Cancer Metabolism

Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma

Abstract

Background

High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses.

Methods

We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects.

Results

We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment.

Conclusion

We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Delgado-Lopez, P. D. & Corrales-Garcia, E. M. Survival in glioblastoma: a review on the impact of treatment modalities. Clin. Transl. Oncol. 18, 1062–1071 (2016).

  2. 2.

    Aiken, R. Molecular neuro-oncology and the challenge of the blood-brain barrier. Semin. Oncol. 41, 438–445 (2014).

  3. 3.

    Andronesi, O. C., Loebel, F., Bogner, W., Marjanska, M., Vander Heiden, M. G., Iafrate, A. J. et al. Treatment response assessment in IDH-mutant glioma patients by noninvasive 3D functional spectroscopic mapping of 2-hydroxyglutarate. Clin. Cancer Res. 22, 1632–1641 (2016).

  4. 4.

    Khan, M. N., Sharma, A. M., Pitz, M., Loewen, S. K., Quon, H., Poulin, A. et al. High-grade glioma management and response assessment-recent advances and current challenges. Curr. Oncol. 23, e383–e391 (2016).

  5. 5.

    Reardon, D. A., Ballman, K. V., Buckner, J. C., Chang, S. M. & Ellingson, B. M. Impact of imaging measurements on response assessment in glioblastoma clinical trials. Neuro Oncol. 16(Suppl 7), vii24–vii35 (2014).

  6. 6.

    Dalesandro, M. F. & Andre, J. B. Posttreatment evaluation of brain gliomas. Neuroimaging Clin. N. Am. 26, 581–599 (2016).

  7. 7.

    Telles, B. A., D’Amore, F., Lerner, A., Law, M. & Shiroishi, M. S. Imaging of the Posttherapeutic Brain. Top Magn. Reson. Imaging 24, 147–154 (2015).

  8. 8.

    Jordan, J. P., Hand, C. M., Markowitz, R. S. & Black, P. Test for chemotherapeutic sensitivity of cerebral gliomas: use of colorimetric MTT assay. J. Neurooncol. 14, 19–35 (1992).

  9. 9.

    Carminati, P. O., Mello, S. S., Fachin, A. L., Junta, C. M., Sandrin-Garcia, P., Carlotti, C. G. et al. Alterations in gene expression profiles correlated with cisplatin cytotoxicity in the glioma U343 cell line. Genet. Mol. Biol. 33, 159–168 (2010).

  10. 10.

    Wolff, J. E., Trilling, T., Molenkamp, G., Egeler, R. M. & Jurgens, H. Chemosensitivity of glioma cells in vitro: a meta analysis. J. Cancer Res. Clin. Oncol. 125, 481–486 (1999).

  11. 11.

    Dropcho, E. J., Rosenfeld, S. S., Vitek, J., Guthrie, B. L. & Morawetz, R. B. Phase II study of intracarotid or selective intracerebral infusion of cisplatin for treatment of recurrent anaplastic gliomas. J. Neurooncol. 36, 191–198 (1998).

  12. 12.

    Bergenheim, A. T., Roslin, M., Ungerstedt, U., Waldenstrom, A., Henriksson, R. & Ronquist, G. Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB). J. Neurooncol. 80, 285–293 (2006).

  13. 13.

    Wibom, C., Surowiec, I., Moren, L., Bergstrom, P., Johansson, M., Antti, H. et al. Metabolomic patterns in glioblastoma and changes during radiotherapy: a clinical microdialysis study. J. Proteome Res. 9, 2909–2919 (2010).

  14. 14.

    Moren, L., Bergenheim, A. T., Ghasimi, S., Brannstrom, T., Johansson, M. & Antti, H. Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information. Metabolites 5, 502–520 (2015).

  15. 15.

    Sandstrom, M., Laudius, M., Lindqvist, T., Asklund, T. & Johansson, M. A retrospective evaluation of Bevacizumab treatment in patients with progressive malignant glioma in Northern Sweden. Anticancer Res. 37, 1869–1874 (2017).

  16. 16.

    Roslin, M., Henriksson, R., Bergstrom, P., Ungerstedt, U. & Bergenheim, A. T. Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis. J. Neurooncol. 61, 151–160 (2003).

  17. 17.

    Bjorkblom, B., Wibom, C., Jonsson, P., Moren, L., Andersson, U., Johannesen, T. B. et al. Metabolomic screening of pre-diagnostic serum samples identifies association between alpha- and gamma-tocopherols and glioblastoma risk. Oncotarget 7, 37043–37053 (2016).

  18. 18.

    Jonsson, P., Wuolikainen, A., Thysell, E., Chorell, E., Stattin, P., Wikstrom, P. et al. Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples. Metabolomics 11, 1667–1678 (2015).

  19. 19.

    Barclay, T., Ginic-Markovic, M., Johnston, M. R., Cooper, P. & Petrovsky, N. Observation of the keto tautomer of D-fructose in D(2)O using (1)H NMR spectroscopy. Carbohydrate Res. 347, 136–141 (2012).

  20. 20.

    Bylesjo, M., Rantalainen, M., Cloarec, O., Nicholson, J. K., Holmes, E. & Trygg, J. OPLS discriminant analysis: combining the strengths of PLS-DA and SIMCA classification. J. Chemometr. 20, 341–351 (2006).

  21. 21.

    Wold, S. Cross-validatory estimation of number of components in factor and principal components models. Technometrics 20, 397–405 (1978).

  22. 22.

    Eriksson, L., Trygg, J. & Wold, S. CV-ANOVA for significance testing of PLS and OPLS (R) models. J. Chemometr. 22, 594–600 (2008).

  23. 23.

    Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate - a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995).

  24. 24.

