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Background/aim: Fucoxanthin (Fx), a dietary marine xanthophyll, exerts potent anticancer effects in various colorectal cancer (CRC) animal models. However, therapeutic effects of Fx in human cancer tissues remain unclear. A patient-derived xenograft (PDX) mouse model transplanted with cancer tissues from patients is widely accepted as the best preclinical model for evaluating the anticancer potential of drug candidates., Materials and Methods: Herein, we investigated the anticancer effects of Fx in PDX mice transplanted with cancer tissues derived from a patient with CRC (CRC-PDX) using LC-MS/MS- and western blot-based proteome analysis., Results: The tumor in the patient with CRC was a primary adenocarcinoma (T3N0M0, stage II) showing mutations of certain genes that were tumor protein p53 (TP53), AT-rich interaction domain 1A (ARID1A), neuroblastoma RAS viral oncogene homolog (NRAS), and PMS1 homolog 2 (PMS2). Administration of Fx significantly suppressed the tumor growth (0.6-fold) and tended to induce differentiation in CRC-PDX mice. Fx up-regulated glycanated-decorin (Gc-DCN) expression, and down-regulated Kinetochore-associated protein DSN1 homolog (DSN1), phospho(p) focal adhesion kinase (pFAK)(Tyr 397 ), pPaxillin(Tyr 31 ), and c-MYC involved in growth, adhesion, and/or cell cycle, in the tumors of CRC-PDX mice than in control mice. Alterations in the five proteins were consistent with those in human CRC HT-29 and HCT116 cells treated with fucoxanthinol (FxOH, a major metabolite of Fx)., Conclusion: Fx suppresses development of human-like CRC tissues, especially through growth, adhesion, and cell cycle signals., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Fucoxanthin (Fx) is a critical pigment required for photosynthesis in brown algae and microalgae. Fx is also a dietary marine carotenoid that with potent anticancer activity in vitro and in vivo. Some popular light meals for increased satiety, such as biscuits, cereals, and crackers, are frequently fortified with micronutrients for human health benefits. However, data on the anticancer potential of Fx-supplemented light meals in humans and animal models remain limited. In the present study, we investigated the anticancer effects of a Fx-supplemented biscuit using a carcinogenic murine azoxymethane/dextran sodium sulfate (AOM/DSS) model. We observed that periodic administration of biscuits containing 0.3% Fx (Fx-biscuit) at an interval of 3 days (each 15 h) per week for 15 weeks significantly inhibited colorectal carcinogenesis in AOM/DSS mice. Comprehensive gene analysis demonstrated that the Fx-biscuit significantly altered the expression of 138 genes in the colorectal mucosal tissue of the mice. In particular, the expression of heat shock protein 70 (HSP70) genes, Hspa1b (-35.7 - fold) and Hspa1a (-34.9 - fold), was markedly downregulated. HSP70 is a polyfunctional chaperone protein that is involved in cancer development. Compared to the control-biscuit group, the number of cells with markedly high fluorescence for HSP70 protein (HSP70 high ) in colorectal mucosal crypts and adenocarcinomas significantly reduced by 0.3- and 0.2-fold, respectively, in the Fx-biscuit group. Our results suggested that Fx-biscuit possesses chemopreventive potential in the colorectal cancer of AOM/DSS mice via the downregulation of HSP70.

Background/aim: A xanthophyll of fucoxanthin (Fx) is a potential chemopreventive agent. Familial adenomatous polyposis (FAP) is an inherited disease that is associated with a high risk of developing colorectal cancer. However, it remains unclear whether Fx can modify colorectal tumorigenesis in Apc Min/+ mice, a model mouse for human FAP., Materials and Methods: We investigated the chemopreventive effect of Fx in dextran sodium sulfate (DSS)-treated Apc Min/+ mice., Results: Administration of Fx in the diet for 5 weeks significantly suppressed the number of colorectal adenocarcinomas in DSS-treated male Apc Min/+ mice, although the treatment did not affect the occurrence of colorectal dysplastic crypts and adenoma in the mice. In addition, Fx down-regulated cyclin D1 expression (0.6-fold) in colorectal mucosa of Apc Min/+ mice when compared with that of the control mice., Conclusion: Fx possesses chemopreventive potential against progression of colorectal carcinogenesis in Apc Min/+ mice that receive inflammatory stimuli., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Fucoxanthin is a marine xanthophyll found in edible brown algae, and a metabolite, fucoxanthinol (FxOH), possesses a potent apoptosis inducing effect in many cancer cells. Chloride intracellular channel 4 (CLIC4) is a member of the CLIC family that plays an important role in cancer development and apoptosis. However, the role of CLIC4 in FxOH-induced apoptosis is not well understood. In this study, we investigated whether CLIC4 affects the apoptotic properties of FxOH in human colorectal cancer (CRC) cells under FxOH treatment. Treating human CRC DLD-1 cells with 5.0 μmol/L FxOH significantly induced apoptosis. FxOH downregulated CLIC4, integrin β1, NHERF2 and pSmad2 (Ser 465/467 ) by 0.6-, 0.7-, 0.7-, and 0.5-fold, respectively, compared with control cells without alteration of Rab35 expression. No colocalizing change was observed in CLIC4-related proteins in either control or FxOH-treated cells. CLIC4 knockdown suppressed cell growth and apoptosis. Interestingly, apoptosis induction by FxOH almost disappeared with CLIC4 knockdown. Our findings suggested that CLIC4 could be involved in FxOH-induced apoptosis in human CRC.

