Open Access

Prognostic implication of ABC transporters and cancer stem cell markers in patients with stage III colon cancer receiving adjuvant FOLFOX‑4 chemotherapy

  • Authors:
    • Song‑Hee Han
    • Jin Won Kim
    • Milim Kim
    • Jee Hyun Kim
    • Keun‑Wook Lee
    • Bo‑Hyung Kim
    • Heung‑Kwon Oh
    • Duck‑Woo Kim
    • Sung‑Bum Kang
    • Hyunchul Kim
    • Eun Shin
  • View Affiliations

  • Published online on: April 9, 2019     https://doi.org/10.3892/ol.2019.10234
  • Pages: 5572-5580
  • Copyright: © Han et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Cancer stem cell (CSC) and ATP‑binding cassette (ABC) transporters are associated with treatment resistance and outcomes of patients with cancer. The present study investigated the prognostic implications of pre‑therapeutic expression of ABC transporters and CSC markers in patients with colon cancer (CC) who received adjuvant 5‑fluorouracil, leucovorin and oxaliplatin combination therapy (FOLFOX‑4). The immunohistochemical expression of 3 ABC transporters, including ABC subfamily C member 2 (ABCC2), ABCC3 and ABC subfamily G member 2 (ABCG2), and 3 CSC markers, including sex determining region Y‑box 2 (SOX2), leucine‑rich repeat‑containing G protein‑coupled receptor 5 and aldehyde dehydrogenase 1, were determined in 164 CC tissues from patients with stage III CC, who underwent postoperative FOLFOX‑4 chemotherapy. The association between the protein expression and patients' prognoses was statistically analyzed. ABCG2 was associated with favorable overall survival rate (OS; P=0.001), and ABCC2, ABCG2 and SOX2 were associated with increased disease‑free survival rate (DFS; P=0.001, 0.002 and 0.013, respectively). In multivariate analyses, ABCG2 was an independent prognostic factor for OS [hazard ratio (HR)=2.877; P=0.046], and ABCC2 and SOX2 were independent prognostic factors for DFS (HR=2.831; P=0.014; HR=2.558, P=0.020, respectively). ABCC2, ABCG2 and SOX2 may be promising prognostic markers for patients with CC receiving FOLFOX‑4 therapy.

References

1 

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV and Mayer RJ: Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 23:8671–8678. 2005. View Article : Google Scholar : PubMed/NCBI

3 

Twelves C, Wong A, Nowacki MP, Abt M, Burris H III, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, et al: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 352:2696–2704. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, et al: Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 24:2059–2064. 2006. View Article : Google Scholar : PubMed/NCBI

5 

André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, et al Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators, : Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 350:2343–2351. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Gramont A, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Marceau-Suissa J, Lorenzato C and André T: Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: efficacy results with a median follow-up of 4 years. J Clin Oncol. 23 (Suppl 16):35012005. View Article : Google Scholar

7 

Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, et al: Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 25:2198–2204. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Maenhaut C, Dumont JE, Roger PP and van Staveren WC: Cancer stem cells: a reality, a myth, a fuzzy concept or a misnomer? An analysis. Carcinogenesis. 31:149–158. 2010. View Article : Google Scholar : PubMed/NCBI

9 

O'Brien CA, Kreso A and Jamieson CH: Cancer stem cells and self-renewal. Clin Cancer Res. 16:3113–3120. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Donnenberg VS and Donnenberg AD: Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J Clin Pharmacol. 45:872–877. 2005. View Article : Google Scholar : PubMed/NCBI

11 

Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Dave B and Chang J: Treatment resistance in stem cells and breast cancer. J Mammary Gland Biol Neoplasia. 14:79–82. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Crea F, Danesi R and Farrar WL: Cancer stem cell epigenetics and chemoresistance. Epigenomics. 1:63–79. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Vinogradov S and Wei X: Cancer stem cells and drug resistance: The potential of nanomedicine. Nanomedicine (Lond). 7:597–615. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Fábián A, Barok M, Vereb G and Szöllosi J: Die hard: Are cancer stem cells the Bruce Willises of tumor biology? Cytometry A. 75:67–74. 2009. View Article : Google Scholar : PubMed/NCBI

16 

Moitra K, Lou H and Dean M: Multidrug efflux pumps and cancer stem cells: Insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther. 89:491–502. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Shervington A and Lu C: Expression of multidrug resistance genes in normal and cancer stem cells. Cancer Invest. 26:535–542. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Gillet JP, Efferth T and Remacle J: Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochim Biophys Acta. 1775:237–262. 2007.PubMed/NCBI

19 

Li W, Zhang H, Assaraf YG, Zhao K, Xu X, Xie J, Yang DH and Chen ZS: Overcoming ABC transporter-mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies. Drug Resist Updat. 27:14–29. 2016. View Article : Google Scholar : PubMed/NCBI

20 

Artells R, Moreno I, Díaz T, Martínez F, Gel B, Navarro A, Ibeas R, Moreno J and Monzó M: Tumour CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patients. Eur J Cancer. 46:642–649. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Kahlert C, Gaitzsch E, Steinert G, Mogler C, Herpel E, Hoffmeister M, Jansen L, Benner A, Brenner H, Chang-Claude J, et al: Expression analysis of aldehyde dehydrogenase 1A1 (ALDH1A1) in colon and rectal cancer in association with prognosis and response to chemotherapy. Ann Surg Oncol. 19:4193–4201. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Liu Z, Dai W, Jiang L and Cheng Y: Over-expression of LGR5 correlates with poor survival of colon cancer in mice as well as in patients. Neoplasma. 61:177–185. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Wang X, Xia B, Liang Y, Peng L, Wang Z, Zhuo J, Wang W and Jiang B: Membranous ABCG2 expression in colorectal cancer independently correlates with shortened patient survival. Cancer Biomark. 13:81–88. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Hlavata I, Mohelnikova-Duchonova B, Vaclavikova R, Liska V, Pitule P, Novak P, Bruha J, Vycital O, Holubec L, Treska V, et al: The role of ABC transporters in progression and clinical outcome of colorectal cancer. Mutagenesis. 27:187–196. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Mirakhorli M, Shayanfar N, Rahman SA, Rosli R, Abdullah S and Khoshzaban A: Lack of association between expression of MRP2 and early relapse of colorectal cancer in patients receiving FOLFOX-4 chemotherapy. Oncol Lett. 4:893–897. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C and Kusunoki M: Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol. 16:3488–3498. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Hsu HC, Liu YS, Tseng KC, Hsu CL, Liang Y, Yang TS, Chen JS, Tang RP, Chen SJ and Chen HC: Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer. Int J Colorectal Dis. 28:1535–1546. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Hongo K, Tanaka J, Tsuno NH, Kawai K, Nishikawa T, Shuno Y, Sasaki K, Kaneko M, Hiyoshi M, Sunami E, et al: CD133(−) cells, derived from a single human colon cancer cell line, are more resistant to 5-fluorouracil (FU) than CD133(+) cells, dependent on the β1-integrin signaling. J Surg Res. 175:278–288. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Liu YS, Hsu HC, Tseng KC, Chen HC and Chen SJ: Lgr5 promotes cancer stemness and confers chemoresistance through ABCB1 in colorectal cancer. Biomed Pharmacother. 67:791–799. 2013. View Article : Google Scholar : PubMed/NCBI

30 

Yu Z, Zhang C, Wang H, Xing J, Gong H, Yu E, Zhang W, Zhang X, Cao G and Fu C: Multidrug resistance-associated protein 3 confers resistance to chemoradiotherapy for rectal cancer by regulating reactive oxygen species and caspase-3-dependent apoptotic pathway. Cancer Lett. 353:182–193. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Lin PC, Lin HH, Lin JK, Lin CC, Yang SH, Li AF, Chen WS and Chang SC: Expression of ABCG2 associated with tumor response in metastatic colorectal cancer patients receiving first-line FOLFOX therapy-preliminary evidence. Int J Biol Markers. 28:182–186. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Shima H, Kutomi G, Satomi F, Maeda H, Hirohashi Y, Hasegawa T, Mori M, Torigoe T and Takemasa I: SOX2 and ALDH1 as predictors of operable breast cancer. Anticancer Res. 36:2945–2953. 2016.PubMed/NCBI

33 

Chen J, Xia Q, Jiang B, Chang W, Yuan W, Ma Z, Liu Z and Shu X: Prognostic value of cancer stem cell marker ALDH1 expression in colorectal cancer: a systematic review and meta-analysis. PLoS One. 10:e01451642015. View Article : Google Scholar : PubMed/NCBI

34 

Yoshihama R, Yamaguchi K, Imajyo I, Mine M, Hiyake N, Akimoto N, Kobayashi Y, Chigita S, Kumamaru W, Kiyoshima T, et al: Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma. Oncol Lett. 11:1435–1446. 2016. View Article : Google Scholar : PubMed/NCBI

