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Methionine Dependency Determination of Human Patient Tumors in Gelfoam® Histoculture

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 1760))

Abstract

The elevated requirement of methionine by cancer cells (methionine dependence) is a general metabolic abnormality in cancer. Methionine-dependent cancer cells are unable to proliferate and arrest in the late S/G2 phase of the cell cycle when methionine is restricted in vitro or in vivo. Cell-cycle arrest in late S/G2 was used as a biomarker of methionine dependence for patient tumors in Gelfoam® histoculture. Human cancer patient tumors, including tumors of the colon, breast, ovary, prostate, and a melanoma, were observed to be methionine dependent in Gelfoam® histoculture based on cell cycle analysis. This simple method can be used to screen patient tumors for methionine dependence and then subsequently apply appropriate chemotherapy for these patients to target this cancer-specific metabolic abnormality.

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References

  1. Hoffman RM (2017) The wayward methyl group and the cascade to cancer. Cell Cycle 16:825–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hoffman RM (2015) Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. Expert Opin Biol Ther 15:21–31

    Article  CAS  PubMed  Google Scholar 

  3. Stern PH, Hoffman RM (1984) Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro 20:663–670

    Article  CAS  PubMed  Google Scholar 

  4. Murakami T, Li S, Han Q, Tan Y, Kiyuna T, Igarashi K, Kawaguchi K, Hwang HK, Miyaki K, Singh AS et al (2017) Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8:35630–35638

    PubMed  PubMed Central  Google Scholar 

  5. Hoffman RM, Jacobsen SJ (1980) Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci U S A 77:7306–7310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yano S, Li S, Han Q, Tan Y, Bouvet M, Fujiwara T, Hoffman RM (2014) Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity. Oncotarget 5:8729–8736

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hoffman RM, Jacobsen SJ, Erbe RW (1978) Reversion to methionine independence by malignant rat and SV40-transformed human fibroblasts. Biochem Biophys Res Commun 82:228–234

    Article  CAS  PubMed  Google Scholar 

  8. Judde JG, Ellis M, Frost P (1989) Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Cancer Res 49:4859–4865

    CAS  PubMed  Google Scholar 

  9. Hoffman RM, Jacobsen SJ, Erbe RW (1979) Reversion to methionine independence in simian virus 40-transformed human and malignant rat fibroblasts is associated with altered ploidy and altered properties of transformation. Proc Natl Acad Sci U S A 76:1313–1317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Grosu AL, Weber WA, Riedel E, Jeremic B, Nieder C, Franz M, Gumprecht H, Jaeger R, Schwaiger M, Molls M (2005) L-(methyl-11C) methionine positron emission tomography for target delineation in resected high-grade gliomas before radiotherapy. Int J Radiat Oncol Biol Phys 63:64–74

    Article  CAS  PubMed  Google Scholar 

  11. Glaudemans AW, Enting RH, Heesters MA, Dierckx RA, van Rheenen RW, Walenkamp AM, Slart RH (2013) Value of 11C-methionine PET in imaging brain tumours and metastases. Eur J Nucl Med Mol Imaging 40:615–635

    Article  CAS  PubMed  Google Scholar 

  12. Tsuyuguchi N, Takami T, Sunada I, Iwai Y, Yamanaka K, Tanaka K, Nishikawa M, Ohata K, Torii K, Morino M et al (2004) Methionine positron emission tomography for differentiation of recurrent brain tumor and radiation necrosis after stereotactic radiosurgery–in malignant glioma. Ann Nucl Med 18:291–296

    Article  CAS  PubMed  Google Scholar 

  13. Nariai T, Tanaka Y, Wakimoto H, Aoyagi M, Tamaki M, Ishiwata K, Senda M, Ishii K, Hirakawa K, Ohno K (2005) Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg 103:498–507

    Article  PubMed  Google Scholar 

  14. Tamura K, Yoshikawa K, Ishikawa H, Hasebe M, Tsuji H, Yanagi T, Suzuki K, Kubo A, Tsujii H (2009) Carbon-11-methionine PET imaging of choroidal melanoma and the time course after carbon ion beam radiotherapy. Anticancer Res 29:1507–1514

    PubMed  Google Scholar 

  15. Singhal T, Narayanan TK, Jacobs MP, Bal C, Mantil JC (2012) 11C-methionine PET for grading and prognostication in gliomas: a comparison study with 18F-FDG PET and contrast enhancement on MRI. J Nucl Med 53:1709–1715

