Skip to main content

Advertisement

SpringerLink
Log in

Non-cell-autonomous tumor suppression: oncogene-provoked apoptosis promotes tumor cell senescence via stromal crosstalk

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Activated oncogenes evoke cellular fail-safe programs such as apoptosis, senescence, or autophagy to protect the organism from the expansion of damaged and potentially harmful cells. Non-cell-autonomous interactions between tumor cells and nonmalignant bystander cells add to cell-autonomous modes of tumor suppression during tumor development and progression. In particular, the role of stroma or host immune cells converting tumor-generated signals into a response that feeds back to the tumor cell population has been experimentally underappreciated. Using the Eμ-myc transgenic mouse lymphoma model, we elucidated how constitutive Myc signaling indirectly promotes cellular senescence via cytokines that were released by nonmalignant cells in response to oncogene-evoked cell-autonomous effects. Specifically, Myc primarily promotes apoptosis in a subset of the tumor cell population, leading to the attraction of macrophages, which subsequently engulf the apoptotic remainders. Phagocytosis-activated macrophages, in turn, exhibit strongly increased secretion of various cytokines, among them transforming growth factor beta to an extent that is capable of inducing cellular senescence in surrounding malignant cells. Our findings, recapitulated in human aggressive B-cell lymphomas, unveil that apoptosis and senescence are not simply two context-dependent cell-autonomous choices of stress responses, but rather cooperate via extracellular mediators—namely cells of the innate immune system—to profoundly limit tumorigenesis in vivo. A deeper mechanistic understanding of the organismic interconnection between different fail-safe programs will help to identify cellular components of the tumor stroma and their signal mediators that are readily available to impose a second line of host defense against cancer cells. This will open new perspectives for the development of antineoplastic therapies, whose targets not only encompass tumor but also stroma cell populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  PubMed  CAS  Google Scholar 

  2. Schmitt CA (2003) Senescence, apoptosis and therapy—cutting the lifelines of cancer. Nat Rev Cancer 3:286–295

    Article  PubMed  CAS  Google Scholar 

  3. Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR (1992) Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 257:212–214

    Article  PubMed  CAS  Google Scholar 

  4. Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC (1992) Induction of apoptosis in fibroblasts by c-myc protein. Cell 69:119–128

    Article  PubMed  CAS  Google Scholar 

  5. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602

    Article  PubMed  CAS  Google Scholar 

  6. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dörken B, Jenuwein T, Schmitt CA (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436:660–665

    Article  PubMed  CAS  Google Scholar 

  7. Burnet M (1957) Cancer: a biological approach. I. The processes of control. Br Med J 1:779–786

    Article  PubMed  CAS  Google Scholar 

  8. Parmiani G, De Filippo A, Novellino L, Castelli C (2007) Unique human tumor antigens: immunobiology and use in clinical trials. J Immunol 178:1975–1979

    PubMed  CAS  Google Scholar 

  9. Cullen SP, Brunet M, Martin SJ (2010) Granzymes in cancer and immunity. Cell Death Differ 17:616–623

    Article  PubMed  CAS  Google Scholar 

  10. Waldhauer I, Steinle A (2008) NK cells and cancer immunosurveillance. Oncogene 27:5932–5943

    Article  PubMed  CAS  Google Scholar 

  11. Bui JD, Schreiber RD (2007) Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr Opin Immunol 19:203–208

    Article  PubMed  CAS  Google Scholar 

  12. O' Reilly LA, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang JG, Belz GT et al (2009) Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 461:659–663

    Article  PubMed  Google Scholar 

  13. Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H (2003) Nature's TRAIL—on a path to cancer immunotherapy. Immunity 18:1–6

    Article  PubMed  CAS  Google Scholar 

  14. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, Traver D, van Rooijen N, Weissman IL (2009) CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138:271–285

    Article  PubMed  CAS  Google Scholar 

  15. Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6:836–848

    Article  PubMed  CAS  Google Scholar 

  16. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111

    Article  PubMed  CAS  Google Scholar 

  17. Lauber K, Bohn E, Kröber SM, Xiao YJ, Blumenthal SG, Lindemann RK, Marini P, Wiedig C, Zobywalski A, Baksh S et al (2003) Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113:717–730

    Article  PubMed  CAS  Google Scholar 

  18. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A 98:12072–12077

    Article  PubMed  CAS  Google Scholar 

  19. Parrinello S, Coppe JP, Krtolica A, Campisi J (2005) Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 118(Pt 3):485–496

    Article  PubMed  CAS  Google Scholar 

  20. Coppé JP, Kauser K, Campisi J, Beauséjour CM (2006) Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem 281:29568–29574

    Article  PubMed  Google Scholar 

  21. Coppé JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118

    Article  PubMed  Google Scholar 

  22. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660

    Article  PubMed  CAS  Google Scholar 

  23. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N et al (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133:1006–1018

    Article  PubMed  CAS  Google Scholar 

  24. 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  PubMed  CAS  Google Scholar 

  25. Kuilman C, Michaloglou LC, Vredeveld S, Douma R, van Doorn CJ, Desmet LA, Aarden WJ, Mooi WJ, Peeper DS (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031

    Article  PubMed  CAS  Google Scholar 

  26. Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, Tavaré S, Arakawa S, Shimizu S, Watt FM et al (2009) Autophagy mediates the mitotic senescence transition. Genes Dev 23:798–803

    Article  PubMed  CAS  Google Scholar 

  27. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon HU (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8:1124–1132

    Article  PubMed  CAS  Google Scholar 

  28. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8:741–752

    Article  PubMed  CAS  Google Scholar 

  29. Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan RN, Gilpin C, Levine B (2007) Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128:931–946

