Skip to main content

Advertisement

SpringerLink
Log in

Metabolomic characterization of experimental ovarian cancer ascitic fluid

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Introduction

Malignant ascites (MA) is a major cause of morbidity that occurs in 37% of ovarian cancer patients. The accumulation of MA in the peritoneal cavity due to cancer results in debilitating symptoms and extremely poor quality of life. There is an urgent unmet need to expand the understanding of MA to design effective treatment strategies, and to improve MA diagnosis.

Objective

Our purpose here is to contribute to a better characterization of MA metabolic composition in ovarian cancer.

Method

We determined the metabolic composition of ascitic fluids resulting from orthotopic growth of two ovarian cancer cell lines, the mouse ID8- vascular endothelial growth factor (VEGF)-Defb29 cell line and the human OVCAR3 cell line using high-resolution 1H MRS. ID8-VEGF-Defb29 tumors induce large volumes of ascites, while OVCAR3 tumors induce ascites less frequently and at smaller volumes. To better understand the factors driving the metabolic composition of the fluid, we characterized the metabolism of these ovarian cancer cells in culture by analyzing cell lysates and conditioned culture media with 1H NMR.

Results

Distinct metabolite patterns were detected in ascitic fluid collected from OVCAR3 and ID8-VEGF-Defb29 tumor bearing mice that were not reflected in the corresponding cell culture or conditioned medium.

Conclusion

High-resolution 1H NMR metabolic markers of MA can be used to improve characterization and diagnosis of MA. Metabolic characterization of MA can provide new insights into how MA fluid supports cancer cell growth and resistance to treatment, and has the potential to identify metabolic targeting strategies to reduce or eliminate the formation of MA.

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

Chk:

Choline kinase

Cho:

Free choline

CSI:

Chemical shift imaging

GPC:

Glycerophosphocholine

PC:

Phosphocholine

PtCho:

Phosphatidylcholine

PUFA:

Poly unsaturated fatty acids

tCho:

Total choline

VEGF:

Vascular endothelial growth factor

References

  • Adosraku, R. K., Choi, G. T., Constantinou-Kokotos, V., Anderson, M. M., & Gibbons, W. A. (1994). NMR lipid profiles of cells, tissues, and body fluids: Proton NMR analysis of human erythrocyte lipids. Journal of Lipid Research, 35(11), 1925–1931.

    CAS  PubMed  Google Scholar 

  • Ahmed, N., & Stenvers, K. L. (2013). Getting to know ovarian cancer ascites: Opportunities for targeted therapy-based translational research. [Review]. Frontiers in Oncology, 3, 256. doi:10.3389/fonc.2013.00256.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ammouri, L., & Prommer, E. E. (2010). Palliative treatment of malignant ascites: Profile of catumaxomab. Biologics, 4, 103–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bala, L., Sharma, A., Yellapa, R. K., Roy, R., Choudhuri, G., & Khetrapal, C. L. (2008). H-1 NMR spectroscopy of ascitic fluid: Discrimination between malignant and benign ascites and comparison of the results with conventional methods. NMR in Biomedicine, 21(6), 606–614. doi:10.1002/nbm.1232.

    Article  CAS  PubMed  Google Scholar 

  • Beckonert, O., Keun, H. C., Ebbels, T. M., Bundy, J., Holmes, E., Lindon, J. C., et al. (2007). Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nature Protocols, 2(11), 2692–2703. doi:10.1038/nprot.2007.376.

    Article  CAS  PubMed  Google Scholar 

  • Bharti, S. K., & Roy, R. (2012). Quantitative 1H NMR spectroscopy. TrAC Trends in Analytical Chemistry, 35, 5–26.

    Article  CAS  Google Scholar 

  • Bharti, S. K., & Roy, R. (2014). Metabolite identification in NMR-based metabolomics. Current Metabolomics, 2, 163–173.

    Article  CAS  Google Scholar 

  • Conejo-Garcia, J. R., Benencia, F., Courreges, M. C., Kang, E., Mohamed-Hadley, A., Buckanovich, R. J., et al. (2004). Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. [Comparative Study, Research Support, Non-U.S. Gov’t, Research Support Gov’t, P.H.S.]. Nature Medicine, 10(9), 950–958. doi:10.1038/nm1097.

    Article  CAS  PubMed  Google Scholar 

  • Cruz, T., Balayssac, S., Gilard, V., Martino, R., Vincent, C., Pariente, J., et al. (2014). 1H NMR Analysis of cerebrospinal fluid from Alzheimer’s disease patients: An example of a possible misinterpretation due to non-adjustment of pH. Metabolites, 4(1), 115–128. doi:10.3390/metabo4010115.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gowda, G. A. N., & Raftery, D. (2014). Quantitating metabolites in protein precipitated serum using NMR spectroscopy. Analytical Chemistry, 86(11), 5433–5440. doi:10.1021/ac5005103.

    Article  CAS  PubMed Central  Google Scholar 

  • Herr, D., Sallmann, A., Bekes, I., Konrad, R., Holzheu, I., Kreienberg, R., et al. (2012). VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5. Gynecologic Oncology, 127(1), 210–216. doi:10.1016/j.ygyno.2012.05.002.

    Article  CAS  PubMed  Google Scholar 

  • Hilvo, M., de Santiago, I., Gopalacharyulu, P., Schmitt, W. D., Budczies, J., Kuhberg, M., et al. (2016). Accumulated metabolites of hydroxybutyric acid serve as diagnostic and prognostic biomarkers of ovarian high-grade serous carcinomas. Cancer Research, 76(4), 796–804. doi:10.1158/0008-5472.CAN-15-2298.

