Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Dec;81(8):1311–1317. doi: 10.1038/sj.bjc.6694369

The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease

G P Pidgeon 1, J H Harmey 1, E Kay 2, M Da Costa 1, H P Redmond 1, D J Bouchier-Hayes 1
PMCID: PMC2362969  PMID: 10604727

Abstract

Surgical removal of a primary tumour is often followed by rapid growth of previously dormant metastases. Endotoxin or lipopolysaccharide, a cell wall constituent of Gram-negative bacteria, is ubiquitously present in air and may be introduced during surgery. BALB/c mice received a tail vein injection of 105 4T1 mouse mammary carcinoma cells. Two weeks later, animals were subjected to surgical trauma or an intraperitoneal injection of endotoxin (10 μg per animal). Five days later, animals which underwent open surgery, laparoscopy with air sufflation or received an endotoxin injection displayed increased lung metastasis compared to anaesthetic controls. These increases in metastatic tumour growth were reflected in increased tumour cell proliferation and decreased apoptosis within lung metastases. Circulating levels of the angiogenic cytokine, vascular endothelial growth factor (VEGF), were also elevated in these groups and correlated with increased plasma levels of endotoxin. Endotoxin treatment for 18 h (>10 ng ml–1) directly up-regulated VEGF production by the 4T1 tumour cells in vitro. Metastatic tumour growth in mice undergoing carbon dioxide laparoscopy, where air is excluded, was similar to anaesthetic controls. These data indicate that endotoxin introduced during surgery is associated with the enhanced growth of metastases following surgical trauma, by altering the critical balances governing cellular growth and angiogenesis. © 1999 Cancer Research Campaign

