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Expression of complement protein C5a in a murine mammary cancer model: tumor regression by interference with the cell cycle

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Abstract

The C5a anaphylatoxin protein plays a central role in inflammation associated with complement activation. This protein is commonly regarded as one of the most potent inducers of the inflammatory response and a C5a peptide agonist was used as a molecular adjuvant. However, the full length C5a protein has not been tested as a potential tumor therapy. In this report, we describe the creation of a mini-gene construct that directs C5a expression to any cell of interest. Functional expression could be demonstrated in the murine mammary sarcoma, EMT6. When C5a expressing cells were injected into syngeneic mice, most C5a-expressing clones had significantly reduced tumor growth. Further characterization of a clone expressing low levels of C5a demonstrated that one-third of mice injected with this line had complete tumor regression. The mice whose tumors regressed were immune to subsequent challenge with unmodified EMT6 cells, suggesting that a component of the innate immune response can be used to augment adaptive immunity. Cellular analyses demonstrated that a significant difference in actual tumor cell number could be detected as early as day 10. A block in cell cycle progression was evident at all time points and high levels of apoptosis were observed early in the regression event. These data demonstrate that the complement protein C5a can play a significant protective role in tumor immunity.

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Acknowledgments

The authors would like to thank the following persons: Dr. Jenny P.-Y. Ting, in whose laboratory these experiments were initiated. Her help and guidance were invaluable for the completion of these studies; Dr. J. G. Frelinger for the gift of EMT6 tumor cells, the pHβ construct and the mouse IFN-γ gene; Dr. T. Collins for his help in setting up the apoptosis assays and Ting laboratory members for their helpful discussions; Dr. Scott Barnum for the gift of C5aR antibody. This work was supported by an American Cancer Society Seed Grant (IRG - IN122V) administered through the Holden Comprehensive Cancer Center of The University of Iowa.

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Authors and Affiliations

  1. Department of Microbiology, The University of Iowa, Iowa City, IA, 52242, USA

    Do-Yeun Kim, Carol B. Martin & Brian K. Martin

  2. Holden Comprehensive Cancer Center and Interdisciplinary Graduate Immunology Program, The University of Iowa, Iowa City, IA, 52242, USA

    Brian K. Martin

  3. Department of Medicine, College of Medicine & Ewha Medical Research Center, Ewha Womans University, Seoul, Korea

    Do-Yeun Kim & Soon Nam Lee

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  1. Do-Yeun Kim
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  2. Carol B. Martin
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Correspondence to Brian K. Martin.

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Kim, DY., Martin, C.B., Lee, S.N. et al. Expression of complement protein C5a in a murine mammary cancer model: tumor regression by interference with the cell cycle. Cancer Immunol Immunother 54, 1026–1037 (2005). https://doi.org/10.1007/s00262-005-0672-7

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  • DOI: https://doi.org/10.1007/s00262-005-0672-7

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