    Tseng, Y. Y., Su, C. H., Yang, S. T., Huang, Y. C., Lee, W. H., Wang, Y. C. et al. Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes. Oncotarget 7, 59902–59916 (2016).

  25. 25.

    Barua, N. U., Hopkins, K., Woolley, M., O’Sullivan, S., Harrison, R., Edwards, R. J. et al. A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma. Drug Deliv 23, 167–173 (2016).

  26. 26.

    Baklaushev, V. P., Nukolova, N. N., Khalansky, A. S., Gurina, O. I., Yusubalieva, G. M., Grinenko, N. P. et al. Treatment of glioma by cisplatin-loaded nanogels conjugated with monoclonal antibodies against Cx43 and BSAT1. Drug Deliv. 22, 276–285 (2015).

  27. 27.

    Feldhaeusser, B., Platt, S. R., Marrache, S., Kolishetti, N., Pathak, R. K., Montgomery, D. J. et al. Evaluation of nanoparticle delivered cisplatin in beagles. Nanoscale 7, 13822–13830 (2015).

  28. 28.

    Bancroft, D. P., Lepre, C. A. & Lippard, S. J. Pt-195 Nmr kinetic and mechanistic studies of cis-diamminedichloroplatinum and trans-diamminedichloroPLATINUM(II) BINDing to DNA. J Am. Chem. Soc. 112, 6860–6871 (1990).

  29. 29.

    Segal, E. & Lepecq, J. B. Role of ligand-exchange processes in the reaction-kinetics of the antitumor drug cis-diamminedichloroplatinum(ii) with its targets. Cancer Res. 45, 492–498 (1985).

  30. 30.

    Mezencev, R. Interactions of cisplatin with non-DNA targets and their influence on anticancer activity and drug toxicity: the complex world of the platinum Complex. Curr. Cancer Drug Tar. 14, 794–816 (2014).

  31. 31.

    Zahedi, K., Barone, S., Destefano-Shields, C., Brooks, M., Murray-Stewart, T., Dunworth, M. et al. Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury. PLoS One 12, e0184570 (2017).

  32. 32.

    Pegg, A. E. Functions of polyamines in mammals. J. Biol. Chem. 291, 14904–14912 (2016).

  33. 33.

    Mawatari, K., Yasui, Y., Sugitani, K., Takadera, T. & Kato, S. Reactive oxygen species involved in the glutamate toxicity of C6 glioma cells via xc antiporter system. Neuroscience 73, 201–208 (1996).

  34. 34.

    Fricker, S. P. Cysteine proteases as targets for metal-based drugs. Metallomics 2, 366–377 (2010).

  35. 35.

    Heudi, O., Brisset, H., Cailleux, A. & Allain, P. Chemical instability and methods for measurement of cisplatin adducts formed by interactions with cysteine and glutathione. Int. J. Clin. Pharm. Ther. 39, 344–349 (2001).

  36. 36.

    Noch, E. & Khalili, K. Molecular mechanisms of necrosis in glioblastoma: the role of glutamate excitotoxicity. Cancer Biol. Ther. 8, 1791–1797 (2009).

  37. 37.

    Liu, L., Zhang, X., Lou, Y., Rao, Y. & Zhang, X. Cerebral microdialysis in glioma studies, from theory to application. J. Pharm. Biomed. Anal. 96, 77–89 (2014).

  38. 38.

    Muguruma, K., Nakata, B., Yanagawa, K., Nitta, A., Yashiro, M., Onoda, N. et al. Caspase-1 activity as a possible predictor of apoptosis induced by cisplatin in gastric cancer cells. Int. J. Mol. Med. 6, 553–557 (2000).

  39. 39.

    Yu, W. G., Chen, Y. Y., Dubrulle, J., Stossi, F., Putluri, V., Sreekumar, A. et al. Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism. Sci Rep 8, 4306 (2018). https://doi.org/10.1038/s41598-018-22640-y.

Download references

Acknowledgements

We acknowledge Kristin Nyman at the Department of Neurosurgery for her technical skills in managing the microdialysis bedside and Professor Thomas Brännström at the Department of Pathology, for verification of IDH mutation status.

Author information

A.T.B., P.T., P.B., M.J., T.A., P.J., H.A. and B.B. designed the study. P.T. and A.T.B. performed the neurosurgical procedures. B.B. performed analytical measurements. P.J. and B.B. provided computational analysis. P.B., M.J., T.A., H.A. and A.T.B. provided expert consultation. A.T.B., P.J. and B.B. wrote the manuscript. All authors read and approved the final manuscript.

Correspondence to Benny Björkblom.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The authors confirm that the study have been conducted within appropriate ethical guidelines and legislation. The local ethics committee in Umeå approved the study, and all patients gave their informed consent to participate in the study (09–199 M). The trial was permitted by the Swedish Medical Product Agency, EudraCT number: 2010-018281-23, registered 4 January 2010, http://www.lakemedelsverket.se.

Funding

This study was supported by the Swedish Cancer Society (A.T.B., H.A.), Umeå University Hospital (A.T.B.), the Swedish Research Council (H.A.), the Cancer Research Foundation in Northern Sweden (B.B.), the Research Foundation of Clinical Neuroscience, Umeå University (A.T.B.) and by the regional agreement between Umeå University and Västerbotten County Council on the cooperation in the field of Medicine, Odontology and Health (A.T.B.).

Data availability

Summarised datasets supporting the conclusions of this article are included within the article and as additional supplementary files.

Additional information

Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Björkblom, B., Jonsson, P., Tabatabaei, P. et al. Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma. Br J Cancer 122, 221–232 (2020). https://doi.org/10.1038/s41416-019-0652-x

Download citation

Further reading