Background/ Aim: A high polar xanthophyll of Fucoxanthin (Fx) is abundantly contained in edible brown algae, and it has chemopreventive effects in mouse cancer models, however, the underlying mechanisms of these effects are not well understood. Thus, we aimed to investigate the effects of Fx on the tumor microenvironment in cancer model mice., Materials and Methods: We investigated the effect of Fx (30 mg/kg body weight) in a variety of cell types within the tumor microenvironment of α mouse preclinical colorectal cancer model and analyzed the mouse saliva in search of predictors for cancer chemopreventive effects., Results: Fx administration significantly decreased the number of colorectal polyps and tended to decrease colonic lesions compared to untreated control mice. In addition, Fx administration showed significantly lower numbers of colorectal cancer stem cells-like CD44 high /EpCAM high cells, cancer-associated fibroblasts-like αSMA high cells, tumor-associated macrophages-like and dendritic cells-like CD206 high cells by 0.6-, 0.5- and 0.6-fold, respectively, compared to untreated control mice. Moreover, the treatment also showed significantly lower levels of salivary glycine by 0.5-fold., Conclusion: Our results suggest that salivary glycine may be a predictor representing the chemopreventive effect of Fx in mice., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Fucoxanthin (Fx) and its biotransformed fucoxanthinol (FxOH) present strong anti-cancer effects in vitro and in vivo, however, the underlying mechanisms are not well known. We recently demonstrated that FxOH could induce anoikis-like cells in human colorectal cancer (CRC) cells. Thus, we developed molecular hallmarks for anoikis in vitro, and to confirm induction of such molecular hallmarks in an azoxymethane/ dextran sodium sulfate carcinogenic model by Fx ingestion. During the process of anoikis by FxOH (2.5 μmol/l) in DLD-1 cells, the cells show the characteristics of integrin β1 low/- , p-FAK(Tyr 397 ) low/- or p-Paxillin(Tyr 31 ) low/- cells with cleaved caspase-3 high , which may be useful as molecular hallmarks. Fx administration (30 mg/kg body weight) significantly suppressed the number and size of polyps compared with untreated control mice. In addition, the incidence and multiplicity of colonic lesions tended to reduce. Moreover, cells showing integrin β1 low/- , p-FAK(Tyr 397 ) low/- and p-Paxillin(Tyr 31 ) low/- with cleaved caspase-3 high in colonic crypts were significantly increased 2.2-, 4.8- and 5.2-fold by Fx administration compared with untreated control mice, respectively. Our results suggest that Fx showed a chemopreventive effect in the carcinogenic models through anoikis-like cells induction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

