Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch

Sylvie Giuriato, Sandra Ryeom, Alice C. Fan, Pavan Bachireddy, Ryan C. Lynch, Matthew J. Rioth, Jan Van Riggelen, Andrew M. Kopelman, Emmanuelle Passegué, Flora Tang, Judah Folkman, Dean W. Felsher

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107 Scopus citations

Abstract

The targeted inactivation of oncogenes offers a rational therapeutic approach for the treatment of cancer. However, the therapeutic inactivation of a single oncogene has been associated with tumor recurrence. Therefore, it is necessary to develop strategies to override mechanisms of tumor escape from oncogene dependence. We report here that the targeted inactivation of MYC is sufficient to induce sustained regression of hematopoietic tumors in transgenic mice, except in tumors that had lost p53 function. p53 negative tumors were unable to be completely eliminated, as demonstrated by the kinetics of tumor cell elimination revealed by bioluminescence imaging. Histological examination revealed that upon MYC inactivation, the loss of p53 led to a deficiency in thrombospondin-1 (TSP-1) expression, a potent antiangiogenic protein, and the subsequent inability to shut off angiogenesis. Restoration of p53 expression in these tumors re-established TSP-1 expression. This permitted the suppression of angiogenesis and subsequent sustained tumor regression upon MYC inactivation. Similarly, the restoration of TSP-1 alone in p53 negative tumors resulted in the shut down of angiogenesis and led to sustained tumor regression upon MYC inactivation. Hence, the complete regression of tumor mass driven by inactivation of the MYC oncogene requires the p53-dependent induction of TSP-1 and the shut down of angiogenesis. Notably, overexpression of TSP-1 alone did not influence tumor growth. Therefore, the combined inactivation of oncogenes and angiogenesis may be a more clinically effective treatment of cancer. We conclude that angiogenesis is an essential component of oncogene addiction.

Original languageEnglish (US)
Pages (from-to)16266-16271
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number44
DOIs
StatePublished - Oct 31 2006

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Keywords

  • Angiogenesis inhibitors
  • Tumorigenesis

ASJC Scopus subject areas

  • General

Cite this

Giuriato, S., Ryeom, S., Fan, A. C., Bachireddy, P., Lynch, R. C., Rioth, M. J., Van Riggelen, J., Kopelman, A. M., Passegué, E., Tang, F., Folkman, J., & Felsher, D. W. (2006). Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proceedings of the National Academy of Sciences of the United States of America, 103(44), 16266-16271. https://doi.org/10.1073/pnas.0608017103