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.

  • Review Article
  • Published:

New approaches for imaging tumour responses to treatment

Nature Reviews Cancer volume 8, pages 94–107 (2008)Cite this article

Key Points

  • Detection of the early responses of tumours to treatment could be used to guide subsequent therapy, allowing rapid selection of the most appropriate therapy, with attendant welfare benefits for the patient and cost benefits for the health-care system.

  • Tumour responses to treatment are conventionally assessed by imaging measurements of tumour size. However, tumour shrinkage can take weeks or even months to become apparent or, with some therapies, might not occur at all, despite a positive response to treatment.

  • Imaging measurements of tumour biochemistry or cell biology can give an earlier indication of whether a tumour is responding to treatment than measurements of tumour size. For example, measurements of the reduction in tumour uptake of a radiolabelled glucose analogue, 2-[18F]fluoro-2-deoxy-D-glucose, are already used clinically to detect tumour responses to treatment, often before there is any change in tumour size.

  • The radionuclide imaging techniques, positron-emission tomography and single photon-emission computed tomography, can be used to monitor receptor expression using appropriately labelled receptor ligands. As these techniques are so sensitive (they can detect concentrations in the 10−12–10−10 M range), the agents can be administered at sub-pharmacological doses.

  • Labelling of cell metabolites (for example, amino acids, acetate, the glucose analogue fluorodeoxyglucose) with positron-emitting isotopes (11C and 18F) allows imaging of tumour metabolism in the clinic.

  • Magnetic resonance imaging of the protons in tissue water gives relatively high-resolution images of tissue morphology. By using receptor ligands that have been labelled with paramagnetic tags that affect the spin relaxation times, magnetic resonance imaging measurements of tissue water can be used to image receptor expression indirectly.

  • Magnetic resonance spectroscopy (MRS) can be used to detect tumour metabolites in vivo. Phosphorus-31 MRS can be used to monitor the levels of ATP, inorganic phosphate and intracellular pH and 1H MRS the levels of various abundant metabolites, including lactate, neutral lipids and phospholipid metabolites, such as phosphocholine.

  • Nuclear spin hyperpolarization can be used to dramatically enhance the sensitivity

    (> 10,000×) of the magnetic resonance experiment. Hyperpolarization of injected molecules allows spectroscopic imaging of their distribution in the body and subsequent metabolism.

  • The availability of these clinical imaging modalities in configurations that can be used with animal models of disease in the laboratory should promote the translation of new imaging techniques from the laboratory into the clinic.

Abstract

Tumour responses to treatment are still largely assessed from imaging measurements of reductions in tumour size. However, this can take several weeks to become manifest and in some cases may not occur at all, despite a positive response to treatment. There has been considerable interest, therefore, in non-invasive techniques for imaging tissue function that can give early evidence of response. These can be used in clinical trials of new drugs to give an early indication of drug efficacy, and subsequently in the clinic to select the most effective therapy at an early stage of treatment.

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: Ultrasound imaging.
Figure 2: Some basic principles of magnetic resonance.
Figure 3: The basic principles of an MRI experiment.
Figure 4: Magnetic resonance spectroscopy.
Figure 5: 13C spectroscopic imaging using hyperpolarized [1-13C]pyruvate.
Figure 6: Tumour response detected using FDG PET.
Figure 7: Tumour responses detected by diffusion-weighted MRI.

Similar content being viewed by others

References

  1. Paez, J. G. et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).

    CAS  PubMed  Google Scholar 

  2. Sotiriou, C. & Piccart, M. J. Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nature Rev. Cancer 7, 545–553 (2007).

    CAS  Google Scholar 

  3. Galbraith, S. M. et al. Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J. Clin. Oncol. 21, 2831–2842 (2003).

    CAS  PubMed  Google Scholar 

  4. Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst. 92, 205–216 (2000).

    CAS  PubMed  Google Scholar 

  5. Michaelis, L. C. & Ratain, M. J. Measuring response in a post-RECIST world: from black and white to shades of grey. Nature Rev. Cancer 6, 409–414 (2006).

    CAS  Google Scholar 

  6. Weissleder, R. & Mahmood, U. Molecular imaging. Radiology 219, 316–333 (2001). A relatively early review from a pioneer (R.W.) of the field of molecular imaging.

    CAS  PubMed  Google Scholar 

  7. Weissleder, R. Scaling down imaging: molecular mapping of cancer in mice. Nature Rev. Cancer 2, 1–8 (2001).

    Google Scholar 

  8. Boone, J. M., Velazquez, O. & Cherry, S. R. Small-animal X-ray dose from micro-CT. Mol. Imaging 3, 149–158 (2004).

    PubMed  Google Scholar 

  9. von Schulthess, G. K., Steinert, H. C. & Hany, T. F. Integrated PET/CT: Current applications and future directions. Radiology 238, 405–422 (2006).

