Metastasis-associated Factors Facilitating the Progression of Colorectal Cancer

  • Zhang, Yao-Yao (Reproductive Medical Center, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University) ;
  • Chen, Bin (Department of Oncology, General Hospital of Guangzhou Military Command of PLA) ;
  • Ding, Yan-Qing (Department of Pathology, School of Basic Medical Sciences, Southern Medical University)
  • Published : 2012.06.30


Tumor metastasis remains the principal cause of treatment failure and poor prognosis in patients with colorectal cancer. It is a multistage process which includes proteolysis, motility and migration of cells, proliferation in a new site, and neoangiogenesis. A crucial step in the process of intra- and extra-vasation is the activation of proteolytic enzymes capable of degrading the extracellular matrix (ECM). In this stage, urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinases (MMPs) are necessary. Micrometastases need the presence of growth factor and vascular growth factor so that they can form macrometastasis. In addition, cell adhesion molecules (CAMs) and guanine nucleotide exchange factors (GEFs) play important roles in the progression of colorectal cancer and metastatic migration. Further elucidation of the mechanisms of how these molecules contribute will aid in the identification of diagnostic and prognostic markers as well as therapeutic targets for patients with colorectal metastasis.


  1. Adachi Y, Yamamoto H, Itoh F, et al (1999). Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers. Gut, 45, 252-8.
  2. Adam L, Vadlamudi, RK, McCrea P, et al (2001). Tiam1 overexpression potentiates heregulin-induced lymphoid enhancer factor-1/beta -catenin nuclear signaling in breast cancer cells by modulating the intercellular stability. J Biol Chem, 276, 28443-50.
  3. Ahmed N, Oliva K, Wang Y, Quinn M, Rice G (2003a). Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells. Br J Cancer, 89, 374-84.
  4. Ahmed N, Oliva K, Wang Y, Quinn M, Rice G (2003b). Proteomic profiling of proteins associated with urokinase plasminogen activator receptor in a colon cancer cell line using an antisense approach. Proteomics, 3, 288-98.
  5. Al-Maghrabi J, Gomaa W, Buhmeida A, et al (2012). Decreased Immunoexpression of standard form of CD44 Is an independent favourable predictor of nodal metastasis in colorectal carcinoma. Anticancer Res, 32, 3455-61.
  6. Amirghofran Z, Jalali SA, Hosseini SV, et al (2008). Evaluation of CD44 and CD44v6 in colorectal carcinoma patients: soluble forms in relation to tumor tissue expression and metastasis. J Gastrointest Cancer, 39, 73-8.
  7. Assenat E, Ychou M (2009). [Impact of mutational status of KRAS in the care of patients with colorectal cancer metastasis]. Bull Cancer, 96, S41-6.
  8. Bandres E, Agirre X, Bitarte N, et al (2009). Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer, 125, 2737-43.
  9. Bardelli A, Saha S, Sager JA, et al (2003). PRL-3 expression in metastatic cancers. Clin Cancer Res, 9, 5607-15.
  10. Beckner ME (1999). Factors promoting tumor angiogenesis. Cancer Invest, 17, 594-623.
  11. Bendardaf R, Algars A, Elzagheid A et al (2006). Comparison of CD44 expression in primary tumours and metastases of colorectal cancer. Oncol Rep, 16, 741-6.
  12. Bendardaf R, Elzagheid A, Lamlum H, et al (2005). E-cadherin, CD44s and CD44v6 correlate with tumour differentiation in colorectal cancer. Oncol Rep, 13, 831-5.
  13. Buda A, Pignatelli M (2011). E-cadherin and the cytoskeletal network in colorectal cancer development and metastasis. Cell Commun Adhes, 18, 133-43.
  14. Buongiorno P, Pethe VV, Charames GS, et al (2008). Rac1 GTPase and the Rac1 exchange factor Tiam1 associate with Wnt-responsive promoters to enhance beta-catenin/TCF-dependent transcription in colorectal cancer cells. Mol Cancer, 7, 73.
  15. Cantero D, Friess H, Deflorin J, et al (1997). Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer, 75, 388-95.
  16. Choi SH, Takahashi K, Eto H, et al (2000). CD44s expression in human colon carcinomas influences growth of liver metastases. Int J Cancer, 85, 523-6.<523::AID-IJC13>3.0.CO;2-6
  17. de Lima JM, de Souza LG, da Silva ID, Forones NM (2009). E-cadherin and metalloproteinase-1 and -7 polymorphisms in colorectal cancer. Int J Biol Markers, 24, 99-106.
  18. Gangopadhyay A, Lazure DA, Thomas P (1997). Carcinoembryonic antigen induces signal transduction in Kupffer cells. Cancer Lett, 118, 1-6.
