Virchows Archiv

, Volume 461, Issue 3, pp 231–243 | Cite as

Understanding molecular mechanisms in peritoneal dissemination of colorectal cancer

Future possibilities for personalised treatment by use of biomarkers
  • E. M. V. de Cuba
  • R. Kwakman
  • M. van Egmond
  • L. J. W. Bosch
  • H. J. Bonjer
  • G. A. Meijer
  • E. A. te Velde
Review and Perspectives


When colorectal cancer (CRC) metastasizes, this is mostly to the liver via the portal circulation. In addition, 10–25 % of CRC patients eventually show metastases in the peritoneum. A selection of these patients is treated with cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC). However, several clinical needs still exist in which biomarkers could play an important role. Relatively little is known about the biology of peritoneal spread of CRC. The development of peritoneal metastases (PM) involves several steps, including: detachment of malignant cells; anoikis evasion; attachment to and invasion of the peritoneal surface ultimately ending in a colonization phase in which the malignant cells thrive in the newly formed niche. In this paper, we provide an overview of molecules associated with peritoneal dissemination and explore the clinical possibilities of these candidate biomarkers. A literature search was conducted using the PubMed database of the U.S. National Library of Medicine and Medline to identify studies on the biological behaviour of PM of CRC. In a series of over 100 studies on PM published between 1990 and 2010, IGF-1, HIF1α, VEGF, EGFR and ITGB1 emerge as the most interesting candidates for possible clinical application. Even though these promising candidate biomarkers have been identified, all of these require extensive further validation prior to clinical application. Yet, the pace of the omics revolution makes that the question is not if, but when biomarkers will be introduced to improve diagnosis and ultimately outcome of patients with PM due to CRC.


Peritoneal metastases Colorectal cancer Cytoreductive surgery HIPEC Biomarkers Targets 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Bird NC, Mangnall D, Majeed AW (2006) Biology of colorectal liver metastases: a review. J Surg Oncol 94(1):68–80PubMedCrossRefGoogle Scholar
  3. 3.
    Koppe MJ, Boerman OC, Oyen WJG, Bleichrodt RP (2006) Peritoneal carcinomatosis of colorectal origin. Ann Surg 243(2):212–222PubMedCrossRefGoogle Scholar
  4. 4.
    Maggiori L, Elias D (2010) Curative treatment of colorectal peritoneal carcinomatosis: current status and future trends. Eur J Surg Oncol 36(7):599–603PubMedCrossRefGoogle Scholar
  5. 5.
    Cao C, Yan TD, Black D, Morris DL (2009) A systematic review and meta-analysis of cytoreductive surgery with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol 16(8):2152–2165PubMedCrossRefGoogle Scholar
  6. 6.
    Klaver YLB, Lemmens VEPP, Creemers GJ, Rutten HJT, Nienhuijs SW, de Hingh IHJT (2011) Population-based survival of patients with peritoneal carcinomatosis from colorectal origin in the era of increasing use of palliative chemotherapy. Ann Oncol 22(10):2250–2256PubMedCrossRefGoogle Scholar
  7. 7.
    Sugarbaker PH (1995) Patient selection and treatment of peritoneal carcinomatosis from colorectal and appendiceal cancer. World J Surg 19(2):235–240PubMedCrossRefGoogle Scholar
  8. 8.
    Sugarbaker PH, Jablonski KA (1995) Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg 221(2):124–132PubMedCrossRefGoogle Scholar
  9. 9.
    Cavaliere F, De Simone M, Virzì S et al (2011) Prognostic factors and oncologic outcome in 146 patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: Italian multicenter study S.I.T.I.L.O. Eur J Surg Oncol 37(2):148–154PubMedCrossRefGoogle Scholar
  10. 10.
    Verwaal VJ (2003) Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 21(20):3737–3743PubMedCrossRefGoogle Scholar
  11. 11.
    Abdalla EK, Vauthey J-N, Ellis LM, Ellis V, Pollock R, Broglio KR, Hess K, Curley SA (2004) Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Annals of Surgery 239(6):818–825, discussion 825–7PubMedCrossRefGoogle Scholar
  12. 12.
