Top

Published in:

01-03-2016

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

Authors: Ghilsuk Yoon, Sol-Min Kim, Hye Jin Kim, An Na Seo

Published in: Tumor Biology | Issue 3/2016

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.

Available only for authorised users

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.PubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

18.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.

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.CrossRefPubMed

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.

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.CrossRefPubMed

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.CrossRefPubMed

28.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

35.

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

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

Title: Clinical influence of cancer stem cells on residual disease after preoperative chemoradiotherapy for rectal cancer
Authors: Ghilsuk Yoon
Sol-Min Kim
Hye Jin Kim
An Na Seo
Publication date: 01-03-2016
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 3/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-4201-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2016

Silencing of FGFR4 could influence the biological features of gastric cancer cells and its therapeutic value in gastric cancer

The potential role of the NEK6, AURKA, AURKB, and PAK1 genes in adenomatous colorectal polyps and colorectal adenocarcinoma

Lin28: an emerging important oncogene connecting several aspects of cancer

Evaluation of cannabinoid CB1 and CB2 receptors expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients’ survival

Apoptotic effects of salinomycin on human ovarian cancer cell line (OVCAR-3)

Deregulation of miR-93 and miR-143 in human esophageal cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer