Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Cellular features of senescence during the evolution of human and murine ductal pancreatic cancer

Oncogene volume 31, pages 1599–1608 (2012)Cite this article

Abstract

During tumor initiation, oncogene-induced senescence (OIS) is proposed to limit the progression of preneoplasms to invasive carcinoma unless circumvented by the acquisition of certain tumor suppressor mutations. Using a variety of biomarkers, OIS has been previously reported in a wide range of human and murine precursor lesions, including the pancreas, lung, colon and skin. Here, we have characterized a panel of potential OIS biomarkers in human and murine pancreatic intraepithelial neoplasia (PanIN), and found that only senescence-associated β-galactosidase (SAβgal) activity is specifically enriched in these precursors, compared with pancreatic ductal adenocarcinoma (PDA). Indeed, many of the other proposed OIS biomarkers are detected in actively proliferating PanIN epithelium and in cells within the microenvironment. Surprisingly, acinar to ductal metaplasia (ADM), a distinct preneoplasm that is potentially a precursor for PanIN, also exhibits SAβgal activity and contains a higher content of p21 and p53 than PanIN. Therefore, SAβgal activity is the only biomarker that accurately identifies a small and heterogeneous population of non-proliferating premalignant cells in the pancreas, and the concomitant expression of p53 and p21 in ADM supports the possibility that PanIN and ADM each exhibit discrete senescence blocks.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S et al. (2008). Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133: 1006–1018.

    Article  CAS  PubMed  Google Scholar 

  • Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N et al. (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444: 633–637.

    Article  CAS  PubMed  Google Scholar 

  • Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B et al. (2005). Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436: 660–665.

    Article  CAS  PubMed  Google Scholar 

  • Campisi J, d'Adda di Fagagna F . (2007). Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8: 729–740.

    Article  CAS  PubMed  Google Scholar 

  • Chien Y, Lowe SW . (2008). Secreting tumor suppression. Cell 132: 339–341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collado M, Blasco MA, Serrano M . (2007). Cellular senescence in cancer and aging. Cell 130: 223–233.

    Article  CAS  PubMed  Google Scholar 

  • Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M et al. (2005). Tumour biology: senescence in premalignant tumours. Nature 436: 642.

    Article  CAS  PubMed  Google Scholar 

  • Collado M, Serrano M . (2006). The power and the promise of oncogene-induced senescence markers. Nat Rev Cancer 6: 472–476.

    Article  CAS  PubMed  Google Scholar 

  • Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM et al. (2006). A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10: 459–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Courtois-Cox S, Jones SL, Cichowski K . (2008). Many roads lead to oncogene-induced senescence. Oncogene 27: 2801–2809.

    Article  CAS  PubMed  Google Scholar 

  • d'Adda di Fagagna F . (2008). Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8: 512–522.

    Article  CAS  PubMed  Google Scholar 

  • Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M . (2007). A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev 21: 379–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De La OJ, Emerson LL, Goodman JL, Froebe SC, Illum BE, Curtis AB et al. (2008). Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci U S A 105: 18907–18912.

    Article  Google Scholar 

  • Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V et al. (2009). Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15: 294–303.

    Article  CAS  PubMed  Google Scholar 

  • Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C et al. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444: 638–642.

    Article  CAS  PubMed  Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C et al. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92: 9363–9367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guerra C, Collado M, Navas C, Schuhmacher AJ, Hernandez-Porras I, Canamero M et al. (2011). Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19: 728–739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Habbe N, Shi G, Meguid RA, Fendrich V, Esni F, Chen H et al. (2008). Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc Natl Acad Sci U S A 105: 18913–18918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halazonetis TD, Gorgoulis VG, Bartek J . (2008). An oncogene-induced DNA damage model for cancer development. Science 319: 1352–1355.

    Article  CAS  PubMed  Google Scholar 

  • Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA et al. (2003). Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4: 437–450.

    Article  CAS  PubMed  Google Scholar 

  • Hruban RH, Adsay NV, Albores-Saavedra J, Anver MR, Biankin AV, Boivin GP et al. (2006). Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res 66: 95–106.

    Article  CAS  PubMed  Google Scholar 

  • Hruban RH, Goggins M, Parsons J, Kern SE . (2000). Progression model for pancreatic cancer. Clin Cancer Res 6: 2969–2972.

