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

Research output: Contribution to journalArticle

104 Citations (Scopus)

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

Fingerprint

Thrombospondin 1
Oncogenes
Neoplasms
Tumor Escape
Transgenic Mice

Keywords

  • Angiogenesis inhibitors
  • Tumorigenesis

ASJC Scopus subject areas

  • General

Cite this

Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. / Giuriato, Sylvie; Ryeom, Sandra; Fan, Alice C.; Bachireddy, Pavan; Lynch, Ryan C.; Rioth, Matthew J.; Van Riggelen, Jan; Kopelman, Andrew M.; Passegué, Emmanuelle; Tang, Flora; Folkman, Judah; Felsher, Dean W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 44, 31.10.2006, p. 16266-16271.

Research output: Contribution to journalArticle

Giuriato, S, Ryeom, S, Fan, AC, Bachireddy, P, Lynch, RC, Rioth, MJ, Van Riggelen, J, Kopelman, AM, Passegué, E, Tang, F, Folkman, J & Felsher, DW 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, vol. 103, no. 44, pp. 16266-16271. https://doi.org/10.1073/pnas.0608017103
Giuriato, Sylvie ; Ryeom, Sandra ; Fan, Alice C. ; Bachireddy, Pavan ; Lynch, Ryan C. ; Rioth, Matthew J. ; Van Riggelen, Jan ; Kopelman, Andrew M. ; Passegué, Emmanuelle ; Tang, Flora ; Folkman, Judah ; Felsher, Dean W. / Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 44. pp. 16266-16271.
@article{4ebdf41e7a3347638f8cfdcc4c103eb9,
title = "Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch",
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.",
keywords = "Angiogenesis inhibitors, Tumorigenesis",
author = "Sylvie Giuriato and Sandra Ryeom and Fan, {Alice C.} and Pavan Bachireddy and Lynch, {Ryan C.} and Rioth, {Matthew J.} and {Van Riggelen}, Jan and Kopelman, {Andrew M.} and Emmanuelle Passegu{\'e} and Flora Tang and Judah Folkman and Felsher, {Dean W.}",
year = "2006",
month = "10",
day = "31",
doi = "10.1073/pnas.0608017103",
language = "English (US)",
volume = "103",
pages = "16266--16271",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "44",

}

TY - JOUR

T1 - Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch

AU - Giuriato, Sylvie

AU - Ryeom, Sandra

AU - Fan, Alice C.

AU - Bachireddy, Pavan

AU - Lynch, Ryan C.

AU - Rioth, Matthew J.

AU - Van Riggelen, Jan

AU - Kopelman, Andrew M.

AU - Passegué, Emmanuelle

AU - Tang, Flora

AU - Folkman, Judah

AU - Felsher, Dean W.

PY - 2006/10/31

Y1 - 2006/10/31

N2 - 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.

AB - 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.

KW - Angiogenesis inhibitors

KW - Tumorigenesis

UR - http://www.scopus.com/inward/record.url?scp=33750800316&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750800316&partnerID=8YFLogxK

U2 - 10.1073/pnas.0608017103

DO - 10.1073/pnas.0608017103

M3 - Article

C2 - 17056717

AN - SCOPUS:33750800316

VL - 103

SP - 16266

EP - 16271

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 44

ER -