    PubMed  Google Scholar 

  10. Gee, M. S. et al. Doppler ultrasound imaging detects changes in tumor perfusion during antivascular therapy associated with vascular anatomic alterations. Cancer Res. 61, 2974–2982 (2001).

    CAS  PubMed  Google Scholar 

  11. Czarnota, G. J. et al. Ultrasound imaging of apoptosis: high-resolution non-invasive monitoring of programmed cell death in vitro, in situ and in vivo. Br. J. Cancer 81, 520–527 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Pellot-Barakat, C., Sridhar, M., Lindfors, K. K. & Insana, M. F. Ultrasonic elasticity imaging as a tool for breast cancer diagnosis and research. Curr. Med. Imaging Rev. 2, 157–164 (2006).

    Google Scholar 

  13. Sinkus, R. et al. High-resolution tensor MR elastography for breast tumour detection. Phys. Med. Biol. 45, 1649–1664 (2000).

    CAS  PubMed  Google Scholar 

  14. Kaufmann, B. A. & Lindner, J. R. Molecular imaging with targeted contrast ultrasound. Curr. Opin. Biotechnol. 18, 11–16 (2007).

    CAS  PubMed  Google Scholar 

  15. Johnson, G. A., Cofer, G., Gewalt, S. L. & Hedlund, L. W. Morphologic phenotyping with MR microscopy: The visible mouse. Radiology 222, 789–793 (2002).

    PubMed  Google Scholar 

  16. Artemov, D., Mori, N., Ravi, R. & Bhujwalla, Z. M. Magnetic resonance molecular imaging of the HER-2/neu receptor. Cancer Res. 63, 2723–2727 (2003).

    CAS  PubMed  Google Scholar 

  17. Sipkins, D. A. et al. Detection of tumour angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging. Nature Med. 4, 623–626 (1998). A relatively early and much cited example of receptor imaging using MRI. A forerunner of later attempts to image angiogenesis using MRI.

    CAS  PubMed  Google Scholar 

  18. Winter, P. M. et al. Molecular imaging of angiogenesis in nascent vx-2 rabbit tumors using a novel αvβ3-targeted nanoparticle and 1.5 Tesla magnetic resonance imaging. Cancer Res. 63, 5838–5843 (2003).

    CAS  PubMed  Google Scholar 

  19. Zhao, M., Beauregard, D. A., Loizou, L., Davletov, B. & Brindle, K. M. Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent. Nature Med. 7, 1241–1244 (2001).

    CAS  PubMed  Google Scholar 

  20. Schellenberger, E. A. et al. Annexin V-CLIO: a nanoparticle for detecting apoptosis by MRI. Mol. Imaging 1, 102–107 (2002).

    CAS  PubMed  Google Scholar 

  21. Jung, H. I., Kettunen, M. I., Davletov, B. & Brindle, K. M. Detection of apoptosis using the C2A domain of synaptotagmin, I. Bioconjug. Chem. 15, 983–987 (2004).

    CAS  PubMed  Google Scholar 

  22. Bulte, J. W. M. & Kraitchman, D. L. Monitoring cell therapy using iron oxide MR contrast agents. Curr. Pharm. Biotech. 5, 567–584 (2004).

    CAS  Google Scholar 

  23. Aime, S., Barge, A., Cabella, C., Crich, S. G. & Gianolio, E. Targeting cells with MR imaging probes based on paramagnetic Gd(III) chelates. Curr. Pharm. Biotech. 5, 509–518 (2004).

    CAS  Google Scholar 

  24. Dodd, S. J. et al. Detection of single mammalian cells by high resolution magnetic resonance imaging. Biophys. J. 76, 103–109 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Franklin, R. J. M. et al. Magnetic resonance imaging of transplanted oligodendrocyte precursors in the rat brain. NeuroReport 10, 1–5 (1999).

    Google Scholar 

  26. Bulte, J. W. M. et al. Neurotransplantation of magnetically labeled oligodendrocyte progenitors: Magnetic resonance tracking of cell migration and myelination. Proc. Natl Acad. Sci. USA 96, 15256–15261 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kircher, M. F. et al. In vivo high resolution three-dimensional imaging of antigen-specific cytotoxic T-lymphocyte trafficking to tumors. Cancer Res. 63, 6838–6846 (2003).

    CAS  PubMed  Google Scholar 

  28. Hu, D.-E., Kettunen, M. I. & Brindle, K. M. Monitoring T-lymphocyte trafficking in tumors undergoing immune rejection. Magn. Reson. Med. 54, 1473–1479 (2005).

