.PubMedCrossRefGoogle Scholar
  9. 9.
    Fender A, Nutter J, Fitzgerald T, Bertrand F, Sigounas G. Notch1 promotes stemness and epithelial to mesenchymal transition in colorectal cancer. J Cell. 2015;116(11):2517–27.Google Scholar
  10. 10.
    Frank N, Schatton T, Frank M. The therapeutic promise of the cancer stem cell concept. J Clin Investig. 2010;120(1):41.PubMedCrossRefGoogle Scholar
  11. 11.
    Gado A, Ebeid B, Abdelmohsen A, Axon A. Colorectal cancer in Egypt is commoner in young people: is this cause for alarm? Alex J Med. 2014;50(3):197–201.CrossRefGoogle Scholar
  12. 12.
    Ginestier C, Hur M, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cancer Stem Cell. 2007;1(5):555–67.Google Scholar
  13. 13.
    Goossens-Beumer I, Zeestraten E, Benard A, Christen T, Reimers M, Keijzer R, et al. The clinical prognostic value of combined analysis of Aldh1, Survivin, and EpCAM expression in colorectal cancer. Br J Cancer. 2014;110(12):2935–44.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Hamilton S, Bosman F, Boffetta P, et al. Carcinoma of the colon and rectum. In: Bosman F, Carneiro F, Hruban R, Theise N, editors. WHO classification of tumors of the digestive system. 4th ed. Lyon: IARC; 2010. p. 134–46.Google Scholar
  15. 15.
    Hessman C, Bubbers E, Billingsley K, Herzig D, Wong M. Loss of expression of the cancer stem cell marker aldehyde dehydrogenase 1 correlates with advanced-stage colorectal cancer. Am J Surg. 2012;203(5):649–53.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Holah N, Aiad H, Asaad N, Elkhouly E, Lasheen A. Evaluation of the role of ALDH1 as cancer stem cell marker in colorectal carcinoma: an immunohistochemical study. J Clin Diagn Res. 2017;11(1):EC17.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Hong I, Hong S, Chang Y, Lee W, Lee B, Kang Y, et al. Expression of the cancer stem cell markers CD44 and CD133 in colorectal cancer: an immunohistochemical staining analysis. Ann Coloproctol. 2015;31(3):84–91.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hou Y, Liu Y, Zhao X. Expression of aldehyde dehydrogenase 1 in colon cancer. Asian Pac J Trop Med. 2013;6(7):574–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Huang F, Zhu X, Hu X, Fang Z, Tang L, Lu X, et al. Mesenchymal stem cells modified with miR-126 release angiogenic factors and activate notch ligand Delta-like-4, enhancing ischemic angiogenesis and cell survival. Int J Mol Med. 2013;31(2):484–92.PubMedCrossRefGoogle Scholar
  20. 20.
    Huh J, Kim H, Kim Y, Lee J, Park Y, Cho S, et al. Expression of standard CD44 in human colorectal carcinoma: association with prognosis. Pathol Int. 2009;59(4):241–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Lee S, Choi S, Kim W, et al. Combined aberrant expression of E-cadherin and S100A4, but not beta-catenin is associated with disease-free survival and overall survival in colorectal cancer patients. Diagn Pathol. 2013;8(1):99.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Liu D, Sun J, Zhu J, Zhou H, Zhang X, Zhang Y, et al. Expression and clinical significance of colorectal cancer stem cell marker EpCAMhigh/CD44+ in colorectal cancer. Oncol Lett. 2014;7:1544–8.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Mina L, Sledge G. Rethinking the metastatic cascade as a therapeutic target. Nat Rev Clin Oncol. 2011;8(6):325–32.PubMedCrossRefGoogle Scholar
  24. 24.
    Nour El Hoda S, Sharaf W, Helmy D, Zaki M, Badawi M, Soliman A. Detection of cancer stem cells in colorectal cancer: Histopathological and Immunohistochemical Study. Open Access Maced J Med Sci. 2016;4(4):543.CrossRefGoogle Scholar
  25. 25.
    Park I, Yu C, Lim S, et al. Ratio of metastatic lymph nodes is more important for rectal cancer patients treated with preoperative Chemoradiotherapy. World J Gastroenterol. 2015;21(11):3274–81.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Shinto E, Mochizuki H, Ueno H, Matsubara O, Jass JR. A novel classification of tumor budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci. Histopathology. 2005;47:25–31.PubMedCrossRefGoogle Scholar
  27. 27.
    Ueda K, Ogasawara S, Akiba J, Nakayama M, Todoroki K, Ueda K, et al. Aldehyde dehydrogenase 1 identifies cells with cancer stem cell-like properties in a human renal cell carcinoma cell line. PloS one. 2013;8(10):e75463.  https://doi.org/10.1371/journal.pone.0075463.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology. 2004;127:385–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Van Dussen K, Carulli A, Keeley T, Patel S, Puthoff B, Magness S, et al. nNotch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development. 2012;139(3):488–97.CrossRefGoogle Scholar
  30. 30.
    Vinson K, George D, Fender A, Bertrand F, Sigounas G. The notch pathway in colorectal cancer. Int J Cancer. 2016;138(8):1835–42.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Xu H, Tian Y, Yuan X, Wu H, Liu Q, Pestell R, et al. The role of CD44 in epithelial-mesenchymal transition and cancer development. Onco Targets Ther. 2015;8:3783.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Zavrides H, Zizi-Sermpetzoglou A, Panousopoulos D, Athanasas G, Elemenoglou I, Peros G. Prognostic evaluation of CD44 expression in correlation with bcl-2 and p53 in colorectal cancer. Folia Histochem Cytobiol. 2005;43(1):31–6.PubMedGoogle Scholar
  33. 33.
    Zhang Y, Li B, Ji Z, Zheng P. Notch1 regulates the growth of human colon cancers. Cancer. 2010;116(22):5207–18.PubMedCrossRefGoogle Scholar
  34. 34.
    Zheng C, Chen R, Xie J, Liu C, Jin Z, Jin C. Immunohistochemical expression of Notch1, Jagged1, NF-κB and MMP-9 in colorectal cancer patients and the relationship to clinicopathological parameters. Cancer Biomark. 2015;15(6):889–97.PubMedCrossRefGoogle Scholar
  35. 35.
    Zhou F, Mu Y, Liang J, Liu Z, Chen H, Zhang J. Expression and prognostic value of tumor stem cell markers ALDH1 and CD133 in colorectal carcinoma. Oncol Lett. 2014;7:507–12.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Gastroenterology and Hepatology Unit, Internal Medicine Department, Faculty of MedicineZagazig UniversityMarkaz El-ZakazikEgypt
  2. 2.Department of Pathology, Faculty of MedicineZagazig UniversityMarkaz El-ZakazikEgypt
  3. 3.Department of Clinical Oncology, Faculty of MedicineZagazig UniversityMarkaz El-ZakazikEgypt
  4. 4.Department of General Surgery, Faculty of MedicineZagazig UniversityMarkaz El-ZakazikEgypt

Personalised recommendations