    CAS  PubMed  Google Scholar 

  • Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN et al. (1993). K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143: 545–554.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ivanova A, Liao SY, Lerman MI, Ivanov S, Stanbridge EJ . (2005). STRA13 expression and subcellular localisation in normal and tumour tissues: implications for use as a diagnostic and differentiation marker. J Med Genet 42: 565–576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C et al. (2008). Senescence of activated stellate cells limits liver fibrosis. Cell 134: 657–667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuilman T, Michaloglou C, Mooi WJ, Peeper DS . (2010). The essence of senescence. Genes Dev 24: 2463–2479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ et al. (2008). Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133: 1019–1031.

    Article  CAS  PubMed  Google Scholar 

  • Kuilman T, Peeper DS . (2009). Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9: 81–94.

    Article  CAS  PubMed  Google Scholar 

  • Lee KE, Bar-Sagi D . (2010). Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. Cancer Cell 18: 448–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Majumder PK, Grisanzio C, O'Connell F, Barry M, Brito JM, Xu Q et al. (2008). A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression. Cancer Cell 14: 146–155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mallette FA, Gaumont-Leclerc MF, Ferbeyre G . (2007). The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev 21: 43–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM et al. (2005). BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436: 720–724.

    Article  CAS  PubMed  Google Scholar 

  • Morton JP, Jamieson NB, Karim SA, Athineos D, Ridgway RA, Nixon C et al. (2010). LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology 139: 586–597, 597 e1–6.

    Article  CAS  PubMed  Google Scholar 

  • Morton JP, Timpson P, Karim SA, Ridgway RA, Athineos D, Doyle B et al. (2009). Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci U S A 107: 246–251.

    Article  PubMed  PubMed Central  Google Scholar 

  • Moskaluk CA, Hruban RH, Kern SE . (1997). p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57: 2140–2143.

    CAS  PubMed  Google Scholar 

  • Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA et al. (2003). Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113: 703–716.

    Article  CAS  PubMed  Google Scholar 

  • Prieur A, Peeper DS . (2008). Cellular senescence in vivo: a barrier to tumorigenesis. Curr Opin Cell Biol 20: 150–155.

    Article  CAS  PubMed  Google Scholar 

  • Shi C, Hong SM, Lim P, Kamiyama H, Khan M, Anders RA et al. (2009). KRAS2 mutations in human pancreatic acinar-ductal metaplastic lesions are limited to those with PanIN: implications for the human pancreatic cancer cell of origin. Mol Cancer Res 7: 230–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, Jessell TM et al. (2001). Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1: 4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R et al. (2007). PRAK is essential for ras-induced senescence and tumor suppression. Cell 128: 295–308.

    Article  CAS  PubMed  Google Scholar 

  • Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR . (2008). Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132: 363–374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF et al. (2009). Autophagy mediates the mitotic senescence transition. Genes Dev 23: 798–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu L, Shi G, Schmidt CM, Hruban RH, Konieczny SF . (2007). Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Am J Pathol 171: 263–273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank P Krimpenfort, A Berns, R Taneja, F Alt, A Harris, M Malumbres C, Trejo, M McMahon, M Ferreira and F Watt for tissues and reagents. We thank Frances Connor and other members of the Tuveson lab for assistance and advice, the CRI animal care staff; S Vowler for statistical advice; Cancer Research UK Histopathology and In situ Hybridization Core, and the Microscopy and Imaging Core. This research was supported by the University of Cambridge and Cancer Research UK, The Li Ka Shing Foundation and Hutchison Whampoa Limited, the NIHR Cambridge Biomedical Research Centre and the NIH (grants CA101973, CA111294, CA084291 and CA105490) to DAT.

Author information

Authors and Affiliations

  1. Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge, UK

    M E Caldwell, G M DeNicola, C P Martins, M A Jacobetz & D A Tuveson

  2. Department of Pathology and Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A Maitra & R H Hruban

Authors
  1. M E Caldwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G M DeNicola
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C P Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M A Jacobetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Maitra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R H Hruban
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D A Tuveson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D A Tuveson.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Caldwell, M., DeNicola, G., Martins, C. et al. Cellular features of senescence during the evolution of human and murine ductal pancreatic cancer. Oncogene 31, 1599–1608 (2012). https://doi.org/10.1038/onc.2011.350

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.350

Keywords

This article is cited by

Search

Advanced search

Quick links