Clinical & Experimental Metastasis

, Volume 22, Issue 6, pp 449–459 | Cite as

ICAM-1 Mediated Peritoneal Carcinomatosis, A Target for Therapeutic Intervention

  • Nawar A. Alkhamesi
  • Paul Ziprin
  • Katherine Pfistermuller
  • David H. Peck
  • Ara W. Darzi


Development of peritoneal metastasis is a significant issue in the treatment of abdominal cancers. Primary interaction between tumour cells and the mesothelium is a vital step in initiating this process. Our aim was to determine the role of the intercellular adhesion molecule-1 (ICAM-1) in mesothelial–tumour adhesion and the effectiveness of therapeutic intervention. Mesothelial cells were derived from omental tissue. ICAM-1 expression in resting state, in the presence of TNF-α or after the application of heparin or hyaluronan was determined by flow cytometry. Functional effects on tumour adhesion to a mesothelial monolayer were determined via a Calcein-AM in vitro adhesion assay. In vivo studies were performed utilising 30 WAG/rij rats, which underwent mini-laparotomy with the injection of 1 × 105 CC513 tumour cells intraperitoneally. Tumour growth was assessed macroscopically and microscopically by two independent examiners. Mesothelial cells expressed high level of ICAM-1, which was up-regulated by the presence of TNF-α. The introduction of heparin caused a decrease in ICAM-1 expression, however hyaluronan did not affect the expression. A significant decrease in tumour–mesothelial cell adhesion in vitro and complete aberration of tumour growth in vivo was observed with heparin application. In vitro studies showed utilisation of high molecular weight hyaluronan, which was more limited in vivo. These data imply that heparin may be used as a potential therapeutic through a defined molecular mechanism both in vitro and in vivo. Hyaluronan appears to function as a barrier and hence may be unreliable in blocking peritoneal recurrence.


colorectal cancer CD43 mesothelial cells heparin hyaluronan ICAM-1 intraperitoneal therapeutics peritoneal metastases TNF-α 


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  1. 1.
    Buchholtz, TW, Welch, CE, Malt, RA 1978Clinical correlates of resectability and survival in gastric carcinomaAnn Surg1887115PubMedGoogle Scholar
  2. 2.
    Merchant, NB, Conlon, KC, Saigo, P,  et al. 1999Positive peritoneal cytology predicts unresectability of pancreatic adenocarcinomaJ Am Coll Surg1884216CrossRefPubMedGoogle Scholar
  3. 3.
    Omura, GA, Brady, MF, Homesley, HD,  et al. 1991Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experienceJ Clin Oncol9113850PubMedGoogle Scholar
  4. 4.
    Sugarbaker, PH, Schellinx, ME, Chang, D,  et al. 1996Peritoneal carcinomatosis from adenocarcinoma of the colonWorld J Surg2058591CrossRefPubMedGoogle Scholar
  5. 5.
    Vogel, I, Kruger, U, Marxsen, J,  et al. 1999Disseminated tumor cells in pancreatic cancer patients detected by immunocytology: a new prognostic factorClin Cancer Res55939PubMedGoogle Scholar
  6. 6.
    Hase, K, Ueno, H, Kuranaga, N,  et al. 1998Intraperitoneal exfoliated cancer cells in patients with colorectal cancerDis Colon Rectum41113440PubMedGoogle Scholar
  7. 7.
    Solomon, MJ, Egan, M, Roberts, RA,  et al. 1997Incidence of free colorectal cancer cells on the peritoneal surfaceDis Colon Rectum4012948CrossRefPubMedGoogle Scholar
  8. 8.
    Schlaeppi, M, Ruegg, C, Tran-thang, C,  et al. 1997Role of integrins and evidence for two distinct mechanisms mediating human colorectal carcinoma cell interaction with peritoneal mesothelial cells and extracellular matrixCell Adhes Commun443955PubMedGoogle Scholar
  9. 9.
    Lessan, K, Aguiar, DJ, Oegema, T,  et al. 1999CD44 and beta-1 integrin mediate overian carcinoma cell adhesion to peritoneal mesothelial cellsAm J Pathol154152537PubMedGoogle Scholar
  10. 10.
    Cannistra, SA, Kansas, SG, Niloff, J,  et al. 1993Binding of overian cancer cells to peritoneal mesothelium in vitro is partly mediated by CD44HCancer Res5338308PubMedGoogle Scholar
  11. 11.
    Strobel, T, Swanson, L, Cannistra, SA 1997 In vivo inhibition of CD44 limits intra-abdominal spread of a human ovarian cancer xenograft in nude mice: a novel role for CD44 in the process of peritoneal implantationCancer Res57122832PubMedGoogle Scholar
  12. 12.
    Ziprin, P, Ridgway, PF, Pfistermuller, KL,  et al. 2003ICAM-1 mediated tumor-mesothelial cell adhesion is modulated by IL-6 and TNF-alpha: A potential mechanism by which surgical trauma increases peritoneal metastasesCell Adhes Commun1014154CrossRefGoogle Scholar
  13. 13.
    Nakashio, T, Narita, T, Sato, M,  et al. 1997The association of metastasis with the expression of adhesion molecules in cell lines derived from human gastric cancerAnticancer Res172939PubMedGoogle Scholar
  14. 14.
    Stolpe, A, Saag, PT 1996Intercellular adhesion molecule-1J Mol Med741333CrossRefPubMedGoogle Scholar
  15. 15.
    Ziprin, P, Alkhamesi, NA, Ridgway, PF 2004Tumour-expressed CD43 (sialophorin) mediates tumourmesothelial cell adhesionBiol Chem38575561CrossRefPubMedGoogle Scholar
  16. 16.
    Miller, SJ, Hoggat, AM, Faulk, WP 1998Heparin regulates ICAM-1 expression in human endothelial cells: An example of non-cytokine-mediated endothelial activationThromb Haemost804817PubMedGoogle Scholar
  17. 17.
    Neuhaus, SJ, Ellis, T, Jamieson, GG,  et al. 1999Experimental studies of the effect of intraperitoneal heparin on tumour implantation following laparoscopyBr J Surg86400404CrossRefPubMedGoogle Scholar
  18. 18.
    Smorenburg, SM, Noorden, CJ 2001The complex effects of heparin on cancer progression and metastasis in experimental studiesPharmacol Rev5393105PubMedGoogle Scholar
  19. 19.
    Alkhamesi, NA, Ziprin, P, Pfistermuller, K,  et al. 2003Role of therapeutic intervention in peritoneal carcinomatosis via an ICAM-1 dependent mechanismBr J Surg906Google Scholar
  20. 20.
    Yamaguchi, K, Hirabayashi, Y, Shiromizu, A,  et al. 2001Enhancement of port site metastasis by hyaluronic acid under CO2 pneumoperitoneum in a murine modelSurg Endosc155047CrossRefPubMedGoogle Scholar
  21. 21.
    Hayne, W, Goebeler, M, Kumar, S,  et al. 1999Hyaluronan stimulates tumour cell migration by modulating the fibrin fiber architectureJ Cell Sci112224151Google Scholar
  22. 22.
    Stylianou, E, Jenner, LA, Coles, GA,  et al. 1990Isolation, culture and characterization of human peritoneal mesothelial cellsKidney Int37156370PubMedGoogle Scholar
