Skip to main content

The Molecular Basis of Metastatic Colorectal Cancer

Abstract

Purpose of Review

Metastatic colorectal cancer (CRC) is a vexing clinical problem. In contrast to early-stage disease, once CRC metastasizes to other organs, long-term survival is compromised. We seek to review the molecular pathogenesis, animal models, and functional genomics for an enhanced understanding of how CRC metastasizes and how this can be exploited therapeutically.

Recent Findings

Mouse models may recapitulate certain aspects of metastatic human CRC and allow for studies to identify regulators of metastasis. Modulation of transcription factors, onco-proteins, or tumor suppressors has been identified to activate known metastatic pathways. CD44 variants, microRNAs, and RNA binding proteins are emerging as metastatic modulators.

Summary

CRC metastasis is a multi-faceted and heterogeneous disease. Despite common pathways contributing to metastatic development, there are numerous variables that modulate metastatic signals in subsets of patients. It is paramount that studies continue to investigate metastatic drivers, enhancers, and inhibitors in CRC to develop therapeutic targets and improve disease outcomes.

This is a preview of subscription content, access via your institution.

Fig. 1

References

Papers of particular interest, published recently, have been highlighted as: • of importance •• of major importance

  1. Cancer Facts & Figures [database on the Internet]. American Cancer Society. 2018. Accessed:

  2. Health NIo. National Cancer Institue. 2018. https://www.cancer.gov/. Accessed 1/25/2018 2018.

  3. Oh BY, Hong HK, Lee WY, Cho YB. Animal models of colorectal cancer with liver metastasis. Cancer Lett. 2017;387:114–20. https://doi.org/10.1016/j.canlet.2016.01.048.

    CAS  Article  PubMed  Google Scholar 

  4. • Fumagalli A, Suijkerbuijk SJE, Begthel H, Beerling E, Oost KC, Snippert HJ, et al. A surgical orthotopic organoid transplantation approach in mice to visualize and study colorectal cancer progression. Nat Protoc. 2018;13(2):235–47. https://doi.org/10.1038/nprot.2017.137. This methods paper describes a new model of metastasis using organoids derived from mouse or human patient tumors. The generation of these organoids allows for ex vivo genetic manipulation following orthotopic transplantation into the cecum of mice. These tumor organoids exhibit metastatic spread that closely mimics human disease and they can be observed in real time by intravital imaging.

    CAS  Article  PubMed  Google Scholar 

  5. •• 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. https://doi.org/10.1016/j.stem.2014.01.009. This study exemplifies the use of patient-derived tumor cells in metastatic animal models. Herein they demonstrate a critical role for CD44v6+ cells in driving metastatic spread in CRC. They also show the importance of tumor-associated fibroblasts signals in simulating these metastatic tumor initiators.

    CAS  Article  PubMed  Google Scholar 

  6. Sun FX, Sasson AR, Jiang P, An Z, Gamagami R, Li L, et al. An ultra-metastatic model of human colon cancer in nude mice. Clin Exp Metastasis. 1999;17(1):41–8.

    CAS  Article  PubMed  Google Scholar 

  7. Kashtan H, Rabau M, Mullen JB, Wong AH, Roder JC, Shpitz B, et al. Intra-rectal injection of tumour cells: a novel animal model of rectal cancer. Surg Oncol. 1992;1(3):251–6.

    CAS  Article  PubMed  Google Scholar 

  8. Alamo P, Gallardo A, Di Nicolantonio F, Pavon MA, Casanova I, Trias M, et al. Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model. FASEB J. 2015;29(2):464–76. https://doi.org/10.1096/fj.14-262303.

    CAS  Article  PubMed  Google Scholar 

  9. Morikawa K, Walker SM, Nakajima M, Pathak S, Jessup JM, Fidler IJ. Influence of organ environment on the growth, selection, and metastasis of human colon carcinoma cells in nude mice. Cancer Res. 1988;48(23):6863–71.

    CAS  PubMed  Google Scholar 

  10. •• Fumagalli A, Drost J, Suijkerbuijk SJ, van Boxtel R, de Ligt J, Offerhaus GJ, et al. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proc Natl Acad Sci U S A. 2017;114(12):E2357–E64. https://doi.org/10.1073/pnas.1701219114. Utilized human organoids genetically modified with CRISPR/Cas 9 to contain combinations of APC, TRP53, KRAS, and SMAD4 deletions or mutations. These were transplanted into the cecal wall of immune-deficient mice to examine roles for each genetic combination in tumor formation and metastasis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. •• O'Rourke KP, Loizou E, Livshits G, Schatoff EM, Baslan T, Manchado E, et al. Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. Nat Biotechnol. 2017;35(6):577–82. https://doi.org/10.1038/nbt.3837. Utilized novel method of organoid fragment delivery to the mouse colon via enema for rapid generation of colonic tumors that recapitulate the human adenoma – carcinoma – metastasis malignant progression. System is easily adaptable to mouse into mouse or human into mouse experiments and allows for ex vivo manipulation of organoids prior to transplantation.

    Article  PubMed  PubMed Central  Google Scholar 

  12. •• Roper J, Tammela T, Cetinbas NM, Akkad A, Roghanian A, Rickelt S, et al. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat Biotechnol. 2017;35(6):569–76. https://doi.org/10.1038/nbt.3836. Demonstrated colonoscopy-guided mucosal injection of adeno-Cre or lentivirus carrying guides for Apc or Trp53 into the colonic mucosa of mice carrying conditional genetic alleles for Apc or Cas9 resulting in tumor formation. Elegant use of conditional Cre or CRISPR/Cas9 technology in organoids derived from mouse and human sources. These organoids were injected into the colonic mucosa of NSG or humanized mice to model tumor formation and/or metastasis following genetic recombination.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. •• de Sousa e Melo F, Kurtova AV, Harnoss JM, Kljavin N, Hoeck JD, Hung J, et al. A distinct role for Lgr5(+) stem cells in primary and metastatic colon cancer. Nature. 2017;543(7647):676–80. https://doi.org/10.1038/nature21713. Developed organoids from Lgr5 DTR-eGFP mice bearing mutations in Apc , Kras, Trp53, and Smad4 , which were generated through a combination of mouse genetics and CRISPR/Cas9 technology. Using these tools they demonstrated that Lgr5+ cells initiate tumor formation and metastasis, but that ablation of Lgr5+ cells within a formed tumor only slows tumor growth and does not lead to tumor regression.

    Article  PubMed  Google Scholar 

  14. Nunes M, Vrignaud P, Vacher S, Richon S, Lievre A, Cacheux W, et al. Evaluating patient-derived colorectal cancer xenografts as preclinical models by comparison with patient clinical data. Cancer Res. 2015;75(8):1560–6. https://doi.org/10.1158/0008-5472.CAN-14-1590.

    CAS  Article  PubMed  Google Scholar 

  15. Margolin DA, Myers T, Zhang X, Bertoni DM, Reuter BA, Obokhare I, et al. The critical roles of tumor-initiating cells and the lymph node stromal microenvironment in human colorectal cancer extranodal metastasis using a unique humanized orthotopic mouse model. FASEB J. 2015;29(8):3571–81. https://doi.org/10.1096/fj.14-268938.

    CAS  Article  PubMed  Google Scholar 

  16. Feng Y, Bommer GT, Zhao J, Green M, Sands E, Zhai Y, et al. Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology. 2011;141(3):1003–13 e1–10. https://doi.org/10.1053/j.gastro.2011.05.007.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Janssen KP, Alberici P, Fsihi H, Gaspar C, Breukel C, Franken P, et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology. 2006;131(4):1096–109. https://doi.org/10.1053/j.gastro.2006.08.011.

    CAS  Article  PubMed  Google Scholar 

  18. Sakamoto N, Feng Y, Stolfi C, Kurosu Y, Green M, Lin J, Green ME, Sentani K, Yasui W, McMahon M, Hardiman KM, Spence JR, Horita N, Greenson JK, Kuick R, Cho KR, Fearon ER BRAF (V600E) cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis. elife 2017; 6. doi:https://doi.org/10.7554/eLife.20331.

  19. Bennecke M, Kriegl L, Bajbouj M, Retzlaff K, Robine S, Jung A, et al. Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis. Cancer Cell. 2010;18(2):135–46. https://doi.org/10.1016/j.ccr.2010.06.013.

    CAS  Article  PubMed  Google Scholar 

  20. Rad R, Cadinanos J, Rad L, Varela I, Strong A, Kriegl L, et al. A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell. 2013;24(1):15–29. https://doi.org/10.1016/j.ccr.2013.05.014.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Rustgi AK. BRAF: a driver of the serrated pathway in colon cancer. Cancer Cell. 2013;24(1):1–2. https://doi.org/10.1016/j.ccr.2013.06.008.

    CAS  Article  PubMed  Google Scholar 

  22. • Sakai E, Nakayama M, Oshima H, Kouyama Y, Niida A, Fujii S, Ochiai A, Nakayama KI, Mimori K, Suzuki Y, Hong CP, Ock CY, Kim SJ, Oshima M Combined mutation of Apc, Kras and Tgfbr2 effectively drives metastasis of intestinal cancer. Cancer Res 2017. doi:https://doi.org/10.1158/0008-5472.CAN-17-3303. This study used compound genetic mouse models and organoids to assess stepwise drivers of primary tumor formation and metastasis in vivo. They performed RNA sequencing analysis to identify common changes in gene expression downstream of metastatic drivers.

  23. Munoz NM, Upton M, Rojas A, Washington MK, Lin L, Chytil A, et al. Transforming growth factor beta receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation. Cancer Res. 2006;66(20):9837–44. https://doi.org/10.1158/0008-5472.CAN-06-0890.

    CAS  Article  PubMed  Google Scholar 

  24. Trobridge P, Knoblaugh S, Washington MK, Munoz NM, Tsuchiya KD, Rojas A, et al. TGF-beta receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a beta-catenin-independent pathway. Gastroenterology. 2009;136(5):1680–8 e7. https://doi.org/10.1053/j.gastro.2009.01.066.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. •• Boutin AT, Liao WT, Wang M, Hwang SS, Karpinets TV, Cheung H, et al. Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes Dev. 2017;31(4):370–82. https://doi.org/10.1101/gad.293449.116. Developed a genetic mouse model with colon-specific, inducible Apc and Trp53 loss coupled with mutant Kras expression. These mice recapitulate many aspects of human CRC, including liver metastasis. This study demonstrates the importance of mutant KRAS and TGF-β signaling for invasion and metastasis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Hung KE, Maricevich MA, Richard LG, Chen WY, Richardson MP, Kunin A, et al. Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment. Proc Natl Acad Sci U S A. 2010;107(4):1565–70. https://doi.org/10.1073/pnas.0908682107.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Taketo MM, Edelmann W. Mouse models of colon cancer. Gastroenterology. 2009;136(3):780–98.

    CAS  Article  PubMed  Google Scholar 

  28. Brembeck FH, Schwarz-Romond T, Bakkers J, Wilhelm S, Hammerschmidt M, Birchmeier W. Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions. Genes Dev. 2004;18(18):2225–30. https://doi.org/10.1101/gad.317604.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol. 2007;19(2):150–8. https://doi.org/10.1016/j.ceb.2007.02.007.

    CAS  Article  PubMed  Google Scholar 

  30. Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12(5):468–76. https://doi.org/10.1038/ncb2048.

    CAS  Article  PubMed  Google Scholar 

  31. Wang S, Dong Y, Zhang Y, Wang X, Xu L, Yang S, et al. DACT2 is a functional tumor suppressor through inhibiting Wnt/beta-catenin pathway and associated with poor survival in colon cancer. Oncogene. 2015;34(20):2575–85. https://doi.org/10.1038/onc.2014.201.

    CAS  Article  PubMed  Google Scholar 

  32. Ragusa S, Cheng J, Ivanov KI, Zangger N, Ceteci F, Bernier-Latmani J, et al. PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt(high) metastatic colon cancer cells. Cell Rep. 2014;8(6):1957–73. https://doi.org/10.1016/j.celrep.2014.08.041.

    CAS  Article  PubMed  Google Scholar 

  33. Rodrigues P, Macaya I, Bazzocco S, Mazzolini R, Andretta E, Dopeso H, et al. RHOA inactivation enhances Wnt signalling and promotes colorectal cancer. Nat Commun. 2014;5:5458. https://doi.org/10.1038/ncomms6458.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S, et al. Beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 2012;18(6):892–901. https://doi.org/10.1038/nm.2772.

    CAS  Article  PubMed  Google Scholar 

  35. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268(5215):1336–8.

    CAS  Article  PubMed  Google Scholar 

  36. Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22(5):571–84. https://doi.org/10.1016/j.ccr.2012.08.013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Fritzmann J, Morkel M, Besser D, Budczies J, Kosel F, Brembeck FH, et al. A colorectal cancer expression profile that includes transforming growth factor beta inhibitor BAMBI predicts metastatic potential. Gastroenterology. 2009;137(1):165–75. https://doi.org/10.1053/j.gastro.2009.03.041.

    CAS  Article  PubMed  Google Scholar 

  38. Itatani Y, Kawada K, Fujishita T, Kakizaki F, Hirai H, Matsumoto T, et al. Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis. Gastroenterology. 2013;145(5):1064–75 e11. https://doi.org/10.1053/j.gastro.2013.07.033.

    CAS  Article  PubMed  Google Scholar 

  39. McCormick F. K-Ras protein as a drug target. J Mol Med (Berl). 2016;94(3):253–8. https://doi.org/10.1007/s00109-016-1382-7.

    CAS  Article  Google Scholar 

  40. Urosevic J, Garcia-Albeniz X, Planet E, Real S, Cespedes MV, Guiu M, et al. Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH. Nat Cell Biol. 2014;16(7):685–94. https://doi.org/10.1038/ncb2977.

    CAS  Article  PubMed  Google Scholar 

  41. Strickler JH, Wu C, Bekaii-Saab T. Targeting BRAF in metastatic colorectal cancer: maximizing molecular approaches. Cancer Treat Rev. 2017;60:109–19. https://doi.org/10.1016/j.ctrv.2017.08.006.

    CAS  Article  PubMed  Google Scholar 

  42. Mazzone M, Comoglio PM. The Met pathway: master switch and drug target in cancer progression. FASEB J. 2006;20(10):1611–21. https://doi.org/10.1096/fj.06-5947rev.

    CAS  Article  PubMed  Google Scholar 

  43. Cui YM, Jiao HL, Ye YP, Chen CM, Wang JX, Tang N, et al. FOXC2 promotes colorectal cancer metastasis by directly targeting MET. Oncogene. 2015;34(33):4379–90. https://doi.org/10.1038/onc.2014.368.

    CAS  Article  PubMed  Google Scholar 

  44. Stein U, Walther W, Arlt F, Schwabe H, Smith J, Fichtner I, et al. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med. 2009;15(1):59–67. https://doi.org/10.1038/nm.1889.

    CAS  Article  PubMed  Google Scholar 

  45. Pichorner A, Sack U, Kobelt D, Kelch I, Arlt F, Smith J, et al. In vivo imaging of colorectal cancer growth and metastasis by targeting MACC1 with shRNA in xenografted mice. Clin Exp Metastasis. 2012;29(6):573–83. https://doi.org/10.1007/s10585-012-9472-6.

    CAS  Article  PubMed  Google Scholar 

  46. Juneja M, Kobelt D, Walther W, Voss C, Smith J, Specker E, et al. Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1. PLoS Biol. 2017;15(6):e2000784. https://doi.org/10.1371/journal.pbio.2000784.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Orian-Rousseau V, Ponta H. Perspectives of CD44 targeting therapies. Arch Toxicol. 2015;89(1):3–14. https://doi.org/10.1007/s00204-014-1424-2.

    CAS  Article  PubMed  Google Scholar 

  48. Wielenga VJ, Heider KH, Offerhaus GJ, Adolf GR, van den Berg FM, Ponta H, et al. Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res. 1993;53(20):4754–6.

    CAS  PubMed  Google Scholar 

  49. Zeilstra J, Joosten SP, Dokter M, Verwiel E, Spaargaren M, Pals ST. Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 2008;68(10):3655–61. https://doi.org/10.1158/0008-5472.CAN-07-2940.

    CAS  Article  PubMed  Google Scholar 

  50. Zeilstra J, Joosten SP, van Andel H, Tolg C, Berns A, Snoek M, et al. Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling. Oncogene. 2014;33(5):665–70. https://doi.org/10.1038/onc.2012.611.

    CAS  Article  PubMed  Google Scholar 

  51. Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev. 2002;16(23):3074–86. https://doi.org/10.1101/gad.242602.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Joosten SPJ, Zeilstra J, van Andel H, Mijnals RC, Zaunbrecher J, Duivenvoorden AAM, et al. MET signaling mediates intestinal crypt-villus development, regeneration, and adenoma formation and is promoted by stem cell CD44 isoforms. Gastroenterology. 2017;153(4):1040–53 e4. https://doi.org/10.1053/j.gastro.2017.07.008.

    CAS  Article  PubMed  Google Scholar 

  53. Su YJ, Lai HM, Chang YW, Chen GY, Lee JL. Direct reprogramming of stem cell properties in colon cancer cells by CD44. EMBO J. 2011;30(15):3186–99. https://doi.org/10.1038/emboj.2011.211.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Zhang LL, Mu GG, Ding QS, Li YX, Shi YB, Dai JF, et al. Phosphatase and tensin homolog (PTEN) represses colon cancer progression through inhibiting paxillin transcription via PI3K/AKT/NF-kappaB pathway. J Biol Chem. 2015;290(24):15018–29. https://doi.org/10.1074/jbc.M115.641407.

    CAS  Article  PubMed  Google Scholar 

  55. Chen DL, Wang DS, Wu WJ, Zeng ZL, Luo HY, Qiu MZ, et al. Overexpression of paxillin induced by miR-137 suppression promotes tumor progression and metastasis in colorectal cancer. Carcinogenesis. 2013;34(4):803–11. https://doi.org/10.1093/carcin/bgs400.

    CAS  Article  PubMed  Google Scholar 

  56. Rychahou PG, Kang J, Gulhati P, Doan HQ, Chen LA, Xiao SY, et al. Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc Natl Acad Sci U S A. 2008;105(51):20315–20. https://doi.org/10.1073/pnas.0810715105.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Bartolome RA, Garcia-Palmero I, Torres S, Lopez-Lucendo M, Balyasnikova IV, Casal JI. IL13 receptor alpha2 signaling requires a scaffold protein, FAM120A, to activate the FAK and PI3K pathways in colon cancer metastasis. Cancer Res. 2015;75(12):2434–44. https://doi.org/10.1158/0008-5472.CAN-14-3650.

    CAS  Article  PubMed  Google Scholar 

  58. Rychahou PG, Jackson LN, Silva SR, Rajaraman S, Evers BM. Targeted molecular therapy of the PI3K pathway: therapeutic significance of PI3K subunit targeting in colorectal carcinoma. Ann Surg. 2006;243(6):833–42; discussion 43-4. https://doi.org/10.1097/01.sla.0000220040.66012.a9.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011;71(9):3246–56. https://doi.org/10.1158/0008-5472.CAN-10-4058.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Yuge R, Kitadai Y, Shinagawa K, Onoyama M, Tanaka S, Yasui W, et al. mTOR and PDGF pathway blockade inhibits liver metastasis of colorectal cancer by modulating the tumor microenvironment. Am J Pathol. 2015;185(2):399–408. https://doi.org/10.1016/j.ajpath.2014.10.014.

    CAS  Article  PubMed  Google Scholar 

  61. Roberts RB, Min L, Washington MK, Olsen SJ, Settle SH, Coffey RJ, et al. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc Natl Acad Sci U S A. 2002;99(3):1521–6. https://doi.org/10.1073/pnas.032678499.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Miyamoto Y, Suyama K, Baba H. Recent advances in targeting the EGFR signaling pathway for the treatment of metastatic colorectal cancer. Int J Mol Sci. 2017;18(4) https://doi.org/10.3390/ijms18040752.

  63. Tong WM, Ellinger A, Sheinin Y, Cross HS. Epidermal growth factor receptor expression in primary cultured human colorectal carcinoma cells. Br J Cancer. 1998;77(11):1792–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Radinsky R, Risin S, Fan D, Dong Z, Bielenberg D, Bucana CD, et al. Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res. 1995;1(1):19–31.

    CAS  PubMed  Google Scholar 

  65. De Jong KP, Stellema R, Karrenbeld A, Koudstaal J, Gouw AS, Sluiter WJ, et al. Clinical relevance of transforming growth factor alpha, epidermal growth factor receptor, p53, and Ki67 in colorectal liver metastases and corresponding primary tumors. Hepatology. 1998;28(4):971–9. https://doi.org/10.1002/hep.510280411.

    Article  PubMed  Google Scholar 

  66. Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21(7):795–801. https://doi.org/10.1038/nm.3870.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Srivatsa S, Paul MC, Cardone C, Holcmann M, Amberg N, Pathria P, et al. EGFR in tumor-associated myeloid cells promotes development of colorectal cancer in mice and associates with outcomes of patients. Gastroenterology. 2017;153(1):178–90 e10. https://doi.org/10.1053/j.gastro.2017.03.053.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Higginbotham JN, Zhang Q, Jeppesen DK, Scott AM, Manning HC, Ochieng J, et al. Identification and characterization of EGF receptor in individual exosomes by fluorescence-activated vesicle sorting. J Extracell Vesicles. 2016;5:29254. https://doi.org/10.3402/jev.v5.29254.