  19. Delektorskaia VV, Perevoshchikov AG, Golovkov DA, Kushlinskii NE (2005). [Immunohistochemical study of E-cadherin, beta-catenin and CD-44v6 expression in the cells of primary colon cancer and its metastases]. Arkh Patol, 67, 34-8.
  20. Delektorskaia VV, Perevoshchikov AG, Kushlinskii NE (2003). [Expression of nm23 and c-erbB-2 proteins in cells of primary colorectal cancer and its metastases]. Arkh Patol, 65, 11-5.
  21. Emara M, Cheung PY, Grabowski K, et al (2009). Serum levels of matrix metalloproteinase-2 and -9 and conventional tumor markers (CEA and CA 19-9) in patients with colorectal and gastric cancers. Clin Chem Lab Med, 47, 993-1000.
  22. Feng F, Li YH, An X, et al (2009). [Efficacy and prognostic analysis on surgical resection of pulmonary metastasis from colorectal cancer]. Zhonghua Wei Chang Wai Ke Za Zhi, 12, 471-3.
  23. Filiz AI, Senol Z, Sucullu I, et al (2009). The survival effect of e-cadherin and catenins in colorectal carcinomas. Colorectal Dis, 12, 1223-30.
  24. Fushida S, Miwa K (2003). [Invasiveness and metastasis in colorectal cancer: P53 gene alteration associated with hepatic metastasis]. Nihon Rinsho, 7, 107-10.
  25. Ganesh S, Sier CF, Heerding MM, et al (1994). Urokinase receptor and colorectal cancer survival. Lancet, 344, 401-2.
  26. Gangopadhyay A, Lazure DA, Thomas P (1998). Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. Clin Exp Metastasis, 16, 703-12.
  27. Georgieva M, Krasteva M, Angelova E, et al (2008). Analysis of the K-ras/B-raf/Erk signal cascade, p53 and CMAP as markers for tumor progression in colorectal cancer patients. Oncol Rep, 20, 3-11.
  28. Gisterek I, Kornafel J (2006). [VEGF and its receptors as therapeutic target in cancer therapy]. Przegl Lek, 63, 155-7.
  29. Gotley DC, Fawcett J, Walsh MD, et al (1996). Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer. Br J Cancer, 74, 342-51.
  30. Hatate K, Yamashita K, Hirai K, et al (2008). Liver metastasis of colorectal cancer by protein-tyrosine phosphatase type 4A, 3 (PRL-3) is mediated through lymph node metastasis and elevated serum tumor markers such as CEA and CA19-9. Oncol Rep, 20 737-43.
  31. Huh JW, Kim HR, Kim YJ, et al (2009). Expression of standard CD44 in human colorectal carcinoma: association with prognosis. Pathol Int, 59 241-6.
  32. Ignar DM, Andrews JL, Witherspoon SM, et al (1998). Inhibition of establishment of primary and micrometastatic tumors by a urokinase plasminogen activator receptor antagonist. Clin Exp Metastasis, 16, 9-20.
  33. Inaba T, Maesawa C, Masuda T, Terashima M (2001). [Molecular mechanism of carcinogenesis in human stomach cancer: Bub1 gene]. Nippon Rinsho, 59, 44-7.
  34. Ishigami SI, Arii S, Furutani M, et al (1998). Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer, 78, 1379-84.
  35. Iwasaki J, Nihira S (2009). Anti-angiogenic therapy against gastrointestinal tract cancers. Jpn J Clin Oncol, 39, 543-51.
  36. Kahlert C, Bandapalli OR, Schirmacher P, et al (2008). Invasion front-specific overexpression of tissue inhibitor of metalloproteinase-1 in liver metastases from colorectal cancer. Anticancer Res, 28, 1459-65.
  37. Kaneko I, Tanaka S, Oka S, et al (2007). Immunohistochemical molecular markers as predictors of curability of endoscopically resected submucosal colorectal cancer. World J Gastroenterol, 13, 3829-35.
  38. Kang SM, Maeda K, Onoda N, et al (1997). Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. Int J Cancer, 74, 502-7.<502::AID-IJC4>3.0.CO;2-7
  39. Kato H, Semba S, Miskad UA, et al (2004). High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases. Clin Cancer Res, 10 7318-28.
  40. Katoh H, Yamashita K, Kokuba Y, et al (2008). Diminishing impact of preoperative carcinoembryonic antigen (CEA) in prognosis of Dukes' C colorectal cancer. Anticancer Res, 28, 1933-41.
  41. Kim TD, Song KS, Li G, et al (2006). Activity and expression of urokinase-type plasminogen activator and matrix metalloproteinases in human colorectal cancer. BMC Cancer, 6, 211.
  42. Klinge U, Rosch R, Junge K, et al (2007). Different matrix microenvironments in colon cancer and diverticular disease. Int J Colorectal Dis, 22, 515-20.
