Strategies to Prevent or Remediate Cancer and Treatment-Related Aging.

Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Experts assembled to share evidence of promising strategies to prevent, slow, or reverse the aging consequences of cancer and its treatment. The meeting identified research and resource needs, including geroscience-guided clinical trials; comprehensive assessments of functional, cognitive, and psychosocial vulnerabilities to assess and predict age-related outcomes; preclinical and clinical research to determine the optimal dosing for behavioral (eg, diet, exercise) and pharmacologic (eg, senolytic) therapies; health-care delivery research to evaluate the efficacy of integrated cancer care delivery models; optimization of intervention implementation, delivery, and uptake; and patient and provider education on cancer and treatment-related late and long-term adverse effects. Addressing these needs will expand knowledge of aging-related consequences of cancer and cancer treatment and inform strategies to promote healthy aging of cancer survivors.

Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors.

Observational data have shown that some cancer survivors develop chronic conditions like frailty, sarcopenia, cardiac dysfunction, and mild cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to systemic or targeted cancer therapies. In aggregate, cancer- and treatment-related physical, cognitive, and psychosocial late- and long-term morbidities experienced by cancer survivors are hypothesized to represent accelerated or accentuated aging trajectories. However, conceptual, measurement, and methodological challenges have constrained efforts to identify, predict, and mitigate aging-related consequences of cancer and cancer treatment. In July 2018, the National Cancer Institute convened basic, clinical, and translational science experts for a think tank titled "Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors." Through the resulting deliberations, several research and resource needs were identified, including longitudinal studies to examine aging trajectories that include detailed data from before, during, and after cancer treatment; mechanistic studies to elucidate the pathways that lead to the emergence of aging phenotypes in cancer survivors; long-term clinical surveillance to monitor survivors for late-emerging effects; and tools to integrate multiple data sources to inform understanding of how cancer and its therapies contribute to the aging process. Addressing these needs will help expand the evidence base and inform strategies to optimize healthy aging of cancer survivors.

TGFbeta1 and TGFalpha contrarily affect alveolar survival and tumorigenesis in mouse mammary epithelium.

Growth factors and hormones are responsible for development of the mammary gland and can contribute to mammary carcinogenesis. The transforming growth factors (TGF) alpha and beta1 demonstrate opposing effects on the mammary epithelium. TGFalpha is a mitogen and survival factor for mammary secretory cells and is often upregulated in cancer, while TGFbeta1 may act as a growth suppressor and has been shown to inhibit alveolar development and lactogenesis. To examine the contradistinct effects of TGFalpha and TGFbeta1 on normal mammary epithelium, we crossed MT-TGFalpha mice with WAP-TGFbeta1 transgenic mice. The newly generated bitransgenic mice failed to nurse their pups and were resistant to mammary tumorigenesis (0% at 12 months of age), compared to single transgenic MT-TGFalpha in which the majority (65% at 12 months of age) of the mice developed hyperplastic alveolar mammary lesions. Transplantation studies showed that bitransgenic tissue was highly resistant to tumor formation even after multiple pregnancies. WAP-TGFbeta1 mammary transplants often failed to grow and fully fill cleared mammary fat pads upon transplantation. This repression of growth was completely reversed in the bitransgenic implants, which grew as well as normal epithelium upon transplantation. In addition, TGF and bitransgenic TGFalpha/TGFbeta1 mice had reduced rates of apoptosis during involution as compared to wild type and TGFbeta1. These data demonstrate that TGFbeta1 and TGFalpha exhibit opposing effects upon the proliferation and survival of mammary epithelium when expressed alone but when expressed together result in reciprocally suppressive effects upon one another in the context of mammary development and tumorigenesis.

Ultraviolet radiation and cutaneous malignant melanoma.

Recent years have seen a steady rise in the incidence of cutaneous malignant melanoma worldwide. Although it is now appreciated that the key to understanding the process by which melanocytes are transformed into malignant melanoma lies in the interplay between genetic factors and the ultraviolet (UV) spectrum of sunlight, the nature of this relation has remained obscure. Recently, prospects for elucidating the molecular mechanisms underlying such gene-environment interactions have brightened considerably through the development of UV-responsive experimental animal models of melanoma. Genetically engineered mice and human skin xenografts constitute novel platforms upon which to build studies designed to elucidate the pathogenesis of UV-induced melanomagenesis. The future refinement of these in vivo models should provide a wealth of information on the cellular and genetic targets of UV, the pathways responsible for the repair of UV-induced DNA damage, and the molecular interactions between melanocytes and other skin cells in response to UV. It is anticipated that exploitation of these model systems will contribute significantly toward the development of effective approaches to the prevention and treatment of melanoma.

Nitric oxide-induced cellular stress and p53 activation in chronic inflammation.

Free radical-induced cellular stress contributes to cancer during chronic inflammation. Here, we investigated mechanisms of p53 activation by the free radical, NO. NO from donor drugs induced both ataxia-telangiectasia mutated (ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications, leading to an increase in p53 transcriptional targets and a G(2)M cell cycle checkpoint. Such modifications were also identified in cells cocultured with NO-releasing macrophages. In noncancerous colon tissues from patients with ulcerative colitis (a cancer-prone chronic inflammatory disease), inducible NO synthase protein levels were positively correlated with p53 serine 15 phosphorylation levels. Immunostaining of HDM-2 and p21(WAF1) was consistent with transcriptionally active p53. Our study highlights a pivotal role of NO in the induction of cellular stress and the activation of a p53 response pathway during chronic inflammation.

Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf(-/-) mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK4a/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.