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A novel antibody against cancer stem cell biomarker, DCLK1-S, is potentially useful for assessing colon cancer risk after screening colonoscopy.

ABSTRACT: 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 ?-promoter of hDCLK1 gene, while normal colons express long isoform (DCLK1-L; isoform 1) from 5'(?)-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.

SUBMITTER: Sarkar S

PROVIDER: S-EPMC5623180 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A novel antibody against cancer stem cell biomarker, DCLK1-S, is potentially useful for assessing colon cancer risk after screening colonoscopy.

Sarkar Shubhashish S Popov Vsevolod L VL O'Connell Malaney R MR Stevenson Heather L HL Lee Brian S BS Obeid Robert A RA Luthra Gurinder K GK Singh Pomila P

Laboratory investigation; a journal of technical methods and pathology 20170417 10

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 DC ...[more]

PMID: 28414327

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Project description:BACKGROUND:A recent study demonstrated the effectiveness of the New Hampshire Colorectal Cancer Screening Program's (NHCRCSP) patient navigation (PN) program. The PN intervention was delivered by telephone with navigators following a rigorous, six-topic protocol to support low-income patients to complete colonoscopy screening. We applied the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework to examine implementation processes and consider potential scalability of this intervention. METHODS:A mixed-methods evaluation study was conducted including 1) a quasi-experimental, retrospective, comparison group study examining program effectiveness, 2) secondary analysis of NHCRCSP program data, and 3) a case study. Data for all navigated patients scheduled and notified of their colonoscopy test date between July 1, 2012 and September 30, 2013 (N?=?443) were analyzed. Researchers were provided in-depth call details for 50 patients randomly selected from the group of 443. The case study included review of program documents, observations of navigators, and interviews with 27 individuals including staff, patients, and other stakeholders. RESULTS:Program reach was state-wide, with navigators serving patients from across the state. The program successfully recruited patients from the intended priority population who met the established age, income, and insurance eligibility guidelines. Analysis of the 443 NHCRCSP patients navigated during the study period demonstrated effectiveness with 97.3% completing colonoscopy, zero missed appointments (no-shows), and 0.7% late cancellations. Trained and supervised nurse navigators spent an average of 124.3?min delivering the six-topic PN protocol to patients. Navigators benefited from a real-time data system that allowed for patient tracking, communication across team members, and documentation of service delivery. Evaluators identified several factors supporting program maintenance including consistent funding support from CDC, a strong program infrastructure, and partnerships. CONCLUSIONS:Factors supporting implementation included funding for colonoscopies, use of registered nurses, a clinical champion, strong partnerships with primary care and endoscopy sites, fidelity to the PN protocol, significant intervention dose, and a real-time data system. Further study is needed to assess scalability to other locations.

Project description:ImportanceRandomized clinical screening trials have shown that sigmoidoscopy screening reduces colorectal cancer (CRC) incidence and mortality. Colonoscopy has largely replaced sigmoidoscopy for CRC screening, but long-term results from randomized trials on colonoscopy screening are still lacking.ObjectiveTo estimate the additional screening benefit of colonoscopy compared with sigmoidoscopy.Design, setting, and participantsThis comparative effectiveness simulation study pooled data on 358 204 men and women randomly assigned to sigmoidoscopy screening or usual care in 4 randomized sigmoidoscopy screening trials conducted in Norway, Italy, the US, and UK with inclusion periods in the years 1993 to 2001. The primary analysis of the study was conducted from January 19 to December 30, 2021.InterventionInvitation to endoscopic screening.Main outcomes and measuresPrimary outcomes were CRC incidence and mortality. Using pooled 15-year follow-up data, colonoscopy screening effectiveness was estimated assuming that the efficacy of colonoscopy in the proximal colon was similar to that observed in the distal colon in the sigmoidoscopy screening trials. The simulation model was validated using data from Norwegian participants in a colonoscopy screening trial.ResultsThis analysis included 358 204 individuals (181 971 women [51%]) aged 55 to 64 years at inclusion with a median follow-up time ranging from 15 to 17 years. Compared with usual care, colonoscopy prevented an estimated 50 (95% CI, 42-58) CRC cases per 100 000 person-years, corresponding to 30% incidence reduction (rate ratio, 0.70 [95% CI, 0.66-0.75]), and prevented an estimated 15 (95% CI, 11-19) CRC deaths per 100 000 person-years, corresponding to 32% mortality reduction (rate ratio, 0.68 [95% CI, 0.61-0.76]). The additional benefit of colonoscopy screening compared with sigmoidoscopy was 12 (95% CI, 10-14) fewer CRC cases and 4 (95% CI, 3-5) fewer CRC deaths per 100 000 person-years, corresponding to percentage point reductions of 6.9 (95% CI, 6.0-7.9) for CRC incidence and 7.6 (95% CI, 5.7-9.6) for CRC mortality. The number needed to switch from sigmoidoscopy to colonoscopy screening was 560 (95% CI, 486-661) to prevent 1 CRC case and 1611 (95% CI, 1275-2188) to prevent 1 CRC death.Conclusions and relevanceThe findings of this comparative effectiveness study assessing long-term follow-up after CRC screening suggest that there was an additional preventive effect on CRC incidence and mortality associated with colonoscopy screening compared with sigmoidoscopy screening, but the additional preventive effect was less than what was achieved by introducing sigmoidoscopy screening where no screening existed. The results probably represent the upper limit of what may be achieved with colonoscopy screening compared with sigmoidoscopy screening.

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A novel antibody against cancer stem cell biomarker, DCLK1-S, is potentially useful for assessing colon cancer risk after screening colonoscopy.

Publications

A novel antibody against cancer stem cell biomarker, DCLK1-S, is potentially useful for assessing colon cancer risk after screening colonoscopy.

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