Tumor Biology

, Volume 36, Issue 5, pp 3417–3422 | Cite as

Protein interactions of cortactin in relation to invadopodia formation in metastatic renal clear cell carcinoma

  • Hong-Liang Shen
  • Qing-Jun Liu
  • Pei-Qian Yang
  • Ye Tian
Research Article


In the present study, we wanted to examine the predominant factor/s in the initiation of metastasis. We used samples of advanced grades of renal clear cell carcinoma with documented clinical history of vena caval spread as the experimental group. The major rationale for this selection is the fact that renal cell carcinoma metastasize extensively through the inferior vena cava up to the pulmonary bed and often exist as a continuous mass of metastatic tissue. As cortactin plays a significant role in invadopodia formation during initiation of metastasis, in the present study, we tested expression of cortactin and phosphotyr421-cortactin in different grades of renal cell clear carcinoma and examined its property to bind to actin. The findings of the present study suggest that the variations of the local physiological milieu are the driving forces for metastasis by enhancing molecular mechanisms for lamellipodia formation. We conclude that localization of cortactin in cancer cells and interaction between actin and its nucleators are crucial for cancer progression.


Invadopodia Lamellipodia Cortactin Renal cell carcinoma Metastasis 


Conflicts of interest



  1. 1.
    McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. 2014;16:717–27.CrossRefPubMedGoogle Scholar
  2. 2.
    Orgaz JL, Herraiz C, Sanz-Moreno V. Rho GTPases modulate malignant transformation of tumor cells. Small GTPases. 2014;5:e29019.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol. 2012;22:396–403.CrossRefPubMedGoogle Scholar
  4. 4.
    Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Nantajit D, Lin D, Li JJ. The network of epithelial-mesenchymal transition: potential new targets for tumor resistance. J Cancer Res Clin Oncol. 2014.Google Scholar
  6. 6.
    Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7:re8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Derynck R, Muthusamy BP, Saeteurn KY. Signaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition. Curr Opin Cell Biol. 2014;31C:56–66.CrossRefGoogle Scholar
  8. 8.
    Giarnieri E, Bellipanni G, Macaluso M, Mancini R, Holstein AC, Milanese C, et al. Review: cell dynamics in malignant pleural effusions. J Cell Physiol. 2014.Google Scholar
  9. 9.
    Moyret-Lalle C, Ruiz E, Puisieux A. Epithelial-mesenchymal transition transcription factors and miRNAs: “plastic surgeons” of breast cancer. World J Clin Oncol. 2014;5:311–22.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    O’Connor JW, Gomez EW. Biomechanics of TGFβ-induced epithelial-mesenchymal transition: implications for fibrosis and cancer. Clin Transl Med. 2014;3:23.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Martin TA. The role of tight junctions in cancer metastasis. Semin Cell Dev Biol. 2014.Google Scholar
  12. 12.
    Wong TS, Gao W, Chan JY. Transcription regulation of E-cadherin by zinc finger E-box binding homeobox proteins in solid tumors. Biomed Res Int. 2014;2014:921564.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Chiodoni C, Colombo MP, Sangaletti S. Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer Metastasis Rev. 2010;29:295–307.CrossRefPubMedGoogle Scholar
  14. 14.
    Wells A, Chao YL, Grahovac J, Wu Q, Lauffenburger DA. Epithelial and mesenchymal phenotypic switchings modulate cell motility in metastasis. Front Biosci (Landmark Ed). 2011;16:815–37.CrossRefGoogle Scholar
  15. 15.
    Conti A, Santoni M, Amantini C, Burattini L, Berardi R, Santoni G, et al. Progress of molecular targeted therapies for advanced renal cell carcinoma. Biomed Res Int. 2013;2013:419176.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Géraud C, Koch PS, Damm F, Schledzewski K, Goerdt S. The metastatic cycle: metastatic niches and cancer cell dissemination. J Dtsch Dermatol Ges. 2014.Google Scholar
  17. 17.
