Early Detection of Pancreatic Cancer: Applying Artificial Intelligence to Electronic Health Records.

ABSTRACT: The potential of artificial intelligence (AI) applied to clinical data from electronic health records (EHRs) to improve early detection for pancreatic and other cancers remains underexplored. The Kenner Family Research Fund, in collaboration with the Cancer Biomarker Research Group at the National Cancer Institute, organized the workshop entitled: "Early Detection of Pancreatic Cancer: Opportunities and Challenges in Utilizing Electronic Health Records (EHR)" in March 2021. The workshop included a select group of panelists with expertise in pancreatic cancer, EHR data mining, and AI-based modeling. This review article reflects the findings from the workshop and assesses the feasibility of AI-based data extraction and modeling applied to EHRs. It highlights the increasing role of data sharing networks and common data models in improving the secondary use of EHR data. Current efforts using EHR data for AI-based modeling to enhance early detection of pancreatic cancer show promise. Specific challenges (biology, limited data, standards, compatibility, legal, quality, AI chasm, incentives) are identified, with mitigation strategies summarized and next steps identified.

Prediagnostic Image Data, Artificial Intelligence, and Pancreatic Cancer: A Tell-Tale Sign to Early Detection.

Pancreatic cancer continues to be one of the deadliest malignancies and is the third leading cause of cancer-related mortality in the United States. Based on several models, it is projected to become the second leading cause of cancer-related deaths by 2030. Although the overall survival rate for patients diagnosed with pancreatic cancer is less than 10%, survival rates are increasing in those whose cancers are detected at an early stage, when intervention is possible. There are, however, no reliable biomarkers or imaging technology that can detect early-stage pancreatic cancer or accurately identify precursors that are likely to progress to malignancy. The Alliance of Pancreatic Cancer Consortia, a virtual consortium of researchers, clinicians, and advocacies focused on early diagnosis of pancreatic cancer, was formed in 2016 to provide a platform and resources to discover and validate biomarkers and imaging methods for early detection. The focus of discussion at the most recent alliance meeting was on imaging methods and the use of artificial intelligence for early detection of pancreatic cancer.

Validation of Biomarkers for Early Detection of Pancreatic Cancer: Summary of The Alliance of Pancreatic Cancer Consortia for Biomarkers for Early Detection Workshop.

Pancreatic cancer is the third leading cause of cancer death in the United States, and the 5-year relative survival for patients diagnosed with pancreatic cancer is less than 10%. Early intervention is the key to a better survival outcome. Currently, there are no biomarkers that can reliably detect pancreatic cancer at an early stage or identify precursors that are destined to progress to malignancy. The National Cancer Institute in partnership with the Kenner Family Research Fund and the Pancreatic Cancer Action Network convened a Data Jamboree on Biomarkers workshop on December 5, 2016, to discuss and evaluate existing or newly developed biomarkers and imaging methods for early detection of pancreatic cancer. The primary goal of this workshop was to determine if there are any promising biomarkers for early detection of pancreatic cancer that are ready for clinical validation. The Alliance of Pancreatic Cancer Consortia for Biomarkers for Early Detection, formed under the auspices of this workshop, will provide the common platform and the resources necessary for validation. Although none of the biomarkers evaluated seemed ready for a large-scale biomarker validation trial, a number of them had sufficiently high sensitivity and specificity to warrant additional research, especially if combined with other biomarkers to form a panel.

US National Cancer Institute-China Collaborative Studies on Chinese Medicine and Cancer.

Since 2007, the US National Cancer Institute (NCI) Office of Cancer Complementary and Alternative Medicine (OCCAM), together with the Cancer Institute of the China Academy of Chinese Medical Sciences (CICACMS), institutes at China Academy of Sciences and Chinese Academy of Medical Sciences, have engaged in collaborations on Chinese medicine (CM) and cancer research. Through these collaborations, CM drugs and compounds have been studied at NCI labs. This paper summarizes the discoveries and progress on these research projects, exploring the aspects of cancer prevention, botanical drug mechanisms of action and component analysis/quality control (QC), and anticancer activity screening. These and other related projects have been presented in various jointly convened workshops and have provided the backdrop for establishing a new organization, the International Consortium for CM and Cancer, to promote international collaborations in this field.

