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Clinical influence of cancer stem cells on residual disease after preoperative chemoradiotherapy for rectal cancer

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Tumor Biology

Abstract

We evaluated the clinical influence of cancer stem cells (CSCs) on residual disease after preoperative chemoradiotherapy (CRT) in patients with rectal cancer. The surgical specimens of 145 patients with residual rectal cancer after preoperative CRT were assessed. To identify CSCs, immunohistochemistry was performed using their surrogate makers (CD44 and aldehyde dehydrogenase 1 [ALDH1]) in full section tissues. Of the 145 cases, ALDH1 and CD44 positivity was found in 80.0 % (n = 116) and 47.6 % (n = 69), respectively; ALDH1 positivity showed weakly positive correlation with CD44 (r s  = 0.269, P = 0.002). ALDH1 and CD44 positivity was related to lower tumor regression grade (TRG) (P = 0.009 and 0.003, respectively). Additionally, ALDH1 positivity was associated with positive circumferential resection margin (P = 0.019). However, ALDH1 and CD44 positivity showed no relationship with KRAS or BRAF mutation. In univariate analysis, ALDH1 positivity was associated with short recurrence-free survival (RFS) (P = 0.005) and rectal cancer-specific survival (RCSS) (P = 0.043), but not CD44 positivity (RFS, P = 0.725; RCSS, P = 0.280). In multivariate analysis, ALDH1 positivity was an independent prognostic factor for poor RFS (P = 0.039; hazard ratio = 2.997; 95 % confidence interval = 1.059–8.478), but not RCSS (P = 0.571). The expression of ALDH1 assessment independently predicts RFS in patients with residual disease after CRT. These results suggest that targeting CSCs could be an effective therapeutic approach to rectal cancer patients receiving preoperative CRT.

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References

  1. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–40. doi:10.1056/NEJMoa040694.

    Article  CAS  PubMed  Google Scholar 

  2. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30(16):1926–33. doi:10.1200/jco.2011.40.1836.

    Article  CAS  PubMed  Google Scholar 

  3. Rodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23(34):8688–96. doi:10.1200/jco.2005.02.1329.

    Article  PubMed  Google Scholar 

  4. Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458(7239):780–3. doi:10.1038/nature07733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Boman BM, Wicha MS. Cancer stem cells: a step toward the cure. J Clin Oncol. 2008;26(17):2795–9. doi:10.1200/jco.2008.17.7436.

    Article  PubMed  Google Scholar 

  6. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11. doi:10.1038/35102167.

    Article  CAS  PubMed  Google Scholar 

  7. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3(12):895–902. doi:10.1038/nrc1232.

    Article  CAS  PubMed  Google Scholar 

  8. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63(18):5821–8.

    CAS  PubMed  Google Scholar 

  9. Ginestier C, Hur MH, 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. Cell Stem Cell. 2007;1(5):555–67. doi:10.1016/j.stem.2007.08.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kakarala M, Wicha MS. Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol. 2008;26(17):2813–20. doi:10.1200/jco.2008.16.3931.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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(7123):106–10. doi:10.1038/nature05372.

    Article  CAS  PubMed  Google Scholar 

  12. 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(7123):111–5. doi:10.1038/nature05384.

    Article  CAS  PubMed  Google Scholar 

  13. Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One. 2008;3(6):e2428. doi:10.1371/journal.pone.0002428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sprenger T, Conradi LC, Beissbarth T, Ermert H, Homayounfar K, Middel P, et al. Enrichment of CD133-expressing cells in rectal cancers treated with preoperative radiochemotherapy is an independent marker for metastasis and survival. Cancer. 2013;119(1):26–35. doi:10.1002/cncr.27703.

    Article  CAS  PubMed  Google Scholar 

  15. Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest. 2008;118(6):2111–20. doi:10.1172/jci34401.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lugli A, Iezzi G, Hostettler I, Muraro MG, Mele V, Tornillo L, et al. Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer. Br J Cancer. 2010;103(3):382–90. doi:10.1038/sj.bjc.6605762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Du L, Wang H, He L, Zhang J, Ni B, Wang X, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008;14(21):6751–60. doi:10.1158/1078-0432.ccr-08-1034.

    Article  CAS  PubMed  Google Scholar 

  18. Nagano O, Saya H. Mechanism and biological significance of CD44 cleavage. Cancer Sci. 2004;95(12):930–5.

    Article  CAS  PubMed  Google Scholar 

  19. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990;61(7):1303–13.

    Article  CAS  PubMed  Google Scholar 

  20. Deng Y, Zhou J, Fang L, Cai Y, Ke J, Xie X, et al. ALDH1 is an independent prognostic factor for patients with stages II-III rectal cancer after receiving radiochemotherapy. Br J Cancer. 2014;110(2):430–4. doi:10.1038/bjc.2013.767.

    Article  CAS  PubMed  Google Scholar 

  21. Oh SY, Sohn SH, Yim H, Lee D, Suh KW, Kim YB. ALDH1 is a prognostic factor for patients treated with neoadjuvant chemoradiotherapy and radical resection for stage III rectal cancer. J Surg Oncol. 2014. doi:10.1002/jso.23792.

