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Clinical biomarkers and imaging for radiotherapy-induced cell death

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Abstract

Introduction

Radiotherapy, like most anticancer treatments, achieves its therapeutic effect by inducing different types of cell death in tumors.

Cell death markers and imaging modalities

To evaluate treatment efficacy a variety of routine anatomical imaging modalities is used. However, changes in tumor physiology, metabolism and proliferation often precede these volumetric changes. Therefore, reliable biomarkers and imaging modalities that could assess treatment response more rapidly or even predict tumor responsiveness to treatment in an early phase would be very useful to identify responders and/or avoid ineffective, toxic therapies. A better understanding of cell death mechanisms following irradiation is essential for the development of such tools.

Cell death and available assays

In this review the most prominent types of radiation-induced cell death are discussed. In addition, the currently available assays to detect apoptosis, necrosis, mitotic catastrophe, autophagy and senescence in vitro and, if applicable, in vivo, are presented.

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References

  1. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.

    Article  PubMed  CAS  Google Scholar 

  2. Kroemer, G., El-Deiry, W. S., Golstein, P., Peter, M. E., Vaux, D., Vandenabeele, P., et al. (2005). Classification of cell death: Recommendations of the Nomenclature Committee on Cell Death. Cell Death and Differentiation, 12, 1463–1467.

    Article  PubMed  CAS  Google Scholar 

  3. Hengartner, M. O. (2000). The biochemistry of apoptosis. Nature, 407, 770–776.

    Article  PubMed  CAS  Google Scholar 

  4. Wang, X. (2001). The expanding role of mitochondria in apoptosis. Genes & Development, 15, 2922–2233.

    CAS  Google Scholar 

  5. Puthalakath, H., & Strasser, A. (2002). Keeping killers on a tight leash: Transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death and Differentiation, 9, 505–512.

    Article  PubMed  CAS  Google Scholar 

  6. Zong, W. X., Lindsten, T., Ross, A. J., MacGregor, G. R., & Thompson, C. B. (2001). BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes & Development, 15, 1481–1486.

    Article  CAS  Google Scholar 

  7. Wei, M. C., Lindsten, T., Mootha, V. K., Weiler, S., Gross, A., Ashiya, M., et al. (2000). tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes & Development, 14, 2060–2071.

    CAS  Google Scholar 

  8. Desagher, S., Osen-Sand, A., Nichols, A., Eskes, R., Montessuit, S., Lauper, S., et al. (1999). Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. Journal of Cell Biology, 144, 891–901.

    Article  PubMed  CAS  Google Scholar 

  9. Antonsson, B., Montessuit, S., Sanchez, B., & Martinou, J. C. (2001). Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. Journal of Biological Chemistry, 276, 11615–11623.

    Article  PubMed  CAS  Google Scholar 

  10. Cheng, E. H., Wei, M. C., Weiler, S., Flavell, R. A., Mak, T. W., Lindsten, T., et al. (2001). BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Molecular Cell, 8, 705–711.

    Article  PubMed  CAS  Google Scholar 

  11. Letai, A., Bassik, M. C., Walensky, L. D., Sorcinelli, M. D., Weiler, S., & Korsmeyer, S. J. (2002). Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell, 2, 183–192.

    Article  PubMed  CAS  Google Scholar 

  12. Datta, R., Kojima, H., Banach, D., Bump, N. J., Talanian, R. V., Alnemri, E. S., et al. (1997). Activation of a CrmA-insensitive, p35-sensitive pathway in ionizing radiation-induced apoptosis. Journal of Biological Chemistry, 272, 1965–1969.

    Article  PubMed  CAS  Google Scholar 

  13. Kataoka, T., Schröter, M., Hahne, M., Schneider, P., Irmler, M., Thome, M., et al. (1998). FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation. Journal of Immunology, 161, 3936–3942.

    CAS  Google Scholar 

  14. Tepper, A. D., de Vries, E., van Blitterswijk, W. J., & Borst, J. (1999). Ordering of ceramide formation, caspase activation, and mitochondrial changes during CD95- and DNA damage-induced apoptosis. Journal of Clinical Investigation, 103, 971–978.

    Article  PubMed  CAS  Google Scholar 

  15. Sentman, C. L., Shutter, C. L., Hockenberry, D., Kanagaa, O., & Korsmeyer, S. J. (1991). Bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell, 67, 879–888.

    Article  PubMed  CAS  Google Scholar 

  16. Strasser, A., Harris, A. W., Jacks, T., & Cory, S. (1994). DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell, 79, 189–192.

