Advertisement

Impact of the Microenvironment on Tumour Budding in Colorectal Cancer

  • Laurent MC Georges
  • Laurine Verset
  • Inti Zlobec
  • Pieter Demetter
  • Olivier De WeverEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1110)

Abstract

Tumour Budding (TB) is recognized as an adverse prognostic factor in colorectal cancer (CRC). TB is the detachment of isolated cancer cells or small clusters of such cells mainly at the invasion front. One question that arises is of the role of the tumour stroma regarding the permissiveness of the formation and progression of TB. In this review, we will examine potential factors affecting TB, in particular we will analyse the potential effect of inflammation, hypoxia, extracellular matrix and Cancer-Associated Fibroblasts (CAFs).

Keywords

Budding Cancer-associated fibroblast Epithelial-mesenchymal transition Migration Tumor-environment 

References

  1. Armin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR (eds) (2017) AJCC cancer staging manual, 8th edn. Springer Nature Publishing, ISBN 978-3-319-40617-6Google Scholar
  2. Bronsert P, Enderle-Ammour K, Bader M, Timme S, Kuehs M, Csanadi A, Kayser G, Kohler I, Bausch D, Hoeppner J, Hopt U, Keck T, Stickeler E, Passlick B, Schilling O, Reiss C, Vashist Y, Brabletz T, Berger J, Lotz J, Olesch J, Werner M, Wellner U (2014) Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface: 3D cancer-host interface. J Pathol 234:410–422.  https://doi.org/10.1002/path.4416 CrossRefPubMedGoogle Scholar
  3. Calon A, Tauriello DVF, Batlle E (2014) TGF-beta in CAF-mediated tumor growth and metastasis. Semin Cancer Biol 25:15–22.  https://doi.org/10.1016/j.semcancer.2013.12.008 CrossRefPubMedGoogle Scholar
  4. Casasent AK, Schalck A, Gao R, Sei E, Long A, Pangburn W, Casasent T, Meric-Bernstam F, Edgerton ME, Navin NE (2018) Multiclonal invasion in breast tumors identified by topographic single cell sequencing. Cell 172:205–217.e12.  https://doi.org/10.1016/j.cell.2017.12.007 CrossRefPubMedGoogle Scholar
  5. Centeno I, Paasinen Sohns A, Flury M, Galván JA, Zahnd S, Koelzer VH, Sokol L, Dawson HE, Lugli A, Cathomas G, Zlobec I (2017) DNA profiling of tumor buds in colorectal cancer indicates that they have the same mutation profile as the tumor from which they derive. Virchows Arch 470:341–346.  https://doi.org/10.1007/s00428-017-2071-9 CrossRefPubMedGoogle Scholar
  6. Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD, Fairchild AN, Gorin MA, Verdone JE, Pienta KJ, Bader JS, Ewald AJ (2016) Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci U S A 113:E854–E863.  https://doi.org/10.1073/pnas.1508541113 CrossRefPubMedPubMedCentralGoogle Scholar
  7. De Boeck A, Hendrix A, Maynard D, Van Bockstal M, Daniëls A, Pauwels P, Gespach C, Bracke M, De Wever O (2013a) Differential secretome analysis of cancer-associated fibroblasts and bone marrow-derived precursors to identify microenvironmental regulators of colon cancer progression. Proteomics 13:379–388.  https://doi.org/10.1002/pmic.201200179 CrossRefPubMedGoogle Scholar
  8. De Boeck A, Pauwels P, Hensen K, Rummens J-L, Westbroek W, Hendrix A, Maynard D, Denys H, Lambein K, Braems G, Gespach C, Bracke M, Wever OD (2013b) Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. Gut 62:550–560.  https://doi.org/10.1136/gutjnl-2011-301393 CrossRefPubMedGoogle Scholar
  9. De Smedt L, Palmans S, Andel D, Govaere O, Boeckx B, Smeets D, Galle E, Wouters J, Barras D, Suffiotti M, Dekervel J, Tousseyn T, De Hertogh G, Prenen H, Tejpar S, Lambrechts D, Sagaert X (2017) Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching. Br J Cancer 116:58–65.  https://doi.org/10.1038/bjc.2016.382 CrossRefPubMedGoogle Scholar
  10. De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion: stroma and cancer invasion. J Pathol 200:429–447.  https://doi.org/10.1002/path.1398 CrossRefPubMedGoogle Scholar