    Google Scholar 

  22. Avoranta ST, Korkeila EA, Ristamaki RH, Syrjanen KJ, Carpen OM, Pyrhonen SO, et al. ALDH1 expression indicates chemotherapy resistance and poor outcome in node-negative rectal cancer. Hum Pathol. 2013;44(6):966–74. doi:10.1016/j.humpath.2012.10.003.

    Article  CAS  PubMed  Google Scholar 

  23. Kim HJ, Choi GS, Park JS, Park S, Kawai K, Watanabe T. Clinical significance of thrombocytosis before preoperative chemoradiotherapy in rectal cancer: predicting pathologic tumor response and oncologic outcome. Ann Surg Oncol. 2014. doi:10.1245/s10434-014-3988-8.

    Google Scholar 

  24. Edge SB, Byrd DR, Compton C, Fritz A, Greene F, Trotti A (2010) American joint committee on cancer staging manual. American Joint Committee on Cancer Staging Manual

  25. Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) WHO classification of tumours of the digestive system, vol Ed. 4. World Health Organization

  26. Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet. 1986;2(8514):996–9.

    Article  CAS  PubMed  Google Scholar 

  27. Rullier A, Gourgou-Bourgade S, Jarlier M, Bibeau F, Chassagne-Clement C, Hennequin C, et al. Predictive factors of positive circumferential resection margin after radiochemotherapy for rectal cancer: the French randomised trial ACCORD12/0405 PRODIGE 2. Eur J Cancer. 2013;49(1):82–9. doi:10.1016/j.ejca.2012.06.028.

    Article  PubMed  Google Scholar 

  28. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Color Dis. 1997;12(1):19–23.

    Article  CAS  Google Scholar 

  29. Resetkova E, Reis-Filho JS, Jain RK, Mehta R, Thorat MA, Nakshatri H, et al. Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment. Breast Cancer Res Treat. 2010;123(1):97–108. doi:10.1007/s10549-009-0619-3.

    Article  PubMed  Google Scholar 

  30. Yoshioka T, Umekita Y, Ohi Y, Souda M, Sagara Y, Sagara Y, et al. Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study. Histopathology. 2011;58(4):608–16. doi:10.1111/j.1365-2559.2011.03781.x.

    Article  PubMed  Google Scholar 

  31. Morimoto K, Kim SJ, Tanei T, Shimazu K, Tanji Y, Taguchi T, et al. Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression. Cancer Sci. 2009;100(6):1062–8. doi:10.1111/j.1349-7006.2009.01151.x.

    Article  CAS  PubMed  Google Scholar 

  32. Diaz LK, Zhou X, Wright ET, Cristofanilli M, Smith T, Yang Y, et al. CD44 expression is associated with increased survival in node-negative invasive breast carcinoma. Clin Cancer Res. 2005;11(9):3309–14. doi:10.1158/1078-0432.ccr-04-2184.

    Article  CAS  PubMed  Google Scholar 

  33. Kwon MJ, Lee SE, Kang SY, Choi YL. Frequency of KRAS, BRAF, and PIK3CA mutations in advanced colorectal cancers: Comparison of peptide nucleic acid-mediated PCR clamping and direct sequencing in formalin-fixed, paraffin-embedded tissue. Pathol Res Pract. 2011;207(12):762–8. doi:10.1016/j.prp.2011.10.002.

    Article  CAS  PubMed  Google Scholar 

  34. Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology. 2010;138(6):2151–62. doi:10.1053/j.gastro.2009.12.063.

    Article  CAS  PubMed  Google Scholar 

  35. Kemper K, Grandela C, Medema JP. Molecular identification and targeting of colorectal cancer stem cells. Oncotarget. 2010;1(6):387–95.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 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(4):389–402. doi:10.1016/j.stem.2007.08.001.

    Article  CAS  PubMed  Google Scholar 

  37. Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren 2nd G. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 2009;69(5):1951–7. doi:10.1158/0008-5472.can-08-2023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (grant number: NRF-2015R1C1A1A02037597).

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Authors and Affiliations

  1. Department of Pathology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, 807 Hogukno, Buk-gu, Daegu, 41404, South Korea

    Ghilsuk Yoon, Sol-Min Kim & An Na Seo

  2. Colorectal Cancer Center, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, 807 Hogukno, Buk-gu, Daegu, 41404, South Korea

    Hye Jin Kim

  3. Department of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, South Korea

    An Na Seo

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Figure S1

Prognostic values of ALDH1 on residual rectal cancer after preoperative CRT. Kaplan-Meier estimates of rectal cancer specific survival (A) for patients with downstaging and (B) for patients without downstaging. (GIF 9 kb)

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Yoon, G., Kim, SM., Kim, H.J. et al. Clinical influence of cancer stem cells on residual disease after preoperative chemoradiotherapy for rectal cancer. Tumor Biol. 37, 3571–3580 (2016). https://doi.org/10.1007/s13277-015-4201-9

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  • DOI: https://doi.org/10.1007/s13277-015-4201-9

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