    Article  CAS  PubMed  Google Scholar 

  • Kipps, E., Tan, D. S., & Kaye, S. B. (2013). Meeting the challenge of ascites in ovarian cancer: New avenues for therapy and research. [Research Support, Non-U.S. Gov’t]. Nature Reviews Cancer, 13(4), 273–282. doi:10.1038/nrc3432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolomeyevskaya, N., Eng, K. H., Khan, A. N., Grzankowski, K. S., Singel, K. L., Moysich, K., et al. (2015). Cytokine profiling of ascites at primary surgery identifies an interaction of tumor necrosis factor-alpha and interleukin-6 in predicting reduced progression-free survival in epithelial ovarian cancer. [Research Support, N.I.H., Extramural]. Gynecologic Oncology, 138(2), 352–357. doi:10.1016/j.ygyno.2015.05.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Landskron, J., Helland, O., Torgersen, K. M., Aandahl, E. M., Gjertsen, B. T., Bjorge, L., et al. (2015). Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. [Research Support, Non-U.S. Gov’t]. Cancer Immunology, Immunotherapy : CII, 64(3), 337–347. doi:10.1007/s00262-014-1636-6.

    Article  CAS  PubMed  Google Scholar 

  • Lu, W. Q., Pelicano, H., & Huang, P. (2010). Cancer metabolism: Is glutamine sweeter than glucose? Cancer Cell, 18(3), 199–200. doi:10.1016/j.ccr.2010.08.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Masoumi Moghaddam, S., Amini, A., Morris, D. L., & Pourgholami, M. H. (2012). Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer. [Review]. Cancer Metastasis Reviews, 31(1–2), 143–162. doi:10.1007/s10555-011-9337-5.

    Article  CAS  PubMed  Google Scholar 

  • Odunsi, K., Wollman, R. M., Ambrosone, C. B., Hutson, A., McCann, S. E., Tammela, J., et al. (2005). Detection of epithelial ovarian cancer using 1H-NMR-based metabonomics. [Comparative Study, Research Support, Non-U.S. Gov’t, Research Support., Gov’t, U. S. P.H.S.]. International Journal of Cancer, 113(5), 782–788, doi:10.1002/ijc.20651.

    Article  CAS  PubMed  Google Scholar 

  • Penet, M. F., Krishnamachary, B., Wildes, F., Mironchik, Y., Mezzanzanica, D., Podo, F., et al. (2016). Effect of pantethine on ovarian tumor progression and choline metabolism. Frontiers in Oncology, 6, 244. doi:10.3389/fonc.2016.00244.

    Article  PubMed  PubMed Central  Google Scholar 

  • Robinson-Smith, T. M., Isaacsohn, I., Mercer, C. A., Zhou, M., Van Rooijen, N., Husseinzadeh, N., et al. (2007). Macrophages mediate inflammation-enhanced metastasis of ovarian tumors in mice. [Research Support, Non-U.S. Gov’t]. Cancer Research, 67(12), 5708–5716. doi:10.1158/0008-5472.CAN-06-4375.

    Article  CAS  PubMed  Google Scholar 

  • Serkova, N. J., & Brown, M. S. (2012). Quantitative analysis in magnetic resonance spectroscopy: From metabolic profiling to in vivo biomarkers. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Review]. Bioanalysis, 4(3), 321–341. doi:10.4155/bio.11.320.

    Article  CAS  PubMed  Google Scholar 

  • Trape, J., Gurt, G., Franquesa, J., Montesinos, J., Arnau, A., Sala, M., et al. (2015). Diagnostic accuracy of tumor markers CYFRA21-1 and CA125 in the differential diagnosis of ascites. Anticancer Research, 35(10), 5655–5660.

    CAS  PubMed  Google Scholar 

  • Van, Q. N., Chmurny, G. N., & Veenstra, T. D. (2003). The depletion of protein signals in metabonomics analysis with the WET-CPMG pulse sequence. [Research Support., Gov’t, U. S. P.H.S.]. Biochemical and Biophysical Research Communications, 301(4), 952–959.

    Article  CAS  PubMed  Google Scholar 

  • Vettukattil, R., Hetland, T. E., Florenes, V. A., Kaern, J., Davidson, B., & Bathen, T. F. (2013). Proton magnetic resonance metabolomic characterization of ovarian serous carcinoma effusions: Chemotherapy-related effects and comparison with malignant mesothelioma and breast carcinoma. Human Pathology, 44(9), 1859–1866. doi:10.1016/j.humpath.2013.02.009.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Tina’s Wish Foundation, by NIH P50CA013175, R01CA193365, R01CA136576 and P30CA06973.

Author information

Authors and Affiliations

  1. Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 212 Traylor Building, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Santosh K. Bharti, Flonné Wildes, Zaver M. Bhujwalla & Marie-France Penet

  2. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Chien-Fu Hung & T. C. Wu

  3. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Zaver M. Bhujwalla & Marie-France Penet

Authors
  1. Santosh K. Bharti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Flonné Wildes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chien-Fu Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. C. Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zaver M. Bhujwalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marie-France Penet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marie-France Penet.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human and animal participants

This article does not contain any studies with human participants performed by any of the authors.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 82947 KB)

Supplementary material 2 (DOCX 12 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bharti, S.K., Wildes, F., Hung, CF. et al. Metabolomic characterization of experimental ovarian cancer ascitic fluid. Metabolomics 13, 113 (2017). https://doi.org/10.1007/s11306-017-1254-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11306-017-1254-3

Keywords

Search

Navigation