Keywords: endotoxin, lipopolysaccharide, metastasis, murine tumour, surgery

Full Text

The Full Text of this article is available as a PDF (241.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anan K., Morisaki T., Katano M., Ikubo A., Kitsuki H., Uchiyama A., Kuroki S., Tanaka M., Torisu M. Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery. 1996 Mar;119(3):333–339. doi: 10.1016/s0039-6060(96)80120-6. [DOI] [PubMed] [Google Scholar]
  2. Arai K., Asakura T., Nemir P., Jr Effect of local tumor removal and retained oncolysate on lung metastasis. J Surg Res. 1992 Jul;53(1):30–38. doi: 10.1016/0022-4804(92)90009-o. [DOI] [PubMed] [Google Scholar]
  3. Clauss M., Gerlach M., Gerlach H., Brett J., Wang F., Familletti P. C., Pan Y. C., Olander J. V., Connolly D. T., Stern D. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990 Dec 1;172(6):1535–1545. doi: 10.1084/jem.172.6.1535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Crissman J. D., Hatfield J. S., Menter D. G., Sloane B., Honn K. V. Morphological study of the interaction of intravascular tumor cells with endothelial cells and subendothelial matrix. Cancer Res. 1988 Jul 15;48(14):4065–4072. [PubMed] [Google Scholar]
  5. Freeman M. R., Schneck F. X., Gagnon M. L., Corless C., Soker S., Niknejad K., Peoples G. E., Klagsbrun M. Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. Cancer Res. 1995 Sep 15;55(18):4140–4145. [PubMed] [Google Scholar]
  6. Hansen E., Wolff N., Knuechel R., Ruschoff J., Hofstaedter F., Taeger K. Tumor cells in blood shed from the surgical field. Arch Surg. 1995 Apr;130(4):387–393. doi: 10.1001/archsurg.1995.01430040049007. [DOI] [PubMed] [Google Scholar]
  7. Harmey J. H., Dimitriadis E., Kay E., Redmond H. P., Bouchier-Hayes D. Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol. 1998 Apr-May;5(3):271–278. doi: 10.1007/BF02303785. [DOI] [PubMed] [Google Scholar]
  8. Holmgren L., O'Reilly M. S., Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995 Feb;1(2):149–153. doi: 10.1038/nm0295-149. [DOI] [PubMed] [Google Scholar]
  9. Jiang W. G., Puntis M. C., Hallett M. B. Molecular and cellular basis of cancer invasion and metastasis: implications for treatment. Br J Surg. 1994 Nov;81(11):1576–1590. doi: 10.1002/bjs.1800811107. [DOI] [PubMed] [Google Scholar]
  10. Kenyon B. M., Voest E. E., Chen C. C., Flynn E., Folkman J., D'Amato R. J. A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci. 1996 Jul;37(8):1625–1632. [PubMed] [Google Scholar]
  11. Kodama M., Kodama T., Nishi Y., Totani R. Does surgical stress cause tumor metastasis? Anticancer Res. 1992 Sep-Oct;12(5):1603–1616. [PubMed] [Google Scholar]
  12. Li W. W., Grayson G., Folkman J., D'Amore P. A. Sustained-release endotoxin. A model for inducing corneal neovascularization. Invest Ophthalmol Vis Sci. 1991 Oct;32(11):2906–2911. [PubMed] [Google Scholar]
  13. Marmé D. Tumor angiogenesis: the pivotal role of vascular endothelial growth factor. World J Urol. 1996;14(3):166–174. doi: 10.1007/BF00186896. [DOI] [PubMed] [Google Scholar]
  14. Mattsby-Baltzer I., Jakobsson A., Sörbo J., Norrby K. Endotoxin is angiogenic. Int J Exp Pathol. 1994 Jun;75(3):191–196. [PMC free article] [PubMed] [Google Scholar]
  15. Nakamura T., Ebihara I., Fukui M., Tomino Y., Koide H. Modulation of endothelin family gene expression in renal hypertrophy. Nephron. 1996;73(2):228–234. doi: 10.1159/000189045. [DOI] [PubMed] [Google Scholar]
  16. O'Reilly M. S., Boehm T., Shing Y., Fukai N., Vasios G., Lane W. S., Flynn E., Birkhead J. R., Olsen B. R., Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997 Jan 24;88(2):277–285. doi: 10.1016/s0092-8674(00)81848-6. [DOI] [PubMed] [Google Scholar]
  17. O'Reilly M. S., Holmgren L., Shing Y., Chen C., Rosenthal R. A., Moses M., Lane W. S., Cao Y., Sage E. H., Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315–328. doi: 10.1016/0092-8674(94)90200-3. [DOI] [PubMed] [Google Scholar]
  18. Peters K. G., De Vries C., Williams L. T. Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8915–8919. doi: 10.1073/pnas.90.19.8915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rylander R., Bake B., Fischer J. J., Helander I. M. Pulmonary function and symptoms after inhalation of endotoxin. Am Rev Respir Dis. 1989 Oct;140(4):981–986. doi: 10.1164/ajrccm/140.4.981. [DOI] [PubMed] [Google Scholar]
  20. Shapira L., Takashiba S., Champagne C., Amar S., Van Dyke T. E. Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF-alpha and IL-1 beta production by human monocytes. J Immunol. 1994 Aug 15;153(4):1818–1824. [PubMed] [Google Scholar]
  21. Skipper D., Jeffrey M. J., Cooper A. J., Alexander P., Taylor I. Enhanced growth of tumour cells in healing colonic anastomoses and laparotomy wounds. Int J Colorectal Dis. 1989 Aug;4(3):172–177. doi: 10.1007/BF01649697. [DOI] [PubMed] [Google Scholar]
  22. Sunderkötter C., Steinbrink K., Goebeler M., Bhardwaj R., Sorg C. Macrophages and angiogenesis. J Leukoc Biol. 1994 Mar;55(3):410–422. doi: 10.1002/jlb.55.3.410. [DOI] [PubMed] [Google Scholar]
  23. Watson R. W., Redmond H. P., McCarthy J., Burke P. E., Bouchier-Hayes D. Exposure of the peritoneal cavity to air regulates early inflammatory responses to surgery in a murine model. Br J Surg. 1995 Aug;82(8):1060–1065. doi: 10.1002/bjs.1800820820. [DOI] [PubMed] [Google Scholar]
  24. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. doi: 10.1056/NEJM199101033240101. [DOI] [PubMed] [Google Scholar]
  25. Weinstein S. L., Sanghera J. S., Lemke K., DeFranco A. L., Pelech S. L. Bacterial lipopolysaccharide induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in macrophages. J Biol Chem. 1992 Jul 25;267(21):14955–14962. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES