In Kang et al.’s model, NrasG12V alone was not able to drive hepatic tumorigenesis in wildtype mice. Surprisingly, NrasG12V did drive massive tumor development in CD4−/− hosts, implicating a role for the adaptive immune system (Th cells) in surveillance of cells undergoing oncogenic stress. Furthermore, the authors found Nras G12V peptide epitope-specific Th cells indicating specificity for the driving oncogene. The authors also presented evidence that monocytes/macrophages function as effectors in Dabrafenib chemical structure clearing initiated cells but

antibody-mediated depletion of neutrophils and NK cells showed only marginal or no effect. It has been noted that immunosuppressed individuals display a higher cancer rate (reviewed22) and in the case

of hepatitis C, senescent hepatocytes build-up in infected livers of immunosuppressed patients.19 This is consistent with immune-mediated surveillance of senescence providing a major barrier to tumorigenesis by eliminating the reservoir of premalignant senescent cells that are primed for escape to transformation. However, additional studies, including single-cell analyses, are needed to formally exclude the possible preexistence of senescence-resistant or otherwise transformed cells. The Myc oncogene has been Kinase Inhibitor Library chemical structure implicated in hepatocellular senescence (tumor regression), malignant progression, and tumor-dependent immunoregulation. Overexpression of wildtype Myc is a feature in most HCC patients. Induction of Myc-driven genes also marks the transition from dysplastic nodules to “early” HCC,23 indicating medchemexpress that Myc may initiate or be an “effector” of transformation in HCC. Myc is the only oncogene24 in its wildtype form that can induce high penetrance tumors with short latencies in most transgenic

models. The Myc transgenic tumor model displays decreased latencies in response to hepatotoxins and hydrodynamic damage, implying that Myc may collaborate with inflammation-driven signaling pathways.25 Interestingly, Myc is an addictive oncogene in models of lymphoma and HCC where tumor regression occurs when Myc is shut down. In lymphoma, Myc evokes apoptosis that attracts and signals macrophages to secrete TGF-β inducing senescence. Just as CD4 T cells are required for successful surveillance of NrasG12V-induced senescent cells, sustained tumor regression following Myc inactivation also depends on CD4 T cells for induction of senescence, collapse of angiogenesis, and long-term suppression of minimal residual disease.26 Myc-driven transgenic HCC models also display the ability to modulate the adaptive immune response.