Even though it has been evident for decades that aging is a fundamental risk factor in cancer development, we still don't fully understand the causes for this increase. A primary reason for this incomplete understanding is because we still don't know a significant amount about progressive changes that occur in our tissues on the cellular and molecular levels as we get older. To address this critical and unresolved issue, we have been working towards characterizing these changes for several years. Published and ongoing studies in our laboratory have demonstrated an aging associated, and sometime dramatic, accumulation of senescent cells displaying dysfunctional telomeres in various tissues of long lived mammals, including humans. Significantly, cells that had undergone Telomere Dysfunction Induced cellular Senescence (TDIS) also secrete a large number of signaling molecules and matrix remodeling enzymes, suggesting that these cells not only increasing alter structural components of the tissue, but also generate a tissue microenvironment that may promote growth of inactive cancer cells. Indeed, components of this Senescence Associated Secretory Phenotype (SASP) have been demonstrated to promote growth of cancers in animal model systems, although antiproliferative properties of this SASP have also been reported. We have uncovered the reasons for the opposing effects of the SASP on cell proliferation. In this application we will therefore explore whether and to what extent TDIS and the accompanying SASP of stromal and pre- malignant human cells alters tissue microenvironment and therefore contributes to increasing cancer incidences in the aging population. We will 1) identify signaling molecules that trigger TDIS and SASP in somatic human cells, 2) characterize signaling pathways that mediate TDIS in response to extracellular factors, and 3) determine the biological significance of paracrine signaling mediated-TDIS in cancer development. Our comprehensive and multifaceted study will reveal the contributions of the stromal and tumor SASP to aging associated increases in cancer incidences and will therefore provide critical knowledge essential for combating aging associated cancer development.

Public Health Relevance

Proposed studies will reveal whether aging associated changes to cancer development in humans is a direct consequence of the progressively increasing abundance of senescent cells in tissue. Not only is this knowledge critical for a better understanding of the association between aging and cancer on the molecular level, but it is critical for developing therapeutic strategies to reduce the increasing incidences of cancer in the aging population.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA184572-02
Application #
8847689
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Hildesheim, Jeffrey
Project Start
2014-06-01
Project End
2018-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Rutgers University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
Razdan, Neetu; Vasilopoulos, Themistoklis; Herbig, Utz (2018) Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts. Aging Cell 17:e12838
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Patel, Priyanka L; Herbig, Utz (2017) Detection of Dysfunctional Telomeres in Oncogene-Induced Senescence. Methods Mol Biol 1534:69-78
Hansen, Matthew E B; Hunt, Steven C; Stone, Rivka C et al. (2016) Shorter telomere length in Europeans than in Africans due to polygenetic adaptation. Hum Mol Genet 25:2324-2330
Patel, Priyanka L; Suram, Anitha; Mirani, Neena et al. (2016) Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence. Proc Natl Acad Sci U S A 113:E5024-33
Boccardi, Virginia; Razdan, Neetu; Kaplunov, Jessica et al. (2015) Stn1 is critical for telomere maintenance and long-term viability of somatic human cells. Aging Cell 14:372-81
Suram, Anitha; Herbig, Utz (2014) The replicometer is broken: telomeres activate cellular senescence in response to genotoxic stresses. Aging Cell 13:780-6