Advertisement

Pathology & Oncology Research

, Volume 18, Issue 2, pp 371–376 | Cite as

Increase of α-SMA+ and CK+ Cells as an Early Sign of Epithelial-Mesenchymal Transition during Colorectal Carcinogenesis

  • Gábor Valcz
  • Ferenc Sipos
  • Tibor Krenács
  • Jeannette Molnár
  • Árpád V. Patai
  • Katalin Leiszter
  • Kinga Tóth
  • Barna Wichmann
  • Béla Molnár
  • Zsolt Tulassay
Research

Abstract

Our aim was to examine cell transition events by detecting the frequency of intrapithelial α-smooth muscle actin (SMA)+/cytokeratin (CK)+ cells during colorectal adenoma–carcinoma sequence, in relation to E-cadherin expression. Our further aim was to determine the proliferative activity of intraepithelial α-SMA+ cells. Histologically healthy, adenoma, and colorectal cancer (CRC) biopsy samples were taken during routine colonoscopy and were included into tissue microarrays (TMAs). Slides immunostained for Ki-67, α-SMA, E-cadherin and pan-cytokeratin were digitalized and analyzed by using a digital microscope software. The proportion of α-SMA+/CK+ cells was significantly higher in CRC samples (3.34 ± 1.01%) compared to healthy (1.94 ± 0.69%) or adenoma (1.62 ± 0.78%) samples (p < 0.01). E-cadherin expression negatively correlated with the number of α-SMA+ cells. The majority of intraepithelial α-SMA+ cells were in the proliferative phase. During tumor progression, the appearance of dot-like α-SMA staining in CK positive cells may indicate the initial phase of the epithelial-to-mesenchymal transition (EMT). The high proportion of intraepithelial α-SMA+ proliferating cells may refer to their increased plasticity compared to differentiated cells. The negative correlation between E-cadherin and intraepithelial α-SMA expression suggests that EMT is facilitated by a loss of epithelial cell contact.

Keywords

Epithelial–myofibroblast transition Adenoma–carcinoma sequence Cytokeratin Alpha–smooth muscle actin 