    CAS  PubMed  Google Scholar 

  29. de Vries, I. J. M. et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nature Biotech. 23, 1407–1413 (2005).

    CAS  Google Scholar 

  30. Ahrens, E. T., Flores, R., Xu, H. Y. & Morel, P. A. In vivo imaging platform for tracking immunotherapeutic cells. Nature Biotech. 23, 983–987 (2005).

    CAS  Google Scholar 

  31. Preul, M. C. et al. Accurate, non-invasive diagnosis of human brain tumors by using proton magnetic resonance spectroscopy. Nature Med. 2, 232–325 (1996). An early example of the use of MRS and pattern-recognition techniques to classify brain tumours.

    Google Scholar 

  32. Tate, A. R. et al. Development of a decision support system for diagnosis and grading of brain tumours using in vivo magnetic resonance single voxel spectra. NMR Biomed. 19, 411–434 (2006).

    CAS  PubMed  Google Scholar 

  33. Gillies, R. J. & Morse, D. L. In vivo magnetic resonance spectroscopy in cancer. Ann. Rev. Biomed. Bioeng. 7, 287–326 (2005).

    CAS  Google Scholar 

  34. Jeffrey, F. M. H., Rajagopal, A., Malloy, C. R. & Sherry, A. D. 13C NMR: A simple yet comprehensive method for analysis of intermediary metabolism. Trends Biochem. Sci. 16, 5–10 (1991). A readily accessible review from a group that pioneered 13C NMR and 13C-labeling techniques, particularly with multiply labeled compounds, for interrogating cellular metabolism.

    CAS  PubMed  Google Scholar 

  35. Golman, K., Ardenkjær-Larsen, J. H., Petersson, J. S., Månsson, S. & Leunbach, I. Molecular imaging with endogenous substances. Proc. Natl Acad. Sci. USA 100, 10435–10439 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Golman, K., in ' t Zandt, R. & Thaning, M. Real-time metabolic imaging. Proc. Natl Acad. Sci. USA 103, 11270–11275 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Golman, K., Zandt, R. I., Lerche, M., Pehrson, R. & Ardenkjaer-Larsen, J. H. Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Res. 66, 10855–10860 (2006).

    CAS  PubMed  Google Scholar 

  38. Golman, K. & Petersson, J. S. Metabolic imaging and other applications of hyperpolarized 13C. Acad. Radiol. 13, 932–942 (2006).

    PubMed  Google Scholar 

  39. Gambhir, S. S. Molecular imaging of cancer with positron emisson tomography. Nature Rev. Cancer 2, 683–693 (2002).

    CAS  Google Scholar 

  40. Folli, S. et al. Antibody-indocyanin conjugates for immunophotodetection of human squamous cell carcinoma in nude mice. Cancer Res. 54, 2643–2649 (1994).

    CAS  PubMed  Google Scholar 

  41. Becker, A. et al. Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands. Nature Biotech. 19, 327–331 (2001). A good example of using a targeted optical agent for tumour detection.

    CAS  Google Scholar 

  42. Kelly, K., Alencar, H., Funovics, M., Mahmood, U. & Weissleder, R. Detection of invasive colon cancer using a novel, targeted, library-derived fluorescent peptide. Cancer Res. 64, 6247–6251 (2004).

    CAS  PubMed  Google Scholar 

  43. Weissleder, R., Tung, C.-H., Mahmood, U. & Bogdanov, A. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nature Biotech. 17, 375–378 (1999). A classic and much cited example of a molecular beacon for measuring tumour-associated protease activity.

    CAS  Google Scholar 

  44. Alencar, H. et al. Colonic adenocarcinomas: near-infrared microcatheter imaging of smart probes for early detection—study in mice. Radiology 244, 232–238 (2007).

    PubMed  Google Scholar 

  45. Ntziachristos, V., Yodh, A. G., Schnall, M. & Chance, B. Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement. Proc. Natl Acad. Sci. USA 97, 2767–2772 (2000). A paper that describes NIR imaging in the human.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Inoue, H., Kudo, S.-e. & Shiokawa, A. Technology Insight: laser scanning confocal microscopy and endocytoscopy for cellular observation of the gastrointestinal tract. Nature Clin. Prac. Gasteroenterol. Hepatol. 2, 31–37 (2005).

    Google Scholar 

  47. Yun, S. H. et al. Comprehensive volumetric optical microscopy in vivo. Nature Med. 12, 1429–1433 (2006).

    CAS  PubMed  Google Scholar 

  48. Boppart, S. A., Oldenburg, A. L., Xu, C. Y. & Marks, D. L. Optical probes and techniques for molecular contrast enhancement in coherence imaging. J. Biomed. Optics 10, 041208 (2005).

