Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein

Christopher T. Siegel, Karin Schreiber, Stephen C. Meredith, Gabriele B. Beck-Engeser, David W. Lancki, Christopher A. Lazarski, Yang Xin Fu, Donald A. Rowley, Hans Schreiber

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Abstract

One major objective of tumor immunologists is to prevent cancer development in individuals at high risk. (TG.AC X C57BL/6)F1 mice serve as a model for testing the feasibility of this objective. The mice carry in the germline a mutant ras oncogene that has an arginine at codon 12 instead of glycine present in the wild-type, and after physical (wounding) or chemical promotion, these mice have a high probability for developing papillomas that progress to cancer. Furthermore, F1 mice immunized with: Arg12 mutant ras peptide in complete Freund's adjuvant (CFA) develop T cells within 10 d that proliferate in vitro on stimulation with the Arg12 mutant ras peptide. Within 14 d, these mice have delayed-type hypersensitive to the peptide. Immunization with CFA alone or with a different Arg12 mutant ras peptide in CFA induced neither response. To determine the effect of immunization on development of tumors, mice immunized 3 wk earlier were painted on the back with phorbol 12-myristate 13-acetate every 3 d for 8 wk. The time of appearance and the number of papillomas were about the same in immunized and control mice, but the tumors grew faster and became much larger in the mice immunized with the Arg12 mutant ras peptide. Thus, the immunization failed to protect against growth of papillomas. The peptide-induced CD4+ T cells preferentially recognized the peptide but not the native mutant ras protein. On the other hand, mice immunized with Arg12 mutant ras peptide and bearing papillomas had serum antibodies that did bind native mutant ras protein. Together, these studies indicate that active immunization of cancer-prone individuals may result in immune responses that fail to eradicate mutant oncogene-expressing tumor cells, but rather induce a remarkable enhancement of tumor growth.

Original languageEnglish (US)
Pages (from-to)1945-1956
Number of pages12
JournalJournal of Experimental Medicine
Volume191
Issue number11
DOIs
StatePublished - Jun 5 2000

Fingerprint

Oncogene Proteins
Immunization
Peptides
Growth
Papilloma
Neoplasms
Freund's Adjuvant
ras Proteins
Mutant Proteins
T-Lymphocytes
ras Genes
Oncogenes
Codon
Glycine
Arginine
Vaccination
Acetates
Antibodies

Keywords

  • Active immunization
  • Immune stimulation
  • Mutant ras gene cancer-prone mice
  • Primary tumor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Siegel, C. T., Schreiber, K., Meredith, S. C., Beck-Engeser, G. B., Lancki, D. W., Lazarski, C. A., ... Schreiber, H. (2000). Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein. Journal of Experimental Medicine, 191(11), 1945-1956. https://doi.org/10.1084/jem.191.11.1945

Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein. / Siegel, Christopher T.; Schreiber, Karin; Meredith, Stephen C.; Beck-Engeser, Gabriele B.; Lancki, David W.; Lazarski, Christopher A.; Fu, Yang Xin; Rowley, Donald A.; Schreiber, Hans.

In: Journal of Experimental Medicine, Vol. 191, No. 11, 05.06.2000, p. 1945-1956.

Research output: Contribution to journalArticle

Siegel, CT, Schreiber, K, Meredith, SC, Beck-Engeser, GB, Lancki, DW, Lazarski, CA, Fu, YX, Rowley, DA & Schreiber, H 2000, 'Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein', Journal of Experimental Medicine, vol. 191, no. 11, pp. 1945-1956. https://doi.org/10.1084/jem.191.11.1945
Siegel, Christopher T. ; Schreiber, Karin ; Meredith, Stephen C. ; Beck-Engeser, Gabriele B. ; Lancki, David W. ; Lazarski, Christopher A. ; Fu, Yang Xin ; Rowley, Donald A. ; Schreiber, Hans. / Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein. In: Journal of Experimental Medicine. 2000 ; Vol. 191, No. 11. pp. 1945-1956.
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abstract = "One major objective of tumor immunologists is to prevent cancer development in individuals at high risk. (TG.AC X C57BL/6)F1 mice serve as a model for testing the feasibility of this objective. The mice carry in the germline a mutant ras oncogene that has an arginine at codon 12 instead of glycine present in the wild-type, and after physical (wounding) or chemical promotion, these mice have a high probability for developing papillomas that progress to cancer. Furthermore, F1 mice immunized with: Arg12 mutant ras peptide in complete Freund's adjuvant (CFA) develop T cells within 10 d that proliferate in vitro on stimulation with the Arg12 mutant ras peptide. Within 14 d, these mice have delayed-type hypersensitive to the peptide. Immunization with CFA alone or with a different Arg12 mutant ras peptide in CFA induced neither response. To determine the effect of immunization on development of tumors, mice immunized 3 wk earlier were painted on the back with phorbol 12-myristate 13-acetate every 3 d for 8 wk. The time of appearance and the number of papillomas were about the same in immunized and control mice, but the tumors grew faster and became much larger in the mice immunized with the Arg12 mutant ras peptide. Thus, the immunization failed to protect against growth of papillomas. The peptide-induced CD4+ T cells preferentially recognized the peptide but not the native mutant ras protein. On the other hand, mice immunized with Arg12 mutant ras peptide and bearing papillomas had serum antibodies that did bind native mutant ras protein. Together, these studies indicate that active immunization of cancer-prone individuals may result in immune responses that fail to eradicate mutant oncogene-expressing tumor cells, but rather induce a remarkable enhancement of tumor growth.",
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