  11. De Wever O, Nguyen Q-D, Van Hoorde L, Bracke M, Bruyneel E, Gespach C, Mareel M (2004) Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J 18:1016–1018.  https://doi.org/10.1096/fj.03-1110fje CrossRefPubMedGoogle Scholar
  12. De Wever O, Van Bockstal M, Mareel M, Hendrix A, Bracke M (2014) Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol 25:33–46.  https://doi.org/10.1016/j.semcancer.2013.12.009 CrossRefPubMedGoogle Scholar
  13. D’Ignazio L, Batie M, Rocha S (2017) Hypoxia and inflammation in cancer, focus on HIF and NF-κB. Biomedicines 5:21.  https://doi.org/10.3390/biomedicines5020021 CrossRefPubMedCentralGoogle Scholar
  14. Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Alison MR, Wright NA (2004) Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 64:8492–8495.  https://doi.org/10.1158/0008-5472.CAN-04-1708 CrossRefPubMedGoogle Scholar
  15. Dvorak HF (1986) Tumors: wounds that do not heal. N Engl J Med 315:1650–1659CrossRefGoogle Scholar
  16. EV-TRACK Consortium, Van Deun J, Mestdagh P, Agostinis P, Akay Ö, Anand S, Anckaert J, Martinez ZA, Baetens T, Beghein E, Bertier L, Berx G, Boere J, Boukouris S, Bremer M, Buschmann D, Byrd JB, Casert C, Cheng L, Cmoch A, Daveloose D, De Smedt E, Demirsoy S, Depoorter V, Dhondt B, Driedonks TAP, Dudek A, Elsharawy A, Floris I, Foers AD, Gärtner K, Garg AD, Geeurickx E, Gettemans J, Ghazavi F, Giebel B, Kormelink TG, Hancock G, Helsmoortel H, Hill AF, Hyenne V, Kalra H, Kim D, Kowal J, Kraemer S, Leidinger P, Leonelli C, Liang Y, Lippens L, Liu S, Lo Cicero A, Martin S, Mathivanan S, Mathiyalagan P, Matusek T, Milani G, Monguió-Tortajada M, Mus LM, Muth DC, Németh A, Nolte-’t Hoen ENM, O’Driscoll L, Palmulli R, Pfaffl MW, Primdal-Bengtson B, Romano E, Rousseau Q, Sahoo S, Sampaio N, Samuel M, Scicluna B, Soen B, Steels A, Swinnen JV, Takatalo M, Thaminy S, Théry C, Tulkens J, Van Audenhove I, van der Grein S, Van Goethem A, van Herwijnen MJ, Van Niel G, Van Roy N, Van Vliet AR, Vandamme N, Vanhauwaert S, Vergauwen G, Verweij F, Wallaert A, Wauben M, Witwer KW, Zonneveld MI, De Wever O, Vandesompele J, Hendrix A (2017) EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research. Nat Methods 14:228–232.  https://doi.org/10.1038/nmeth.4185 CrossRefGoogle Scholar
  17. Fan X-J, Wan X-B, Yang Z-L, Fu X-H, Huang Y, Chen D-K, Song S-X, Liu Q, Xiao H-Y, Wang L, Wang J-P (2013) Snail promotes lymph node metastasis and twist enhances tumor deposit formation through epithelial-mesenchymal transition in colorectal cancer. Hum Pathol 44:173–180.  https://doi.org/10.1016/j.humpath.2012.03.029 CrossRefPubMedGoogle Scholar
  18. Forse CL, Rahimi M, Diamandis EP, Assarzadegan N, Dawson H, Grin A, Kennedy E, O’Connor B, Messenger DE, Riddell RH, Kirsch R, Karagiannis GS (2017) HtrA3 stromal expression is correlated with tumor budding in stage II colorectal cancer. Exp Mol Pathol 103:94–100.  https://doi.org/10.1016/j.yexmp.2017.07.002 CrossRefPubMedGoogle Scholar
  19. Giger OT, Comtesse SCM, Lugli A, Zlobec I, Kurrer MO (2012) Intra-tumoral budding in preoperative biopsy specimens predicts lymph node and distant metastasis in patients with colorectal cancer. Mod Pathol 25:1048–1053.  https://doi.org/10.1038/modpathol.2012.56 CrossRefPubMedGoogle Scholar
  20. Grigore A, Jolly M, Jia D, Farach-Carson M, Levine H (2016) Tumor budding: the name is EMT. Partial EMT. J Clin Med 5:51.  https://doi.org/10.3390/jcm5050051 CrossRefPubMedCentralGoogle Scholar