    Verwaal VJ, Zoetmulder FAN (2004) Follow-up of patients treated by cytoreduction and chemotherapy for peritoneal carcinomatosis of colorectal origin. Eur J Surg Oncol (EJSO) 30(3):280–285CrossRefGoogle Scholar
  13. 13.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedCrossRefGoogle Scholar
  14. 14.
    Nguyen DX, Bos PD, Massagué J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284PubMedCrossRefGoogle Scholar
  15. 15.
    van der Wal JBC, Jeekel J (2007) Biology of the peritoneum in normal homeostasis and after surgical trauma. Colorectal Dis 9(Suppl 2):9–13PubMedGoogle Scholar
  16. 16.
    Yonemura Y, Endou Y, Fujita H, Fushida S, Bandou E, Taniguchi K, Miwa K, Sugiyama K, Sasaki T (2000) Role of MMP-7 in the formation of peritoneal dissemination in gastric cancer. Gastric Cancer 3(2):63–70PubMedCrossRefGoogle Scholar
  17. 17.
    Yilmaz M, Christofori G (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28(1–2):15–33PubMedCrossRefGoogle Scholar
  18. 18.
    Paschos KA, Canovas D, Bird NC (2009) The role of cell adhesion molecules in the progression of colorectal cancer and the development of liver metastasis. Cell Signal 21(5):665–674PubMedCrossRefGoogle Scholar
  19. 19.
    Guarino M, Rubino B, Ballabio G (2007) The role of epithelial–mesenchymal transition in cancer pathology. Pathology 39(3):305–318PubMedCrossRefGoogle Scholar
  20. 20.
    Terauchi M, Kajiyama H, Yamashita M et al (2007) Possible involvement of TWIST in enhanced peritoneal metastasis of epithelial ovarian carcinoma. Clin Exp Metastasis 24(5):329–339PubMedCrossRefGoogle Scholar
  21. 21.
    Ma PC, Maulik G, Christensen J, Salgia R (2003) c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 22(4):309–325PubMedCrossRefGoogle Scholar
  22. 22.
    Gentile A, D'Alessandro L, Lazzari L, Martinoglio B, Bertotti A, Mira A, Lanzetti L, Comoglio PM, Medico E (2008) Met-driven invasive growth involves transcriptional regulation of Arhgap12. Oncogene 27(42):5590–5598PubMedCrossRefGoogle Scholar
  23. 23.
    Boccaccio C, Comoglio PM (2006) Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer 6(8):637–645PubMedCrossRefGoogle Scholar
  24. 24.
    Osada S, Matsui S, Komori S et al (2010) Effect of hepatocyte growth factor on progression of liver metastasis in colorectal cancer. Hepatogastroenterology 57(97):76–80PubMedGoogle Scholar
  25. 25.
    Sawada K, Radjabi AR, Shinomiya N et al (2007) c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res 67(4):1670–1679PubMedCrossRefGoogle Scholar
  26. 26.
    Davies RL, Grosse VA, Kucherlapati R, Bothwell M (1980) Genetic analysis of epidermal growth factor action: assignment of human epidermal growth factor receptor gene to chromosome 7. Proc Natl Acad Sci U S A 77(7):4188–4192PubMedCrossRefGoogle Scholar
  27. 27.
    Cowden Dahl KD, Symowicz J, Ning Y, Gutierrez E, Fishman DA, Adley BP, Stack MS, Hudson LG (2008) Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent E-cadherin loss in ovarian carcinoma cells. Cancer Res 68(12):4606–4613PubMedCrossRefGoogle Scholar
  28. 28.
    Nicosia SV, Bai W, Cheng JQ, Coppola D, Kruk PA (2003) Oncogenic pathways implicated in ovarian epithelial cancer. Hematol Oncol Clin North Am 17(4):927–943PubMedCrossRefGoogle Scholar
  29. 29.
    Davidson B, Goldberg I, Gotlieb WH, Kopolovic J, Ben-Baruch G, Nesland JM, Berner A, Bryne M, Reich R (1999) High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin Exp Metastasis 17(10):799–808PubMedCrossRefGoogle Scholar
  30. 30.