    Google Scholar 

  49. Kendall, C. et al. Raman spectroscopy, a potential tool for the objective identification and classification of neoplasia in Barrett's oesophagus. J. Pathol. 200, 602–609 (2003).

    PubMed  Google Scholar 

  50. Short, K. W., Carpenter, S., Freyer, J. P. & Mourant, J. R. Raman spectroscopy detects biochemical changes due to proliferation in mammalian cell cultures. Biophys. J. 88, 4274–4288 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Massoud, T. F. & Gambhir, S. S. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 17, 545–580 (2003). An encyclopaedic review from another pioneer (S.S.G.) in the field of molecular imaging.

    CAS  PubMed  Google Scholar 

  52. Bhaumik, S. & Gambhir, S. S. Optical imaging of Renilla luciferase reporter gene expression in living mice. Proc. Natl Acad. Sci. USA 99, 377–382 (2002).

    CAS  PubMed  Google Scholar 

  53. Hardy, J. et al. Bioluminescence imaging of lymphocyte trafficking in vivo. Exp. Hematol. 29, 1353–1360 (2001).

    CAS  PubMed  Google Scholar 

  54. Sweeney, T. J. et al. Visualizing the kinetics of tumor-cell clearance in living animals. Proc. Natl Acad. Sci. USA 96, 12044–12049 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Vooijs, M., Jonkers, J., Lyons, S. & Berns, A. Noninvasive imaging of spontaneous retinoblastoma pathway-dependent tumors in mice. Cancer Res. 62, 1862–1867 (2002). An elegant example of how to detect early-stage tumours in a mouse model using bioluminescent imaging.

    CAS  PubMed  Google Scholar 

  56. Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004).

    CAS  Google Scholar 

  57. Brown, R., Leung, J. & Fisher, S. Intratumoral distribution of tritiated fluorodeoxyglucose in breast carcinoma: correlation between Glut-1 expression and FDG uptake. J. Nucl. Med. 37, 1042–1047 (1996).

    CAS  PubMed  Google Scholar 

  58. Smith, T. A. D. The rate-limiting step for tumor [18F]fluoro-2-deoxy-D-glucose (FDG) incorporation. Nucl. Med. Biol. 28, 1–4 (2001).

    CAS  PubMed  Google Scholar 

  59. Juweid, M. E. & Cheson, B. D. Positron-emission tomography and assessment of cancer therapy. N. Engl. J. Med. 354, 496–507 (2006).

    CAS  PubMed  Google Scholar 

  60. Weber, W. A et al. Positron emission tomography in non-small-cell lung cancer: Prediction of response to chemotherapy by quantitative assessment of glucose use. J. Clin. Oncol. 21, 2651–2657 (2003).

    CAS  PubMed  Google Scholar 

  61. Weber, W. A. et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J. Clin. Oncol. 19, 3058–3065 (2001).

    CAS  PubMed  Google Scholar 

  62. Spaepen, K. et al. Prognostic value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after first-line chemotherapy in non-Hodgkin's lymphoma: is [18F]FDG PET a valid alternative to conventional diagnostic methods? J. Clin. Oncol. 19, 414–419 (2001).

    CAS  PubMed  Google Scholar 

  63. Schelling, M. et al. Positron emission tomography using [18F]fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer. J. Clin. Oncol. 18, 1689–1695 (2000).

    CAS  PubMed  Google Scholar 

  64. Avril, N. et al. Prediction of response to neoadjuvant chemotherapy by sequential F-18-fluorodeoxyglucose positron emission tomography in patients with advanced-stage ovarian cancer. J. Clin. Oncol. 23, 7445–7453 (2005).

    PubMed  Google Scholar 

  65. Stroobants, S. et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur. J. Cancer 39, 2012–2020 (2003). A well-known example of how FDG PET can detect response before changes in tumour size.

    CAS  PubMed  Google Scholar 

  66. Cullinane, C. et al. An in vivo tumor model exploiting metabolic response as a biomarker for targeted drug development. Cancer Res. 65, 9633–9636 (2005).

    CAS  PubMed  Google Scholar 

  67. Su, H. et al. Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors. Clin. Cancer Res. 12, 5659–5667 (2006).

    CAS  PubMed  Google Scholar 

  68. Weber, W. A. Positron emission tomography as an imaging biomarker. J. Clin. Oncol. 24, 3282–3292 (2006). A recent and well-written review of the role of PET in oncology.

    CAS  PubMed  Google Scholar 

  69. Poptani, H. et al. Detecting early response to cyclophosphamide treatment of RIF-1 tumors using selective multiple quantum spectroscopy (SelMQC) and dynamic contrast enhanced imaging. NMR Biomed. 16, 102–111 (2003).