  21. Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, Marisa L, Roepman P, Nyamundanda G, Angelino P, Bot BM, Morris JS, Simon IM, Gerster S, Fessler E, De Sousa E, Melo F, Missiaglia E, Ramay H, Barras D, Homicsko K, Maru D, Manyam GC, Broom B, Boige V, Perez-Villamil B, Laderas T, Salazar R, Gray JW, Hanahan D, Tabernero J, Bernards R, Friend SH, Laurent-Puig P, Medema JP, Sadanandam A, Wessels L, Delorenzi M, Kopetz S, Vermeulen L, Tejpar S (2015) The consensus molecular subtypes of colorectal cancer. Nat Med 21:1350–1356.  https://doi.org/10.1038/nm.3967 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Haeger A, Krause M, Wolf K, Friedl P (2014) Cell jamming: collective invasion of mesenchymal tumor cells imposed by tissue confinement. Biochim Biophys Acta – Gen Subj 1840:2386–2395.  https://doi.org/10.1016/j.bbagen.2014.03.020 CrossRefGoogle Scholar
  23. Hanley CJ, Mellone M, Ford K, Thirdborough SM, Mellows T, Frampton SJ, Smith DM, Harden E, Szyndralewiez C, Bullock M, Noble F, Moutasim KA, King EV, Vijayanand P, Mirnezami AH, Underwood TJ, Ottensmeier CH, Thomas GJ (2018) Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. J Natl Cancer Inst 110:109–120.  https://doi.org/10.1093/jnci/djx121 CrossRefGoogle Scholar
  24. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJ (1998) Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 102:538–549.  https://doi.org/10.1172/JCI1018 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Jansen S, Gosens R, Wieland T, Schmidt M (2018) Paving the Rho in cancer metastasis: Rho GTPases and beyond. Pharmacol Ther 183:1–21.  https://doi.org/10.1016/j.pharmthera.2017.09.002 CrossRefPubMedGoogle Scholar
  26. Jass JR (2002) HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences. Familial Cancer 3:93–100.  https://doi.org/10.1023/B:FAME.0000039849.86008.b7 CrossRefGoogle Scholar
  27. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90.  https://doi.org/10.3322/caac.20107 CrossRefPubMedGoogle Scholar
  28. Kalluri R, Weinberg RA (2010) The basics of epithelial-mesenchymal transition. J Clin Invest 120:1786–1786.  https://doi.org/10.1172/JCI39104C1 CrossRefPubMedCentralGoogle Scholar
  29. Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP (2012) Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res 10:1403–1418.  https://doi.org/10.1158/1541-7786.MCR-12-0307 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Karamitopoulou E, Lugli A, Panayiotides I, Karakitsos P, Peros G, Rallis G, Patsouris ES, Terracciano L, Zlobec I (2010) Systematic assessment of protein phenotypes characterizing high-grade tumour budding in mismatch repair-proficient colorectal cancer: tumour budding in colorectal cancer. Histopathology 57:233–243.  https://doi.org/10.1111/j.1365-2559.2010.03615.x CrossRefPubMedGoogle Scholar
  31. Koelzer VH, Lugli A, Dawson H, Hädrich M, Berger MD, Borner M, Mallaev M, Galván JA, Amsler J, Schnüriger B, Zlobec I, Inderbitzin D (2014) CD8/CD45RO T-cell infiltration in endoscopic biopsies of colorectal cancer predicts nodal metastasis and survival. J Transl Med 12:81.  https://doi.org/10.1186/1479-5876-12-81 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Labernadie A, Kato T, Brugués A, Serra-Picamal X, Derzsi S, Arwert E, Weston A, González-Tarragó V, Elosegui-Artola A, Albertazzi L, Alcaraz J, Roca-Cusachs P, Sahai E, Trepat X (2017) A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat Cell Biol 19:224–237.  https://doi.org/10.1038/ncb3478 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Li H, Xu F, Li S, Zhong A, Meng X, Lai M (2016) The tumor microenvironment: an irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis. Cell Adhes Migr 10:1–13.  https://doi.org/10.1080/19336918.2015.1129481 CrossRefGoogle Scholar
  34. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151:1542–1556.  https://doi.org/10.1016/j.cell.2012.11.024 CrossRefGoogle Scholar