  43. Kopp R, Fichter M, Schalhorn G, et al(2009). Frequent expression of the high molecular, 673-bp CD44v3,v8-10 variant in colorectal adenomas and carcinomas. Int J Mol Med, 24, 677-83.
  44. Koyama Y, Naruo H, Yoshitomi Y, et al (2008). Matrix metalloproteinase-9 associated with heparan sulphate chains of GPI-anchored cell surface proteoglycans mediates motility of murine colon adenocarcinoma cells. J Biochem, 143, 581-92.
  45. Krupitskaya Y, Wakelee HA (2009). Ramucirumab, a fully human mAb to the transmembrane signaling tyrosine kinase VEGFR-2 for the potential treatment of cancer. Curr Opin Investig Drugs, 10, 597-605.
  46. Kuester D, Lippert H, Roessner A, Krueger S (2008). The cathepsin family and their role in colorectal cancer. Pathol Res Pract, 204, 491-500.
  47. Kunimura T, Yoshida T, Sugiyama T, Morohoshi T (2009). The relationships between loss of standard CD44 expression and lymph node, liver metastasis in T3 colorectal carcinoma. J Gastrointest Cancer, 40, 115-8.
  48. Lankiewicz S, Rother E, Zimmermann S, et al (2008). Tumour-associated transcripts and EGFR deletion variants in colorectal cancer in primary tumour, metastases and circulating tumour cells. Cell Oncol, 30, 463-71.
  49. Liu L, Xu AG, Zhang QL, et al (2007). [Effect of Tiam1 overexpression on proliferation and metastatic potential of human colorectal cancer]. Zhonghua Bing Li Xue Za Zhi, 36, 390-3.
  50. Liu L, Zhang Q, Zhang Y, Wang S, Ding Y (2006). Lentivirusmediated silencing of Tiam1 gene influences multiple functions of a human colorectal cancer cell line. Neoplasia, 8, 917-24.
  51. Lund IK, Illemann M, Thurison T, et al (2011). uPAR as anticancer target: evaluation of biomarker potential, histological localization, and antibody-based therapy. Curr Drug Targets, 12, 1744-60.
  52. Malliri A, Rygiel TP, van der Kammen RA, et al (2006). The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development. J Biol Chem, 281, 543-8.
  53. Marti J, Modolo MM, Fuster J, et al(2009). Prognostic factors and time-related changes influence results of colorectal liver metastases surgical treatment: a single-center analysis.World J Gastroenterol, 15, 2587-94.
  54. Masson D, Denis MG, Denis M, et al (1999). Soluble CD44: quantification and molecular repartition in plasma of patients with colorectal cancer. Br J Cancer, 80, 1995-2000.
  55. McMillan DC, McArdle CS (2007). Epidemiology of colorectal liver metastases. Surg Oncol, 16, 3-5.
  56. Miyazono K, Ehata S, Koinuma D (2012). Tumor-promoting functions of transforming growth factor-beta in progression of cancer. Ups J Med Sci, 117, 143-52.
  57. Morita S, Sato A, Hayakawa H, et al (1998). Cancer cells overexpress mRNA of urokinase-type plasminogen activator, its receptor and inhibitors in human non-small-cell lung cancer tissue: analysis by Northern blotting and in situ hybridization. Int J Cancer, 78, 286-92.<286::AID-IJC4>3.0.CO;2-R
  58. Mourtzikou A, Stamouli M, Kroupis C, et al (2012). Evaluation of carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule EpCAM (GA733-2), and carbohydrate antigen 19-9 (CA 19-9) levels in colorectal cancer patients and correlation with clinicopathological characteristics. Clin Lab, 58, 441-8.
  59. Ogawa M, Watanabe M, Eto K, et al (2008). Poorly differentiated adenocarcinoma of the colon and rectum: clinical characteristics. Hepatogastroenterology, 55, 907-11.
  60. Portera CA, Jr Berman RS, Ellis LM (1998). Molecular determinants of colon cancer metastasis. Surg Oncol, 7, 183-95.
  61. Rudin CM, Liu W, Desai A, et al (2008). Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol, 26, 1119-27.
  62. Rudmik LR, Magliocco AM (2005). Molecular mechanisms of hepatic metastasis in colorectal cancer. J Surg Oncol, 92, 347-59.
  63. Saha S, Bardelli A, Buckhaults P, et al (2001). A phosphatase associated with metastasis of colorectal cancer. Science, 294, 1343-6.
  64. Sliutz G, Eder H, Koelbl H, et al (1996). Quantification of uPA receptor expression in human breast cancer cell lines by cRT-PCR. Breast Cancer Res Treat, 40, 257-63.
  65. Szajda SD, Snarska J, Jankowska A, et al(2008). Cathepsin D and carcino-embryonic antigen in serum, urine and tissues of colon adenocarcinoma patients. Hepatogastroenterology, 55, 388-93.