    CAS  PubMed  Google Scholar 

  70. Ardenkjaer-Larsen, J. H. et al. Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR. Proc. Natl Acad. Sci. USA 100, 10158–10163 (2003). The first description of dissolution dynamic nuclear polarization, a technique that could have an enormous effect on imaging tissue function using magnetic resonance.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Day, S. E. et al. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nature Med. 13, 1382–1387 (2007). The first example of the use of hyperpolarized magnetic resonance spectroscopic imaging to detect the response of tumours to therapy.

    CAS  PubMed  Google Scholar 

  72. Shields, A. F. et al. Carbon-11-thymidine and FDG to measure therapy response. J. Nucl. Med. 39, 1757–1762 (1998).

    CAS  PubMed  Google Scholar 

  73. Wells, P. et al. Assessment of proliferation in vivo using 2-[11C]thymidine positron emission tomography in advanced intra-abdominal malignancies. Cancer Res. 62, 5698–5702 (2002).

    CAS  PubMed  Google Scholar 

  74. Shields, A. F. et al. Imaging proliferation in vivo with [18F]FLT and positron emission tomography. Nature Med. 11, 1334–1336 (1998). The first description of FLT as a PET probe of cell proliferation.

    Google Scholar 

  75. Vesselle, H. et al. In vivo validation of 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) as a proliferation imaging tracer in humans: correlation of [18F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin. Cancer Res. 8, 3315–3323 (2002).

    CAS  PubMed  Google Scholar 

  76. Pio, B. S. et al. Usefulness of 3′-[18F]fluoro-3′-deoxythymidine with positron emission tomography in predicting breast cancer response to therapy. Mol. Imaging Biol. 8, 36–42 (2006).

    PubMed  Google Scholar 

  77. an Waarde, A., Been, L. B., Ishiwata, K., Dierckx, R. A. & Elsinga, P. H. Early response of sigma-receptor ligands and metabolic PET tracers to 3 forms of chemotherapy: an in vitro study in glioma cells. J. Nucl. Med. 47, 1538–1545 (2006).

    Google Scholar 

  78. Jager, P. L. et al. Radiolabeled amino acids: basic aspects and clinical applications in oncology. J. Nucl. Med. 42, 432–445 (2001).

    CAS  PubMed  Google Scholar 

  79. Nuutinen, J., Jyrkkiö, S., Lehikoinen, P., Lindholm, P. & Minn, H. Evaluation of early response to radiotherapy in head and neck cancer measured with [11C]methionine-positron emission tomography. Radiother. Oncol. 52, 225–232 (1999).

    CAS  PubMed  Google Scholar 

  80. Wieder, H. et al. PET imaging with [11C]methyl-L-methionine for therapy monitoring in patients with rectal cancer. Eur. J. Nuc. Med. Mol. Imaging 29, 789–796 (2002).

    CAS  Google Scholar 

  81. Ishimori, T. et al. 18F-FDG and 11C-methionine PET for evaluation of treatment response of lung cancer after stereotactic radiotherapy. Ann. Nucl. Med. 18, 669–674 (2004).

    PubMed  Google Scholar 

  82. Galldiks, N. et al. Use of 11C-methionine PET to monitor the effects of temozolomide chemotherapy in malignant gliomas. Eur. J. Nuc. Med. Mol. Imaging 33, 516–524 (2006).

    CAS  Google Scholar 

  83. Nuutinen, J. et al. Radiotherapy treatment planning and long-term follow-up with [11C]methionine pet in patients with low-grade astrocytoma. Int. J. Radiat. Oncol. Biol. Phys. 48, 43–52 (2000).

    CAS  PubMed  Google Scholar 

  84. Yoshimoto, M. et al. Characterization of acetate metabolism in tumor cells in relation to cell proliferation: Acetate metabolism in tumor cells. Nucl. Med. Biol. 28, 117–122 (2001).

    CAS  PubMed  Google Scholar 

  85. Jana, S. & Blaufox, M. D. Nuclear medicine studies of the prostate, testes, and bladder. Semin. Nucl. Med. 36, 51–72 (2006).

    PubMed  Google Scholar 

  86. Oyama, N. et al. 11C-acetate PET imaging of prostate cancer: detection of recurrent disease at PSA relapse. J. Nucl. Med. 44, 549–555 (2003).

    CAS  PubMed  Google Scholar 

  87. Glunde, K., Jacobs, M. A. & Bhujwalla, Z. M. Choline metabolism in cancer: implications for diagnosis and therapy. Expert Rev. Mol. Diag. 6, 821–829 (2006). A recent review of the role of choline metabolism in tumour cell proliferation and different ways of imaging this from a group that has been very active in this field.

    CAS  Google Scholar 

  88. Meisamy, S. et al. Neoadjuvant chemotherapy of locally advanced breast cancer: predicting response with in vivo1H MR spectroscopy — A pilot study. Radiology 233, 424–431 (2004).

