Tumor Biology

, Volume 37, Issue 2, pp 2555–2563 | Cite as

EGF enhances low-invasive cancer cell invasion by promoting IMP-3 expression

Original Article

Abstract

The initiation and progression of cancer is closely associated with the tumor microenvironment. The overexpression of oncogenes during tumor growth and progression by stromal stimuli can affect the aggressiveness of the cancer. In this study, in vitro and in vivo studies were performed to examine the role of stromal epidermal growth factor (EGF) in enhancing the invasive potential of in low-invasive cancer. EGF was tested in order to elucidate the specific molecules that participate in increasing the invasive potential of low-invasive cancer cells. EGF stimulation enhanced cancer invasion in an EGF receptor (EGFR)-dependent manner. EGF induced insulin-like growth factor-II mRNA-binding protein-3 (IMP-3) and podoplanin (PDPN) expression, which play an important role in oral squamous cell carcinoma (OSCC) cell invasion. An apparent tumor mass was not observed in the mouse xenograft; however, multiple tumor microfoci were seen in mice injected with IMP-3-overexpressing cells. These results show that EGF stimulates IMP-3 expression, thereby increasing cancer invasion and tumor progression.

Keywords

Epidermal growth factor Stroma IMP-3 PDPN Invasion 

Abbreviations

EGF

Epidermal growth factor

IMP-3

Insulin-like growth factor-II mRNA-binding protein-3

PDPN

Podoplanin

EGFR

Epidermal growth factor receptor

OSCC

Oral squamous cell carcinoma

Notes

Acknowledgments

This work was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1120190), and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2040564).

