Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies
Proteomics
0301 basic medicine
0303 health sciences
Liver Neoplasms
Lipid Metabolism
High-Throughput Screening Assays
Neoplasm Proteins
3. Good health
Gene Expression Regulation, Neoplastic
Genetic Heterogeneity
03 medical and health sciences
0302 clinical medicine
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Humans
Colorectal Neoplasms
DOI:
10.1002/hep.26608
Publication Date:
2013-07-06T04:57:04Z
AUTHORS (13)
ABSTRACT
Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis displayed increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demonstrate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. Conclusion: The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of targetable antigens. (HEPATOLOGY 2014;59:924–934)
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