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Intratumoral heterogeneity of CD44v6 in rectal cancer

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Abstract

Purpose

CD44v6 plays a controversial role in tumor progression and patient outcome in colorectal cancer by plenty of conflicting reports. The purpose of this study was to profile the intratumoral heterogeneity of CD44v6 in rectal cancer and investigate its role in lymph node metastasis.

Methods

Sixty patients were included in this study. Immunohistochemistry for CD44v6 was performed in normal mucosa, primary tumor, and lymph node metastasis with whole tissue sections. The staining intensity in tumor center and invasive front was separately measured. Sampling bias was evaluated by quantitative real-time PCR with 15 pairs of frozen tissues from different sites of the primary tumor.

Results

CD44v6 expression increased from normal mucosa to primary tumor to lymph node metastasis. Multiple intratumoral staining patterns was observed in primary tumor, and CD44v6 expression in invasive front was significantly higher than that in tumor center. In addition, mRNA expression levels differed across different geographical regions of the tumor. No association between CD44v6 expression and lymph node metastasis was revealed.

Conclusions

Substantial intratumoral heterogeneity of CD44v6 exists in rectal cancer that impacts the outcome of individual studies. CD44v6 expression should be assessed in a more precise way with a specified staining pattern and in a designated location.

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References

  1. Zoller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 2011;11(4):254–67. doi:10.1038/nrc3023.

    Article  PubMed  Google Scholar 

  2. Ni J, Cozzi PJ, Hao JL, Beretov J, Chang L, Duan W, et al. CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance. Prostate. 2014;74(6):602–17. doi:10.1002/pros.22775.

    Article  CAS  PubMed  Google Scholar 

  3. Saito S, Okabe H, Watanabe M, Ishimoto T, Iwatsuki M, Baba Y, et al. CD44v6 expression is related to mesenchymal phenotype and poor prognosis in patients with colorectal cancer. Oncol Rep. 2013;29(4):1570–8. doi:10.3892/or.2013.2273.

    CAS  PubMed  Google Scholar 

  4. Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 2014;14(3):342–56. doi:10.1016/j.stem.2014.01.009.

    Article  CAS  PubMed  Google Scholar 

  5. Bendardaf R, Elzagheid A, Lamlum H, Ristamaki R, Collan Y, Pyrhonen S. E-cadherin, CD44 s and CD44v6 correlate with tumour differentiation in colorectal cancer. Oncol Rep. 2005;13(5):831–5.

    CAS  PubMed  Google Scholar 

  6. Zlobec I, Gunthert U, Tornillo L, Iezzi G, Baumhoer D, Terracciano L, et al. Systematic assessment of the prognostic impact of membranous CD44v6 protein expression in colorectal cancer. Histopathology. 2009;55(5):564–75. doi:10.1111/j.1365-2559.2009.03421.x.

    Article  PubMed  Google Scholar 

  7. Wang L, Liu Q, Lin D, Lai M. CD44v6 down-regulation is an independent prognostic factor for poor outcome of colorectal carcinoma. Int J Clin Exp Pathol. 2015;8(11):14283–93.

    PubMed  PubMed Central  Google Scholar 

  8. Afify A, Durbin-Johnson B, Virdi A, Jess H. The expression of CD44v6 in colon: from normal to malignant. Ann Diagn Pathol. 2016;20:19–23. doi:10.1016/j.anndiagpath.2015.10.010.

    Article  PubMed  Google Scholar 

  9. Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501(7467):338–45. doi:10.1038/nature12625.

    Article  CAS  PubMed  Google Scholar 

  10. Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature. 2013;501(7467):355–64. doi:10.1038/nature12627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fisher R, Pusztai L, Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer. 2013;108(3):479–85. doi:10.1038/bjc.2012.581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lv L, Liu HG, Dong SY, Yang F, Wang QX, Guo GL, et al. Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells. Tumour Biol. 2016;. doi:10.1007/s13277-015-4755-6.

    Google Scholar 

  13. de Kok JB, Roelofs RW, Giesendorf BA, Pennings JL, Waas ET, Feuth T, et al. Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes. Lab Invest. 2005;85(1):154–9. doi:10.1038/labinvest.3700208.

    Article  PubMed  Google Scholar 

  14. Coppola D, Hyacinthe M, Fu L, Cantor AB, Karl R, Marcet J, et al. CD44V6 expression in human colorectal carcinoma. Hum Pathol. 1998;29(6):627–35.

    Article  CAS  PubMed  Google Scholar 

  15. Finke LH, Terpe HJ, Zorb C, Haensch W, Schlag PM. Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins. Lancet. 1995;345(8949):583.

    Article  CAS  PubMed  Google Scholar 

  16. Peng J, Lu JJ, Zhu J, Xu Y, Lu H, Lian P, et al. Prediction of treatment outcome by CD44v6 after total mesorectal excision in locally advanced rectal cancer. Cancer J. 2008;14(1):54–61. doi:10.1097/PPO.0b013e3181629a67.

    Article  PubMed  Google Scholar 

  17. Weg-Remers S, Anders M, von Lampe B, Riecken EO, Schuder G, Feifel G, et al. Decreased expression of CD44 splicing variants in advanced colorectal carcinomas. Eur J Cancer. 1998;34(10):1607–11.

    Article  CAS  PubMed  Google Scholar 

  18. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4(1):33–45. doi:10.1038/nrm1004.

    Article  CAS  PubMed  Google Scholar 

  19. Avoranta ST, Korkeila EA, Syrjanen KJ, Pyrhonen SO, Sundstrom JT. Lack of CD44 variant 6 expression in rectal cancer invasive front associates with early recurrence. World J Gastroenterol. 2012;18(33):4549–56. doi:10.3748/wjg.v18.i33.4549.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Huang J, Pan C, Hu H, Zheng S, Ding L. Osteopontin-enhanced hepatic metastasis of colorectal cancer cells. PLoS One. 2012;7(10):e47901. doi:10.1371/journal.pone.0047901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Damm S, Koefinger P, Stefan M, Wels C, Mehes G, Richtig E, et al. HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta. J Invest Dermatol. 2010;130(7):1893–903. doi:10.1038/jid.2010.45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Klingbeil P, Marhaba R, Jung T, Kirmse R, Ludwig T, Zoller M. CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance. Mol Cancer Res. 2009;7(2):168–79. doi:10.1158/1541-7786.MCR-08-0207.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Science Foundation from the Health Bureau of Wenzhou City of Zhejiang, China (Y20140713) and by the Incubation Program from The First Affiliated Hospital of Wenzhou Medical University (FHY2014013).

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Authors and Affiliations

  1. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou Road No. 1838, Guangzhou, 510515, China

    H.-G. Liu & H. Shen

  2. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Shatai Road No. 1023, Guangzhou, 510515, China

    H.-G. Liu & H. Shen

  3. Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road No. 2, Wenzhou, 325000, China

    H.-G. Liu & L. Lv

Authors
  1. H.-G. Liu
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  2. L. Lv
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  3. H. Shen
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Corresponding author

Correspondence to H. Shen.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the clinical ethical committee of the First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China (No. 2014055). All the specimens were obtained after written informed consent. This article does not contain any studies with animals performed by any of the authors.

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Liu, HG., Lv, L. & Shen, H. Intratumoral heterogeneity of CD44v6 in rectal cancer. Clin Transl Oncol 19, 425–431 (2017). https://doi.org/10.1007/s12094-016-1542-9

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  • DOI: https://doi.org/10.1007/s12094-016-1542-9

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