    Kamat AA, Fletcher M, Gruman LM, Mueller P, Lopez A, Landen CN, Han L, Gershenson DM, Sood AK (2006) The clinical relevance of stromal matrix metalloproteinase expression in ovarian cancer. Clin Cancer Res 12(6):1707–1714PubMedCrossRefGoogle Scholar
  31. 31.
    Gentile A, Trusolino L, Comoglio PM (2008) The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev 27(1):85–94PubMedCrossRefGoogle Scholar
  32. 32.
    Benvenuti S, Comoglio PM (2007) The MET receptor tyrosine kinase in invasion and metastasis. J Cell Physiol 213(2):316–325PubMedCrossRefGoogle Scholar
  33. 33.
    Holloway SE, Beck AW, Girard L, Jaber MR, Barnett CC Jr, Brekken RA, Fleming JB (2005) Increased expression of Cyr61 (CCN1) identified in peritoneal metastases from human pancreatic cancer. J Am Coll Surg 200(3):371–377PubMedCrossRefGoogle Scholar
  34. 34.
    Sawada K, Mitra AK, Radjabi AR et al (2008) Loss of E-cadherin promotes ovarian cancer metastasis via 5-integrin, which is a therapeutic target. Cancer Res 68(7):2329–2339PubMedCrossRefGoogle Scholar
  35. 35.
    Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS (2004) Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430(7003):1034–1039PubMedCrossRefGoogle Scholar
  36. 36.
    Chiarugi P, Giannoni E (2008) Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol 76(11):1352–1364PubMedCrossRefGoogle Scholar
  37. 37.
    Horbinski C, Mojesky C, Kyprianou N (2010) Live free or die. Am J Pathol 177(3):1044–1052PubMedCrossRefGoogle Scholar
  38. 38.
    Gimond C, van Der Flier A, van Delft S, Brakebusch C, Kuikman I, Collard JG, Fässler R, Sonnenberg A (1999) Induction of cell scattering by expression of beta1 integrins in beta1-deficient epithelial cells requires activation of members of the rho family of GTPases and downregulation of cadherin and catenin function. J Cell Biol 147(6):1325–1340PubMedCrossRefGoogle Scholar
  39. 39.
    Weinberg RA (2006) The biology of cancer. 1st ed. 850. Garland Science, Taylor & Francis Group, LLC. New York, NY USAGoogle Scholar
  40. 40.
    Dong Y, Tan OL, Loessner D, Stephens C, Walpole C, Boyle GM, Parsons PG, Clements JA (2010) Kallikrein-related peptidase 7 promotes multicellular aggregation via the 5 1 integrin pathway and paclitaxel chemoresistance in serous epithelial ovarian carcinoma. Cancer Res 70(7):2624–2633PubMedCrossRefGoogle Scholar
  41. 41.
    Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E (1987) Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 317(15):909–916PubMedCrossRefGoogle Scholar
  42. 42.
    Bhaskar V, Zhang D, Fox M, Seto P, Wong MHL, Wales PE, Powers D, Chao DT, DuBridge RB, Ramakrishnan V (2007) A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 5:61PubMedCrossRefGoogle Scholar
  43. 43.
    Ramakrishnan V, Bhaskar V, Law DA et al (2006) Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent. J Exp Ther Oncol 5(4):273–286PubMedGoogle Scholar
  44. 44.
    Oosterling SJ, van der Bij GJ, Bögels M, Raa ST, Post JA, Meijer GA, Beelen RHJ, Egmond MV (2008) Anti-β1 integrin antibody reduces surgery-induced adhesion of colon carcinoma cells to traumatized peritoneal surfaces. Ann Surg 247(1):85–94PubMedCrossRefGoogle Scholar
  45. 45.
    Talieri M, Mathioudaki K, Prezas P, Alexopoulou DK, Diamandis EP, Xynopoulos D, Ardavanis A, Arnogiannaki N, Scorilas A (2009) Clinical significance of kallikrein-related peptidase 7 (KLK7) in colorectal cancer. Thromb Haemost. doi: 10.1160/TH08-07-0471
  46. 46.
    Talieri M, Li L, Zheng Y, Alexopoulou DK, Soosaipillai A, Scorilas A, Xynopoulos D, Diamandis EP (2009) The use of kallikrein-related peptidases as adjuvant prognostic markers in colorectal cancer. Br J Canc 100(10):1659–1665Google Scholar
  47. 47.