    Article  Google Scholar 

  17. Miyashita, T., Kralewski, S., Krajewska, M., Wang, H. G., Lin, H. K., Liebermann, D. A., et al. (1994). Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene, 9, 1799–1805.

    PubMed  CAS  Google Scholar 

  18. Miyashita, T., & Reed, J. C. (1995). Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell, 80, 293–299.

    Article  PubMed  CAS  Google Scholar 

  19. Fei, P., Bernhard, E. J., & El-Deiry, W. S. (2002). Tissue-specific induction of p53 targets in vivo. Cancer Research, 62, 7316–7327.

    PubMed  CAS  Google Scholar 

  20. Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., et al. (2003). p53 has a direct apoptogenic role at the mitochondria. Molecular Cell, 11, 577–590.

    Article  PubMed  CAS  Google Scholar 

  21. Friesen, C., Herr, I., Krammer, P. H., & Debatin, K. M. (1996). Involvement of the CD95 (APO-1/Fas) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nature Medicine, 2, 574–577.

    Article  PubMed  CAS  Google Scholar 

  22. Müller, M., Strand, S., Hug, H., Heinemann, E. M., Walczak, H., Hofmann, W. J., et al. (1997). Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. Journal of Clinical Investigation, 99, 403–413.

    Article  PubMed  Google Scholar 

  23. Belka, C., Schmid, B., Marini, P., Durand, E., Rudner, J., Faltin, H., et al. (2001). Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL. Oncogene, 20, 2190–2196.

    Article  PubMed  CAS  Google Scholar 

  24. Zong, W. X., Ditsworth, D., Bauer, D. E., Wang, Z. Q., & Thompson, C. B. (2004). Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes & Development, 18, 1272–1282.

    Article  CAS  Google Scholar 

  25. Sun, X., Li, Y., Li, W., Zhang, B., Wang, A. J., Sun, J., et al. (2006). Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage response pathway. Cell Cycle, 5, 2029–2035.

    PubMed  CAS  Google Scholar 

  26. Takai, H., Tominaga, K., Motoyama, N., Minamishima, Y. A., Nagahama, H., Tsukiyama, T., et al. (2000). Aberrant cell cycle checkpoint function and early embryonic death in Chk1(−/−) mice. Genes & Development, 14, 1439–1447.

    CAS  Google Scholar 

  27. Ianzini, F., & Mackey, M. A. (1998). Delayed DNA damage associated with mitotic catastrophe following X-irradiation of HeLa S3 cells. Mutagenesis, 13, 337–344.

    Article  PubMed  CAS  Google Scholar 

  28. Blank, M., Lerenthal, Y., Mittelman, L., & Shiloh, Y. (2006). Condensin I recruitment and uneven chromatin condensation precede mitotic cell death in response to DNA damage. Journal of Cell Biology, 74, 195–206.

    Article  CAS  Google Scholar 

  29. Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., & Craig, R. (1991). Participation of p53 protein in the cellular response to DNA damage. Cancer Research, 51, 6304–6311.

    PubMed  CAS  Google Scholar 

  30. Wang, C. W., & Klionsky, D. J. (2003). The molecular mechanism of autophagy. Molecular Medicine, 9, 65–76.

    PubMed  Google Scholar 

  31. Paglin, S., Hollister, T., Delohery, T., Hackett, N., McMahill, M., Sphicas, E., et al. (2001). A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Research, 61, 439–444.

    PubMed  CAS  Google Scholar 

  32. Paglin, S., & Yahalom, J. (2006). Pathways that regulate autophagy and their role in mediating tumor response to treatment. Autophagy, 2, 291–293.

    PubMed  CAS  Google Scholar 

  33. Levine, B., & Klionsky, D. J. (2004). Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Developmental Cell, 6, 463–747.

    Article  PubMed  CAS  Google Scholar 

  34. Degenhardt, K., Mathew, R., Beaudoin, B., Bray, K., Anderson, D., Chen, G., et al. (2006). Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 10, 51–64.

    Article  PubMed  CAS  Google Scholar 

  35. Kelekar, A. (2005). Autophagy. Annals of the New York Academy of Sciences, 1066, 259–271.

    Article  PubMed  CAS  Google Scholar 

  36. Campisi, J. (2000). Cancer, aging and cellular senescence. In Vivo, 14, 183–188.

    PubMed  CAS  Google Scholar 

  37. Roninson, I. B. (2003). Tumor cell senescence in cancer treatment. Cancer Research, 63, 2705–2715.

    PubMed  CAS  Google Scholar 

  38. Verheij, M., van Blitterswijk, W. J., & Bartelink, H. (1998). Radiation-induced apoptosis: The ceramide-SAPK signaling pathway and clinical aspects. Acta Oncológica, 37, 575–581.