Use of a handheld terahertz pulsed imaging device to differentiate benign and malignant breast tissue.

Since nearly 20% of breast-conserving surgeries (BCS) require re-operation, there is a clear need for developing new techniques to more accurately assess tumor resection margins intraoperatively. This study evaluates the diagnostic accuracy of a handheld terahertz pulsed imaging (TPI) system to discriminate benign from malignant breast tissue ex vivo. Forty six freshly excised breast cancer samples were scanned with a TPI handheld probe system, and histology was obtained for comparison. The image pixels on TPI were classified using (1) parameters in combination with support vector machine (SVM) and (2) Gaussian wavelet deconvolution in combination with Bayesian classification. The results were an accuracy, sensitivity, specificity of 75%, 86%, 66% for method 1, and 69%, 87%, 54% for method 2 respectively. This demonstrates the probe can discriminate invasive breast cancer from benign breast tissue with an encouraging degree of accuracy, warranting further study.

Systemic Metabolite Changes in Wild-type C57BL/6 Mice Fed Black Raspberries.

INTRODUCTION: Freeze-dried black raspberries (BRBs) elicit chemopreventive effects against colorectal cancer in humans and in rodents. The objective of this study was to investigate potential BRB-caused metabolite changes using wild-type (WT) C57BL/6 mice. METHODS AND RESULTS: WT mice were fed either control diet or control diet supplemented with 5% BRBs for 8 wk. A nontargeted metabolomic analysis was conducted on colonic mucosa, liver, and fecal specimens collected from both diet groups. BRBs significantly changed the levels of 41 colonic mucosa metabolites, 40 liver metabolites, and 34 fecal metabolites compared to control diet-fed mice. BRBs reduced 34 lipid metabolites in colonic mucosa and increased levels of amino acids in liver. One metabolite, 3-[3-(sulfooxy) phenyl] propanoic acid, might be a useful biomarker of BRB consumption. In addition, BRB powder was found to contain 30-fold higher levels of linolenate compared to control diets. Consistently, multiple omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including stearidonate, docosapentaenoate (ω-3 DPA), eicosapentaenoate (EPA), and docosahexaenoate (DHA), were significantly elevated in livers of BRB-fed mice. CONCLUSION: The data from the current study suggest that BRBs produce systemic metabolite changes in multiple tissue matrices, supporting our hypothesis that BRBs may serve as both a chemopreventive agent and a beneficial dietary supplement.

Diallyl Disulfide (DADS), a Constituent of Garlic, Inactivates NF-κB and Prevents Colitis-Induced Colorectal Cancer by Inhibiting GSK-3ß.

There is a strong belief that garlic has medicinal properties and may even reduce the risk of developing certain cancers including those of the gastrointestinal tract. The chemopreventive effects of garlic may be attributed to the anti-inflammatory properties of the sulfur-containing constituents of garlic, which includes diallyl disulfide (DADS). Here, we demonstrate that DADS prevented colorectal tumorigenesis in a mouse model of colitis-induced colorectal cancer. Supplementation with 85 ppm of DADS (60 mg daily human equivalent dose) in the diet of FVB/N mice treated with chemical carcinogen azoxymethane (AOM) and colonic irritant dextran sodium sulfate (DSS) resulted in the reduction in tumor incidence, tumor number, and tumor burden by 21.54%, 47.3%, and 66.4%, respectively. Further analysis revealed that mice fed the DADS-supplemented diet resolved the initial DSS-induced inflammation faster than those on the control diet, preventing prolonged inflammation and cellular transformation. Subsequent mechanistic studies in vitro suggest that DADS chemopreventive effects are mediated through NF-κB signaling. When SW480 colorectal cancer cells were treated with DADS, NF-κB nuclear localization and activity were diminished. Interestingly, NF-κB suppression was found to be dependent on DADS inhibition of GSK-3ß, a positive regulator of NF-κB. Inhibition of GSK-3ß and loss of nuclear NF-κB activity were also observed in vivo in AOM/DSS-treated mice fed a diet supplemented with 85 ppm DADS. Our results indicate that DADS can prevent tumorigenesis by suppressing inflammation, a process largely involving GSK-3ß inhibition and consequential reduction in NF-κB nuclear localization. Cancer Prev Res; 9(7); 607-15. ©2016 AACR.