    Article  PubMed  Google Scholar 

  69. Iliou MS, da Silva-Diz V, Carmona FJ, Ramalho-Carvalho J, Heyn H, Villanueva A, et al. Impaired DICER1 function promotes stemness and metastasis in colon cancer. Oncogene. 2014;33(30):4003–15. https://doi.org/10.1038/onc.2013.398.

    CAS  Article  PubMed  Google Scholar 

  70. Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 2010;467(7318):986–90. https://doi.org/10.1038/nature09459.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014;124(4):1853–67. https://doi.org/10.1172/JCI73531.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Siemens H, Neumann J, Jackstadt R, Mansmann U, Horst D, Kirchner T, et al. Detection of miR-34a promoter methylation in combination with elevated expression of c-Met and beta-catenin predicts distant metastasis of colon cancer. Clin Cancer Res. 2013;19(3):710–20. https://doi.org/10.1158/1078-0432.CCR-12-1703.

    CAS  Article  PubMed  Google Scholar 

  73. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17(2):211–5. https://doi.org/10.1038/nm.2284.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Shi L, Jackstadt R, Siemens H, Li H, Kirchner T, Hermeking H. p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer. Cancer Res. 2014;74(2):532–42. https://doi.org/10.1158/0008-5472.CAN-13-2203.

    CAS  Article  PubMed  Google Scholar 

  75. Jackstadt R, Roh S, Neumann J, Jung P, Hoffmann R, Horst D, et al. AP4 is a mediator of epithelial-mesenchymal transition and metastasis in colorectal cancer. J Exp Med. 2013;210(7):1331–50. https://doi.org/10.1084/jem.20120812.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Keene JD. RNA regulons: coordination of post-transcriptional events. Nat Rev Genet. 2007;8(7):533–43. https://doi.org/10.1038/nrg2111.

    CAS  Article  PubMed  Google Scholar 

  77. King CE, Cuatrecasas M, Castells A, Sepulveda AR, Lee JS, Rustgi AK. LIN28B promotes colon cancer progression and metastasis. Cancer Res. 2011;71(12):4260–8. https://doi.org/10.1158/0008-5472.CAN-10-4637.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Madison BB, Jeganathan AN, Mizuno R, Winslow MM, Castells A, Cuatrecasas M, et al. Let-7 represses carcinogenesis and a stem cell phenotype in the intestine via regulation of Hmga2. PLoS Genet. 2015;11(8):e1005408. https://doi.org/10.1371/journal.pgen.1005408.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Dimitriadis E, Trangas T, Milatos S, Foukas PG, Gioulbasanis I, Courtis N, et al. Expression of oncofetal RNA-binding protein CRD-BP/IMP1 predicts clinical outcome in colon cancer. Int J Cancer. 2007;121(3):486–94. https://doi.org/10.1002/ijc.22716.

    CAS  Article  PubMed  Google Scholar 

  80. Vainer G, Vainer-Mosse E, Pikarsky A, Shenoy SM, Oberman F, Yeffet A, et al. A role for VICKZ proteins in the progression of colorectal carcinomas: regulating lamellipodia formation. J Pathol. 2008;215(4):445–56. https://doi.org/10.1002/path.2376.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Li D, Yan D, Tang H, Zhou C, Fan J, Li S, et al. IMP3 is a novel prognostic marker that correlates with colon cancer progression and pathogenesis. Ann Surg Oncol. 2009;16(12):3499–506. https://doi.org/10.1245/s10434-009-0648-5.

    Article  PubMed  Google Scholar 

  82. Wei Q, Huang X, Fu B, Liu J, Zhong L, Yang Q, et al. IMP3 expression in biopsy specimens of colorectal cancer predicts lymph node metastasis and TNM stage. Int J Clin Exp Pathol. 2015;8(9):11024–32.

    PubMed  PubMed Central  Google Scholar 

  83. Yoo PS, Sullivan CA, Kiang S, Gao W, Uchio EM, Chung GG, et al. Tissue microarray analysis of 560 patients with colorectal adenocarcinoma: high expression of HuR predicts poor survival. Ann Surg Oncol. 2009;16(1):200–7. https://doi.org/10.1245/s10434-008-0209-3.