    Article  PubMed  Google Scholar 

  16. Guo HY, Herrera H, Groce A, Hoffman RM (1993) Expression of the biochemical defect of methionine dependence in fresh patient tumors in primary histoculture. Cancer Res 53:2479–2483

    CAS  PubMed  Google Scholar 

  17. Mecham JO, Rowitch D, Wallace CD, Stem PH, Hoffman RM (1983) The metabolic defect of methionine dependence occurs frequently in human tumor cell lines. Biochem Biophys Res Commun 117:429–434

    Article  CAS  PubMed  Google Scholar 

  18. Tan Y, Xu M, Tan X, Tan X, Wang X, Saikawa Y, Nagahama T, Sun X, Lenz M, Hoffman RM (1997) Overexpression and large-scale production of recombinant L-methionine-alpha- deamino-gamma- mercaptomethane-lyase for novel anticancer therapy. Protein Expr Purif. 9:233–245

    Google Scholar 

  19. Takakura T, Ito T, Yagi S, Notsu Y, Itakura T, Nakamura T, Inagaki K, Esaki N, Hoffman RM, Takimoto A (2006) High-level expression and bulk crystallization of recombinant l-methionine g-lyase, an anticancer agent. Appl Microbiol Biotechnol 70:183–192

    Google Scholar 

  20. Takakura T, Takimoto A, Notsu Y, Yoshida H, Ito T, Nagatome H, Ohno M, Kobayashi Y, Yoshioka T, Inagaki K, Yagi S, Hoffman RM, Esaki N (2006) Physicochemical and pharmacokinetic characterization of highly potent recombinant l-methionine g-lyase conjugated with polyethylene glycol as an antitumor agent. Cancer Res 66:2807–2814

    Google Scholar 

  21. Takakura T, Misaki S, Yamashita M, Tamura T, Takakura T, Yoshioka T, Yagi S, Hoffman RM, Takimoto A, Esaki N, Inagaki K (2004) Assay method for antitumor l-methionine g-lyase: comprehensive kinetic analysis of the complex reaction with l-methionine. Anal Biochem 327:233–240

    Google Scholar 

  22. Kudou D, Misaki S, Yamashita M, Tamura T, Takakura T, Yoshioka T, Yagi S, Hoffman RM, Takimoto A, Esaki N, Inagaki K (2007) Structure of the antitumour enzyme l-methionine g-lyase from Pseudomonas putida at 1.8Å resolution. J Biochem 141:535–544

    Google Scholar 

  23. Kawaguchi K, Igarashi K, Li S, Han Q, Tan Y, Kiyuna T, Miyake K, Murakami T, Chmielowski B, Nelson SD, et al (2017) Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma growth in a patient-derived orthotopic xenograft. Oncotarget 8:85516–85525

    Google Scholar 

  24. Kawaguchi K, Igarashi K, Li S, Han Q, Tan Y, Miyake K, Kiyuna T, Miyake M, Murakami T, Chmielowski S, et al (2018) Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models. Oncotarget 9:915–923 

    Google Scholar 

  25. Igarashi K, Li S, Han Q, Tan Y, Kawaguchi K, Murakami T, Kiyuna T, Miyake K, Li Y, Nelson SD, et al (2018) Growth of a doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase. J Cell Biochem, in press

    Google Scholar 

  26. Igarashi K, Kawaguchi K, Kiyuna T, Miyake K, Miyake M, Li S, Han Q, Tan Y, Zhao M, Li Y, et al (2018) Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: Decoy, trap and kill chemotherapy moves toward the clinic. Cell Cycle, in press

    Google Scholar 

  27. Kawaguchi K, Han Q, Li S, Tan Y, Igarashi K, Kiyuna T, Miyake K, Miyake M, Chmielowski B, Nelson SD, et al (2018) Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for clinical cancer therapy and prevention. Cell Cycle, in press

    Google Scholar 

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Correspondence to Robert M. Hoffman .

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Hoffman, R.M. (2018). Methionine Dependency Determination of Human Patient Tumors in Gelfoam® Histoculture. In: Hoffman, R. (eds) 3D Sponge-Matrix Histoculture. Methods in Molecular Biology, vol 1760. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7745-1_13

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  • DOI: https://doi.org/10.1007/978-1-4939-7745-1_13

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7743-7

  • Online ISBN: 978-1-4939-7745-1

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