DDX1, a member of the DEAD box RNA helicase family, plays a critical role in testicular tumors. However, it remains to be clarified whether DDX1 is involved in other types of malignant tumors such as colorectal cancer. We disrupted the DDX1 gene in a human colorectal cancer cell line LoVo using the CRISPR/Cas9-mediated gene-targeting system. DDX1-KO LoVo cells exhibited a much slower growth rate, produced fewer colonies in soft agar medium, and generated smaller solid tumors in nude mice than parental LoVo cells. Such phenotypes of the DDX1-KO cells were mostly reversed by exogenous expression of DDX1. These results indicate that DDX1 is required for tumorigenicity of colorectal cancer cells. In the DDX1-KO cells, the cancer stem cell marker genes LGR5, CD133, ALDH1 and SOX2 were markedly suppressed. Among them, expression of LGR5, which is essential for tumorigenicity of colorectal cancer cells, was restored in the DDX1-transfected DDX1-KO cells. Consistently, the DDX1-KO cells lost sphere-forming capacity in a DDX1-dependent fashion. Reporter and chromatin immunoprecipitation assays revealed that DDX1 directly bound to the -1837 to -1662 region of the enhancer/promoter region of the human LGR5 gene and enhanced its transcription in LoVo cells. Repression of LGR5 by DDX1 knockdown was observed in 2 other human colorectal cancer cell lines, Colo320 and SW837. These results suggest that LGR5 is a critical effector of DDX1 in colorectal cancer cells. The DDX1-LGR5 axis could be a new drug target for this type of malignant cancer., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Fucoxanthinol (FxOH) is a strong anticancer metabolite of fucoxanthin that accumulates in abundance in edible brown algae and promises human health benefits. FxOH has been shown to suppress tumorigenicity and sphere formation in human colorectal cancer stem cell (CCSC)-like spheroids (colonospheres, Csps). In the present study, we aimed to clarify the inhibitory activity of FxOH on epithelial-mesenchymal transition (EMT), which is essential for cancer recurrence and distant metastasis, and to identify intracellular low-molecular-weight metabolites that may be useful for evaluating the cellular effects of FxOH on CCSCs. FxOH significantly suppressed sphere-forming activity, migration and invasion in a dose-dependent manner. In addition, treatment with 50 µmol/l FxOH suppressed N-cadherin and vimentin expression and the activation of integrin signaling linked to EMT suppression by western blot analysis. MAPK signaling and STAT signaling related to cell growth and apoptosis in Csps derived from human CRC HT-29 and HCT116 cells were also altered. According to our metabolite profiling by GC-MS analysis, reduced glycine and succinic acid levels were correlated with EMT suppression and apoptosis induction in Csps. Our data indicate that simple amino acids such as glycine and succinic acid may be good prognostic indicators of physiological changes to CCSCs induced by FxOH treatment.

Fucoxanthin (Fx), one of the major xanthophylls in brown algae, is known to be effective for colorectal cancer (CRC) chemoprevention through inhibiting cell growth, cell cycle and caspase activation. Recently, we observed fucoxanthinol (FuOH), an anti-cancer active metabolite of Fx, treatment of human CRC cells resulted in plenty of living floating cells several hours after exposure, and induced apoptosis. In the present study, we investigated whether FuOH induced anchorage-dependent apoptosis, that is "anoikis", along with integrin signal suppression in human CRC cells. We found that cells exposed to 2.5 μM FuOH clearly showed anti-proliferative and apoptotic effects to DLD-1 cells, human CRC cells. FuOH treatment of DLD-1 cells led to an increase in anoikis-like changes represented by Calcein AM negative/ethidium homodimer-1 positive cell and living floating cells. Moreover, FuOH decreased FAK activation, and altered integrin β1 expression and distribution after 6 h treatment. After 24 h, the cells decreased PPARγ expression and Akt activation and increased integrin β1 expression. Our findings suggested that FuOH can induce anoikis in CRC cells through suppression of integrin signals in human CRC cells.

Genomic sequences encoding the 3' exonuclease (proofreading) domains of both replicative DNA polymerases, pol delta and pol epsilon, were explored simultaneously in human colorectal carcinomas including six established cell lines. Three unequivocal sequence alterations, including one previously reported, were found, and all these were considered as dysfunctional mutations in light of the local amino-acid sequences. In particular, the F367S mutation found in the POLE gene encoding the pol epsilon catalytic subunit, which includes the proofreading domain, is the first found in human diseases. Surprisingly, the tumours carrying these proofreading domain mutations were all defective in DNA mismatch repair (MMR). In addition to the two cell lines with acknowledged MMR gene mutations, the third tumour was also demonstrated to harbour a distinct mutation in MLH1, and indeed exhibited a microsatellite-unstable phenotype. These findings suggest that, in concert with MMR deficiency, defective polymerase proofreading may also contribute to the mutator phenotype observed in human colorectal cancer. Our observations may suggest previously unrecognised complexities in the molecular abnormalities underlying the mutator phenotype in human neoplasms., (© 2011 Macmillan Publishers Limited All rights reserved 1018-4813/11)

