Imaging of branched chain amino acid metabolism in tumors with hyperpolarized 13C ketoisocaproate.
Powerful analytical tools are vital for characterizing the complex molecular changes underlying oncogenesis and cancer treatment. This is particularly true, if information is to be collected in vivo by noninvasive approaches. In the recent past, hyperpolarized (13)C magnetic resonance (MR) spectroscopy has been employed to quickly collect detailed spectral information on the chemical fate of tracer molecules in different tissues at high sensitivity. Here, we report a preclinical study showing that alpha-ketoisocaproic acid (KIC) can be used to assess molecular signatures of tumors with hyperpolarized MR spectroscopy. KIC is metabolized to leucine by the enzyme branched chain amino acid transferase (BCAT), which is found upregulated in some tumors. BCAT is a putative marker for metastasis and a target of the proto-oncogene c-myc. Very different fluxes through the BCAT-catalyzed reaction can be detected for murine lymphoma (EL4) and rat mammary adenocarcinoma (R3230AC) tumors in vivo. EL4 tumors show a more than 7-fold higher hyperpolarized (13)C leucine signal relative to the surrounding healthy tissue. In R3230AC tumor on the other hand branched chain amino acid metabolism is not enhanced relative to surrounding tissues. The distinct molecular signatures of branched chain amino acid metabolism in EL4 and R3230AC tumors correlate well with ex vivo assays of BCAT activity.
Karlsson
Magnus
M
Imagnia AB, Box 8225, 200 41 Malmö, Sweden.
Jensen
Pernille R
PR
in 't Zandt
René
R
Gisselsson
Anna
A
Hansson
Georg
G
Duus
Jens Ø
JØ
Meier
Sebastian
S
Lerche
Mathilde H
MH
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D055162:Biocatalysis; D002247:Carbon Isotopes; D045744:Cell Line, Tumor; D005260:Female; D007651:Keto Acids / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D000637:Transaminases / Q000378:metabolism
D000596:Amino Acids; D002247:Carbon Isotopes; D007651:Keto Acids; C013082:alpha-ketoisocaproic acid; D000637:Transaminases