Conflicts of interest

None

References

  1. 1.
    Ottewell PD, O’Donnell L, Holen I. Molecular alterations that drive breast cancer metastasis to bone. Bonekey Rep. 2015;18:643.Google Scholar
  2. 2.
    Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA, et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci U S A. 2001;98:10356–61.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  4. 4.
    De Wever O, Mareel M. Role of myofibroblasts at the invasion front. Biol Chem. 2002;383:55–67.CrossRefPubMedGoogle Scholar
  5. 5.
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.CrossRefPubMedGoogle Scholar
  6. 6.
    Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999;59:5002–11.PubMedGoogle Scholar
  7. 7.
    Dimanche-Boitrel MT, Vakaet Jr L, Pujuguet P, Chauffert B, Martin MS, Hammann A, et al. In vivo and in vitro invasiveness of a rat colon-cancer cell line maintaining E-cadherin expression: an enhancing role of tumor-associated myofibroblasts. Int J Cancer. 1994;56:512–21.CrossRefPubMedGoogle Scholar
  8. 8.
    Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol. 1999;277:C183–201.PubMedGoogle Scholar
  9. 9.
    Orimo A, Tomioka Y, Shimizu Y, Sato M, Oigawa S, Kamata K, et al. Cancer-associated myofibroblasts possess various factors to promote endometrial tumor progression. Clin Cancer Res. 2001;7:3097–105.PubMedGoogle Scholar
  10. 10.
    Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22.CrossRefPubMedGoogle Scholar
  11. 11.
    Matsumoto K, Nakamura T. Hepatocyte growth factor and the Met system as a mediator of tumor-stromal interactions. Int J Cancer. 2006;119:477–83.CrossRefPubMedGoogle Scholar
  12. 12.
    Peña C, Céspedes MV, Lindh MB, Kiflemariam S, Mezheyeuski A, Edqvist PH, et al. STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res. 2013;73:1287–97.CrossRefPubMedGoogle Scholar
  13. 13.
    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–48.CrossRefPubMedGoogle Scholar
  14. 14.
    Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316:1324–31.CrossRefPubMedGoogle Scholar
  15. 15.
    Wells A. Tumor invasion: role of growth factor-induced cell motility. Adv Cancer Res. 2000;78:31–101.CrossRefPubMedGoogle Scholar
  16. 16.
    Ribeiro FA, Noguti J, Oshima CT, Ribeiro DA. Effective targeting of the epidermal growth factor receptor (EGFR) for treating oral cancer: a promising approach. Anticancer Res. 2014;34:1547–52.PubMedGoogle Scholar
  17. 17.
    Lee HJ, Seo AN, Kim EJ, Jang MH, Kim YJ, Kim JH, et al. Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer. Br J Cancer. 2015;112:103–11.CrossRefPubMedGoogle Scholar
  18. 18.
    Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010;2:48–51.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Di Lorenzo G, Tortora G, D’Armiento FP, De Rosa G, Staibano S, Autorino R, et al. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res. 2002;8:3438–44.PubMedGoogle Scholar
  20. 20.
    Hatanpaa KJ, Burma S, Zhao D, Habib AA. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia. 2010;12:675–84.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol. 1997;8:1197–206.CrossRefPubMedGoogle Scholar
  22. 22.
    Köhler J, Schuler M. Afatinib, erlotinib and gefitinib in the first-line therapy of EGFR mutation-positive lung adenocarcinoma: a review. Onkologie. 2013;36:510–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Hwang YS, Xianglan Z, Park KK, Chung WY. Functional invadopodia formation through stabilization of the PDPN transcript by IMP-3 and cancer-stromal crosstalk for PDPN expression. Carcinogenesis. 2012;33:2135–46.CrossRefPubMedGoogle Scholar
  24. 24.
    Bowden ET, Coopman PJ, Mueller SC. Invadopodia: unique methods for measurement of extracellular matrix degradation in vitro. Methods Cell Biol. 2001;63:613–27.CrossRefPubMedGoogle Scholar
  25. 25.
    Kim S, Lee JW. Membrane proteins involved in epithelial-mesenchymal transition and tumor invasion: studies on TMPRSS4 and TM4SF5. Genomics Inform. 2014;12:12–20.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res. 2012;10:1403–18.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Neville BW, Day TA. Oral cancer and precancerous lesions. CA Cancer J Clin. 2002;52:195–215.CrossRefPubMedGoogle Scholar
  28. 28.
    Koontongkaew S. The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas. J Cancer. 2013;4:66–83.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Weber CE, Kuo PC. The tumor microenvironment. Surg Oncol. 2012;21:172–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Hwang YS, Park KK, Cha IH, Kim J, Chung WY. Role of insulin-like growth factor-II mRNA-binding protein-3 in invadopodia formation and the growth of oral squamous cell carcinoma in athymic nude mice. Head Neck. 2012;34:1329–39.CrossRefPubMedGoogle Scholar
  31. 31.
    Wicki A, Christofori G. The potential role of podoplanin in tumour invasion. Br J Cancer. 2007;96:1–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Scholl FG, Gamallo C, Vilaró S, Quintanilla M. Identification of PA2.26 antigen as a novel cell-surface mucin-type glycoprotein that induces plasma membrane extensions and increased motility in keratinocytes. J Cell Sci. 1999;112:4601–13.PubMedGoogle Scholar
  33. 33.
    Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G. Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell. 2006;9:261–72.CrossRefPubMedGoogle Scholar
  34. 34.
    Pei X, Li M, Zhan J, Yu Y, Wei X, Guan L, et al. Enhanced IMP3 expression activates NF-кB pathway and promotes renal cell carcinoma progression. PLoS One. 2015;10, e0124338.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Müeller-Pillasch F, Lacher U, Wallrapp C, Micha A, Zimmerhackl F, Hameister H, et al. Cloning of a gene highly overexpressed in cancer coding for a novel KH-domain containing protein. Oncogene. 1997;14:2729–33.CrossRefPubMedGoogle Scholar
  36. 36.
    Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol. 1999;19:1262–70.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Atlas R, Behar L, Elliott E, Ginzburg I. The insulin-like growth factor mRNA binding-protein IMP-1 and the Ras-regulatory protein G3BP associate with tau mRNA and HuD protein in differentiated P19 neuronal cells. J Neurochem. 2004;89:613–26.CrossRefPubMedGoogle Scholar
  38. 38.
    Deshler JO, Highett MI, Abramson T, Schnapp BJ. A highly conserved RNA-binding protein for cytoplasmic mRNA localization in vertebrates. Curr Biol. 1998;8:489–96.CrossRefPubMedGoogle Scholar
  39. 39.
    Doyle GA, Betz NA, Leeds PF, Fleisig AJ, Prokipcak RD, Ross J. The c-myc coding region determinant-binding protein: a member of a family of KH domain RNA-binding proteins. Nucleic Acids Res. 1998;26:5036–44.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ross AF, Oleynikov Y, Kislauskis EH, Taneja KL, Singer RH. Characterization of a beta-actin mRNA zipcode-binding protein. Mol Cell Biol. 1997;17:2158–65.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Runge S, Nielsen FC, Nielsen J, Lykke-Andersen J, Wewer UM, Christiansen J. H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein. J Biol Chem. 2000;275:29562–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Vikesaa J, Hansen TV, Jønson L, Borup R, Wewer UM, Christiansen J, et al. RNA-binding IMPs promote cell adhesion and invadopodia formation. EMBO J. 2006;25:1456–68.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Samanta S, Sharma VM, Khan A, Mercurio AM. Regulation of IMP3 by EGFR signaling and repression by ERβ: implications for triple-negative breast cancer. Oncogene. 2012;31:4689–97.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kim EJ, Che ZM, Park YJ, Hwang YS, Kim KY, da Jung W, et al. Morphogenesis and biological significance of spindle cell transformation in a spindle cell carcinoma. Cancer Lett. 2009;275:61–71.CrossRefPubMedGoogle Scholar
  45. 45.
    Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11:9–22.CrossRefPubMedGoogle Scholar
  46. 46.
    Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer. 2009;10:281–9.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Giles KM, Kalinowski FC, Candy PA, Epis MR, Zhang PM, Redfern AD, et al. Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib. Mol Cancer Ther. 2013;12:2541–58.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Xianglan Zhang
    • 2
    • 3
  • Im-hee Jung
    • 1
  • Young Sun Hwang
    • 1
  1. 1.Department of Dental Hygiene, College of Health ScienceEulji UniversitySeongnamRepublic of Korea
  2. 2.Oral Cancer Research InstituteYonsei University College of DentistrySeoulRepublic of Korea
  3. 3.Department of PathologyYanbian University HospitalYanji CityChina

Personalised recommendations