Dissecting Oncogenic RTK Pathways in Colorectal Cancer Initiation and Progression

  • Stephen McManus
  • Walid Chababi
  • Dominique Arsenault
  • Claire M. Dubois
  • Caroline Saucier
Part of the Methods in Molecular Biology book series (MIMB, volume 1765)


Colorectal cancer (CRC) is a progressive disorder associated with an accumulation of multiple heterogeneous genetic alterations in intestinal epithelial cells (IEC). However, when these cells undergo neoplastic transformation and become cancerous and metastatic, they invariably acquire hallmarks conferring them the ability to hyperproliferate, escape growth-inhibitory and death-inducing cues, and promote angiogenesis as well as epithelial-to-mesenchymal transformation (EMT), fostering their invasive dissemination from primary tumor into distant tissues. Compelling clinical and experimental evidence suggest that aberrant engagement of cell surface growth factor receptor tyrosine kinase (RTK) signaling, like that of the hepatocyte growth factor (HGF)/MET receptor, underlies CRC metastatic progression by promoting these cancer hallmarks. To date, though, the use of RTK-targeting agents has been viewed as a promising approach for the treatment of metastatic CRC, clinical success has been modest.

Our vision is that the prospect of designing RTK-based, improved and innovative CRC therapies and prognostic markers likely rests on a comprehensive understanding of the biological processes and underlying regulatory molecular mechanisms by which deregulation of RTK signaling governs IEC’s neoplastic transformation and their transition from noninvasive to metastatic and malignant cells. Herein, we describe our scheme for defining the full scope of oncogenic MET-driven cancer biological processes, in cellulo and in vivo, as well as the individual contribution of MET-binding effectors in a nontransformed IEC model, the IEC-6 cell line.

Key words

Receptor tyrosine kinase Hepatocyte growth factor (HGF) MET receptor Intestinal epithelial cells GRB2 SHC EMT Angiogenesis Tumorigenesis Metastasis 



This work was supported by an operating grant from the Canadian Institutes of Health Research (CIHR, MOP-106476) awarded to CS.