  35. Lugli A, Karamitopoulou E, Panayiotides I, Karakitsos P, Rallis G, Peros G, Iezzi G, Spagnoli G, Bihl M, Terracciano L, Zlobec I (2009) CD8+ lymphocytes/ tumour-budding index: an independent prognostic factor representing a ‘pro-/anti-tumour’ approach to tumour host interaction in colorectal cancer. Br J Cancer 101:1382–1392.  https://doi.org/10.1038/sj.bjc.6605318 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lugli A, Vlajnic T, Giger O, Karamitopoulou E, Patsouris ES, Peros G, Terracciano LM, Zlobec I (2011) Intratumoral budding as a potential parameter of tumor progression in mismatch repair–proficient and mismatch repair–deficient colorectal cancer patients. Hum Pathol 42:1833–1840.  https://doi.org/10.1016/j.humpath.2011.02.010 CrossRefPubMedGoogle Scholar
  37. Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, El Zimaity H, Fléjou J-F, Hansen TP, Hartmann A, Kakar S, Langner C, Nagtegaal I, Puppa G, Riddell R, Ristimäki A, Sheahan K, Smyrk T, Sugihara K, Terris B, Ueno H, Vieth M, Zlobec I, Quirke P (2017) Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol 30:1299–1311.  https://doi.org/10.1038/modpathol.2017.46 CrossRefPubMedGoogle Scholar
  38. Max N, Harbaum L, Pollheimer MJ, Lindtner RA, Kornprat P, Langner C (2016) Tumour budding with and without admixed inflammation: two different sides of the same coin? Br J Cancer 114:368–371.  https://doi.org/10.1038/bjc.2015.454 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Mertens JC, Fingas CD, Christensen JD, Smoot RL, Bronk SF, Werneburg NW, Gustafson MP, Dietz AB, Roberts LR, Sirica AE, Gores GJ (2013) Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 73:897–907.  https://doi.org/10.1158/0008-5472.CAN-12-2130 CrossRefPubMedGoogle Scholar
  40. Meyer S, Zahnd S, Galván JA, Centeno I, Sokol L, Dawson HE, Koelzer VH, Lugli A, Zlobec I (2016) The search for an epithelial-mesenchymal phenotype in colorectal cancer reveals a subset of cytokeratin-positive/vimentin-positive cells derived from the tumour. Virchows Arch 469:1–346.  https://doi.org/10.1007/s00428-016-1997-7 CrossRefGoogle Scholar
  41. Mlecnik B, Bindea G, Kirilovsky A, Angell HK, Obenauf AC, Tosolini M, Church SE, Maby P, Vasaturo A, Angelova M, Fredriksen T, Mauger S, Waldner M, Berger A, Speicher MR, Pagès F, Valge-Archer V, Galon J (2016) The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med 8:327ra26-327ra26. doi:  https://doi.org/10.1126/scitranslmed.aad6352 CrossRefGoogle Scholar
  42. Morodomi T, Isomoto H, Shirouzu K, Kakegawa K, Irie K, Morimatsu M (1989) An index for estimating the probability of lymph node metastasis in rectal cancers. Lymph node metastasis and the histopathology of actively invasive regions of cancer. Cancer 63:539–543.  https://doi.org/10.1002/1097-0142(19890201)63:3<539::AID-CNCR2820630323>3.0.CO;2-S CrossRefPubMedGoogle Scholar
  43. Navab R, Strumpf D, Bandarchi B, Zhu C-Q, Pintilie M, Ramnarine VR, Ibrahimov E, Radulovich N, Leung L, Barczyk M, Panchal D, To C, Yun JJ, Der S, Shepherd FA, Jurisica I, Tsao M-S (2011) Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer. Proc Natl Acad Sci U S A 108:7160–7165.  https://doi.org/10.1073/pnas.1014506108 CrossRefPubMedPubMedCentralGoogle Scholar
  44. New J, Arnold L, Ananth M, Alvi S, Thornton M, Werner L, Tawfik O, Dai H, Shnayder Y, Kakarala K, Tsue TT, Girod DA, Ding W-X, Anant S, Thomas SM (2017) Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target. Cancer Res 77:6679–6691.  https://doi.org/10.1158/0008-5472.CAN-17-1077 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348.  https://doi.org/10.1016/j.cell.2005.02.034 CrossRefPubMedGoogle Scholar
  46. Quante M, Tu SP, Tomita H, Gonda T, Wang SSW, Takashi S, Baik GH, Shibata W, DiPrete B, Betz KS, Friedman R, Varro A, Tycko B, Wang TC (2011) Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19:257–272.  https://doi.org/10.1016/j.ccr.2011.01.020 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Righi A, Sarotto I, Casorzo L, Cavalchini S, Frangipane E, Risio M (2015) Tumour budding is associated with hypoxia at the advancing front of colorectal cancer. Histopathology 66:982–990.  https://doi.org/10.1111/his.12602 CrossRefPubMedGoogle Scholar