    PubMed  Google Scholar 

  89. Kurhanewicz, J., Vigneron, D. B. & Nelson, S. J. Three-dimensional magnetic resonance spectroscopic imaging of brain and prostate cancer. Neoplasia 2, 166–189 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. DeGrado, T. R. et al. Synthesis and evaluation of 18F-labeled choline as an oncologic tracer for positron emission tomography: Initial findings in prostate cancer. Cancer Res. 61, 110–117 (2001).

    CAS  PubMed  Google Scholar 

  91. Liu, D. et al. Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin. Br. J. Cancer 87, 783–789 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Chung, Y. L. et al. Magnetic resonance spectroscopic pharmacodynamic markers of the heat shock protein 90 inhibitor 17-allylamino, 17-demethoxygeldanamycin (17AAG) in human colon cancer models. J. Natl Cancer Inst. 95, 1624–1633 (2003). MRS as a tool for detecting drug action.

    CAS  PubMed  Google Scholar 

  93. Anthony, M. L., Zhao, M. & Brindle, K. M. Inhibition of phosphatidylcholine biosynthesis following induction of apoptosis in HL-60 cells. J. Biol. Chem. 274, 19686–19692 (1999).

    CAS  PubMed  Google Scholar 

  94. Dubray, B. et al. In vitro radiation-induced apoptosis and early response to low-dose radiotherapy in non-Hodgkin's lymphomas. Radiother. Oncol. 46, 185–191 (1998).

    CAS  PubMed  Google Scholar 

  95. Chang, J. et al. Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma. Cancer 89, 2145–2152 (2000).

    CAS  PubMed  Google Scholar 

  96. Ellis, P. A. et al. Preoperative chemotherapy induces apoptosis in early breast cancer. Lancet 349, 849 (1997).

    CAS  PubMed  Google Scholar 

  97. Meyn, R. E. et al. Heterogeneity in apoptosis development in irradiated murine tumours of different histologies. Int. J. Radiat. Biol. 64, 583–591 (1993).

    CAS  PubMed  Google Scholar 

  98. Kettunen, M. I. & Brindle, K. M. Apoptosis detection using magnetic resonance imaging and spectroscopy. Prog. Nucl. Mag. Reson. Spectrosc. 47, 175–185. (2005).

    CAS  Google Scholar 

  99. Moffat, B. A. et al. Functional diffusion map: A noninvasive MRI biomarker for early stratification of clinical brain tumor response. Proc. Natl Acad. Sci. USA 102, 5524–5529 (2005). A clinically applicable and label-free MRI method for detecting early tumour responses to treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Corsten, M. F., Hofstra, L., Narula, J. & Reutelingsperger, C. P. Counting heads in the war against cancer: defining the role of annexin A5 imaging in cancer treatment and surveillance. Cancer Res. 66, 1255–1260 (2006). A recent review describing the use of labelled annexin to detect cell death.

    CAS  PubMed  Google Scholar 

  101. Belhocine, T. et al. Increased uptake of the apoptosis-imaging agent 99mTc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin. Cancer Res. 8, 2766–2774 (2002).

    CAS  PubMed  Google Scholar 

  102. Cauchon, N. et al. PET imaging of apoptosis with 64Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V. Eur. J. Nucl. Med. Mol. Imaging 34, 247–258 (2007).

    CAS  PubMed  Google Scholar 

  103. Neves, A. A. et al. A paramagnetic nanoprobe to detect tumor cell death using magnetic resonance imaging. Nano Lett. 7, 1419–1423 (2007).

    CAS  PubMed  Google Scholar 

  104. Petrovsky, A., Schellenberger, E., Josephson, L., Weissleder, R. & Bogdanov, A. Near-infrared fluorescent imaging of tumor apoptosis. Cancer Res. 63, 1936–1942 (2003).

    CAS  PubMed  Google Scholar 

  105. Boersma, H. H. et al. Past, present, and future of annexin A5: from protein discovery to clinical applications. J. Nucl. Med. 46, 2035–2050 (2005).

    CAS  PubMed  Google Scholar 

  106. Van Den Bossche, B. & de Wiele, C. V. Receptor imaging in oncology by means of nuclear medicine: Current status. J. Clin. Oncol. 22, 3593–3607 (2004).

    CAS  PubMed  Google Scholar 

  107. Teunissen, J. J. M., Kwekkeboom, D. J. & Krenning, E. P. Staging and treatment of differentiated thyroid carcinoma with radiolabeled somatostatin analogs. Trends Endocrinol. Metab. 17, 19–25 (2006).

