Eleven mice were injected with 13C 6-Phe (Cambridge Isotope Laboratories, Andover, MA, USA) at a dose of 1.0 micromole/g body weight, and 3 additional mice were injected with normal saline into the lateral tail vein when the tumors reached 1000 mm 3. They received a regular chow diet, which contains 12% fat, 27% protein, and 61% carbohydrate based on calories. All animals had unrestricted access to food and water before injection. Tumor volume was monitored 3 times per week using a Vernier caliper. Human NCI-H460 non-small cell lung carcinoma (NSCLC) cells suspended in matrigel (BD Biosciences, Breda, The Netherlands) were injected subcutaneously into the flank region of each mouse. In this study, we used our previously developed MALDI-MSI method of 13C 6-Phe to construct spatial and dynamic metabolic flux maps in relation with spatial tumor heterogeneity in a human non-small cell lung carcinoma xenograft model.Ī total of 14 adult female immune-compromised Crl:NU-Foxn1 nu nu/nu nude mice (Charles River, Den Bosch, The Netherlands) were used. We have recently used this method to track the hepatocellular incorporation of L-Phenylalanine ( 13C 6-Phe) and its metabolite L-Tyrosine ( 13C 6-Tyr). However, matrix-assisted laser desorption/ionization (MALDI), a softer ionization technique without suffering from extensive fragmentation and complexity of interpretation of mass spectra, is increasingly applied in biomedical research. Multi-isotope imaging mass spectrometry (MIMS) has been applied to study the heterogeneity of glucose and glutamine utilization in murine tumors recently. Adding isotopically labeled versions of target compounds allows the quantitative study of spatiotemporal metabolic dynamics in these tissues. Mass spectrometry imaging (MSI) enables the in situ visualization of metabolites in biological tissue specimens. Current strategies to personalize treatment response use genomics data which is not able to reflect the dynamics of metabolic processes in the context of the spatial intratumor heterogeneity. The molecular and cellular heterogeneity in a tumor plays a crucial role in cancer treatment efficacy and outcome. Phenylalanine metabolism, however, in relation to the morphology of cancer tissue has not been explored yet. Isotopically labeled phenylalanine has been used in tracer studies as a measure of protein synthesis and liver function. It is also needed to synthesize the amino acid tyrosine (Tyr) by the phenylalanine hydroxylase enzyme mainly in the liver and kidney. Phenylalanine is an indispensable amino acid and phenylalanine flux in the body is entirely derived from the diet and cellular protein turnover. Plasma phenylalanine concentrations are elevated in patients with cancer. ![]() It is also known that phenylalanine consumption correlates with the growth of tumor cell lines and negative patient outcomes. A well-known example is the non-essential amino acid glutamine, which is associated with neoplastic proliferation. The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Ĭancer cells are known to exhibit unusual metabolic activity to sustain their proliferation. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. ![]() ![]() The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. ![]() Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
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