References

  1. 1.
    Schultheiss G, Diener M (1998) K+ and Cl- conductances in the distal colon of the rat. Gen Pharmacol 31:337–342PubMedCrossRefGoogle Scholar
  2. 2.
    Lu L, Walker WA (2001) Pathologic and physiologic interactions of bacteria with thegastrointestinal epithelium. Am J Clin Nutr 73:1124–1130Google Scholar
  3. 3.
    Edmonds CJ (1984) Absorption and secretion of fluid and electrolytes by the rectum. Scand J Gastroenterol Suppl 93:79–87PubMedGoogle Scholar
  4. 4.
    Hollier BG, Evans K, Mani SA (2009) The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 14:29–43PubMedCrossRefGoogle Scholar
  5. 5.
    Thiery JP, Acloque H, Huang RY et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890PubMedCrossRefGoogle Scholar
  6. 6.
    Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428PubMedCrossRefGoogle Scholar
  7. 7.
    Kalluri R (2009) EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119:1417–1419PubMedCrossRefGoogle Scholar
  8. 8.
    Hugo H, Ackland ML, Blick T et al (2007) Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol 213:374–383PubMedCrossRefGoogle Scholar
  9. 9.
    Radisky DC (2005) Epithelial-mesenchymal transition. J Cell Sci 118:4325–4326PubMedCrossRefGoogle Scholar
  10. 10.
    Boyer B, Vallés AM, Edme N (2000) Induction and regulation of epithelial-mesenchymal transitions. Biochem Pharmacol 60:1091–1099PubMedCrossRefGoogle Scholar
  11. 11.
    Zavadil J, Bottinger EP (2005) TGF-β and epithelial-to-mesenchymal transitions. Oncogene 24:5764–5774PubMedCrossRefGoogle Scholar
  12. 12.
    Lorusso G, Rüegg C (2008) The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol 130:1091–1103PubMedCrossRefGoogle Scholar
  13. 13.
    Miyazono K (2009) Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci 85:314–323PubMedCrossRefGoogle Scholar
  14. 14.
    Masszi A, Speight P, Charbonney E et al (2010) Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for Smad3. J Cell Biol 188:383–399PubMedCrossRefGoogle Scholar
  15. 15.
    Masszi A, Fan L, Rosivall L, McCulloch CA et al (2004) Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. Am J Pathol 165:1955–1967PubMedCrossRefGoogle Scholar
  16. 16.
    Reichert M, Müller T, Hunziker W (2000) The PDZ domains of zonula occludens-1 induce an epithelial to mesenchymal transition of Madin-Darby canine kidney I cells. Evidence for a role of beta-catenin/Tcf/Lef signaling. J Biol Chem 275:9492–9500PubMedCrossRefGoogle Scholar
  17. 17.
    Wang J, Zohar R, McCulloch CA (2006) Multiple roles of alpha-smooth muscle actin in mechanotransduction. Exp Cell Res 312:205–214PubMedCrossRefGoogle Scholar
  18. 18.
    Li H, Fan X, Houghton J (2007) Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem 101:805–815PubMedCrossRefGoogle Scholar
  19. 19.
    Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130PubMedCrossRefGoogle Scholar
  20. 20.
    Storch KN, Taatjes DJ, Bouffard NA et al (2007) Alpha smooth muscle actin distribution in cytoplasm and nuclear invaginations of connective tissue fibroblasts. Histochem Cell Biol 127:523–530PubMedCrossRefGoogle Scholar
  21. 21.
    Thomas CH, Collier JH, Sfeir CS et al (2002) Engineering gene expression and protein synthesis by modulation of nuclear shape. Proc Natl Acad Sci USA 99:1972–1977PubMedCrossRefGoogle Scholar
  22. 22.
    Wang J, Chen H, Seth A et al (2003) Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 285:1871–1881Google Scholar
  23. 23.
    Gomez EW, Chen QK, Gjorevski N et al (2010) Tissue geometry patterns epithelial-mesenchymal transition via intercellular mechanotransduction. J Cell Biochem 110:44–51PubMedGoogle Scholar
  24. 24.
    Ng YY, Huang TP, Yang WC et al (1998) Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int 54:864–876PubMedCrossRefGoogle Scholar
  25. 25.
    Zhou BP, Deng J, Xia W et al (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6:931–940PubMedCrossRefGoogle Scholar
  26. 26.
    Batlle E, Sancho E, Franci C et al (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2:84–89PubMedCrossRefGoogle Scholar
  27. 27.
    Brabletz T, Hlubek F, Spaderna S et al (2005) Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs 179:56–65PubMedCrossRefGoogle Scholar
  28. 28.
    Hawinkels LJ, Verspaget HW, van der Reijden JJ et al (2009) Active TGF-beta1 correlates with myofibroblasts and malignancy in the colorectal adenoma-carcinoma sequence. Cancer Sci 100:663–670PubMedCrossRefGoogle Scholar
  29. 29.
    Fan L, Sebe A, Péterfi Z et al (2007) Cell contact-dependent regulation of epithelial-myofibroblast transition via the rho-rho kinase-phospho-myosin pathway. Mol Biol Cell 18:1083–1097PubMedCrossRefGoogle Scholar
  30. 30.
    Masszi A, Di Ciano C, Sirokmány G et al (2003) Central role for Rho in TGF-beta1-induced alpha-smooth muscle actin expression during epithelial-mesenchymal transition. Am J Physiol Renal Physiol 284:911–924Google Scholar
  31. 31.
    Pino MS, Kikuchi H, Zeng M et al (2010) Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology 138:1406–1417PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2011

Authors and Affiliations

  • Gábor Valcz
    • 1
  • Ferenc Sipos
    • 1
  • Tibor Krenács
    • 2
  • Jeannette Molnár
    • 3
  • Árpád V. Patai
    • 1
  • Katalin Leiszter
    • 1
  • Kinga Tóth
    • 1
  • Barna Wichmann
    • 1
  • Béla Molnár
    • 4
  • Zsolt Tulassay
    • 4
  1. 1.Cell Analysis Laboratory, 2nd Department of Internal MedicineSemmelweis UniversityBudapestHungary
  2. 2.1st Department of Pathology and Experimental Cancer ResearchSemmelweis UniversityBudapestHungary
  3. 3.National Institute of Food and Nutrition ScienceBudapestHungary
  4. 4.Molecular Medicine Research Unit, Hungarian Academy of SciencesBudapestHungary

Personalised recommendations