    Khan MI, Czarnecka AM, Duchnowska R, Kukwa W, Szczylik C. Metastasis-initiating cells in renal cancer. Curr Signal Transduct Ther. 2014;8:240–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Singleton PA. Hyaluronan regulation of endothelial barrier function in cancer. Adv Cancer Res. 2014;123:191–209.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ouderkirk JL, Krendel M. Non-muscle myosins in tumor progression, cancer cell invasion, and metastasis. Cytoskeleton (Hoboken). 2014;71:447–63.CrossRefGoogle Scholar
  20. 20.
    Wang CL, Coluccio LM. New insights into the regulation of the actin cytoskeleton by tropomyosin. Int Rev Cell Mol Biol. 2010;281:91–128.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Chawla A, Mishra D, Bansal R, Chundru M. Rare sites of delayed metastasis in renal cell carcinoma. BMJ Case Rep. 2013;2013.Google Scholar
  22. 22.
    Casey RG, Raheem OA, Elmusharaf E, Madhavan P, Tolan M, Lynch TH. Renal cell carcinoma with IVC and atrial thrombus: a single centre’s 10 year surgical experience. Surgeon. 2013;11:295–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Abel EJ, Wood CG, Eickstaedt N, Fang JE, Kenney P, Bagrodia A, et al. Preoperative pulmonary embolism does not predict poor postoperative outcomes in patients with renal cell carcinoma and venous thrombus. J Urol. 2013;190:452–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Narumiya S, Tanji M, Ishizaki T. Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev. 2009;28:65–76.CrossRefPubMedGoogle Scholar
  25. 25.
    Weed SA, Parsons JT. Cortactin: coupling membrane dynamics to cortical actin assembly. Oncogene. 2001;20:6418–34.CrossRefPubMedGoogle Scholar
  26. 26.
    Schuuring E. The involvement of the chromosome 11q13 region in human malignancies: cyclin D1 and EMS1 are two new candidate oncogenes—a review. Gene. 1995;159:83–96.CrossRefPubMedGoogle Scholar
  27. 27.
    Balzer EM, Whipple RA, Thompson K, Boggs AE, Slovic J, Cho EH, et al. c-Src differentially regulates the functions of microtentacles and invadopodia. Oncogene. 2010;29:6402–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Faragalla H, Al-Haddad S, Stewart R, Yousef GM. The significance of florid giant cell component in renal cell carcinoma: a case report and review of the literature. Can J Urol. 2010;17:5219–22.PubMedGoogle Scholar
  29. 29.
    Macdonald A, Horwitz AR, Lauffenburger DA. Kinetic model for lamellipodal actin-integrin ‘clutch’ dynamics. Cell Adhes Migr. 2008;2:95–105.CrossRefGoogle Scholar
  30. 30.
    Eke I, Deuse Y, Hehlgans S, Gurtner K, Krause M, Baumann M, et al. β1 integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J Clin Invest. 2012;122:1529–40.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhang K, Wang D, Song J. Cortactin is involved in transforming growth factor-beta1-induced epithelial-mesenchymal transition in AML-12 cells. Acta Biochim Biophys Sin (Shanghai). 2009;41:839–45.CrossRefGoogle Scholar
  32. 32.
    Boguslavsky S, Grosheva I, Landau E, Shtutman M, Cohen M, Arnold K, et al. p120 catenin regulates lamellipodial dynamics and cell adhesion in cooperation with cortactin. Proc Natl Acad Sci U S A. 2007;104:10882–7.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kirkbride KC, Sung BH, Sinha S, Weaver AM. Cortactin: a multifunctional regulator of cellular invasiveness. Cell Adhes Migr. 2011;5:187–98.CrossRefGoogle Scholar
  34. 34.
    Wang GC, Hsieh PS, Hsu HH, Sun GH, Nieh S, Yu CP, et al. Expression of cortactin and survivin in renal cell carcinoma associated with tumor aggressiveness. World J Urol. 2009;27:557–63.CrossRefPubMedGoogle Scholar
  35. 35.
    Matsuo T, Miyata Y, Watanabe S, Ohba K, Hayashi T, Kanda S, et al. Pathologic significance and prognostic value of phosphorylated cortactin expression in patients with sarcomatoid renal cell carcinoma. Urology. 2011;78(2):476.e9–15.CrossRefGoogle Scholar
  36. 36.
    Zhang Y, Zhang M, Dong H, Yong S, Li X, Olashaw N, et al. Deacetylation of cortactin by SIRT1 promotes cell migration. Oncogene. 2009;28(3):445–60.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Hong-Liang Shen
    • 1
  • Qing-Jun Liu
    • 1
  • Pei-Qian Yang
    • 1
  • Ye Tian
    • 1
  1. 1.Department of Urology, Beijing Friendship HospitalCapital Medical UniversityBeijingChina

Personalised recommendations