    Article  PubMed  CAS  Google Scholar 

  39. Chapman, J. D., & Anderson, P. R. (1999). Predicting and overcoming the radioresistance of individual tumors. International Journal of Radiation Oncology, Biology, Physics, 44, 477–479.

    Article  PubMed  CAS  Google Scholar 

  40. Ong, F., Moonen, L. M. F., Gallee, M. P. W., ten Bosch, C., Zerp, S. F., Hart, A. A. M., et al. (2001). Prognostic factors in transitional cell cancer of the bladder: An emerging role for Bcl-2 and p53. Radiotherapy and Oncology, 61, 169–175.

    Article  PubMed  CAS  Google Scholar 

  41. Gerke, V., & Moss, S. E. (2002). Annexins: From structure to function. Physiological Reviews, 82, 331–371.

    PubMed  CAS  Google Scholar 

  42. Andree, H. A., Stuart, M. C., Hermens, W. T., Reutelingsperger, C. P., Hemker, H. C., Frederik, P. M., et al. (1992). Clustering of lipid-bound annexin V may explain its anticoagulant effect. Journal of Biological Chemistry, 267, 17907–17912.

    PubMed  CAS  Google Scholar 

  43. Ahn, N. G., Teller, D. C., Bienkowski, M. J., McMullen, B. A., Lipkin, E. W., & de Haen, C. (1988). Sedimentation equilibrium analysis of five lipocortin-related phospholipase A2 inhibitors from human placenta. Evidence against a mechanistically relevant association between enzyme and inhibitor. Journal of Biological Chemistry, 263, 18657–18663.

    PubMed  CAS  Google Scholar 

  44. van Heerde, W. L., de Groot, P. G., & Reutelingsperger, C. P. (1995). The complexity of the phospholipid binding protein Annexin V. Thrombosis and Haemostasis, 73, 172–179.

    PubMed  Google Scholar 

  45. Sun, J., Bird, P., & Salem, H. H. (1993). Interaction of annexin V and platelets: Effects on platelet function and protein S binding. Thrombosis Research, 69, 289–296.

    Article  PubMed  CAS  Google Scholar 

  46. Sugimura, M., Donato, R., Kakkar, V. V., & Scully, M. F. (1994). Annexin V as a probe of the contribution of anionic phospholipids to the procoagulant activity of tumour cell surfaces. Blood Coagulation & Fibrinolysis, 5, 365–373.

    CAS  Google Scholar 

  47. Blankenberg, F. G., Katsikis, P. D., Tait, J. F., Davis, R. E., Naumovski, L., Ohtsuki, K., et al. (1999). Imaging of apoptosis (programmed cell death) with 99mTc annexin V. Journal of Nuclear Medicine, 40, 184–191.

    PubMed  CAS  Google Scholar 

  48. Hofstra, L., Liem, I. H., Dumont, E. A., Boersma, H. H., van Heerde, W. L., Doevendans, P. A., et al. (2000). Visualisation of cell death in vivo in patients with acute myocardial infarction. Lancet, 356, 209–212.

    Article  PubMed  CAS  Google Scholar 

  49. Blankenberg, F. G., Robbins, R. C., Stoot, J. H., Vriens, P. W., Berry, G. J., Tait, J. F., et al. (2000). Radionuclide imaging of acute lung transplant rejection with annexin V. Chest, 117, 834–840.

    Article  PubMed  CAS  Google Scholar 

  50. Lorberboym, M., Blankenberg, F. G., Sadeh, M., & Lampl, Y. (2006). In vivo imaging of apoptosis in patients with acute stroke: Correlation with blood–brain barrier permeability. Brain Research, 1103, 13–19.

    Article  PubMed  CAS  Google Scholar 

  51. Belhocine, T., Steinmetz, N., Hustinx, R., Bartsch, P., Jerusalem, G., Seidel, L., et al. (2002). Increased uptake of the apoptosis-imaging agent (99m)Tc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clinical Cancer Research, 8, 2766–2774.