  48. Rogers AC, Gibbons D, Hanly AM, Hyland JM, O’Connell PR, Winter DC, Sheahan K (2014) Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy. Mod Pathol 27:156–162.  https://doi.org/10.1038/modpathol.2013.124 CrossRefPubMedGoogle Scholar
  49. Rogers AC, Winter DC, Heeney A, Gibbons D, Lugli A, Puppa G, Sheahan K (2016) Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer. Br J Cancer 115:831–840.  https://doi.org/10.1038/bjc.2016.274 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Satoh K, Nimura S, Aoki M, Hamasaki M, Koga K, Iwasaki H, Yamashita Y, Kataoka H, Nabeshima K (2014) Tumor budding in colorectal carcinoma assessed by cytokeratin immunostaining and budding areas: possible involvement of c-Met. Cancer Sci 105:1487–1495.  https://doi.org/10.1111/cas.12530 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Tao L, Huang G, Song H, Chen Y, Chen L (2017) Cancer associated fibroblasts: an essential role in the tumor microenvironment. Oncol Lett 14:2611–2620.  https://doi.org/10.3892/ol.2017.6497 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Te Boekhorst V, Preziosi L, Friedl P (2016) Plasticity of cell migration in vivo and in silico. Ann Rev Cell Dev Biol 32:491–526.  https://doi.org/10.1146/annurev-cellbio-111315-125201 CrossRefGoogle Scholar
  53. Thanki K, Nicholls ME, Gajjar A, Senagore AJ, Qiu S, Szabo C, Hellmich MR, Chao C (2017) Consensus molecular subtypes of colorectal cancer and their clinical implications. Int Biol Biomed J 3:105–111PubMedPubMedCentralGoogle Scholar
  54. Trinh A, Lädrach C, Dawson HE, ten Hoorn S, Kuppen P, Reimers MS, Koopman M, Punt C, Lugli A, Vermeulen L, Zlobec I (in press) Tumor budding is associated with the mesenchymal colon cancer subtype and RAS/RAF mutations: a study of 1320 colorectal cancers with consensus. Br J CancerGoogle Scholar
  55. Tsujino T, Seshimo I, Yamamoto H, Ngan CY, Ezumi K, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Monden M (2007) Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res 13:2082–2090.  https://doi.org/10.1158/1078-0432.CCR-06-2191 CrossRefPubMedGoogle Scholar
  56. Ueno H (2004) Histological categorisation of fibrotic cancer stroma in advanced rectal cancer. Gut 53:581–586.  https://doi.org/10.1136/gut.2003.028365 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Ulintz PJ, Greenson JK, Wu R, Fearon ER, Hardiman KM (2018) Lymph node metastases in colon cancer are polyclonal. Clin Cancer Res 24:2214–2224.  https://doi.org/10.1158/1078-0432.CCR-17-1425 CrossRefPubMedGoogle Scholar
  58. Yang M-H, Wu M-Z, Chiou S-H, Chen P-M, Chang S-Y, Liu C-J, Teng S-C, Wu K-J (2008) Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biol 10:295–305.  https://doi.org/10.1038/ncb1691 CrossRefPubMedGoogle Scholar
  59. Zlobec I, Lugli A (2018) Tumour budding in colorectal cancer: molecular rationale for clinical translation. Nat Rev Cancer 18:203–204.  https://doi.org/10.1038/nrc.2018.1 CrossRefPubMedGoogle Scholar
  60. Zlobec I, Hädrich M, Dawson H, Koelzer VH, Borner M, Mallaev M, Schnüriger B, Inderbitzin D, Lugli A (2014) Intratumoural budding (ITB) in preoperative biopsies predicts the presence of lymph node and distant metastases in colon and rectal cancer patients. Br J Cancer 110:1008–1013.  https://doi.org/10.1038/bjc.2013.797 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Laurent MC Georges
    • 1
  • Laurine Verset
    • 1
  • Inti Zlobec
    • 2
  • Pieter Demetter
    • 1
  • Olivier De Wever
    • 3
    • 4
    Email author
  1. 1.Department of Pathology, Erasme University HospitalUniversité Libre de BruxellesBrusselsBelgium
  2. 2.Institute of PathologyUniversity of BernBernSwitzerland
  3. 3.Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer ResearchGhent UniversityGhentBelgium
  4. 4.Cancer Research Institute Ghent (CRIG)GhentBelgium

Personalised recommendations