    Article  PubMed  Google Scholar 

  84. Li N, Yousefi M, Nakauka-Ddamba A, Li F, Vandivier L, Parada K, et al. The Msi family of RNA-binding proteins function redundantly as intestinal Oncoproteins. Cell Rep. 2015;13(11):2440–55. https://doi.org/10.1016/j.celrep.2015.11.022.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Rezza A, Skah S, Roche C, Nadjar J, Samarut J, Plateroti M. The overexpression of the putative gut stem cell marker Musashi-1 induces tumorigenesis through Wnt and Notch activation. J Cell Sci. 2010;123(Pt 19):3256–65. https://doi.org/10.1242/jcs.065284.

    CAS  Article  PubMed  Google Scholar 

  86. Wang S, Li N, Yousefi M, Nakauka-Ddamba A, Li F, Parada K, et al. Transformation of the intestinal epithelium by the MSI2 RNA-binding protein. Nat Commun. 2015;6:6517. https://doi.org/10.1038/ncomms7517.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Kudinov AE, Karanicolas J, Golemis EA, Boumber Y. Musashi RNA-binding proteins as cancer drivers and novel therapeutic targets. Clin Cancer Res. 2017;23(9):2143–53. https://doi.org/10.1158/1078-0432.CCR-16-2728.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Zong Z, Zhou T, Rao L, Jiang Z, Li Y, Hou Z, et al. Musashi2 as a novel predictive biomarker for liver metastasis and poor prognosis in colorectal cancer. Cancer Med. 2016;5(4):623–30. https://doi.org/10.1002/cam4.624.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Li D, Peng X, Yan D, Tang H, Huang F, Yang Y, et al. Msi-1 is a predictor of survival and a novel therapeutic target in colon cancer. Ann Surg Oncol. 2011;18(7):2074–83. https://doi.org/10.1245/s10434-011-1567-9.

    Article  PubMed  Google Scholar 

  90. Conway AE, Van Nostrand EL, Pratt GA, Aigner S, Wilbert ML, Sundararaman B, et al. Enhanced CLIP uncovers IMP protein-RNA targets in human pluripotent stem cells important for cell adhesion and survival. Cell Rep. 2016;15(3):666–79. https://doi.org/10.1016/j.celrep.2016.03.052.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Mongroo PS, Noubissi FK, Cuatrecasas M, Kalabis J, King CE, Johnstone CN, et al. IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2. Cancer Res. 2011;71(6):2172–82. https://doi.org/10.1158/0008-5472.CAN-10-3295.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Vikesaa J, Hansen TV, Jonson L, Borup R, Wewer UM, Christiansen J, et al. RNA-binding IMPs promote cell adhesion and invadopodia formation. EMBO J. 2006;25(7):1456–68. https://doi.org/10.1038/sj.emboj.7601039.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. Mahapatra L, Andruska N, Mao C, Le J, Shapiro DJ. A novel IMP1 inhibitor, BTYNB, targets c-Myc and inhibits melanoma and ovarian cancer cell proliferation. Transl Oncol. 2017;10(5):818–27. https://doi.org/10.1016/j.tranon.2017.07.008.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Kim TW, Havighurst T, Kim K, Albertini M, Xu YG, Spiegelman VS. Targeting insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in metastatic melanoma to increase efficacy of BRAF(V600E) inhibitors. Mol Carcinog 2018. https://doi.org/10.1002/mc.22786.

Download references

Acknowledgments

The authors were supported by the NIH/NIDDK P30DK050306, R01DK056645, AGA Research Scholar Award (SFA), HHMI Research Fellowship (KNW), Hansen Foundation, Lustgarten Family colon cancer grants, and the Penn Colon Cancer Translational Center of Excellence.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sarah F. Andres.

Ethics declarations

Conflict of Interest

Sarah F. Andres, Kathy N. Williams, and Anil K. Rustgi declare they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Basic Science Foundations in Colorectal Cancer

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Andres, S.F., Williams, K.N. & Rustgi, A.K. The Molecular Basis of Metastatic Colorectal Cancer. Curr Colorectal Cancer Rep 14, 69–79 (2018). https://doi.org/10.1007/s11888-018-0403-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11888-018-0403-z

Keywords

  • Signaling pathways
  • WNT
  • TGFβ
  • HGF
  • CD44
  • KRAS