Black raspberries suppress colonic adenoma development in ApcMin/+ mice: relation to metabolite profiles.

Freeze-dried black raspberries (BRBs) have demonstrated chemopreventive effects in a dietary intervention trial with human colorectal cancer patients. The aim of this study was to investigate BRB-caused metabolite changes using the Apc(Min/+) mouse as a model of human colorectal cancer. Wild-type (WT) mice were fed control diet, and Apc(Min/+) mice were fed either control diet or control diet supplemented with 5% BRBs for 8 weeks. Colonic and intestinal polyp size and number were measured. A non-targeted metabolomic analysis was conducted on colonic mucosa, liver and fecal specimens. Eight weeks of BRB treatment significantly decreased intestinal and colonic polyp number and size in Apc(Min/+) mice. The apc gene mutation significantly changed 52 metabolites in colonic mucosa associated with increased amino acid and decreased lipid metabolites, as well as 39 liver and 8 fecal metabolites. BRBs significantly reversed 23 apc-regulated metabolites, including 13 colonic mucosa, 8 liver and 2 fecal metabolites that were involved in amino acid, glutathione, lipid and nucleotide metabolism. Of these, changes in eight metabolites were linearly correlated with decreased colonic polyp number and size in BRB-treated Apc(Min/+) mice. Elevated levels of putrescine and linolenate in Apc(Min/+) mice were significantly decreased by BRBs. Ornithine decarboxylase expression, the key enzyme in putrescine generation, was fully suppressed by BRBs. These results suggest that BRBs produced beneficial effects against colonic adenoma development in Apc(Min/+) mice and modulated multiple metabolic pathways. The metabolite changes produced by BRBs might potentially reflect the BRB-mediated chemopreventive effects in colorectal cancer patients.

Exploration of Metal Chloride Uptake for Improved Performance Characteristics of PbSe Quantum Dot Solar Cells.

We explored the uptake of metal chloride salts with +1 to +3 metals of Na(+), K(+), Zn(2+), Cd(2+), Sn(2+), Cu(2+), and In(3+) by PbSe QD solar cells. We also compared CdCl2 to Cd acetate and Cd nitrate treatments. PbSe QD solar cells fabricated with a CdCl2 treatment are stable for more than 270 days stored in air. We studied how temperature and immersion times affect optoelectronic properties and photovoltaic cell performance. Uptake of Cd(2+) and Zn(2+) increase open circuit voltage, whereas In(3+) and K(+) increase the photocurrent without influencing the spectral response or first exciton peak position. Using the most beneficial treatments we varied the bandgap of PbSe QD solar cells from 0.78 to 1.3 eV and find the improved VOC is more prevalent for lower bandgap QD solar cells.

Beneficial Regulation of Metabolic Profiles by Black Raspberries in Human Colorectal Cancer Patients.

Dietary intervention of freeze-dried black raspberries (BRBs) in a group of human colorectal cancer patients has demonstrated beneficial effects, including proapoptosis, antiproliferation, and antiangiogenesis. The aim of this study was to investigate BRB-mediated metabolite changes from this same cohort of patients. Twenty-eight colorectal cancer patients were given 60 g BRB powder daily for 1 to 9 weeks. Urine and plasma specimens were collected before and after BRB intervention. A mass spectrometry-based nontargeted metabolomic analysis was conducted on each specimen. A total of more than 400 metabolites were annotated in each specimen. Of these 34 and 6 metabolites were significantly changed by BRBs in urine and plasma, respectively. Increased levels of 4-methylcatechol sulfate in both post-BRB urine and post-BRB plasma were significantly correlated with a higher level of apoptotic marker (TUNEL) in post-BRB tumors. One tricarboxylic acid (TCA) cycle metabolites, cis-aconitate, was increased in post-BRB urine. Furthermore, BRB-derived polyphenols were absorbed and metabolized to various benzoate species, which were significantly increased in post-BRB specimens. Increased benzoate levels were positively correlated with enhanced levels of amino acid metabolite. These results suggest that BRBs induce significant metabolic changes and affect energy generating pathways.This study supports the hypothesis that BRBs might be beneficial to colorectal cancer patients through the regulation of multiple metabolites.

