MYC Inactivation Elicits Oncogene Addiction through Both Tumor Cell-Intrinsic and Host-Dependent Mechanisms

Abstract

Tumorigenesis is generally caused by genetic changes that activate oncogenes or inactivate tumor suppressor genes. The targeted inactivation of oncogenes can be associated with tumor regression through the phenomenon of oncogene addiction. One of the most common oncogenic events in human cancer is the activation of the MYC oncogene. The inactivation of MYC may be a general and effective therapy for human cancer. Indeed, it has been experimentally shown that the inactivation of MYC can result in dramatic and sustained tumor regression in lymphoma, leukemia, osteosarcoma, hepatocellular carcinoma, squamous carcinoma, and pancreatic carcinoma through a multitude of mechanisms, including proliferative arrest, terminal differentiation, cellular senescence, induction of apoptosis, and the shutdown of angiogenesis. Cell-autonomous and cell-dependent mechanisms have both been implicated, and recent results suggest a critical role for autocrine factors, including thrombospondin-1 and TGF-β. Hence, targeting the inactivation of MYC appears to elicit oncogene addiction and, thereby, tumor regression through both tumor cell-intrinsic and host-dependent mechanisms.

Keywords: MYC; oncogene addiction; tumorigenesis.

Figure 1.

MYC inactivation has different outcomes in different types of tumors, including proliferative arrest, differentiation, apoptosis, and/or cellular senescence. Although the consequences are different for each type of tumor, proliferative arrest, apoptosis, and differentiation/senescence appear to be common mechanisms. Tumors can also become dormant, partially regress, and reoccur.

Figure 2.

MYC inactivation elicits oncogene addiction by multiple mechanisms that differ depending on tumor type. MYC inactivation in lymphoma induces proliferative arrest, differentiation/senescence, and widespread apoptosis. Both tumor cell–intrinsic and host-dependent mechanisms (angiogenesis) have been shown to be important. Secreted factors, such as TSP-1, are important for the regulation of angiogenesis, and TGF-β is important for the regulation of cellular senescence. MYC inactivation in osteosarcoma induces proliferative arrest and differentiation/senescence but not apoptosis. MYC reactivation does not restore tumorigenesis. MYC inactivation in liver adenocarcinoma induces proliferative arrest, differentiation/senescence, and apoptosis. MYC reactivation can result in restoration of the tumor.

Figure 3.

MYC inactivation elicits oncogene addiction through tumor cell–intrinsic and hostdependent mechanisms. Cancers exhibit autonomous behavior resulting in immortality, self-renewal, and proliferation. Cancers also influence the microenvironment to support tumorigenesis. MYC inactivation restores physiological safety switches and results in proliferative arrest, differentiation, apoptosis, cellular senescence, and the restoration of a physiologic microenvironment, including the suppression of angiogenesis. Tumor cell–intrinsic, autocrine, and host-dependent mechanisms are involved in oncogene addiction. The TSP-1 and TGF-β cytokine pathways are 2 examples of secreted factors that may play a critical role in the mechanism by which MYC inactivation elicits oncogene addiction.