Alecio F Lombardi1,2, Jonathan H Wong1,2, Rachel High1,2, Yajun Ma1,2, Saeed Jerban1,2, Qingbo Tang1,2, Jiang Du1,2, Patrick Frost3,4, Mark D Pagel5, Eric Y Chang6,7. 1. Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, CA, 92161, San Diego, USA. 2. Department of Radiology, University of California, San Diego, CA, USA. 3. Research Service, Greater Los Angeles Veteran Administration Healthcare System, Los Angeles, CA, USA. 4. Department of Medicine, University of California, Los Angeles, CA, USA. 5. Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, CA, 92161, San Diego, USA. ericchangmd@gmail.com. 7. Department of Radiology, University of California, San Diego, CA, USA. ericchangmd@gmail.com.
Abstract
PURPOSE: Multiple myeloma (MM) is an incurable disease of malignant plasma cells in the bone marrow (BM). Adaptive responses to hypoxia may be an essential element in MM progression and drug resistance. This metabolic adaptation involves a decrease in extracellular pH (pHe), and it depends on the upregulation of glucose transporters (GLUTs) that is common in hypoxia and in cancer cells. CEST MRI is an imaging technique that assesses pHe indirectly by the exchange rate of magnetic saturation transfer between labile protons on a solute and water. Thus, this study aimed to determine the feasibility of acidoCEST MRI for pHe measurement using an orthotopic mouse model of MM compared with GLUT1 immunofluorescence staining as a reference. PROCEDURES: Orthotopic BM engrafted MM xenografts were established in NSG/NOD mice using the human RPMI8226 myeloma cell line. AcidoCEST MRI was performed approximately 6 weeks after intravenous challenge, before and after intravenous administration of iopamidol. BM pHe values were generated via fitting the CEST spectrum with the Bloch-McConnell equations. Samples were decalcified, sectioned, and immunostained for GLUT1 expression. Pearson's correlation was used to assess the relationship between pHe and [H3O+] versus GLUT1 expression. RESULTS: Ten mice underwent acidoCEST MRI followed by immunofluorescent histologic analysis. A strong negative correlation was seen between pHe versus GLUT1 expression (r = - 0.75, p < 0.001). After transformation of pH to [H3O+], a strong positive correlation between [H3O+] and GLUT1 expression was observed (r = 0.8, p < 0.001). CONCLUSIONS: AcidoCEST MRI can measure the extracellular pH of bone marrow affected by multiple myeloma. In this MM orthotopic mouse model, pHe measured by acidoCEST MRI showed strong correlations with the metabolic phenotype of BM tumor assessed by immunofluorescent histological assessment of GLUT1 overexpression.
PURPOSE: Multiple myeloma (MM) is an incurable disease of malignant plasma cells in the bone marrow (BM). Adaptive responses to hypoxia may be an essential element in MM progression and drug resistance. This metabolic adaptation involves a decrease in extracellular pH (pHe), and it depends on the upregulation of glucose transporters (GLUTs) that is common in hypoxia and in cancer cells. CEST MRI is an imaging technique that assesses pHe indirectly by the exchange rate of magnetic saturation transfer between labile protons on a solute and water. Thus, this study aimed to determine the feasibility of acidoCEST MRI for pHe measurement using an orthotopic mouse model of MM compared with GLUT1 immunofluorescence staining as a reference. PROCEDURES: Orthotopic BM engrafted MM xenografts were established in NSG/NOD mice using the human RPMI8226 myeloma cell line. AcidoCEST MRI was performed approximately 6 weeks after intravenous challenge, before and after intravenous administration of iopamidol. BM pHe values were generated via fitting the CEST spectrum with the Bloch-McConnell equations. Samples were decalcified, sectioned, and immunostained for GLUT1 expression. Pearson's correlation was used to assess the relationship between pHe and [H3O+] versus GLUT1 expression. RESULTS: Ten mice underwent acidoCEST MRI followed by immunofluorescent histologic analysis. A strong negative correlation was seen between pHe versus GLUT1 expression (r = - 0.75, p < 0.001). After transformation of pH to [H3O+], a strong positive correlation between [H3O+] and GLUT1 expression was observed (r = 0.8, p < 0.001). CONCLUSIONS: AcidoCEST MRI can measure the extracellular pH of bone marrow affected by multiple myeloma. In this MM orthotopic mouse model, pHe measured by acidoCEST MRI showed strong correlations with the metabolic phenotype of BM tumor assessed by immunofluorescent histological assessment of GLUT1 overexpression.
Authors: J Stancanello; E Terreno; D Delli Castelli; C Cabella; F Uggeri; S Aime Journal: Contrast Media Mol Imaging Date: 2008 Jul-Aug Impact factor: 3.161
Authors: Lukas Janker; Rupert L Mayer; Andrea Bileck; Dominique Kreutz; Johanna C Mader; Kirsten Utpatel; Daniel Heudobler; Hermine Agis; Christopher Gerner; Astrid Slany Journal: Mol Cell Proteomics Date: 2019-02-21 Impact factor: 5.911
Authors: Veronica Estrella; Tingan Chen; Mark Lloyd; Jonathan Wojtkowiak; Heather H Cornnell; Arig Ibrahim-Hashim; Kate Bailey; Yoganand Balagurunathan; Jennifer M Rothberg; Bonnie F Sloane; Joseph Johnson; Robert A Gatenby; Robert J Gillies Journal: Cancer Res Date: 2013-01-03 Impact factor: 12.701
Authors: Gilbert Gastelum; Eric Y Chang; David Shackleford; Nicholas Bernthal; Jeffery Kraut; Kevin Francis; Victoria Smutko; Patrick Frost Journal: J Vis Exp Date: 2019-01-07 Impact factor: 1.424
Authors: Alecio F Lombardi; Yajun Ma; Hyungseok Jang; Saeed Jerban; Qingbo Tang; Adam C Searleman; Robert Scott Meyer; Jiang Du; Eric Y Chang Journal: Int J Mol Sci Date: 2022-04-18 Impact factor: 6.208