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro.

Cryptotanshinone (CPT) is a natural compound extracted from herbal medicine that has been previously shown to possess antitumor properties in various types of human cancer cells. In the present study, we examined the potential role of CPT in the treatment of colorectal cancer. Using SW480, HCT116, and LOVO colorectal cancer cell lines, the effects of CPT on cell viability, apoptosis, and tumorigenicity were evaluated. The results showed that CPT significantly inhibited the growth and viability of SW480, HCT116, and LOVO cell lines by inducing apoptosis and prevented anchorage dependent growth on agar. In addition, CPT inhibited the activation of Signal transducer and activator of transcription 3 (Stat3) pathways in colorectal cancer cells. Stat3 is a transcription factor that mediates the expression of various genes associated with many cellular processes, such as inflammation and cell growth, and has been shown to promote several cancer types, including colorectal cancer. These findings indicate that CPT may be a potential candidate for the treatment and prevention of colorectal cancer in part by inhibiting the activation of Stat3.

Targeting AMPK for cancer prevention and treatment.

AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis. AMPK is activated in response to a shortage of energy. Once activated, AMPK can promote ATP production and regulate metabolic energy. AMPK is a known target for treating metabolic syndrome and type-2 diabetes; however, recently AMPK is emerging as a possible metabolic tumor suppressor and target for cancer prevention and treatment. Recent epidemiological studies indicate that treatment with metformin, an AMPK activator reduces the incidence of cancer. In this article we review the role of AMPK in regulating inflammation, metabolism, and other regulatory processes with an emphasis on cancer, as well as, discuss the potential for targeting AMPK to treat various types of cancer. Activation of AMPK has been found to oppose tumor progression in several cancer types and offers a promising cancer therapy. This review evaluates the evidence linking AMPK with tumor suppressor function and analyzes the molecular mechanisms involved. AMPK activity opposes tumor development and progression in part by regulating inflammation and metabolism.

Identification and monitoring of metabolite markers of dry bean consumption in parallel human and mouse studies.

SCOPE: Aim of the study was to identify and monitor metabolite markers of dry bean consumption in parallel human and mouse studies that each had shown chemopreventive effects of dry bean consumption on colorectal neoplasia risk. METHODS AND RESULTS: Using LC/mass spectroscopy ± ESI and GC/mass spectroscopy, serum metabolites of dry beans were measured in 46 men before and after a 4-week dry bean enriched diet (250 g/day) and 12 mice that received a standardized diet containing either 0 or 10% navy bean ethanol extract for 6 weeks; we also investigated fecal metabolites in the mice. The serum metabolites identified in these controlled feeding studies were then investigated in 212 polyp-free participants from the Polyp Prevention Trial who self-reported either increased (≥+31 g/day from baseline), high dry bean intake of ≥42 g/day in year 3 or low, unchanged dry bean consumption of <8 g/day; serum was analyzed from baseline and year 3. Serum pipecolic acid and S-methyl cysteine were elevated after dry bean consumption in human and mouse studies and reflected dry bean consumption in the Polyp Prevention Trial. CONCLUSION: Serum levels of pipecolic acid and S-methyl cysteine are useful biomarkers of dry bean consumption.

Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice.

Colorectal cancer, a leading cause of cancer death, has been linked to inflammation and obesity. Berberine, an isoquinoline alkaloid, possesses anti-inflammatory, anti-diabetes and anti-tumor properties. In the azoxymethane initiated and dextran sulfate sodium (AOM/DSS) promoted colorectal carcinogenesis mouse model, berberine treated mice showed a 60% reduction in tumor number (P = 0.009), a 48% reduction in tumors <2 mm, (P = 0.05); 94% reduction in tumors 2-4 mm, (P = 0.001), and 100% reduction in tumors >4 mm (P = 0.02) compared to vehicle treated mice. Berberine also decreased AOM/DSS induced Ki-67 and COX-2 expression. In vitro analysis showed that in addition to its anti-proliferation activity, berberine also induced apoptosis in colorectal cancer cell lines. Berberine activated AMP-activated protein kinase (AMPK), a major regulator of metabolic pathways, and inhibited mammalian target of rapamycin (mTOR), a downstream target of AMPK. Furthermore, 4E-binding protein-1 and p70 ribosomal S6 kinases, downstream targets of mTOR, were down regulated by berberine treatment. Berberine did not affect Liver kinase B1 (LKB1) activity or the mitogen-activated protein kinase pathway. Berberine inhibited Nuclear Factor kappa-B (NF-κB) activity, reduced the expression of cyclin D1 and survivin, induced phosphorylation of p53 and increased caspase-3 cleavage in vitro. Berberine inhibition of mTOR activity and p53 phosphorylation was found to be AMPK dependent, while inhibition NF-κB was AMPK independent. In vivo, berberine also activated AMPK, inhibited mTOR and p65 phosphorylation and activated caspase-3 cleavage. Our data suggests that berberine suppresses colon epithelial proliferation and tumorigenesis via AMPK dependent inhibition of mTOR activity and AMPK independent inhibition of NF-κB.

Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression.

Sporadic and non-hereditary mutations account for the majority of colorectal cancers (CRC). After the loss of adenomatous polyposis coli (APC) function and activation of the ß-catenin/LEF signaling pathway, activating mutations in Kras are major drivers of sporadic CRC. Preventing the outgrowth of cells that develop sporadic mutations will decrease CRC. Resveratrol, a naturally occurring polyphenolic compound has anti-inflammatory, anti-oxidant and anti-cancer activities. We used a genetically engineered mouse model for sporadic CRC where the APC locus is knocked out and Kras is activated specifically in the distal colon to determine the effects of resveratrol on preventing and treating CRC. Feeding mice a diet supplemented with 150 or 300 ppm resveratrol (105 and 210mg daily human equivalent dose, respectively) before tumors were visible by colonoscopy resulted in a 60% inhibition of tumor production. In the 40% of mice that did develop tumors Kras expression was lost in the tumors. In a therapeutic assay where tumors were allowed to develop prior to treatment, feeding tumor bearing mice with resveratrol resulted in a complete remission in 33% of the mice and a 97% decrease in tumor size in the remaining mice. Analysis of miRNA expression in non-tumoral and tumoral colonic tissue of resveratrol treated mice showed an increased expression of miR-96, a miRNA previously shown to regulate Kras translation. These data indicate that resveratrol can prevent the formation and growth of colorectal tumors by downregulating Kras expression.

The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells.

BACKGROUND: The small molecule NSC676914A was previously identified as an NF-κB inhibitor in TPA-stimulated HEK293 cells (Mol Can Ther 8:571-581, 2009). We hypothesized that this effect would also be seen in ovarian cancer cells, and serve as its mechanism of cytotoxicity. OVCAR3 and HEK293 cell lines stably containing a NF-κB luciferase reporter gene were generated. METHODS: Levels of NF-κB activity were assessed by luciferase reporter assays, after stimulation with LPA, LPS, TPA, and TNFα, in the presence or absence of a known NF-κB inhibitor or NSC676914A, and cytotoxicity was measured. RESULTS: NSC676914A was toxic to both OVCAR3 and HEK293 cells. We also investigated the cytotoxicity of NSC676914A on a panel of lymphoma cell lines with well characterized mutations previously shown to determine sensitivity or resistance to NF-κB inhibition. The compound did not show predicted patterns of effects on NF-κB activity in either lymphoma, ovarian or HEK293 cell lines. In HEK293 cells, the small molecule inhibited NF-κB when cells were stimulated, while in OVCAR3 cells it only partially inhibited NF-κB. Interestingly, we observed rescue of cell death with ROS inhibition. CONCLUSIONS: The current study suggests that the effect of NSC676914A on NF-κB depends on cell type and the manner in which the pathway is stimulated. Furthermore, as it is similarly toxic to lymphoma, OVCAR3 and HEK293 cells, NSC676914A shows promising NF-κB-independent anti-cancer activity in ovarian tumor cells.

In vivo MRI virtual colonography in a mouse model of colon cancer.