    PubMed  CAS  Google Scholar 

  52. Haas, R., de Jong, D., Valdés Olmos, R. A., Zerp, S. F., van den Heuvel, I., Bartelink, H., et al. (2004). In vivo imaging of radiation-induced apoptosis by 99mTc-annexin-V scintigraphy in follicular lymphoma patients. International Journal of Radiation Oncology, Biology, Physics, 59, 782–787.

    PubMed  Google Scholar 

  53. Dubray, B., Breton, C., Delic, J., Klijanienko, J., Maciorowski, Z., Vielh, P., et al. (1997). In vitro radiation-induced apoptosis and tumour response to radiotherapy: A prospective study in patients with non-Hodgkin lymphomas treated by low-dose irradiation. International Journal of Radiation Biology, 72, 759–760.

    Article  PubMed  CAS  Google Scholar 

  54. Verheij, M., & Bartelink, H. (2000). Radiation-induced apoptosis. Cell and Tissue Research, 301, 133–142.

    Article  PubMed  CAS  Google Scholar 

  55. Kartachova, M., Haas, R. L. M., Valdés Olmos, R. A., Hoebers, F. J. P., van Zandwijk, N., & Verheij, M. (2004). In vivo imaging of apoptosis by 99m-annexin V scintigraphy: Visual analysis in relation to treatment response. Radiotherapy and Oncology, 72, 333–339.

    Article  PubMed  CAS  Google Scholar 

  56. Kartachova, M., van Zandwijk, N., Burgers, S., van Tinteren, H., Verheij, M., & Valdes Olmos, R. A. (2007). Prognostic significance of 99mTc Hynic-rh-Annexin V scintigraphy during platinum-based chemotherapy in advanced lung cancer. Journal of Clinical Oncology, 25, 2534–2539.

    Article  PubMed  CAS  Google Scholar 

  57. Kartachova, M., Verheij, M., van Eck, B., Hoefnagel, K., & Valdés Olmos, R. (2005). Methodological aspects and applications of in vivo imaging of apoptosis in oncology: An illustrative review. Current Medical Imaging Review, 1, 221–228.

    Article  CAS  Google Scholar 

  58. Kartachova, M., Valdes Olmos, R. A., Haas, R. L. M., Hoebers, F. J. P., van den Brekel, M. W., van Zandwijk, N., et al. (2006). Mapping of treatment-induced apoptosis in normal structures: 99mTc hynic-rh-annexin V SPECT and CT image fusion. European Journal of Nuclear Medicine and Molecular Imaging, 33, 893–899.

    Article  PubMed  CAS  Google Scholar 

  59. Faust, A., Wagner, S., Law, M. P., Hermann, S., Schnockel, U., Keul, P., et al. (2007). The nonpeptidyl caspase binding radioligand (S)-1-(4-(2-[18F]fluoroethoxy)-benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin [18F]CbR) as potential positron emission tomography-compatible apoptosis imaging agent. Quarterly Journal of Nuclear Medicine and Molecular Imaging, 51, 67–73.

    PubMed  CAS  Google Scholar 

  60. Del Vecchio, S., Zannetti, A., Aloj, L., Caraco, C., Ciarmiello, A., & Salvatore, M. (2003). Inhibition of early 99mTc-MIBI uptake by Bcl-2 anti-apoptotic protein overexpression in untreated breast carcinoma. European Journal of Nuclear Medicine and Molecular Imaging, 30, 879–887.

    PubMed  CAS  Google Scholar 

  61. Borst, G. R., Belderbos, J. S., Boellaard, R., Comans, E. F., De Jaeger, K., Lammertsma, A. A., et al. (2005). Standardised FDG uptake: A prognostic factor for inoperable non-small cell lung cancer. European Journal of Cancer, 41, 1533–1541.

    Article  PubMed  Google Scholar 

  62. Martinet, W., De Meyer, G. R., Andries, L., Herman, A. G., & Kockx, M. M. (2006). Detection of autophagy in tissue by standard immunohistochemistry: Possibilities and limitations. Autophagy, 2, 55–57.

    PubMed  Google Scholar 

  63. Itahana, K., Campisi, J., & Dimri, G. P. (2007). Methods to detect biomarkers of cellular senescence: The senescence-associated beta-galactosidase assay. Methods in Molecular Biology, 371, 21–31.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Radiation Oncology and Division of Cellular Biochemistry, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066, Amsterdam, The Netherlands

    Marcel Verheij

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Verheij, M. Clinical biomarkers and imaging for radiotherapy-induced cell death. Cancer Metastasis Rev 27, 471–480 (2008). https://doi.org/10.1007/s10555-008-9131-1

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