    Kim LC, Song L, Haura EB (2009) Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 6(10):587–595PubMedCrossRefGoogle Scholar
  48. 48.
    Hofmann C, Lippert E, Falk W, Schölmerich J, Rogler G, Obermeier F (2009) Primary human colonic epithelial cells are transiently protected from anoikis by a Src-dependent mechanism. Biochem Biophys Res Commun 390(3):908–914PubMedCrossRefGoogle Scholar
  49. 49.
    Windham TC, Parikh NU, Siwak DR, Summy JM, McConkey DJ, Kraker AJ, Gallick GE (2002) Src activation regulates anoikis in human colon tumor cell lines. Oncogene 21(51):7797–7807PubMedCrossRefGoogle Scholar
  50. 50.
    Sakamoto M, Takamura M, Ino Y, Miura A, Genda T, Hirohashi S (2001) Involvement of c-Src in carcinoma cell motility and metastasis. Jpn J Cancer Res 92(9):941–946PubMedCrossRefGoogle Scholar
  51. 51.
    Felding-Habermann B (2003) Integrin adhesion receptors in tumor metastasis. Clin Exp Metastasis 20(3):203–213PubMedCrossRefGoogle Scholar
  52. 52.
    Varner JA, Cheresh DA (1996) Integrins and cancer. Curr Opin Cell Biol 8(5):724–730PubMedCrossRefGoogle Scholar
  53. 53.
    Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392(6674):402–405PubMedCrossRefGoogle Scholar
  54. 54.
    Birchmeier W, Weidner KM, Hülsken J, Behrens J (1993) Molecular mechanisms leading to cell junction (cadherin) deficiency in invasive carcinomas. Semin Cancer Biol 4(4):231–239PubMedGoogle Scholar
  55. 55.
    Pocard M, Debruyne P, Bras-Gonçalves R, Mareel M, Dutrillaux B, Poupon MF (2001) Single alteration of p53 or E-cadherin genes can alter the surgical resection benefit in an experimental model of colon cancer. Dis Colon Rectum 44(8):1106–1112PubMedCrossRefGoogle Scholar
  56. 56.
    Ziprin P, Ridgway PF, Peck DH, Darzi AW (2003) Laparoscopic enhancement of tumour cell binding to the peritoneum is inhibited by anti-intercellular adhesion molecule-1 monoclonal antibody. Surg Endosc 17(11):1812–1817PubMedCrossRefGoogle Scholar
  57. 57.
    Alkhamesi NA, Roberts G, Ziprin P, Peck DH (2007) Induction of proteases in peritoneal carcinomatosis, the role of ICAM-1/CD43 interaction. Biomark Insights 2:377–384PubMedGoogle Scholar
  58. 58.
    Balzar M, Winter MJ, de Boer CJ, Not Available SVL (1999) The biology of the 17-1A antigen (Ep-CAM). J Mol Med 77(10):699–712PubMedCrossRefGoogle Scholar
  59. 59.
    Xie X, Wang C-Y, Cao Y-X, Wang W, Zhuang R, Chen L-H, Dang N-N, Fang L, Jin B-Q (2005) Expression pattern of epithelial cell adhesion molecule on normal and malignant colon tissues. WJG 11(3):344–347PubMedGoogle Scholar
  60. 60.
    Bellone S, Siegel ER, Cocco E, Cargnelutti M, Silasi D-A, Azodi M, Schwartz PE, Rutherford TJ, Pecorelli S, Santin AD (2009) Overexpression of epithelial cell adhesion molecule in primary, metastatic, and recurrent/chemotherapy-resistant epithelial ovarian cancer. Int J Gynecol Canc 19(5):860–866CrossRefGoogle Scholar
  61. 61.
    Lessan K, Aguiar DJ, Oegema T, Siebenson L, Skubitz AP (1999) CD44 and beta1 integrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells. Am J Pathol 154(5):1525–1537PubMedCrossRefGoogle Scholar
  62. 62.
    Herrlich P, Pals S, Ponta H (1995) CD44 in colon cancer. Eur J Cancer 31A(7–8):1110–1112PubMedCrossRefGoogle Scholar
  63. 63.