We have developed a reliable noninvasive method for monitoring colonic tumors and mucosal inflammation in a mouse model of colon cancer using magnetic resonance colonography (MRC). After a mild cleansing enema, the colon is filled with Fluorinert, a perfluorinated liquid that does not produce a proton MR signal. The mouse is placed in a dedicated volume MR receiver coil, and high-resolution images are acquired in three planes. The Fluorinert enema distends the mouse colon, creating an artifact-free black homogeneous background, allowing clear delineation of the inflamed colonic wall and visualization of luminal tumors in various stages of development. A gadolinium-based contrast agent can be administered i.v. to the animal to detect mural inflammation or tumor vascularity. This technique is useful for serial monitoring of the effects of preventive or therapeutic strategies on tumor development without killing the animal or requiring invasive endoscopies. The animal preparation and imaging can be completed in ∼1.5 h.

Tumor promoter-induced sulfiredoxin is required for mouse skin tumorigenesis.

Sulfiredoxin (Srx), the exclusive enzyme that reduces the hyperoxidized inactive form of peroxiredoxins (Prxs), has been found highly expressed in several types of human skin cancer. To determine whether Srx contributed to skin tumorigenesis in vivo, Srx null mice were generated on an FVB background. Mouse skin tumorigenesis was induced by a 7,12-dimethylbenz[α]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) protocol. We found that the number, volume and size of papillomas in Srx(-/-) mice were significantly fewer compared with either wild-type (Wt) or heterozygous (Het) siblings. Histopathological analysis revealed more apoptotic cells in tumors from Srx(-/-) mice. Mechanistic studies in cell culture revealed that Srx was stimulated by TPA in a redox-independent manner. This effect was mediated transcriptionally through the activation of mitogen-activated protein kinase and Jun-N-terminal kinase. We also demonstrated that Srx was capable of reducing hyperoxidized Prxs to facilitate cell survival under oxidative stress conditions. These findings suggested that loss of Srx protected mice, at least partially, from DMBA/TPA-induced skin tumorigenesis. Therefore, Srx has an oncogenic role in skin tumorigenesis and targeting Srx may provide novel strategies for skin cancer prevention or treatment.

Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65.

PDCD4 is a tumor suppressor induced by apoptotic stimuli that regulates both translation and transcription. Previously, we showed that overexpression of PDCD4 leads to decreased anchorage-independent growth in glioblastoma (GBM)-derived cell lines and decreased tumor growth in a GBM xenograft model. In inflammatory cells, PDCD4 stimulates tumor necrosis factor-induced activation of the transcription factor NF-κB, an oncogenic driver in many cancer sites. However, the effect of PDCD4 on NF-κB transcriptional activity in most cancers including GBM is still unknown. We studied the effect of PDCD4 on NF-κB-dependent transcriptional activity in GBM by stably overexpressing PDCD4 in U251 and LN229 cells. Stable PDCD4 expression inhibits NF-κB transcriptional activation measured by a luciferase reporter. The molecular mechanism by which PDCD4 inhibits NF-κB transcriptional activation does not involve inhibited expression of NF-κB p65 or p50 proteins. PDCD4 does not inhibit pathways upstream of NF-κB including the activation of IKKα and IKKß kinases or degradation of IκBα, events needed for nuclear transport of p65 and p50. PDCD4 overexpression does inhibit localization of p65 but not p50 in the nucleus. PDCD4 protein interacts preferentially with p65 protein as shown by co-immunoprecipitation and confocal imaging. PDCD4 overexpression inhibits the mRNA expression of two NF-κB target genes in a p65-dependent manner. These results suggest that PDCD4 can significantly inhibit NF-κB activity in GBM cells by a mechanism that involves direct or indirect protein-protein interaction independent of the expected mRNA-selective translational inhibition. These findings offer novel opportunities for NF-κB-targeted interventions to prevent or treat cancer.

Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and ß-catenin.

Analysis of the Polyp Prevention Trial showed an association between an isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism behind the chemoprotective effects of isorhamnetin remains unclear. Here, we show that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. MRI, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than the control diet. Isorhamnetin inhibited AOM/DSS-induced oncogenic c-Src activation and ß-catenin nuclear translocation, while promoting the expression of C-terminal Src kinase (CSK), a negative regulator of Src family of tyrosine kinases. Similarly, in HT-29 colon cancer cells, isorhamnetin inhibited oncogenic Src activity and ß-catenin nuclear translocation by inducing expression of csk, as verified by RNA interference knockdown of csk. Our observations suggest the chemoprotective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear ß-catenin, activities that are dependent on CSK expression.