Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Aug;85(4):584–589. doi: 10.1054/bjoc.2001.1936

Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors

R M Shaheen 1, S A Ahmad 1, W Liu 2, N Reinmuth 2, Y D Jung 2, W W Tseng 3, K E Drazan 3, C D Bucana 2, D J Hicklin 4, L M Ellis 1,2
PMCID: PMC2364099  PMID: 11506500

Abstract

Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) regulate colon cancer growth and metastasis. Previous studies utilizing antibodies against the VEGF receptor (DC101) or EGF receptor (C225) have demonstrated independently that these agents can inhibit tumour growth and induce apoptosis in colon cancer in in vivo and in vitro systems. We hypothesized that simultaneous blockade of the VEGF and EGF receptors would enhance the therapy of colon cancer in a mouse model of peritoneal carcinomatosis. Nude mice were given intraperitoneal injection of KM12L4 human colon cancer cells to generate peritoneal metastases. Mice were then randomized into one of four treatment groups: control, anti-VEGFR (DC101), anti-EGFR (C225), or DC101 and C225. Relative to the control group, treatment with DC101 or with DC101+C225 decreased tumour vascularity, growth, proliferation, formation of ascites and increased apoptosis of both tumour cells and endothelial cells. Although C225 therapy did not change any of the above parameters, C225 combined with DC101 led to a significant decrease in tumour vascularity and increases in tumour cell and endothelial cell apoptosis (vs the DC101 group). These findings suggest that DC101 inhibits angiogenesis, endothelial cell survival, and VEGF-mediated ascites formation in a murine model of colon cancer carcinomatosis. The addition of C225 to DC101 appears to lead to a further decrease in angiogenesis and ascites formation. Combination anti-VEGF and anti-EGFR therapy may represent a novel therapeutic strategy for the management of colon peritoneal carcinomatosis. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: antiangiogenic therapy, VEGF, EGF, receptor, apoptosis, endothelial cell, DC101, C225

Full Text

The Full Text of this article is available as a PDF (78.8 KB).

Selected References

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

  1. Aparicio T., Kermorgant S., Dessirier V., Lewin M. J., Lehy T. Matrix metalloproteinase inhibition prevents colon cancer peritoneal carcinomatosis development and prolongs survival in rats. Carcinogenesis. 1999 Aug;20(8):1445–1451. doi: 10.1093/carcin/20.8.1445. [DOI] [PubMed] [Google Scholar]
  2. Bruns C. J., Liu W., Davis D. W., Shaheen R. M., McConkey D. J., Wilson M. R., Bucana C. D., Hicklin D. J., Ellis L. M. Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer. 2000 Aug 1;89(3):488–499. [PubMed] [Google Scholar]
  3. Ciardiello F., Bianco R., Damiano V., De Lorenzo S., Pepe S., De Placido S., Fan Z., Mendelsohn J., Bianco A. R., Tortora G. Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res. 1999 Apr;5(4):909–916. [PubMed] [Google Scholar]
  4. Copeland E. M., Miller L. D., Jones R. S. Prognostic factors in carcinoma of the colon and rectum. Am J Surg. 1968 Dec;116(6):875–881. doi: 10.1016/0002-9610(68)90458-3. [DOI] [PubMed] [Google Scholar]
  5. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med. 1995 Dec 28;333(26):1757–1763. doi: 10.1056/NEJM199512283332608. [DOI] [PubMed] [Google Scholar]
  6. Goldstein N. I., Prewett M., Zuklys K., Rockwell P., Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995 Nov;1(11):1311–1318. [PubMed] [Google Scholar]
  7. Ke-Lin, Qu-Hong, Nagy J. A., Eckelhoefer I. A., Masse E. M., Dvorak A. M., Dvorak H. F. Vascular targeting of solid and ascites tumours with antibodies to vascular endothelial growth factor. Eur J Cancer. 1996 Dec;32A(14):2467–2473. doi: 10.1016/s0959-8049(96)00391-7. [DOI] [PubMed] [Google Scholar]
  8. Liu B., Fang M., Schmidt M., Lu Y., Mendelsohn J., Fan Z. Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br J Cancer. 2000 Jun;82(12):1991–1999. doi: 10.1054/bjoc.2000.1201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Marcus E. A., Weber T. K., Rodriguez-Bigas M. A., Driscoll D., Meropol N. J., Petrelli N. J. Prognostic factors affecting survival in patients with colorectal carcinomatosis. Cancer Invest. 1999;17(4):249–252. doi: 10.3109/07357909909040593. [DOI] [PubMed] [Google Scholar]
  10. Morikawa K., Walker S. M., Jessup J. M., Fidler I. J. In vivo selection of highly metastatic cells from surgical specimens of different primary human colon carcinomas implanted into nude mice. Cancer Res. 1988 Apr 1;48(7):1943–1948. [PubMed] [Google Scholar]
  11. Perrotte P., Matsumoto T., Inoue K., Kuniyasu H., Eve B. Y., Hicklin D. J., Radinsky R., Dinney C. P. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 1999 Feb;5(2):257–265. [PubMed] [Google Scholar]
  12. Prewett M., Huber J., Li Y., Santiago A., O'Connor W., King K., Overholser J., Hooper A., Pytowski B., Witte L. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res. 1999 Oct 15;59(20):5209–5218. [PubMed] [Google Scholar]
  13. Radinsky R., Risin S., Fan D., Dong Z., Bielenberg D., Bucana C. D., Fidler I. J. Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res. 1995 Jan;1(1):19–31. [PubMed] [Google Scholar]
  14. Senger D. R., Connolly D. T., Van de Water L., Feder J., Dvorak H. F. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res. 1990 Mar 15;50(6):1774–1778. [PubMed] [Google Scholar]
  15. Shaheen R. M., Davis D. W., Liu W., Zebrowski B. K., Wilson M. R., Bucana C. D., McConkey D. J., McMahon G., Ellis L. M. Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res. 1999 Nov 1;59(21):5412–5416. [PubMed] [Google Scholar]
  16. Takahashi Y., Kitadai Y., Bucana C. D., Cleary K. R., Ellis L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995 Sep 15;55(18):3964–3968. [PubMed] [Google Scholar]
  17. Witte L., Hicklin D. J., Zhu Z., Pytowski B., Kotanides H., Rockwell P., Böhlen P. Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev. 1998 Jun;17(2):155–161. doi: 10.1023/a:1006094117427. [DOI] [PubMed] [Google Scholar]
  18. Zebrowski B. K., Yano S., Liu W., Shaheen R. M., Hicklin D. J., Putnam J. B., Jr, Ellis L. M. Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions. Clin Cancer Res. 1999 Nov;5(11):3364–3368. [PubMed] [Google Scholar]

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

RESOURCES