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Correlation of CD133, OCT4, and SOX2 in Rectal Cancer and Their Association with Distant Recurrence After Chemoradiotherapy

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Cancer stem cells are associated with metastatic potential, treatment resistance, and poor patient prognosis. Distant recurrence remains the major cause of mortality in rectal cancer patients with preoperative chemoradiotherapy (CRT). We investigated the role of three stem cell markers (CD133, OCT4, and SOX2) in rectal cancer and evaluated the association between these gene levels and clinical outcome in rectal cancer patients with preoperative CRT.

Methods

Thirty-three patients with rectal cancer underwent preoperative CRT. Total RNAs of rectal cancer cells before and after CRT were isolated. Residual cancer cells after CRT were obtained from formalin-fixed paraffin-embedded (FFPE) specimens using microdissection. The expression levels of three stem cell genes were measured using real-time reverse-transcription polymerase chain reaction (RT-PCR). The association between these gene levels and radiation was evaluated using colon cancer cell lines. Immunohistochemical staining of these markers after CRT was also investigated.

Results

There were significant positive correlations among the three genes after CRT. Patients who developed distant recurrence had higher levels of the three genes compared with those without recurrence in residual cancer after CRT. These elevated gene levels were significantly associated with poor disease-free survival. The radiation caused upregulation of these gene levels in LoVo and SW480 in vitro. Immunohistochemically, CD133 staining was observed in not only luminal surface but also cytoplasm.

Conclusions

Expression of CD133, OCT4, and SOX2 may predict distant recurrence and poor prognosis of rectal cancer patients treated with preoperative CRT. Correlations among these genes may be associated with tumor regrowth and metastatic relapse after CRT.

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References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  PubMed  Google Scholar 

  4. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.

    Article  CAS  PubMed  Google Scholar 

  5. Ieta K, Tanaka F, Haraguchi N, et al. Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol. 2008;15(2):638–48.

    Article  PubMed  Google Scholar 

  6. Yin S, Li J, Hu C, et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer. 2007;120(7):1444–50.

    Article  CAS  PubMed  Google Scholar 

  7. Horst D, Kriegl L, Engel J, et al. CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br J Cancer. 2008;99(8):1285–9.

    Article  CAS  PubMed  Google Scholar 

  8. Lin EH, Hassan M, Li Y, et al. Elevated circulating endothelial progenitor marker CD133 messenger RNA levels predict colon cancer recurrence. Cancer. 2007;110(3):534–42.

    Article  CAS  PubMed  Google Scholar 

  9. Mehra N, Penning M, Maas J, et al. Progenitor marker CD133 mRNA is elevated in peripheral blood of cancer patients with bone metastases. Clin Cancer Res. 2006;12(16):4859–66.

    Article  CAS  PubMed  Google Scholar 

  10. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    Article  CAS  PubMed  Google Scholar 

  11. Yamanaka S. Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors. Cell Prolif. 2008;41(Suppl 1):51–6.

    PubMed  Google Scholar 

  12. Wernig M, Meissner A, Foreman R, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature. 2007;448(7151):318–24.

    Article  CAS  PubMed  Google Scholar 

  13. Ben-Porath I, Thomson MW, Carey VJ, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008;40(5):499–507.

    Article  CAS  PubMed  Google Scholar 

  14. Tsukamoto T, Mizoshita T, Mihara M, et al. Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes. Histopathology. 2005;46(6):649–58.

    Article  CAS  PubMed  Google Scholar 

  15. Li XL, Eishi Y, Bai YQ, et al. Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma. Int J Oncol. 2004;24(2):257–63.

    CAS  PubMed  Google Scholar 

  16. Cheng L, Sung MT, Cossu-Rocca P, et al. OCT4: biological functions and clinical applications as a marker of germ cell neoplasia. J Pathol. 2007;211(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  17. Jones TD, Ulbright TM, Eble JN, Cheng L. OCT4: A sensitive and specific biomarker for intratubular germ cell neoplasia of the testis. Clin Cancer Res. 2004;10(24):8544–7.

    Article  CAS  PubMed  Google Scholar 

  18. Webster JD, Yuzbasiyan-Gurkan V, Trosko JE, et al. Expression of the embryonic transcription factor Oct4 in canine neoplasms: a potential marker for stem cell subpopulations in neoplasia. Vet Pathol. 2007;44(6):893–900.

    Article  CAS  PubMed  Google Scholar 

  19. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–40.

    Article  CAS  PubMed  Google Scholar 

  20. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114–23.

