Proteomic Profiling and Biomarker Discovery in Colorectal Liver Metastases
Abstract
:1. Introduction
2. Characteristics of Preclinical Exploratory Studies on Proteomic Biomarkers in Colorectal Liver Metastases
3. Proteomic Profiling of Colorectal Liver Metastases Tissue Identifies Prognostically Distinct Groups
4. Adjuvant Treatment Stratification for Stage II and Stage III Colorectal Cancer
5. Comparison of Colorectal Liver Metastases and Primary Colorectal Tumours
6. In-Depth Proteomic Characterisation of Colorectal Liver Metastases
7. Proteomic Profiling of the Extracellular Matrix in Colorectal Liver Metastases
8. Post-Translational Protein Modification in Colorectal Liver Metastases
9. Proteomics as a Principal Component of Multiomics in Colorectal Liver Metastases
10. Limitations in Proteomic Biomarker Discovery in Colorectal Liver Metastases
11. Translational Proteomics in Colorectal Liver Metastases
12. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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First Author/ Reference/Year/Journal | Biospecimen | Mass-Spectrometry-Based Technique | Discovery Cohort Characteristics (Sample Size and Comparator) | Key Biomarkers and Findings |
---|---|---|---|---|
Michal S et al. [37] 2021 Journal of Personalized Medicine | FFPE tissue | Label-free LC-MS/MS | n = 29 with recurrence < 6 months after resection of CLRM Comparison: n = 29 with recurrence 6–12 months after resection of CRLM | Upregulation of matrix metalloproteinase 7 (MMP7) and dehydropeptidase 1 (DPEP1) in poor-prognosis group. Downregulation of lysyl oxidase-like 1 (LOXL1) in poor-prognosis group. A third of differentially expressed proteins associated with extracellular matrix. |
Fahrner M et al. [38] 2021 Neoplasia | FFPE tissue | Label-free LC-MS/MS | n = 7 synchronous CRLM Comparison: n = 7 matched primary CRC | Metabolic proteins: pyruvate carboxylase (PC) and fructose-bisphosphate aldolase B (ALDOB), and fructose-1,6-bisphosphatase 1 (FBP1) upregulated in CRLM. Immune system proteins: enrichment of complement components C1, C4, C5, C9 in CRLM. Structural proteins: depletion of desmin (DES), synemin (SYNM) and filamin-C (FLNC) in CRLM. |
Liu X et al. [39] 2020 Clinical and Translational Oncology | Fresh frozen tissue | TMT-labelling, LC-MS/MS | n = 8 CRLM Comparison: n = 8 primary tumour | Upregulation of fibronectin (FN1), metalloproteinase inhibitor 1 (TIMP1), thrombospondin-1 (THBS1), periostin (POSTN) and in CRLM. |
Voß H et al. [40] 2020 Clinical and Experimental Metastasis | Fresh frozen tissue | Label-free LC-MS/MS | n = 1 with 3 metachronous CRLM Comparison: N/A | Upregulation of 56 extracellular matrix-associated proteins including tenascin C (TNC), nidogen-1 (NID1), fibulin-1 (FBLN1), vitronectin (VTN). |
van Huizen NA [41] 2020. Frontiers in Oncology | FFPE tissue | Label-free nano-LC-MS/MS | n = 14 CRLM Comparison: n = 14 matched liver tissue, matched primary CRC and normal colonic tissue | Overall degree of collagen hydroxylation was significantly lower in CRLM and primary CRC compared to normal colon Downregulation of 11 peptides with a specific number of hydroxylation in CRLM compared to normal liver tissue. |
van Huizen et al. [42] 2019 Journal of Proteome Research | FFPE tissue | Nano-LC-ESI-ETD-HCD | n = 2 CLRM Comparison: n = 2 matched normal liver tissue | Lower ratio of 4xHyp at position 584 of collagen alpha-2(I) chain (COL1A2) in CRLM. |
van Huizen NA [43] 2019 Journal of Biological Chemistry | FFPE tissue | Label-free nano-LC-MS/MS | n = 30 patients Comparison: n = 30 matched normal liver tissue, primary CRC and normal colon tissue | Upregulation of four collagen types in CRLM: COL10A1, COL12A1 (most abundant), COL14A1, COL15A1. Upregulation of six non-collagen colon-specific proteins in CRLM: cadherin-17 (CDH17), protein phosphatase 1 regulatory subunit 1B (PPP1R1B/DARP-32), keratin, type 1 cytoskeletal 20 (KRT20), carcinoembryonic antigen-related cell-adhesion molecule 5 (CEACAM5), cell-surface AA33 antigen (GPA33), mucin-13 (MUC13). |