Background: S-1, a novel oral fluoropyrimidine, is well tolerated in patients with metastatic colorectal cancer (mCRC). The response rate of S-1 for colorectal cancer is high, ranging from 35% to 40%. This study aimed to evaluate the safety and efficacy of S-1 combined with oral leucovorin (LV) to enhance antitumor activity in chemotherapy-naive patients with mCRC., Patients and Methods: S-1 was given orally twice daily for two consecutive weeks at a daily dose of 80-120 mg, followed by a 2-week rest period, within a 4-week cycle. LV was given orally twice a day at a daily dose of 50 mg, simultaneously with S-1., Results: Of the 56 patients with previously untreated mCRC, 32 (57%) had partial responses. The median follow-up period was 27.2 months. The median time to progression was 6.7 months (95% confidence interval 5.4-7.9). The median survival time was 24.3 months. There was no treatment-related death or grade 4 toxicity. The most common grade 3 toxic effects were diarrhea (32%), anorexia (21%), stomatitis (20%), and neutropenia (14%)., Conclusion: S-1 combined with LV therapy demonstrated promising efficacy and acceptable safety in chemotherapy-naive patients with mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs.

Microsatellite instability (MSI) is regarded as reflecting defective DNA mismatch repair (MMR). MMR defects lead to an increase in point mutations, as well as repeat instability, on the genome. However, despite the highly unstable microsatellites, base substitutions in representative oncogenes or tumor suppressors are extremely infrequent in MSI-positive tumors. Recently, the heterogeneity in MSI-positive colorectal tumors is pointed out, and the 'hereditary' and 'sporadic settings' are proposed. Particularly in the former, base substitution mutations in KRAS are regarded as relatively frequent. We sequenced the KRAS gene in a panel of 76 human colorectal carcinomas in which the MSI status has been determined. KRAS mutations were detected in 22 tumors (28.9%). Intriguingly, all of the KRAS-mutant MSI-H (high) tumors harbored sequence alterations in an essential MMR gene, MLH1, which implies that KRAS mutation more frequently and almost exclusively occurs in MMR gene-mutant MSI-H tumors. Furthermore, in contrast with the prevailing viewpoint, some of these tumors are derived from sporadic colorectal cancer patients. The tight connection between MMR gene mutation and KRAS mutation may suggest previously unrecognized complexities in the relationship between MSI and the mutator phenotype derived from defective MMR.

Microsatellite instability (MSI) is associated with defective DNA mismatch repair in various human malignancies. Using a unique fluorescent technique, we have observed two distinct modes of dinucleotide microsatellite alterations in human colorectal cancer. Type A alterations are defined as length changes of < or =6 bp. Type B changes are more drastic and involve modifications of > or =8 bp. We show here that defective mismatch repair is necessary and sufficient for Type A changes. These changes were observed in cell lines and in tumours from mismatch repair gene-knockout mice. No Type B instability was seen in these cells or tumours. In a panel of human colorectal tumours, both Type A MSI and Type B instability were observed. Both types of MSI were associated with hMSH2 or hMLH1 mismatch repair gene alterations. Intriguingly, p53 mutations, which are generally regarded as uncommon in human tumours of the MSI+ phenotype, were frequently associated with Type A instability, whereas none was found in tumours with Type B instability, reflecting the prevailing viewpoint. Inspection of published data reveals that the microsatellite instability that has been observed in various malignancies, including those associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is predominantly Type B. Our findings indicate that Type B instability is not a simple reflection of a repair defect. We suggest that there are at least two qualitatively distinct modes of dinucleotide MSI in human colorectal cancer, and that different molecular mechanisms may underlie these modes of MSI. The relationship between MSI and defective mismatch repair may be more complex than hitherto suspected.

We evaluated the effect of intra-arterial infusion chemotherapy for liver metastasis from colorectal cancer. Of 405 patients undergoing colectomy in our department from July 1993 to February 2002, 38 had liver metastasis. We performed catheterization intra-operatively or postoperatively, and intra-arterial infusion chemotherapy was given for liver metastasis from colorectal cancer. Thirty-eight patients were treated with four different arterial infusion courses that mainly consisted of 5-FU. The 5-year survival rate was 8%. Maximal survival period was 68 months, and mean survival was 22 months. The effective rate was 20% Intra-arterial infusion chemotherapy was a useful treatment for liver metastasis from colorectal cancer. Resection of the liver metastasis was the first choice for operative liver metastases from colorectal cancer, and we performed intra-arterial infusion chemotherapy for patients postoperatively or patients with non-operative liver metastasis.

The potential of purple corn color (PCC), a natural anthocyanin, to modify colorectal carcinogenesis was investigated in male F344/DuCrj rats, initially treated with 1,2-dimethylhydrazine (DMH), receiving 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the diet. After DMH initiation, PCC was given at a dietary level of 5.0% in combination with 0.02% PhIP until week 36. No PCC-treatment-related changes in clinical signs, body weight and food consumption were found. Incidences and multiplicities of colorectal adenomas and carcinomas in rats initiated with DMH were clearly increased by PhIP. In contrast, lesion development was suppressed by PCC administration. Furthermore, in the non-DMH initiation groups, induction of aberrant crypt foci by PhIP tended to be decreased by the PCC supplementation. The results thus demonstrate that while PhIP clearly exerts promoting effects on DMH-induced colorectal carcinogenesis, these can be reduced by 5.0% PCC in the diet, under the present experimental conditions.

