A novel antibody against cancer stem cell biomarker, DCLK1-S, is potentially useful for assessing colon cancer risk after screening colonoscopy
| Autor: | Vsevolod L. Popov, Brian S. Lee, Shubhashish Sarkar, Malaney R. O'Connell, Pomila Singh, Heather L. Stevenson, Gurinder Luthra, Robert A. Obeid |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adenoma Colorectal cancer Colon anti-DCLK1-S antibody Colonoscopy Pharmacology Protein Serine-Threonine Kinases Antibodies Article Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Doublecortin-Like Kinases Colon surgery Cancer stem cell Biomarkers Tumor Medicine Humans Protein Isoforms prognostic biomarker Molecular Biology Early Detection of Cancer Retrospective Studies medicine.diagnostic_test business.industry Cancer stem cells Intracellular Signaling Peptides and Proteins Cancer Cell Biology medicine.disease HCT116 Cells Immunohistochemistry 3. Good health 030104 developmental biology HEK293 Cells 030220 oncology & carcinogenesis Colonic Neoplasms Cancer research Biomarker (medicine) business sub-cellular localization |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology |
| ISSN: | 1530-0307 |
| Popis: | DCLK1 expression is critically required for maintaining growth of human colon cancer cells (hCCCs). Human colorectal tumors (CRCs) and hCCCs express a novel short isoform of DCLK1 (DCLK1-S; isoform 2) from β-promoter of hDCLK1 gene, while normal colons express long isoform (DCLK1-L; isoform 1) from 5'(α)-promoter, suggesting that DCLK1-S, and not DCLK1-L, marks cancer stem cells (CSCs). Even though DCLK1-S differs from DCLK1-L by only six amino acids, we succeeded in generating a monospecific DCLK1-S-Antibody (PS41014), which does not cross-react with DCLK1-L, and specifically detects CSCs. Subcellular localization of S/L-isoforms was examined by immune-electron-microscopy (IEM). Surprisingly, besides plasma membrane and cytosolic fractions, S/L also localized to nuclear/mitochondrial fractions, with pronounced localization of S-isoform in the nuclei and mitochondria. Sporadic CRCs develop from adenomas. Screening colonoscopy is used for detection/resection of growths, and morphological/pathological criteria are used for risk assessment and recommendations for follow-up colonoscopy. But, these features are not precise and majority of the patients will never develop cancer. We hypothesized that antibody-based assay(s), which identify CSCs, will significantly improve prognostic value of morphological/pathological criteria. We conducted a pilot retrospective study with PS41014-Ab, by staining archived adenoma specimens from patients who developed (high-risk), or did not develop (low-risk) adenocarcinomas within 10-15 years. PS41014-Ab stained adenomas from initial and follow-up colonoscopies of high-risk patients, at significantly higher levels (three to fivefold) than adenomas from low-risk patients, suggesting that PS41014-Ab could be used as an additional tool for assessing CRC risk. CRC patients, with high DCLK1-S-expressing tumors (by qRT-PCR), were reported to have worse overall survival than low expressers. We now report that DCLK1-S-specific Ab may help to identify high-risk patients at the time of index/screening colonoscopy. |
| Databáze: | OpenAIRE |
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