    CAS  PubMed  Google Scholar 

  108. Linden, H. M. et al. Quantitative fluoroestradiol positron emission tomography imaging predicts response to endocrine treatment in breast cancer. J. Clin. Oncol. 24, 2793–2799 (2006).

    CAS  PubMed  Google Scholar 

  109. Dehdashti, F. et al. Positron tomographic assessment of androgen receptors in prostatic carcinoma. Eur. J. Nuc. Med. Mol. Imaging 32, 344–350 (2005).

    Google Scholar 

  110. Orlova, A. et al. Tumor imaging using a picomolar affinity HER2 binding affibody molecule. Cancer Res. 66, 4339–4348 (2006).

    CAS  PubMed  Google Scholar 

  111. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    CAS  PubMed  Google Scholar 

  112. Tozer, G. M., Kanthou, C. & Baguley, B. C. Disrupting tumour blood vessels. Nature Rev. Cancer 5, 423–435 (2005).

    CAS  Google Scholar 

  113. Folkman, J. Angiogenesis. Annu. Rev. Med. 57, 1–18 (2006).

    CAS  PubMed  Google Scholar 

  114. Miller, J. C., Pien, H. H., Sahani, D., Sorensen, A. G. & Thrall, J. H. Imaging angiogenesis: Applications and potential for drug development. J. Natl Cancer Inst. 97, 172–187 (2005).

    CAS  PubMed  Google Scholar 

  115. Leach, M. O. et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br. J. Cancer 92, 1599–1610 (2005). A discussion of the methods for assessing response to anti-angiogenic and anti-vascular treatments using dynamic contrast agent-enhanced MRI.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. McDonald, D. M. & Choyke, P. L. Imaging of angiogenesis: from microscope to clinic. Nature Med. 9, 713–725 (2003).

    CAS  PubMed  Google Scholar 

  117. Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies. J. Clin. Oncol. 21, 3955–3964 (2003).

    CAS  PubMed  Google Scholar 

  118. Barrett, T., Kobayashi, H., Brechbiel, M. & Choyke, P. L. Macromolecular MRI contrast agents for imaging tumor angiogenesis. Eur. J. Radiol. 60, 353–366 (2006).

    PubMed  Google Scholar 

  119. Abramovitch, R., Dafni, H., Smouha, E., Benjamin, L. E. & Neeman, M. In vivo prediction of vascular susceptibility to vascular endothelial growth factor withdrawal: magnetic resonance imaging of C6 rat glioma in nude mice. Cancer Res. 59, 5012–5016 (1999).

    CAS  PubMed  Google Scholar 

  120. Beauregard, D. A., Hill, S. A., Chaplin, D. J. & Brindle, K. M. The susceptibility of tumors to the anti-vascular drug combretastatin A4 phosphate correlates with vascular permeability. Cancer Res. 61, 6811–6815 (2001).

    CAS  PubMed  Google Scholar 

  121. Haubner, R. et al. Noninvasive visualization of the activated avb3 integrin in cancer patients by positron emission tomography and [18F]galacto-RGD. PLOS Med. 2, 244–252 (2005).

    CAS  Google Scholar 

  122. Ljungkvist, A. S. E., Bussink, J., Kaanders, J. H. A. M. & Van der Kogel, A. J. Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat. Res. 167, 127–145 (2007).

    CAS  PubMed  Google Scholar 

  123. Eschmann, S. M. et al. Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J. Nucl. Med. 46, 253–260 (2005).

    PubMed  Google Scholar 

  124. Gagel, B. et al. [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography in response evaluation after chemo-/radiotherapy of non-small-cell lung cancer: a feasibility study. BMC Cancer 6, 51 (2006).

    PubMed  PubMed Central  Google Scholar 

  125. Czernin, J., Weber, W. A. & Herschman, H. R. Molecular imaging in the development of cancer therapeutics. Annu. Rev. Med. 57, 99–118 (2006).

    CAS  PubMed  Google Scholar 

  126. Smith, T. A. D., Sharma, R. I., Thompson, A. M. & Paulin, F. E. M. Tumor 18F-FDG incorporation is enhanced by attenuation of p53 function in breast cancer cells in vitro. J. Nucl. Med. 47, 1525–1530 (2006).

    CAS  PubMed  Google Scholar 

  127. Ho, C.-l., Chen, S., Yeung, D. W. C. & Cheng, T. K. C. Dual-tracer PET/CT imaging in evaluation of metastatic hepatocellular carcinoma. J. Nucl. Med. 48, 902–909 (2007).

    CAS  PubMed  Google Scholar 

  128. Segal, E. et al. Decoding global gene expression programs in liver cancer by noninvasive imaging. Nature Biotech. 25, 675–680 (2007). A fascinating study correlating defined imaging traits in CT scans with gene-expression profiles, raising the possibility that gene-expression programmes might be inferred from imaging studies.