    Article  CAS  PubMed  Google Scholar 

  21. Guillem JG, Chessin DB, Cohen AM, et al. Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg. 2005;241(5):829–36; discussion 836–8.

    Article  PubMed  Google Scholar 

  22. Rodel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23(34):8688–96.

    Article  PubMed  Google Scholar 

  23. Benzoni E, Intersimone D, Terrosu G, et al. Prognostic value of tumour regression grading and depth of neoplastic infiltration within the perirectal fat after combined neoadjuvant chemo-radiotherapy and surgery for rectal cancer. J Clin Pathol. 2006;59(5):505–12.

    Article  CAS  PubMed  Google Scholar 

  24. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.

    Article  CAS  PubMed  Google Scholar 

  25. Kusunoki M, Yanagi H, Noda M, et al. Results of pharmacokinetic modulating chemotherapy in combination with hepatic arterial 5-fluorouracil infusion and oral UFT after resection of hepatic colorectal metastases. Cancer. 2000;89(6):1228–35.

    Article  CAS  PubMed  Google Scholar 

  26. Yoshikawa R, Kusunoki M, Yanagi H, et al. Dual antitumor effects of 5-fluorouracil on the cell cycle in colorectal carcinoma cells: a novel target mechanism concept for pharmacokinetic modulating chemotherapy. Cancer Res. 2001;61(3):1029–37.

    CAS  PubMed  Google Scholar 

  27. Japanese Society for Cancer of Colon and Rectum. General rules for clinical and pathological studies on cancer of the colon, rectum, and anus. Tokyo: Kanehara & Co; 2006.

  28. Bijwaard KE, Aguilera NS, Monczak Y, et al. Quantitative real-time reverse transcription-PCR assay for cyclin D1 expression: utility in the diagnosis of mantle cell lymphoma. Clin Chem. 2001;47(2):195–201.

    CAS  PubMed  Google Scholar 

  29. Rodda DJ, Chew JL, Lim LH, et al. Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem. 2005;280(26):24731–7.

    Article  CAS  PubMed  Google Scholar 

  30. Shmelkov SV, Butler JM, Hooper AT, 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

    CAS  PubMed  Google Scholar 

  31. Todaro M, Perez Alea M, Scopelliti A, et al. IL-4-mediated drug resistance in colon cancer stem cells. Cell Cycle. 2008;7(3):309–13.

    CAS  PubMed  Google Scholar 

  32. van den Brink M, Stiggelbout AM, van den Hout WB, et al. Clinical nature and prognosis of locally recurrent rectal cancer after total mesorectal excision with or without preoperative radiotherapy. J Clin Oncol. 2004;22(19):3958–64.

    Article  PubMed  Google Scholar 

  33. Bujko K, Michalski W, Kepka L, et al. Association between pathologic response in metastatic lymph nodes after preoperative chemoradiotherapy and risk of distant metastases in rectal cancer: an analysis of outcomes in a randomized trial. Int J Radiat Oncol Biol Phys. 2007;67(2):369–77.

    PubMed  Google Scholar 

  34. Richardson GD, Robson CN, Lang SH, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci. 2004;117(Pt 16):3539–45.

    Article  CAS  PubMed  Google Scholar 

  35. Haraguchi N, Utsunomiya T, Inoue H, et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006;24(3):506–13.

    Article  CAS  PubMed  Google Scholar 

  36. Immervoll H, Hoem D, Sakariassen PO, et al. Expression of the “stem cell marker” CD133 in pancreas and pancreatic ductal adenocarcinomas. BMC Cancer. 2008;8:48.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie, Japan

    Susumu Saigusa MD, Koji Tanaka MD, Yuji Toiyama MD, Takeshi Yokoe MD, Yoshinaga Okugawa MD, Yasuhiro Ioue MD, PhD, Chikao Miki MD, PhD & Masato Kusunoki MD, PhD

  2. Department of Innovative Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie, Japan

    Masato Kusunoki MD, PhD

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  1. Susumu Saigusa MD
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Correspondence to Susumu Saigusa MD.

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Saigusa, S., Tanaka, K., Toiyama, Y. et al. Correlation of CD133, OCT4, and SOX2 in Rectal Cancer and Their Association with Distant Recurrence After Chemoradiotherapy. Ann Surg Oncol 16, 3488–3498 (2009). https://doi.org/10.1245/s10434-009-0617-z

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  • DOI: https://doi.org/10.1245/s10434-009-0617-z

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