    Article  PubMed  CAS  Google Scholar 

  30. Reimann M, Lee S, Loddenkemper C, Dörr JR, Tabor V, Aichele P, Stein H, Dörken B, Jenuwein T, Schmitt CA (2010) Tumor stroma-derived TGF-β limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell 17:262–272

    Article  PubMed  CAS  Google Scholar 

  31. Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B, Goldschmidt N, Iqbal J, Lymphoma/Leukemia Molecular Profiling Project et al (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359:2313–2323

    Article  PubMed  CAS  Google Scholar 

  32. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, Rimsza LM, Grogan TM et al (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351:2159–2169

    Article  PubMed  CAS  Google Scholar 

  33. Thomas DA, Massagué J (2005) TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. J Cancer Cell 8:369–380

    Article  CAS  Google Scholar 

  34. Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF (1999) Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem 274:35053–35058

    Article  PubMed  CAS  Google Scholar 

  35. Scandura JM, Boccuni P, Massagué J, Nimer SD (2004) Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proc Natl Acad Sci U S A 101:15231–15236

    Article  PubMed  CAS  Google Scholar 

  36. Seoane J, Le HV, Shen L, Anderson SA, Massagué J (2004) Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117:211–223

    Article  PubMed  CAS  Google Scholar 

  37. Massagué J (2008) TGFbeta in cancer. Cell 134:215–230

    Article  PubMed  Google Scholar 

  38. van Riggelen J, Müller J, Otto T, Beuger V, Yetil A, Choi PS, Kosan C, Möröy T, Felsher DW, Eilers M (2010) The interaction between Myc and Miz1 is required to antagonize TGF β-dependent autocrine signaling during lymphoma formation and maintenance. Genes Dev 24(12):1281–1294

    Article  PubMed  Google Scholar 

  39. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217

    Article  PubMed  CAS  Google Scholar 

  40. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  PubMed  CAS  Google Scholar 

  41. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35

    Article  PubMed  CAS  Google Scholar 

  42. Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727

    Article  PubMed  CAS  Google Scholar 

  43. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjällman AH, Ballmer-Hofer K, Schwendener RA (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95:272–281

    Article  PubMed  CAS  Google Scholar 

  44. Hasselblom S, Hansson U, Sigurdardottir M, Nilsson-Ehle H, Ridell B, Andersson PO (2008) Expression of CD68+ tumor-associated macrophages in patients with diffuse large B-cell lymphoma and its relation to prognosis. Pathol Int 58(8):529–532

    Article  PubMed  Google Scholar 

  45. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, Fan AC, Yang Q, Braunstein L, Crosby E, Ryeom S, Felsher DW (2010) CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18(5):485–498

    Article  PubMed  CAS  Google Scholar 

  46. Corthay A, Skovseth DK, Lundin KU, Rosjo E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B (2005) Primary antitumor immune response mediated by CD4+ T cells. Immunity 22:371–383

    Article  PubMed  CAS  Google Scholar 

  47. Reimann M, Loddenkemper C, Rudolph C, Schildhauer I, Teichmann B, Stein H, Schlegelberger B, Dörken B, Schmitt CA (2007) The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo. Blood 110:2996–3004

    Article  PubMed  CAS  Google Scholar 

  48. Griffiths L, Binley K, Iqball S, Kan O, Maxwell P, Ratcliffe P, Lewis C, Harris A, Kingsman S, Naylor S (2000) The macrophage—a novel system to deliver gene therapy to pathological hypoxia. Gene Ther 7:255–262

    Article  PubMed  CAS  Google Scholar 

  49. Carta L, Pastorino S, Melillo G, Bosco MC, Massazza S, Varesio L (2001) Engineering of macrophages to produce IFN-γ in response to hypoxia. J Immunol 166:5374–5380

    PubMed  CAS  Google Scholar 

  50. Burke B, Sumner S, Maitland N, Lewis CE (2002) Macrophages in gene therapy: cellular delivery vehicles and in vivo targets. J Leukoc Biol 72:417–428

    PubMed  CAS  Google Scholar 

  51. Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP (2005) Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 65:3437–3446

    PubMed  CAS  Google Scholar 

  52. Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR (2008) Re-educating tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268

    Article  PubMed  CAS  Google Scholar 

  53. Sinha P, Clements VK, Ostrand-Rosenberg S (2005) Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol 174:636–645

    PubMed  CAS  Google Scholar 

  54. Rauh MJ, Sly LM, Kalesnikoff J, Hughes MR, Cao LP, Lam V, Krystal G (2004) The role of SHIP1 in macrophage programming and activation. Biochem Soc Trans 32(Pt 5):785–788

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

The authors thank members of the Schmitt Lab for critically reading the manuscript.

Conflict of interest statement

The authors declare that they have no conflict of interests.

Author information

Authors and Affiliations

  1. Charité—Universitätsmedizin Berlin/Molekulares Krebsforschungszentrum der Charité—MKFZ, 13353, Berlin, Germany

    Maurice Reimann, Clemens A. Schmitt & Soyoung Lee

  2. Max-Delbrück-Center for Molecular Medicine, 13125, Berlin, Germany

    Clemens A. Schmitt & Soyoung Lee

Authors
  1. Maurice Reimann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clemens A. Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Soyoung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clemens A. Schmitt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reimann, M., Schmitt, C.A. & Lee, S. Non-cell-autonomous tumor suppression: oncogene-provoked apoptosis promotes tumor cell senescence via stromal crosstalk. J Mol Med 89, 869–875 (2011). https://doi.org/10.1007/s00109-011-0770-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-011-0770-2

Keywords

Search

Navigation