To establish the prognostic value of carcinoembryonic antigen (CEA) concentration in tumor tissue (T-CEA), normal colonic mucosa (N-CEA) and pre-operative serum (S-CEA), we studied 79 patients who underwent resections for colorectal cancer. The patients were separated into groups reflecting laboratory values lower or higher than a diagnostic value (S-CEA) or the median value of the entire population (T-CEA, N-CEA). A high S-CEA predicted for more advanced stage (p = 0.028), whereas no association was noted between stage and CEA concentration for T-CEA and N-CEA groups. The high S-CEA and T-CEA groups had a worse clinical outcome (p=0.0036 and p=0.024, respectively), while survival of high versus low N-CEA groups did not differ. By Cox's regression analysis, high T-CEA concentration was an independent variable for poor outcome (Hazard ratio, 3.15), while S-CEA and N-CEA were not. In conclusion, a high T-CEA concentration was the only independent predictor of poor outcome after resection for colorectal cancer.

Complications of hepatic arterial infusion chemotherapy were analyzed in 30 cases with hepatic metastasis from colorectal cancer from July 1993 to February 2000 in our department. Thirty patients were treated with three kinds of arterial infusion course that mainly consisted of 5-FU. Complications resulting in interruption of therapy occurred in 10 patients (33%), and there was no difference in the incidence rate of complications among the three chemotherapy regimens. The complications with our therapy were hepatic arterial occlusion in two patients, catheter tip dislocation in four patients, fistulus between the hepatic artery and common bile duct in two patients, and fistulus between the hepatic artery and duodenal bulb in two patients. Four patients who had severe complications with fistulus all underwent hepatectomy, especially right hepatic lobectomy in two cases. Sixty percent of our patients had complications after hepatectomy, so regular GIF and DSA are necessary to prevent severe complications after hepatectomy.

Numerical aberrations of chromosomes can be detected by fluorescence in situ hybridization (FISH), using chromosome-specific probes. It is possible to observe this in solid tumors from which it is very difficult to obtain metaphase nuclei. The present study employed surgical specimens from 15 cases of colorectal carcinoma, all of which showed DNA diploidy. In the same samples, we analyzed chromosomal numerical aberration by FISH according to the method of Pinkel et al. Biotinylated DNA probes specific to chromosome #7, #11 and #17, were used. The hybridization spots were observed by fluorescent microscopy. As a result, the numerical aberrations of chromosomes detected by FISH were found in DNA diploid cases by FCM. They were trisomy and monosomy. These results indicate that FISH is useful to detect the chromosomal aberrations of DNA diploid cases.

In order to elucidate the effect of tumor vascularity on a various regimens concentration in tumor tissue, correlation among tegafur, 5-fluorouracil (5-FU), uracil concentrations in tissue and the microangiography were examined in 27 patients with colorectal cancer after preoperative administration of UFT (400 mg/day for 7 days). The concentrations of tegafur, 5-FU and uracil in tumor were higher than those in normal tissue (p < 0.01). There was no definite correlation between tissue concentration in each regimen and the extra or intramural vascular changes. A significant high concentration of 5-FU was found in the protuberant cancer and the ulcerative cancer with horizontal growth than that in the ulcerative cancer with vertical growth (p < 0.05). The present study indicates that the vascular changes within a tumor and the vascular pattern of tumor may be a contributing factor affecting the tissue concentration in the regimens.

Sialyl Lewis(x)-i (SLX) as a new tumor-associated antigen was assayed in sera of 133 gastric cancer and 62 colorectal cancer patients with preoperative state in order to elucidate the clinico-pathological features. The percent positives in sera of patients with gastric and colorectal cancer were 12.7% (17/133) and 16.1% (10/62), respectively, and there were few positive cases in the early stages. Therefore, it is suggested that the early diagnosis for gastric and colorectal cancer using SLX alone may be difficult. However, it is revealed that SLX has a high tumor-specificity in consideration of the clinico-pathological properties such as H, P, n, ly, v factors, depth of cancer invasion and operative radicality. These data suggested that SLX could be applicable as a useful tumor-marker which shows the metastasis or extension of carcinoma.