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Tumor Suppression: Cancer and Aging

Research Summary

Charles Sherr studies tumor-suppressor genes that counter uncontrolled cell proliferation in response to mutagenic oncogenic insults. A tumor-suppressor network dominated by the retinoblastoma protein (Rb), p53, and the Ink4-Arf locus may have evolved to limit stem cell self-renewal and maintain tissue homeostasis. This concept explains why three chromosomally linked and coregulated tumor-suppressor genes (Ink4a, Ink4b, and Arf) are conserved in mammals, despite their frequent codeletion in cancers.

Mutations that activate oncogenes in cancer cells stimulate uncontrolled cell proliferation. Tumor-suppressor genes oppose the actions of oncogenes, and their inactivation predisposes to cancer. The realization that oncogenes and tumor-suppressor genes govern diverse biological processes, such as gene expression, cell differentiation, tissue development, and responses to environmental stress, provided key mechanistic insights into tumor formation.

A Hallmark of Cancer: Inactivation of the Rb and p53 Network
Transformation of normal cells to cancer cells commonly involves the disruption of signaling networks regulated by two canonical tumor-suppressor genes encoding the retinoblastoma protein (Rb) and the p53 transcription factor. Although the functions of Rb and p53 are not normally required for cell division, both proteins govern protective "checkpoint" responses that are triggered by DNA damage or by oncogene stimulation. Activation of Rb and p53 induces global changes in gene expression, which either arrest cell division or induce the death of damaged cells. Disruption of Rb and p53 compromises these safeguards, allowing incipient cancer cells to continue to divide, to consolidate mutational damage, and, ultimately, to form tumors.

Lesions affecting other genes governing the Rb and p53 signaling network can mimic Rb and p53 loss of function. Prominent among these are mutations that disrupt the Ink4-Arf gene cluster, a compact genetic locus that specifies three additional tumor-suppressor proteins: p16Ink4a, p15Ink4b, and p19Arf (p14ARF in humans; Figure 1). Expression of the p16Ink4a and p15Ink4b proteins in response to oncogenic stress activates Rb, whereas synthesis of p19Arf induces p53 (Figure 2). Therefore, chromosomal deletions that encompass the entire Ink4-Arf locus simultaneously compromise the activities of both Rb and p53. The Ink4-Arf locus is not highly expressed under most normal physiologic conditions in young mammals. Notably, Ink4-Arf is actively silenced en bloc in embryonic, fetal, and adult stem cells but becomes poised to respond to oncogenic stress signals as stem cells lose their self-renewal capacity and differentiate, thereby providing a potent barrier to tumor formation. The Ink4-Arf locus may have evolved to physiologically restrict the self-renewal capacities and numbers of stem and progenitor cells, with the attendant consequence of limiting tissue regenerative capacity in aging animals. Deletion of Ink4-Arf contributes to the aberrant self-renewal capacity of tumor cells and occurs frequently in many forms of human cancer. By contrast, the increased expression of Ink4-Arf as animals age is associated with degenerative diseases, including coronary artery disease, aortic aneurysm and stroke, and type II diabetes.

D-type Cyclins and their Cyclin-Dependent kinases (CDKs)
Extracellular mitogens that drive cellular proliferation trigger the synthesis of D-type cyclins and their assembly with CDK4 and CDK6. In turn, the latter kinases phosphorylate Rb, releasing Rb-bound transcription factors (E2Fs) that, once freed from Rb constraint, activate a suite of genes necessary for chromosomal DNA replication (Figure 2). In this manner, the D-type cyclins act as growth factor sensors to integrate extracellular cues with the core cell cycle machinery. Oncogenic mutations can target components of cell receptor-mediated signaling pathways to render them constitutively active and independent of the extracellular mitogens that normally govern their functions. Such mutations enforce cyclin D-dependent CDK4/6 activities, Rb inactivation, and chromosomal DNA replication. Indeed, subsets of cancer-specific mutations directly impinge on the D-type cyclin and CDK4/6 genes to amplify their activities and enforce aberrant cell proliferation. Remarkably, the tumor suppressive p16Ink4a and p15Ink4b proteins encoded by the Ink4-Arf locus are induced by inappropriate hyperproliferative signals and serve to protect cells from mutated oncogenic drivers. Cancer cells result both from oncogene activation and a failure of tumor suppressor functions, so that mutations that inactivate the Ink4-Arf locus and Rb, or that increase the expression of D-type cyclins, CDK4, and CDK6 are among the most frequently detected in tumors.

Dating from the early discoveries more than two decades ago of the D-type cyclins, CDK4, and CDK6, there have been longstanding attempts to develop chemical inhibitors of CDK4 and CDK6 that might mimic the anti-proliferative effects of Ink4 proteins. Improvements in chemistry and drug screening have finally led to the generation of highly potent, orally available drugs that specifically inhibit CDK4/6 activities without significant off-target effects or clinically unmanageable dose-limiting toxicities in patients. These CDK4/6 inhibitors synergize with other newly developed drugs that target the signal transduction pathways that induce cyclin D synthesis, enabling the application of new combinatorial targeted therapies to treat various cancers. To date, one such CDK4/6 inhibitor has achieved FDA approval, and its use in combination with inhibitors of estrogen signaling, has led to significant increases in progression-free survival of patients with hormone-responsive breast cancer. Additional CDK4/6 inhibitors are in late clinical trials for a variety of other cancer indications.

Disparate Physiological Functions of Arf Suggest Novel Roles during Tissue Development
Arf is not generally expressed in normal tissues but is induced in response to activated oncogenes, thereby triggering p53-dependent elimination of incipient cancer cells (Figure 2). Paradoxically, we detected Arf expression in three tissues during early mouse development: (1) in the hyaloid vasculature of the eye, (2) in male germ cells (spermatogonia) within seminiferous tubules, and (3) in the fetal yolk sac, a tissue which arises from extraembryonic endoderm. Inactivation of Arf in these three tissues results in focal developmental defects that respectively lead to blindness, impaired spermatogenesis, and delayed formation of extraembryonic endoderm in the earliest stages of embryogenesis. Studies in which Arf deletions were specifically targeted to affected tissues, combined with the use of engineered "indicator strains," in which engagement of the Arf promoter was monitored throughout mouse development, revealed that Arf inactivation provokes these disparate defects in a manner that is independent of p53. By defining the segments of the Arf protein responsible for its unusual developmental activities in the eye, testis, and extraembryonic tissues, we hope to gain further insights into Arf’s p53-independent tumor suppressive functions.

As of March 3, 2016

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St. Jude Children's Research Hospital
Cancer Biology, Medicine and Translational Research