35 

Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, et al: AJCC cancer staging manual. 8th. Springer; New York: 2017, View Article : Google Scholar

36 

U.S. Department of Health Human Services, National Institutes of Health, National Cancer Institute, . Comom Terminology Criteria for Adverse Events (CTCAE). Version 4.0, 2009. simplehttps://www.eortc.be/services/doc/ctc/ctcae_4.03_2010-06-14_quickreference_5×7.pdfMay 28–2009

37 

Huang EH and Wicha MS: Colon cancer stem cells: Implications for prevention and therapy. Trends Mol Med. 14:503–509. 2008. View Article : Google Scholar : PubMed/NCBI

38 

Yoshida A, Rzhetsky A, Hsu LC and Chang C: Human aldehyde dehydrogenase gene family. Eur J Biochem. 251:549–557. 1998. View Article : Google Scholar : PubMed/NCBI

39 

Sophos NA and Vasiliou V: Aldehyde dehydrogenase gene superfamily: the 2002 update. Chem Biol Interact. 143-144:5–22. 2003. View Article : Google Scholar : PubMed/NCBI

40 

Yamanoi K, Fukuma M, Uchida H, Kushima R, Yamazaki K, Katai H, Kanai Y and Sakamoto M: Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in gastric cancer. Pathol Int. 63:13–19. 2013. View Article : Google Scholar : PubMed/NCBI

41 

Avoranta ST, Korkeila EA, Ristamäki RH, Syrjänen KJ, Carpén OM, Pyrhönen SO and Sundström JT: ALDH1 expression indicates chemotherapy resistance and poor outcome in node-negative rectal cancer. Hum Pathol. 44:966–974. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Saigusa S, Inoue Y, Tanaka K, Toiyama Y, Kawamura M, Okugawa Y, Okigami M, Hiro J, Uchida K, Mohri Y, et al: Significant correlation between LKB1 and LGR5 gene expression and the association with poor recurrence-free survival in rectal cancer after preoperative chemoradiotherapy. J Cancer Res Clin Oncol. 139:131–138. 2013. View Article : Google Scholar : PubMed/NCBI

43 

Lugli A, Iezzi G, Hostettler I, Muraro MG, Mele V, Tornillo L, Carafa V, Spagnoli G, Terracciano L and Zlobec I: Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer. Br J Cancer. 103:382–390. 2010. View Article : Google Scholar : PubMed/NCBI

44 

Tomita H, Tanaka K, Tanaka T and Hara A: Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget. 7:11018–11032. 2016. View Article : Google Scholar : PubMed/NCBI

45 

Chang B, Liu G, Xue F, Rosen DG, Xiao L, Wang X and Liu J: ALDH1 expression correlates with favorable prognosis in ovarian cancers. Modern pathology: An official journal of the United States and Canadian Academy of Pathology. Inc. 22:817–823. 2009.

46 

Boumahdi S, Driessens G, Lapouge G, Rorive S, Nassar D, Le Mercier M, Delatte B, Caauwe A, Lenglez S, Nkusi E, et al: SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature. 511:246–250. 2014. View Article : Google Scholar : PubMed/NCBI

47 

Zhu F, Qian W, Zhang H, Liang Y, Wu M, Zhang Y, Zhang X, Gao Q and Li Y: SOX2 is a marker for stem-like tumor cells in bladder cancer. Stem Cell Reports. 9:429–437. 2017. View Article : Google Scholar : PubMed/NCBI

48 

Amini S, Fathi F, Mobalegi J, Sofimajidpour H and Ghadimi T: The expressions of stem cell markers: Oct4, Nanog, Sox2, nucleostemin, Bmi, Zfx, Tcl1, Tbx3, Dppa4, and Esrrb in bladder, colon, and prostate cancer, and certain cancer cell lines. Anat Cell Biol. 47:1–11. 2014. View Article : Google Scholar : PubMed/NCBI

49 

Zhang X, Yu H, Yang Y, Zhu R, Bai J, Peng Z, He Y, Chen L, Chen W, Fang D, et al: SOX2 in gastric carcinoma, but not Hath1, is related to patients' clinicopathological features and prognosis. J Gastrointest Surg. 14:1220–1226. 2010. View Article : Google Scholar : PubMed/NCBI

50 

Kim BW, Cho H, Choi CH, Ylaya K, Chung JY, Kim JH and Hewitt SM: Clinical significance of OCT4 and SOX2 protein expression in cervical cancer. BMC Cancer. 15:10152015. View Article : Google Scholar : PubMed/NCBI