  66. Takahashi Y, Bucana CD, Liu W, et al (1996). Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells. J Natl Cancer Inst, 88, 1146-51.
  67. Takayama T, Miyanishi K, Hayashi T, et al (2006). Colorectal cancer: genetics of development and metastasis. J Gastroenterol, 41, 185-92.
  68. Takeuchi I, Ishida H, Hashimoto D, et al (2003). [Evaluation of liver metastasis of colorectal cancer following hepatic arterial infusion with degradable starch microspheres and adriamycin, mitomycin C as seen in changes in CEA at early stage of therapy]. Gan To Kagaku Ryoho, 30, 1686-8.
  69. Tamiya A, Yamazaki K, Boku N, et al (2009). Safety of bevacizumab treatment in combination with standard chemotherapy for metastatic colorectal cancer: a retrospective review of 65 Japanese patients. Int J Clin Oncol, 14, 513-7.
  70. Tampellini M, Longo M, Cappia S, et al (2007). Co-expression of EGF receptor, TGFalpha and S6 kinase is significantly associated with colorectal carcinomas with distant metastases at diagnosis. Virchows Arch, 450, 321-8.
  71. Thomas P, Forse RA, Bajenova O (2011). Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver. Clin Exp Metastasis, 28, 923-32.
  72. Thomas P, Gangopadhyay A, Steele G, et al (1995). The effect of transfection of the CEA gene on the metastatic behavior of the human colorectal cancer cell line MIP-101. Cancer Lett, 92, 59-66.
  73. Tokunaga T, Oshika Y, Abe, Y, et al (1998). Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer, 77, 998-1002.
  74. Van Buren G, 2nd Gray MJ, Dallas NA, et al (2009). Targeting the urokinase plasminogen activator receptor with a monoclonal antibody impairs the growth of human colorectal cancer in the liver. Cancer, 115, 3360-8.
  75. Vermeulen PB, Van den Eynden GG, Huget P, et al(1999). Prospective study of intratumoral microvessel density, p53 expression and survival in colorectal cancer. Br J Cancer, 79, 316-22.
  76. Wan XB, Pan ZZ, Ren YK, et al (2009). [Expression and clinical significance of metastasis-related tumor markers in colorectal cancer]. Ai Zheng, 28, 950-4.
  77. Wang Y, Li ZF, He J, et a l(2007). Expression of the human phosphatases of regenerating liver (PRLs) in colonic adenocarcinoma and its correlation with lymph node metastasis. Int J Colorectal Dis, 22, 1179-84.
  78. Weber J, McCormack, PL (2008). Panitumumab: in metastatic colorectal cancer with wild-type KRAS. BioDrugs, 22, 403-11.
  79. Yamaguchi A, Urano T, Goi T, et al (1996). Expression of a CD44 variant containing exons 8 to 10 is a useful independent factor for the prediction of prognosis in colorectal cancer patients. J Clin Oncol, 14, 1122-7.
  80. Yamamoto H, Noura S, Okami J, et al (2008). Overexpression of MT1-MMP is insufficient to increase experimental liver metastasis of human colon cancer cells. Int J Mol Med, 22, 757-61.
  81. Yasui W, Oue N, et al (2001). Molecular diagnosis of gastric cancer: present and future. Gastric Cancer, 4 113-21.
  82. Yu B, Li SY, An P, et al (2005). [Expression of cathepsin B and its clinical importance in colorectal cancer]. Zhonghua Wei Chang Wai Ke Za Zhi, 8 507-9.
  83. Yuan SQ, Zhou ZW, Wan DS, et al (2008). The role of half-life of carcinoembryonic antigen (CEA) in prognosis prediction of colorectal cancer patients with preoperatively elevated CEA. Ai Zheng, 27, 612-7.
  84. Zhang B, Halder SK, Zhang S, Datta PK (2009). Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Cancer Lett, 277, 114-20.
  85. Zhong D, Li Y, Peng Q, et al (2009). Expression of Tiam1 and VEGF-C correlates with lymphangiogenesis in human colorectal carcinoma. Cancer Biol Ther, 8 689-95.
  86. Zlobec I, Gunthert U, Tornillo L, et al (2009). Systematic assessment of the prognostic impact of membranous CD44v6 protein expression in colorectal cancer. Histopathology, 55, 564-75.
  87. Zlobec I, Minoo P, Baumhoer D, et al (2008). Multimarker phenotype predicts adverse survival in patients with lymph node-negative colorectal cancer. Cancer, 112, 495-502.
  88. Zuzga DS, Gibbons AV, Li P, et al (2008). Overexpression of matrix metalloproteinase 9 in tumor epithelial cells correlates with colorectal cancer metastasis. Clin Transl Sci, 1, 136-41.

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