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.tumorigenesis ͉ angiogenesis inhibitors

Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16Ink4a loss

“…Specifically, p53 loss promoted relapse of doxycycline-dependent (Dox-dependent), Wnt1-initiated mammary adenocarcinomas following experimental abrogation of oncogenic signaling (15). Similarly, p53 loss promoted relapse in a reversible Myc-initiated lymphoma model (16). Together, these studies suggest that p53 lesions promote drug-resistant tumor escape in diverse tumor types and diverse treatment contexts.…”

“…p19 Arf is known to relay oncogenic stress signals to p53 (28), which supports our conclusion that p19 Arf acts in the p53 pathway to suppress tumor escape and suggests a link between mammary tumor relapse and defective sensing of aberrant mitogenic signals. Others have used reversible tumor models to show that p53 blocks tumor escape in part by inhibiting angiogenesis and enforcing cell senescence (16,47). Whether suppression of escape via one or both of these mechanisms requires upstream signaling to p53 through p19 Arf remains to be determined.…”

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

“…6,[9][10][11][12][13][14] p53 is able to induce tumour dormancy, and the loss of WTp53 reverses the tumour switch from a dormant non-angiogenic state to an angiogenic invasive phenotype. 15,16 Clinical data also suggest that p53 has a crucial role in controlling tumour vascularization. However, nothing is known about the role of D133p53 isoforms (a, b and g) in this process.…”

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

“…Here, we report the development of a conditional transgenic mouse model for MYC-deregulated human RCC. The MYC oncogene contributes to tumorigenesis of many types of cancer through various mechanisms (7-10), including the regulation of proliferation and growth, protein and ribosomal biogenesis, changes in metabolism, lipid synthesis, and induction of angiogenesis (11)(12)(13)(14). MYC reprogramming can result in tumors that are addicted to glucose and/or glutamine for their energy metabolism (15-19).…”