Ku X et al. [44] 2019 Analytical Cellular Pathology | Fresh frozen tissue | TMT labelling, nano-LC-MS/MS | n = 9 CRLM Comparison: n = 9 matched primary tumour and normal colonic tissue | Upregulation of filamin A-interacting protein 1-like (FILIP1L) and plasminogen (PLG) in CRLM. |
Yang W et al. [45] 2019 Proteomics Clinical Applications | Fresh frozen tissue | Label-free nano-LC-MS/MS | n = 17 CRLM Comparison: n = 20 Stage III CRC who did not develop CRLM | Nine key proteins identified in CRLM: heat shock protein family D member 1 (HSPD1), eukaryotic translation elongation factor 1 gamma, heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), fibrinogen beta chain (FGB), Talin 1 (TLN 1), adaptor-related protein complex 2 subunit alpha-2 (AP2A2), serrated RNA effector molecule homolog (SRRT), apolipoprotein C3 (APOC3), and phosphoglucomutase 5 (PGM5). Fibrinogen beta chain is a key biomarker for CRLM. |
Kim EK et al. [46] 2019 Cancer Genomics Proteomics | Fresh frozen tissue | 2D-PAGE, MALDI-TOF MS | n = 5 CRLM Comparison: n = 5 synchronous primary CRC | Upregulation of serpin family A member 1 (SERPINA1), apolipoprotein AI (APOA1), intelectin 1 (ITLN1), desmin (DES), diazepam-binding inhibitor (DBI), succinate dehydrogenase complex flavoprotein subunit A (SDHA), and carbonic anhydrase 1 (CA1) in CRLM. |
Kirana C et al. [47] 2019 Clinical Proteomics | Fresh frozen tissue | 2D-DIGE, MALDI-TOF MS | n = 8 stage II CRC with CRLM within 5 years after surgery Comparison: n = 11 stage II CRC patients with no metastasis within 5 years after surgery | Upregulation of HLA class I histocompatibility antigen, B alpha chain (HLAB), A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2), latent-transforming growth factor beta-binding protein 3 (LTBP3), protein jagged-2 (JAG2) and nucleoside diphosphate kinase B (NME2) on tumour cells was associated with CRC progression and invasion, metastasis and CRC-specific survival. |
Yuzhalin AE et al. [48] 2018 Nature Communications | Fresh frozen tissue | ECM enrichment, label-free, nano-LC-MS/MS | n = 5 CRLM Comparison: n = 5 matched normal liver, primary CRC and normal colon. | Increased amounts of citrullinated proteins in CRLM compared to normal liver. Primary CRC and normal colonic mucosa. Peptidylarginine deiminase 4 (PAD4)-driven citrullination of the extracellular matrix is essential for CRLM growth. Other upregulated proteins included versican (VCAN), metalloproteinase inhibitor 1 precursor (T1MP1), latent-transforming growth factor beta-binding protein (LTBP) 1–3, epithelial discoidin domain-containing receptor 1 (DDR1), and protein S100-A10 (S100A10). |
Yang Q et al. [49] 2017 Journal of Proteomics | Fresh frozen tissue | 1D and 2D-PAGE, nano-LC-MS/MS | n = 8 CRLM Comparison: n = 8 matched primary, CRLM and adjacent normal colon and liver tissues. | Olfactomedin 4 (OLFM4), CD11b/integrin alpha m (ITGAM) and integrin alpha-2 (ITGA2) significantly overexpressed in primary CRC and CRLM |
Shen Z et al. [50] 2016 Journal of Proteomics | Fresh frozen tissue | Acetylated peptide enrichment, TMT labelling, LC-MS/MS | n = 3 CRLM Comparison: n = 3 matched primary CRC | HIST2H3AK19Ac and H2BLK121Ac were the acetylated histones most changed. Tropomyosin beta chain (TPM2), K152Ac and alcohol dehydrogenase 1B (ADH1B), K331Ac were the acetylated non-histones most altered in CRLM. |
Naba et al. [51] 2014 BMC Cancer | Fresh frozen tissue | ECM enrichment, off-gel electrophoresis, LC-MS/MS | n = 3 CRLM Comparison: n = 3 matched primary CRC and normal colonic tissue | Hemopexin (HPX), osteopontin/secreted phospho-protein 1 (SPP1), cartilage oligomeric matrix protein (COMP), insulin-like growth factor-binding protein complex acid labile subunit (IGFALS), fibronectin type III domain-containing protein1 (FNDC1), bone morphogenetic protein 1 (BMP1) and complement C1q tumour necrosis factor-related protein 5 (C1QTNF5). Extracellular matrix protein signatures are potential tissue or serological biomarkers. |
Turtoi A et al. [52] 2014 Hepatology | FFPE tissue | MALDI-MS imaging, nano-UPLC-qTOF MS | n = 8 CRLM Comparison: n = 8 normal liver, n = 3 matched primary CRC | High expression of latent-transforming growth factor beta-binding protein 2 (LTBP2) and transforming growth factor-beta-induced protein ig-h3 (TGFBI) were consistent features of CRLM and are absent in normal tissues. |
Kirana et al. [53] 2012 International Journal of Proteomics | Fresh frozen tissue | 2D-DIGE, MALDI-TOF MS | n = 8 CRLM Comparison: n = 8 matched primary CRC | Overexpression of cathepsin D (CTSD) in cells from the main tumour body showed significant correlation with subsequent distant metastasis and shorter cancer-specific survival. |
Authors | Biospecimen | MS Technique | Sample Number with CRLM | Key Findings |
---|---|---|---|---|
Li C et al. [54] 2020 Cancer Cell | Fresh frozen tissue | Phosphopeptide enrichment, nano-LC-MS/MS | n = 43 Comparator: n = 146 primary CRC, adjacent normal colon and normal liver | Three CRC subtypes with distinct molecular signatures and clinical prognosis were defined using proteomic profiling. Phosphoproteomic pattern distinguishes metastatic from non-metastatic colorectal cancer. |
Blank-Landeshammer B et al. [55] 2019 Cancers (Basel) | Fresh frozen tissue | Phosphopeptide enrichment, stable heavy isotope peptide labelling, nano-LC-MS/MS | n = 8 Comparator: n = 6 paired normal liver tissue | Low expression of actionable somatic mutations including KRASG12V can be predicted by precise quantitation of altered proteins such as SRPX2, S6K-alpha-5, GTPase KRas, PTBP1, ARL2, PPP1R14C and HAUS7 |
Ma YS. [56] 2019 Molecular Therapy Oncolytics | Fresh frozen tissue | Label-free nano-LC-MS/MS | n = 23 Comparator: n = 21 paired normal colorectal cancer tissue with or without liver metastasis | UQCR5 and FDFT1 were frequently overexpressed in the CRLM cohort and shown to have potential prognostic value. High expression of UQCR5 and was associated with worse overall survival and progression-free survival. High expression of FDFT1 was associated with better overall survival and progression-free survival. |
Ma YS et al. [57] 2018 Molecular Cancer | Fresh frozen tissue | Nano-LC-MS/MS-based shotgun proteomics profiling | n = 23 Comparator: n = 21 non-metastatic CRC | Four CNV-mRNA-protein correlated proteins were associated with worse overall survival: HSP90AB1, COL1A2, FABP5 and BGN. Two single amino acid variants were associated with shorter overall and disease-free survival: MYH9 and CCT6A |
Snoeren N et al. [58] 2013. British Journal of Cancer | Fresh frozen tissue | SDS-PAGE gel electrophoresis and in-gel digestion, label-free nano-LC-MS/MS | n = 10 <6 months to recurrence (early), n = 5 >24 months to recurrence (prolonged), n = 5 | SERPINB5 which encodes for Maspin was the most upregulated (~2.1 times higher, p = 0.01) in patients with early recurrence compared to prolonged (>24 months) time to recurrence. Maspin was the only overlapping factor among 14 genes and 46 genes that showed a significant association with recurrence. |
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Wong, G.Y.M.; Diakos, C.; Hugh, T.J.; Molloy, M.P. Proteomic Profiling and Biomarker Discovery in Colorectal Liver Metastases. Int. J. Mol. Sci. 2022, 23, 6091. https://doi.org/10.3390/ijms23116091
Wong GYM, Diakos C, Hugh TJ, Molloy MP. Proteomic Profiling and Biomarker Discovery in Colorectal Liver Metastases. International Journal of Molecular Sciences. 2022; 23(11):6091. https://doi.org/10.3390/ijms23116091
Chicago/Turabian StyleWong, Geoffrey Yuet Mun, Connie Diakos, Thomas J. Hugh, and Mark P. Molloy. 2022. "Proteomic Profiling and Biomarker Discovery in Colorectal Liver Metastases" International Journal of Molecular Sciences 23, no. 11: 6091. https://doi.org/10.3390/ijms23116091
APA StyleWong, G. Y. M., Diakos, C., Hugh, T. J., & Molloy, M. P. (2022). Proteomic Profiling and Biomarker Discovery in Colorectal Liver Metastases. International Journal of Molecular Sciences, 23(11), 6091. https://doi.org/10.3390/ijms23116091