    CAS  Google Scholar 

  129. Zhang, Y. Y., Brady, M. & Smith, S. Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans. Med. Imaging 20, 45–57 (2001).

    CAS  PubMed  Google Scholar 

  130. Frese, K. K. & Tuveson, D. A. Maximizing mouse cancer models. Nature Rev. Cancer 7, 654–658 (2007). Realistic animal models of disease should assist the development of novel clinical imaging methods. This review describes the current state-of-the-art for these models.

    Google Scholar 

  131. Trepel, M., Arap, W. & Pasqualini, R. In vivo phage display and vascular heterogeneity: implications for targeted medicine. Curr. Opin. Chem. Biol. 6, 399–404 (2002).

    CAS  PubMed  Google Scholar 

  132. Haubner, R. & Wester, H. R. Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies. Curr. Pharm. Design 10, 1439–1455 (2004).

    CAS  Google Scholar 

  133. Aina, O. H. et al. From combinatorial chemistry to cancer-targeting peptides. Mol. Pharm. 4, 631–651 (2007).

    CAS  PubMed  Google Scholar 

  134. Serganova, I. & Blasberg, R. Reporter gene imaging: potential impact on therapy. Nucl. Med. Biol. 32, 763–780 (2005).

    CAS  PubMed  Google Scholar 

  135. Tjuvajev, J. G. et al. Imaging adenoviral-mediated Herpes virus thymidine kinase gene transfer and expression in vivo. Cancer Res. 59, 5186–5193 (1999). An early example of a radionuclide-based gene reporter.

    CAS  PubMed  Google Scholar 

  136. Genove, G., DeMarco, U., Xu, H. Y., Goins, W. F. & Ahrens, E. T. A new transgene reporter for in vivo magnetic resonance imaging. Nature Med. 11, 450–454 (2005).

    CAS  PubMed  Google Scholar 

  137. Doubrovin, M. et al. Imaging transcriptional regulation of p53-dependent genes with positron emission tomography in vivo. Proc. Natl Acad. Sci. USA 98, 9300–9305 (2001). An early example of the way a PET-based gene reporter can be used to image specific aspects of cell biology in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Zhou, J. Y. & van Zijl, P. C. M. Chemical exchange saturation transfer imaging and spectroscopy. Prog. Nucl. Mag. Res. Sp. 48, 109–136 (2006).

    CAS  Google Scholar 

  139. Aime, S. et al. Insights into the use of paramagnetic Gd(III) complexes in MR-molecular imaging investigations. J. Mag. Res. Imaging 16, 394–406 (2002).

    Google Scholar 

  140. Schröder, L., Lowery, T. J., Hilty, C., Wemmer, D. E. & Pines, A. Molecular imaging using a targeted magnetic resonance hyperpolarized biosensor. Science 314, 446–449 (2006).

    PubMed  Google Scholar 

  141. Beekman, F. & van der Have, F. The pinhole: gateway to ultra-high-resolution three-dimensional radionuclide imaging. Eur. J. Nuc. Med. Mol. Imaging 34, 151–161 (2007).

    Google Scholar 

  142. Salerno, M. et al. Hyperpolarized noble gas MR imaging of the lung: Potential clinical applications. Eur. J. Radiol. 40, 33–44 (2001).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK

    Kevin Brindle

  2. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK

    Kevin Brindle

Authors
  1. Kevin Brindle
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

Kevin Brindle has a research agreement with GE Healthcare that funds work on imaging of hyperpolarized cell metabolites.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

combretastatin A4

etoposide

gefitinib

imatinib

temozolomide

FURTHER INFORMATION

Kevin Brindle's homepage

Glossary

Isotropic image resolutions

Image resolution in the three orthogonal image axes.

Voxel volume

The volume of the volume elements of the image. For example, an image with a resolution of 0.1 × 0.1 × 1.0 mm would have a voxel volume of 10 nl.

Cyclotron

A particle accelerator. Collision of a particle (for example, a proton or deuteron) with a target can be used to produce a short-lived positron-emitting isotope.

Spin relaxation times

Loss of net magnetization in the x–y plane is described by a time constant (T2) called the spin–spin relaxation time. Return of net magnetization to the z axis is described by the spin-lattice relaxation time (T1). Thus T1 ≥ T2. For water protons in a biological system T1 is usually of the order of seconds and T2 tens of milliseconds.

L-type amino-acid transporter system

The L-type amino-acid transporter is a Na+-independent neutral amino-acid transporter that has a broad substrate selectivity and has been shown to be upregulated in some cancers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brindle, K. New approaches for imaging tumour responses to treatment. Nat Rev Cancer 8, 94–107 (2008). https://doi.org/10.1038/nrc2289

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2289

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing