Proximal Fluid Proteome Profiling of Mouse Colon Tumors Reveals Biomarkers for Early Diagnosis of Human Colorectal Cancer

Abstract

Purpose: Early detection of colorectal cancer (CRC) and its precursor lesions is an effective approach to reduce CRC mortality rates. This study aimed to identify novel protein biomarkers for the early diagnosis of CRC.Experimental Design: Proximal fluids are a rich source of candidate biomarkers as they contain high concentrations of tissue-derived proteins. The FabplCre;Apc 15lox/þ mouse model represents early-stage development of human sporadic CRC. Proximal fluids were collected from normal colon and colon tumors and subjected to in-depth proteome profiling by tandem mass spectrometry. Carcinoembryonic antigen (CEA) and CHI3L1 human serum protein levels were determined by ELISA.Results: Of the 2,172 proteins identified, quantitative comparison revealed 192 proteins that were significantly (P < 0.05) and abundantly (>5-fold) more excreted by tumors than by controls. Further selection for biomarkers with highest specificity and sensitivity yielded 52 candidates, including S100A9, MCM4, and four other proteins that have been proposed as candidate biomarkers for human CRC screening or surveillance, supporting the validity of our approach. For CHI3L1, we verified that protein levels were significantly increased in sera from patients with adenomas and advanced adenomas compared with control individuals, in contrast to the CRC biomarker CEA.Conclusion: These data show that proximal fluid proteome profiling with a mouse tumor model is a powerful approach to identify candidate biomarkers for early diagnosis of human cancer, exemplified by increased CHI3L1 protein levels in sera from patients with CRC precursor lesions.

Proteome Profiling of Cancer-Associated Fibroblasts Identifies Novel Proinflammatory Signatures and Prognostic Markers for Colorectal Cancer

“…The most relevant is its inability to develop metastasis. Recently, an adenomatous polyposis coli (APC) mutant mouse model of sporadic colon cancer was used to analyze the proximal fluid proteome of whole tumor tissues, without isolation of pure cell populations (24). Looking at the candidate protein biomarkers identified in that model, we have observed several coincidences in ECM fibroblast-related proteins: biglycan, cingulin, collagens, decorin, or lamin A/C, confirming the relative similarity of both models.…”

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

“…In addition to tumour-associated antigens, we further report several proteins attributed to overexpression or accumulation in human tumours and biofluids, including melanotransferrin (melanoma-associated antigen p97), protocadherin Fat 1 (FAT1), fibroblast growth factor-binding protein 1, and mucins 5AC/5B/13136137138 (Table 2). Several of these proteins were validated using immunoblotting (Fig.…”

Circulating pEGFR Is a Candidate Response Biomarker of Cetuximab Therapy in Colorectal Cancer

“…Others and we have shown that cancer cell line secretomes consist of proteins that might help in monitoring critical aspects of cancer progression and therapeutics (15)(16)(17). Furthermore, secretome analysis has been used for comparative proteomics to study different aspects of cancer, particularly for tumor biomarker discovery (18,19).…”