MYC activation is a hallmark of cancer initiation and maintenance

Abstract

The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the "hallmark" features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis.

Figure 1.

MYC-induced cancer initiation and maintenance. MYC induces tumorigenesis by evading multiple tumor-suppressing checkpoint mechanisms, including proliferative arrest, apoptosis, and/or senescence. On MYC suppression these barriers are restored, enabling sustained tumor regression.

Figure 2.

Consequences of MYC inactivation in multiple types of cancer. 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. 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 tumor regression through both cell-autonomous and non-cell-autonomous mechanisms of tumor regression. MYC activation leads to tumorigenesis through suppression of critical safeguards such as apoptosis, proliferative arrest, differentiation, and senescence. Activation of MYC also facilitates engagement of hallmarks of tumor growth, as well as cell-extrinsic phenomena such as host immunity. TGF, transforming growth factor.