    Mulder JW, Wielenga VJ, Polak MM, van den Berg FM, Adolf GR, Herrlich P, Pals ST, Offerhaus GJ (1995) Expression of mutant p53 protein and CD44 variant proteins in colorectal tumorigenesis. Gut 36(1):76–80PubMedCrossRefGoogle Scholar
  64. 64.
    Cannistra SA, Kansas GS, Niloff J, DeFranzo B, Kim Y, Ottensmeier C (1993) Binding of ovarian cancer cells to peritoneal mesothelium in vitro is partly mediated by CD44H. Cancer Res 53(16):3830–3838PubMedGoogle Scholar
  65. 65.
    Kajiyama H, Shibata K, Terauchi M, Ino K, Nawa A, Kikkawa F (2008) Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma. Int J Cancer 122(1):91–99PubMedCrossRefGoogle Scholar
  66. 66.
    Gubbels JAA, Belisle J, Onda M et al (2006) Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol Cancer 5(1):50PubMedCrossRefGoogle Scholar
  67. 67.
    Kataoka H, Tanaka H, Nagaike K, Uchiyama S, Itoh H (2003) Role of cancer cell–stroma interaction in invasive growth of cancer cells. Hum Cell 16(1):1–14PubMedCrossRefGoogle Scholar
  68. 68.
    Vihinen P, Kähäri V-M (2002) Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer 99(2):157–166PubMedCrossRefGoogle Scholar
  69. 69.
    Yamada T, Oshima T, Yoshihara K et al (2010) Overexpression of MMP-13 gene in colorectal cancer with liver metastasis. Anticancer Res 30(7):2693–2699PubMedGoogle Scholar
  70. 70.
    Sc EJCB, D GRP, Sc RGB, Sc TRB, Sc MMB, Sc PZB (2010) Investigation of tumor–peritoneal interactions in the pathogenesis of peritoneal metastases using a novel ex vivo peritoneal model1. J Surg Res 164(2):e265–e272Google Scholar
  71. 71.
    Peng L, Xing X, Li W, Qu L, Meng L, Lian S, Jiang B, Wu J, Shou C (2009) PRL-3 promotes the motility, invasion, and metastasis of LoVo colon cancer cells through PRL-3-integrin β1-ERK1/2 and-MMP2 signaling. Mol Cancer 8(1):110PubMedCrossRefGoogle Scholar
  72. 72.
    Aparicio T, Kermorgant S, Dessirier V, Lewin MJ, Lehy T (1999) Matrix metalloproteinase inhibition prevents colon cancer peritoneal carcinomatosis development and prolongs survival in rats. Carcinogenesis 20(8):1445–1451PubMedCrossRefGoogle Scholar
  73. 73.
    Barbolina MV, Adley BP, Shea LD, Stack MS (2008) Wilms tumor gene protein 1 is associated with ovarian cancer metastasis and modulates cell invasion. Cancer 112(7):1632–1641PubMedCrossRefGoogle Scholar
  74. 74.
    Varghese S, Burness M, Xu H, Beresnev T, Pingpank J, Alexander HR (2007) Site-specific gene expression profiles and novel molecular prognostic factors in patients with lower gastrointestinal adenocarcinoma diffusely metastatic to liver or peritoneum. Ann Surg Oncol 14(12):3460–3471PubMedCrossRefGoogle Scholar
  75. 75.
    Hojilla CV, Mohammed FF, Khokha R (2003) Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development. Br J Cancer 89(10):1817–1821PubMedCrossRefGoogle Scholar
  76. 76.
    NCBI (ed) TIMP2 TIMP metallopeptidase inhibitor 2 [Homo sapiens]. Gene, NCBI.Google Scholar
  77. 77.
    Raa ST, Oosterling SJ, van der Kaaij NP, van den Tol MP, Beelen RHJ, Meijer S, van Eijck CHJ, van der Sijp JRM, van Egmond M, Jeekel J (2005) Surgery promotes implantation of disseminated tumor cells, but does not increase growth of tumor cell clusters. J Surg Oncol 92(2):124–129PubMedCrossRefGoogle Scholar
  78. 78.
    van der Bij GJ, Oosterling SJ, Beelen RHJ, Meijer S, Coffey JC, van Egmond M (2009) The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann Surg 249(5):727–734PubMedCrossRefGoogle Scholar
  79. 79.
    Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432(7015):332–337PubMedCrossRefGoogle Scholar
  80. 80.
    Kjeldsen T, Andersen AS, Wiberg FC, Rasmussen JS, Schäffer L, Balschmidt P, Møller KB, Møller NP (1991) The ligand specificities of the insulin receptor and the insulin-like growth factor I receptor reside in different regions of a common binding site. Proc Natl Acad Sci U S A 88(10):4404–4408PubMedCrossRefGoogle Scholar
  81. 81.
    Fuchs CS, Goldberg RM, Sargent DJ, Meyerhardt JA, Wolpin BM, Green EM, Pitot HC, Pollak M (2008) Plasma insulin-like growth factors, insulin-like binding protein-3, and outcome in metastatic colorectal cancer: results from Intergroup Trial N9741. Clin Cancer Res 14(24):8263–8269PubMedCrossRefGoogle Scholar
  82. 82.
    Goldberg RM (2003) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22(1):23–30PubMedCrossRefGoogle Scholar
  83. 83.
    Greijer AE, Delis-van Diemen PM, Fijneman RJA, Giles RH, Voest EE, Hinsbergh VWM, Meijer GA (2008) Presence of HIF-1 and related genes in normal mucosa, adenomas and carcinomas of the colorectum. Virchows Arch 452(5):535–544PubMedCrossRefGoogle Scholar
  84. 84.
    Nijkamp MW, Hoogwater FJH, Steller EJA, Westendorp BF, van der Meulen TA, Leenders MWH, Rinkes IHMB, Kranenburg O (2010) CD95 is a key mediator of invasion and accelerated outgrowth of mouse colorectal liver metastases following radiofrequency ablation. J Hepatol 53(6):1069–1077PubMedCrossRefGoogle Scholar
  85. 85.
    Wu Y, Jin M, Xu H, Shimin Z, He S, Wang L, Zhang Y (2010) Clinicopathologic significance of HIF-1α, CXCR4, and VEGF expression in colon cancer. Clin Dev Immunol 2010:1–10. doi: 10.1155/2010/537531
  86. 86.
    Logan-Collins JM, Lowy AM, Robinson-Smith TM, Kumar S, Sussman JJ, James LE, Ahmad SA (2007) VEGF expression predicts survival in patients with peritoneal surface metastases from mucinous adenocarcinoma of the appendix and colon. Ann Surg Oncol 15(3):738–744PubMedCrossRefGoogle Scholar
  87. 87.
    Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342PubMedCrossRefGoogle Scholar
  88. 88.
    Shaheen RM, Ahmad SA, Liu W, Reinmuth N, Jung YD, Tseng WW, Drazan KE, Bucana CD, Hicklin DJ, Ellis LM (2001) Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 85(4):584–589PubMedCrossRefGoogle Scholar
  89. 89.
    Bruns CJ, Shrader M, Harbison MT, Portera C, Solorzano CC, Jauch K-W, Hicklin DJ, Radinsky R, Ellis LM (2002) Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice. Int J Cancer 102(2):101–108PubMedCrossRefGoogle Scholar
  90. 90.
    Bruns CJ, Liu W, Davis DW, Shaheen RM, McConkey DJ, Wilson MR, Bucana CD, Hicklin DJ, Ellis LM (2000) Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer 89(3):488–499PubMedCrossRefGoogle Scholar
  91. 91.
    Sorensen EW, Gerber SA, Sedlacek AL, Rybalko VY, Chan WM, Lord EM (2009) Omental immune aggregates and tumor metastasis within the peritoneal cavity. Immunol Res. doi: 10.1007/s12026-009-8100-2
  92. 92.
    Gerber SA, Rybalko VY, Bigelow CE, Lugade AA, Foster TH, Frelinger JG, Lord EM (2006) Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am J Pathol 169(5):1739–1752PubMedCrossRefGoogle Scholar
  93. 93.
    Beelen RHJ, Oosterling SJ, van Egmond M, van den Born J, Zareie M (2005) Omental milky spots in peritoneal pathophysiology (spots before your eyes). Perit Dial Int 25(1):30–32PubMedGoogle Scholar
  94. 94.