  23. 23.
    Eggermont, AM, Steller, EP, Sugarbaker, PH 1987Laparotomy enhances intraperitoneal tumour growth and abrogates the antitumour effects of interleukin-2 and lymphokine-activated killer cellsSurgery102718PubMedGoogle Scholar
  24. 24.
    Hubens, G, Pauwels, M, Hubens, A,  et al. 1996The influence of a pneumoperitoneum on the peritoneal implantation of free intraperitoneal colon cancer cellsSurg Endosc1080912PubMedGoogle Scholar
  25. 25.
    Tol, PM, Rossen, EE, Eijck, CH,  et al. 1998Reduction of peritoneal trauma by using non-surgical guaze leads to less implantation metastases of spilled tumour cellsAnn Surg2272428PubMedGoogle Scholar
  26. 26.
    Bonvy, ND, Giuffrida, MC, Tseng, LN,  et al. 1998Effects of carbon dioxid pneumoperitoneum, air pneumoperitoneum and gasless laparoscopy on body weight and tumour growthArch Surg1336526Google Scholar
  27. 27.
    Badia, JM, Whawell, SA, Scott-Coombs, DM,  et al. 1996Peritoneal and systemic cytokine response to laparotomyBr J Surg833478PubMedGoogle Scholar
  28. 28.
    Gangopadhyay, A, Lazure, DA, Thomas, P 1998Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA simulated Kupffer cellsClin Exp Metastasis1670312CrossRefPubMedGoogle Scholar
  29. 29.
    Thodiyil, P, Kakkar, AK 2002Can low-molecular-weight heparins improve outcome in patients with cancer?Cancer Treat Rev281515CrossRefPubMedGoogle Scholar
  30. 30.
    Kakkar, AK, Levine, MN, Kadziola, Z,  et al. 2004Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The fragmin advanced malignancy outcome study (FAMOUS)J Clin Oncol2219448CrossRefPubMedGoogle Scholar
  31. 31.
    Lee, AE, Rogers, LA, Longcroft, JM, Jeffery, RE 1990Reduction of metastasis in a murine mammary tumour model by heparin and polyinosinic-polycytidylic acidClin Exp Metastasis8165171CrossRefPubMedGoogle Scholar
  32. 32.
    Vlodavsky, I, Mohsen, M, Lider, O,  et al. 1994Inhibition of tumor metastasis by heparanase inhibiting species of heparinInvasion Metastasis14290302PubMedGoogle Scholar
  33. 33.
    Mousa, SA, Mohamed, S 2004Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacyOncol Rep126838PubMedGoogle Scholar
  34. 34.
    Mousa, SA, Mohamed, S 2004Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitorThromb Haemost9262733PubMedGoogle Scholar
  35. 35.
    Aoudjit, F, Potworowski, EF, St Pierre, Y 1998Bi-directional induction of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 during T lymphoma/endothelial cell contact: implication of ICAM-1J Immunol160296773PubMedGoogle Scholar
  36. 36.
    Croce, MA, Boraldi, F, Quaglino, D,  et al. 2003Hyaluronan uptake by adult human skin fibroblasts in vitroEur J Histochem476373PubMedGoogle Scholar
  37. 37.
    Fujisaki, T, Tanaka, Y, Fuji, K,  et al. 1999CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrinsCancer Res59442734PubMedGoogle Scholar
  38. 38.
    Nasreen, N, Mohammed, KA, Hardwick, J,  et al. 2002Low molecular weight hyaluronan induces malignant mesothelioma cell (MMC) proliferation and haptotaxis: role of CD44 receptor in MMC proliferation and haptotaxisOncol Res13718PubMedGoogle Scholar
  39. 39.
    Tan, B, Wang, JH, Wu, QD,  et al. 2001Sodium hyaluronate enhances colorectal tumour cell metastatic potential in vitro and in vivo Br J Surg8824650CrossRefPubMedGoogle Scholar
  40. 40.
    Yamaguchi, K, Hirabayashi, Y, Suematsu, T,  et al. 2001Hyaluronic acid secretion during carbon dioxide pneumoperitoneum and its association with port-site metastasis in a murine modelSurg Endosc155962CrossRefPubMedGoogle Scholar
  41. 41.
    Hubbard, SC, Burns, JW 2002Effects of a hyaluronan-based membrane (Seprafilm) on intraperitoneally disseminated human colon cancer cell growth in a nude mouse modelDis Colon Rectum4533441CrossRefPubMedGoogle Scholar
  42. 42.
    Pucciarelli, S, Codello, L, Rosato, A,  et al. 2003Effect of antiadhesive agents on peritoneal carcinomatosis in an experimental modelBr J Surg906671CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Nawar A. Alkhamesi
    • 1
  • Paul Ziprin
    • 1
  • Katherine Pfistermuller
    • 1
  • David H. Peck
    • 1
  • Ara W. Darzi
    • 1
  1. 1.Department of Surgical Oncology and Technology, QEQM WingImperial College London, St. Mary’s HospitalLondonUK

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