Senescent Fibroblasts Promote Epithelial Cell Growth and Tumorigenesis: a Link Between Cancer and Aging

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2001 Oct 11

PMID 11593017

Citations 752

Authors

A Krtolica

S Parrinello

S Lockett

P Y Desprez

J Campisi

Affiliations

Soon will be listed here.

Abstract

Mammalian cells can respond to damage or stress by entering a state of arrested growth and altered function termed cellular senescence. Several lines of evidence suggest that the senescence response suppresses tumorigenesis. Cellular senescence is also thought to contribute to aging, but the mechanism is not well understood. We show that senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and form tumors in mice. In culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast population and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14(ARF), or hydrogen peroxide. Moreover, it was due at least in part to soluble and insoluble factors secreted by senescent cells. In mice, senescent, much more than presenescent, fibroblasts caused premalignant and malignant epithelial cells to form tumors. Our findings suggest that, although cellular senescence suppresses tumorigenesis early in life, it may promote cancer in aged organisms, suggesting it is an example of evolutionary antagonistic pleiotropy.

Citing Articles

Natural Product-Derived Senotherapeutics: Extraction and Biological Evaluation Techniques.

Pratsinis H, Mavrogonatou E, Zervou S, Triantis T, Hiskia A, Kletsas D Methods Mol Biol. 2025; 2906:315-359.

PMID: 40082365 DOI: 10.1007/978-1-0716-4426-3_19.

Current Methodologies to Assess Cellular Senescence in Cancer.

Laouris P, Munoz-Espin D Methods Mol Biol. 2025; 2906:21-44.

PMID: 40082348 DOI: 10.1007/978-1-0716-4426-3_2.

Association of related chronic atrophic gastritis and gastric cancer risk: a literature review.

Zhang Z, Chen S, Li S, Zheng Y, Mai L, Zhang X Front Med (Lausanne). 2025; 12:1504749.

PMID: 40051725 PMC: 11882515. DOI: 10.3389/fmed.2025.1504749.

The complex interplay between aging and cancer.

Trastus L, dAdda di Fagagna F Nat Aging. 2025; .

PMID: 40038418 DOI: 10.1038/s43587-025-00827-z.

A Review of Telomere Attrition in Cancer and Aging: Current Molecular Insights and Future Therapeutic Approaches.

Iskandar M, Xiao Barbero M, Jaber M, Chen R, Gomez-Guevara R, Cruz E Cancers (Basel). 2025; 17(2).

PMID: 39858038 PMC: 11764024. DOI: 10.3390/cancers17020257.

References

McCullough K, Coleman W, Smith G, Grisham J . Age-dependent induction of hepatic tumor regression by the tissue microenvironment after transplantation of neoplastically transformed rat liver epithelial cells into the liver. Cancer Res. 1997; 57(9):1807-13. View

Mishima K, Handa J, Lutty G, Morse L, Hjelmeland L . Senescence-associated beta-galactosidase histochemistry for the primate eye. Invest Ophthalmol Vis Sci. 1999; 40(7):1590-3. View

Pendergrass W, Lane M, Bodkin N, Hansen B, Ingram D, Roth G . Cellular proliferation potential during aging and caloric restriction in rhesus monkeys (Macaca mulatta). J Cell Physiol. 1999; 180(1):123-30. DOI: 10.1002/(SICI)1097-4652(199907)180:1<123::AID-JCP14>3.0.CO;2-W. View

Shelton D, Chang E, Whittier P, Choi D, Funk W . Microarray analysis of replicative senescence. Curr Biol. 1999; 9(17):939-45. DOI: 10.1016/s0960-9822(99)80420-5. View

Cha R, Thilly W, Zarbl H . N-nitroso-N-methylurea-induced rat mammary tumors arise from cells with preexisting oncogenic Hras1 gene mutations. Proc Natl Acad Sci U S A. 1994; 91(9):3749-53. PMC: 43659. DOI: 10.1073/pnas.91.9.3749. View

Olumi A, Grossfeld G, Hayward S, Carroll P, Tlsty T, Cunha G . Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999; 59(19):5002-11. PMC: 3300837. DOI: 10.1186/bcr138. View

Yeager T, DeVries S, Jarrard D, Kao C, Nakada S, Moon T . Overcoming cellular senescence in human cancer pathogenesis. Genes Dev. 1998; 12(2):163-74. PMC: 316442. DOI: 10.1101/gad.12.2.163. View

Dimri G, Lee X, Basile G, Acosta M, Scott G, Roskelley C . A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92(20):9363-7. PMC: 40985. DOI: 10.1073/pnas.92.20.9363. View

Jonason A, Kunala S, Price G, Restifo R, Spinelli H, Persing J . Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci U S A. 1996; 93(24):14025-9. PMC: 19488. DOI: 10.1073/pnas.93.24.14025. View

10.

DePinho R . The age of cancer. Nature. 2000; 408(6809):248-54. DOI: 10.1038/35041694. View

11.

Rinehart C, Torti V . Aging and cancer: the role of stromal interactions with epithelial cells. Mol Carcinog. 1997; 18(4):187-92. View

12.

CAILLEAU R, Olive M, Cruciger Q . Long-term human breast carcinoma cell lines of metastatic origin: preliminary characterization. In Vitro. 1978; 14(11):911-5. DOI: 10.1007/BF02616120. View

13.

Campisi J . Aging and cancer: the double-edged sword of replicative senescence. J Am Geriatr Soc. 1997; 45(4):482-8. DOI: 10.1111/j.1532-5415.1997.tb05175.x. View

14.

Dimri G, Itahana K, Acosta M, Campisi J . Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol Cell Biol. 1999; 20(1):273-85. PMC: 85083. DOI: 10.1128/MCB.20.1.273-285.2000. View

15.

Campisi J . Cancer, aging and cellular senescence. In Vivo. 2000; 14(1):183-8. View

16.

Serrano M, Lin A, McCurrach M, Beach D, Lowe S . Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88(5):593-602. DOI: 10.1016/s0092-8674(00)81902-9. View

17.

Kim S, Kaminker P, Campisi J . TIN2, a new regulator of telomere length in human cells. Nat Genet. 1999; 23(4):405-12. PMC: 4940194. DOI: 10.1038/70508. View

18.

Seshadri T, Campisi J . Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science. 1990; 247(4939):205-9. DOI: 10.1126/science.2104680. View

19.

Reddel R . The role of senescence and immortalization in carcinogenesis. Carcinogenesis. 2000; 21(3):477-84. DOI: 10.1093/carcin/21.3.477. View

20.

Skobe M, Fusenig N . Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci U S A. 1998; 95(3):1050-5. PMC: 18668. DOI: 10.1073/pnas.95.3.1050. View