51 

Zheng S, Pan Y, Wang R, Li Y, Cheng C, Shen X, Li B, Zheng D, Sun Y and Chen H: SOX2 expression is associated with FGFR fusion genes and predicts favorable outcome in lung squamous cell carcinomas. Onco Targets Ther. 8:3009–3016. 2015.PubMed/NCBI

52 

Otsubo T, Akiyama Y, Yanagihara K and Yuasa Y: SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis. Br J Cancer. 98:824–831. 2008. View Article : Google Scholar : PubMed/NCBI

53 

Wang S, Tie J, Wang R, Hu F, Gao L, Wang W, Wang L, Li Z, Hu S, Tang S, et al: SOX2, a predictor of survival in gastric cancer, inhibits cell proliferation and metastasis by regulating PTEN. Cancer Lett. 358:210–219. 2015. View Article : Google Scholar : PubMed/NCBI

54 

Croom E: Metabolism of xenobiotics of human environments. Prog Mol Biol Transl Sci. 112:31–88. 2012. View Article : Google Scholar : PubMed/NCBI

55 

Burger H, Loos WJ, Eechoute K, Verweij J, Mathijssen RH and Wiemer EA: Drug transporters of platinum-based anticancer agents and their clinical significance. Drug Resist Updat. 14:22–34. 2011. View Article : Google Scholar : PubMed/NCBI

56 

Ballatori N, Hammond CL, Cunningham JB, Krance SM and Marchan R: Molecular mechanisms of reduced glutathione transport: Role of the MRP/CFTR/ABCC and OATP/SLC21A families of membrane proteins. Toxicol Appl Pharmacol. 204:238–255. 2005. View Article : Google Scholar : PubMed/NCBI

57 

El-akawi Z, Abu-hadid M, Perez R, Glavy J, Zdanowicz J, Creaven PJ and Pendyala L: Altered glutathione metabolism in oxaliplatin resistant ovarian carcinoma cells. Cancer Lett. 105:5–14. 1996. View Article : Google Scholar : PubMed/NCBI

58 

Smitherman PK, Townsend AJ, Kute TE and Morrow CS: Role of multidrug resistance protein 2 (MRP2, ABCC2) in alkylating agent detoxification: MRP2 potentiates glutathione S-transferase A1-1-mediated resistance to chlorambucil cytotoxicity. J Pharmacol Exp Ther. 308:260–267. 2004. View Article : Google Scholar : PubMed/NCBI

59 

Theile D, Grebhardt S, Haefeli WE and Weiss J: Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy. Biochem Pharmacol. 78:1366–1373. 2009. View Article : Google Scholar : PubMed/NCBI

60 

Krzyżanowski D, Bartosz G and Grzelak A: Collateral sensitivity: ABCG2-overexpressing cells are more vulnerable to oxidative stress. Free Radic Biol Med. 76:47–52. 2014. View Article : Google Scholar : PubMed/NCBI

61 

Brechbuhl HM, Gould N, Kachadourian R, Riekhof WR, Voelker DR and Day BJ: Glutathione transport is a unique function of the ATP-binding cassette protein ABCG2. J Biol Chem. 285:16582–16587. 2010. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 17 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Han, S., Kim, J.W., Kim, M., Kim, J.H., Lee, K., Kim, B. ... Shin, E. (2019). Prognostic implication of ABC transporters and cancer stem cell markers in patients with stage III colon cancer receiving adjuvant FOLFOX‑4 chemotherapy. Oncology Letters, 17, 5572-5580. https://doi.org/10.3892/ol.2019.10234
MLA
Han, S., Kim, J. W., Kim, M., Kim, J. H., Lee, K., Kim, B., Oh, H., Kim, D., Kang, S., Kim, H., Shin, E."Prognostic implication of ABC transporters and cancer stem cell markers in patients with stage III colon cancer receiving adjuvant FOLFOX‑4 chemotherapy". Oncology Letters 17.6 (2019): 5572-5580.
Chicago
Han, S., Kim, J. W., Kim, M., Kim, J. H., Lee, K., Kim, B., Oh, H., Kim, D., Kang, S., Kim, H., Shin, E."Prognostic implication of ABC transporters and cancer stem cell markers in patients with stage III colon cancer receiving adjuvant FOLFOX‑4 chemotherapy". Oncology Letters 17, no. 6 (2019): 5572-5580. https://doi.org/10.3892/ol.2019.10234