  1. 1.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767CrossRefPubMedGoogle Scholar
  2. 2.
    Arends JW (2000) Molecular interactions in the Vogelstein model of colorectal carcinoma. J Pathol 190(4):412–416CrossRefPubMedGoogle Scholar
  3. 3.
    Curley SA (2005) Outcomes after surgical treatment of colorectal cancer liver metastases. Semin Oncol 32(6 Suppl 9):S109–S111CrossRefPubMedGoogle Scholar
  4. 4.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. Scholar
  5. 5.
    Saucier C, Rivard N (2010) Epithelial cell signalling in metastatic colorectal cancer. In: Huot J, Beauchemin N (eds) Metastasis of colon cancer, Cancer metastasis—biology and treatment, vol 14. Springer, Netherlands, pp 205–241CrossRefGoogle Scholar
  6. 6.
    Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4(12):915–925CrossRefPubMedGoogle Scholar
  7. 7.
    Peschard P, Park M (2007) From Tpr-Met to Met, tumorigenesis and tubes. Oncogene 26(9):1276–1285CrossRefPubMedGoogle Scholar
  8. 8.
    Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A, Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A, Gambacorta M, Diaz LA Jr, Sausen M, Velculescu VE, Comoglio P, Trusolino L, Di Nicolantonio F, Giordano S, Siena S (2013) Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 3(6):658–673. Scholar
  9. 9.
    Van Cutsem E, Eng C, Nowara E, Swieboda-Sadlej A, Tebbutt NC, Mitchell E, Davidenko I, Stephenson J, Elez E, Prenen H, Deng H, Tang R, McCaffery I, Oliner KS, Chen L, Gansert J, Loh E, Smethurst D, Tabernero J (2014) Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clin Cancer Res 20(16):4240–4250. Scholar
  10. 10.
    Eng C, Bessudo A, Hart LL, Severtsev A, Gladkov O, Muller L, Kopp MV, Vladimirov V, Langdon R, Kotiv B, Barni S, Hsu C, Bolotin E, von Roemeling R, Schwartz B, Bendell JC (2016) A randomized, placebo-controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild-type KRAS who have received first-line systemic therapy. Int J Cancer 139(1):177–186. Scholar
  11. 11.
    Bendell JC, Hochster H, Hart LL, Firdaus I, Mace JR, McFarlane JJ, Kozloff M, Catenacci D, Hsu JJ, Hack SP, Shames DS, Phan SC, Koeppen H, Cohn AL (2017) A phase II randomized trial (GO27827) of first-line FOLFOX plus bevacizumab with or without the MET inhibitor onartuzumab in patients with metastatic colorectal cancer. Oncologist 22(3):264–271. Scholar
  12. 12.
    Saucier C, Papavasiliou V, Palazzo A, Naujokas MA, Kremer R, Park M (2002) Use of signal specific receptor tyrosine kinase oncoproteins reveals that pathways downstream from Grb2 or Shc are sufficient for cell transformation and metastasis. Oncogene 21(12):1800–1811CrossRefPubMedGoogle Scholar
  13. 13.
    Saucier C, Khoury H, Lai KM, Peschard P, Dankort D, Naujokas MA, Holash J, Yancopoulos GD, Muller WJ, Pawson T, Park M (2004) The Shc adaptor protein is critical for VEGF induction by Met/HGF and ErbB2 receptors and for early onset of tumor angiogenesis. Proc Natl Acad Sci U S A 101(8):2345–2350CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ishimura A, Lee HS, Bong YS, Saucier C, Mood K, Park EK, Daar IO (2006) Oncogenic Met receptor induces ectopic structures in Xenopus embryos. Oncogene 25(31):4286–4299CrossRefPubMedGoogle Scholar
  15. 15.
    Mood K, Saucier C, Ishimura A, Bong YS, Lee HS, Park M, Daar IO (2006) Oncogenic met receptor induces cell-cycle progression in Xenopus oocytes independent of direct Grb2 and Shc binding or mos synthesis, but requires phosphatidylinositol 3-kinase and raf signaling. J Cell Physiol 207(1):271–285CrossRefPubMedGoogle Scholar
  16. 16.
    Mood K, Saucier C, Bong YS, Lee HS, Park M, Daar IO (2006) Gab1 is required for cell cycle transition, cell proliferation, and transformation induced by an oncogenic met receptor. Mol Biol Cell 17(9):3717–3728CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Seiden-Long I, Navab R, Shih W, Li M, Chow J, Zhu CQ, Radulovich N, Saucier C, Tsao MS (2008) Gab1 but not Grb2 mediates tumor progression in Met overexpressing colorectal cancer cells. Carcinogenesis 29(3):647–655CrossRefPubMedGoogle Scholar
  18. 18.
    Bernier J, Chababi W, Pomerleau V, Saucier C (2010) Oncogenic engagement of the Met receptor is sufficient to evoke angiogenic, tumorigenic, and metastatic activities in rat intestinal epithelial cells. Am J Physiol 299(3):G677–G686Google Scholar
  19. 19.
    Pomerleau V, Landry M, Bernier J, Vachon PH, Saucier C (2014) Met receptor-induced Grb2 or Shc signals both promote transformation of intestinal epithelial cells, albeit they are required for distinct oncogenic functions. BMC Cancer 14:240. Scholar
  20. 20.
    Quaroni A, Wands J, Trelstad RL, Isselbacher KJ (1979) Epithelioid cell cultures from rat small intestine. Characterization by morphologic and immunologic criteria. J Cell Biol 80(2):248–265CrossRefPubMedGoogle Scholar
  21. 21.
    Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9(7):671–675CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Vachon PH (2011) Integrin signaling, cell survival, and anoikis: distinctions, differences, and differentiation. J Signal Transduct 2011:738137. Scholar
  23. 23.
    Arsenault D, Lucien F, Dubois CM (2012) Hypoxia enhances cancer cell invasion through relocalization of the proprotein convertase furin from the trans-Golgi network to the cell surface. J Cell Physiol 227(2):789–800. Scholar
  24. 24.
    Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29(6 Suppl 16):15–18. Scholar
  25. 25.
    Sheng H, Shao J, Dubois RN (2001) K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. Cancer Res 61(6):2670–2675PubMedGoogle Scholar
  26. 26.
    Shao J, Evers BM, Sheng H (2004) Roles of phosphatidylinositol 3′-kinase and mammalian target of rapamycin/p70 ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal epithelial cells. Cancer Res 64(1):229–235CrossRefPubMedGoogle Scholar
  27. 27.
    Komatsu K, Buchanan FG, Katkuri S, Morrow JD, Inoue H, Otaka M, Watanabe S, DuBois RN (2005) Oncogenic potential of MEK1 in rat intestinal epithelial cells is mediated via cyclooxygenase-2. Gastroenterology 129(2):577–590. Scholar
  28. 28.
    Nandan MO, McConnell BB, Ghaleb AM, Bialkowska AB, Sheng H, Shao J, Babbin BA, Robine S, Yang VW (2008) Kruppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis. Gastroenterology 134(1):120–130. Scholar
  29. 29.
    Voisin L, Julien C, Duhamel S, Gopalbhai K, Claveau I, Saba-El-Leil MK, Rodrigue-Gervais IG, Gaboury L, Lamarre D, Basik M, Meloche S (2008) Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors. BMC Cancer 8:337CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lemieux E, Bergeron S, Durand V, Asselin C, Saucier C, Rivard N (2009) Constitutively active MEK1 is sufficient to induce epithelial-to-mesenchymal transition in intestinal epithelial cells and to promote tumor invasion and metastasis. Int J Cancer 125(7):1575–1586CrossRefPubMedGoogle Scholar
  31. 31.
    Davis HE, Morgan JR, Yarmush ML (2002) Polybrene increases retrovirus gene transfer efficiency by enhancing receptor-independent virus adsorption on target cell membranes. Biophys Chem 97(2–3):159–172CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Stephen McManus
    • 1
  • Walid Chababi
    • 1
  • Dominique Arsenault
    • 2
    • 3
  • Claire M. Dubois
    • 2
    • 3
  • Caroline Saucier
    • 1
  1. 1.Department of Anatomy and Cell Biology, Faculty of Medicine and Health ScienceUniversité de SherbrookeSherbrookeCanada
  2. 2.Department of Pediatrics, Faculty of Medicine and Health ScienceUniversité de SherbrookeSherbrookeCanada
  3. 3.Department of Immunology Division, Faculty of Medicine and Health ScienceUniversité de SherbrookeSherbrookeCanada

Personalised recommendations