    Beelen RH (1992) Role of omental milky spots in the local immune response. Lancet 339(8794):689PubMedCrossRefGoogle Scholar
  95. 95.
    Krist LF, Koenen H, Calame W, van der Harten JJ, van der Linden JC, Eestermans IL, Meyer S, Beelen RH (1997) Ontogeny of milky spots in the human greater omentum: an immunochemical study. Anat Rec 249(3):399–404PubMedCrossRefGoogle Scholar
  96. 96.
    Yildirim A, Aktaş A, Nergiz Y, Akkuş M (2010) Analysis of human omentum-associated lymphoid tissue components with S-100: an immunohistochemical study. Rom J Morphol Embryol 51(4):759–764PubMedGoogle Scholar
  97. 97.
    Yildirim A, Akkus M, Nergiz Y, Yuruker S (2004) Immunohistochemical analysis of CD31, CD36, and CD44 antigens in human omentum. Saudi Med J 25(3):308–312PubMedGoogle Scholar
  98. 98.
    Babic AM, Kireeva ML, Kolesnikova TV, Lau LF (1998) CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci U S A 95(11):6355–6360PubMedCrossRefGoogle Scholar
  99. 99.
    Fan Y-F, Huang Z-H (2002) Angiogenesis inhibitor TNP-470 suppresses growth of peritoneal disseminating foci of human colon cancer line Lovo. WJG 8(5):853–856PubMedGoogle Scholar
  100. 100.
    Griffith EC, Su Z, Niwayama S, Ramsay CA, Chang YH, Liu JO (1998) Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2. Proc Natl Acad Sci U S A 95(26):15183–15188PubMedCrossRefGoogle Scholar
  101. 101.
    Hines J, Ju R, Dutschman GE, Cheng Y-C, Crews CM (2010) Reversal of TNP-470-induced endothelial cell growth arrest by guanine and guanine nucleosides. J Pharmacol Exp Ther 334(3):729–738PubMedCrossRefGoogle Scholar
  102. 102.
    Yan TD (2006) Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol 24(24):4011–4019PubMedCrossRefGoogle Scholar
  103. 103.
    van Dam GM, Themelis G, Crane LMA, et al (2011) Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nature Medicine 17:1–6Google Scholar
  104. 104.
    Van der Speeten K, Stuart OA, Chang D, Mahteme H, Sugarbaker PH (2011) Changes induced by surgical and clinical factors in the pharmacology of intraperitoneal mitomycin C in 145 patients with peritoneal carcinomatosis. Cancer Chemother Pharmacol 68(1):147–156PubMedCrossRefGoogle Scholar
  105. 105.
    De Roock MD W, De Vriendt MSc V, MD NN, MD PFC, MD PST (2011) KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncology 12(6):594–603Google Scholar
  106. 106.
    Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483(7387):100–103PubMedCrossRefGoogle Scholar
  107. 107.
    Olmos D, Postel-Vinay S, Molife LR et al (2010) Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol 11(2):129–135PubMedCrossRefGoogle Scholar
  108. 108.
    Haluska P, Worden F, Olmos D, Yin D, Schteingart D, Batzel GN, Paccagnella ML, de Bono JS, Gualberto A, Hammer GD (2010) Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 65(4):765–773PubMedCrossRefGoogle Scholar
  109. 109.
    Nijkamp MW, van der Bilt JDW, de Bruijn MT, Molenaar IQ, Voest EE, van Diest PJ, Kranenburg O, Borel Rinkes IHM (2009) Accelerated perinecrotic outgrowth of colorectal liver metastases following radiofrequency ablation is a hypoxia-driven phenomenon. Ann Surg 249(5):814–823PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • E. M. V. de Cuba
    • 1
  • R. Kwakman
    • 1
  • M. van Egmond
    • 1
  • L. J. W. Bosch
    • 2
  • H. J. Bonjer
    • 1
  • G. A. Meijer
    • 2
  • E. A. te Velde
    • 1
  1. 1.Department of Surgical OncologyVU University Medical Center, AmsterdamAmsterdamThe Netherlands
  2. 2.Department of PathologyVU University Medical Center, AmsterdamAmsterdamThe Netherlands

Personalised recommendations