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Sample records for cancer tumor colonization

  1. Colon and Rectal Cancer Survival by Tumor Location and Microsatellite Instability: The Colon Cancer Family Registry

    PubMed Central

    Phipps, Amanda I.; Lindor, Noralane M.; Jenkins, Mark A.; Baron, John A.; Win, Aung Ko; Gallinger, Steven; Gryfe, Robert; Newcomb, Polly A.

    2013-01-01

    Background Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability. Objective We assessed differences in survival by colon or rectal cancer site, considering the contribution of microsatellite instability to such differences. Design This is a population-based prospective cohort study for cancer survival. Settings This study was conducted within the Colon Cancer Family Registry, an international consortium. Participants were identified from population-based cancer registries in the United States, Canada, and Australia. Patients Information on tumor site, microsatellite instability, and survival after diagnosis was available for 3284 men and women diagnosed with incident invasive colon or rectal cancer between 1997–2002, with ages at diagnosis ranging from 18–74. Main Outcome Measures Cox regression was used to calculate hazard ratios for the association between all-cause mortality and tumor location, overall and by microsatellite instability status. Results Distal colon (hazard ratio=0.59, 95% confidence interval: 0.49–0.71) and rectal cancers (hazard ratio=0.68, 95% confidence interval: 0.57–0.81) were associated with lower mortality than proximal colon cancer overall. Compared specifically to cases with proximal colon cancer exhibiting no/low microsatellite instability, cases with distal colon and rectal cancers experienced lower mortality, regardless of microsatellite instability status; cases with proximal colon cancer exhibiting high microsatellite instability had the lowest mortality. Limitations Study limitations include the absence of stage at diagnosis and cause of death information for all but a subset of study participants. Some case groups defined jointly by tumor site and microsatellite instability status are subject to small numbers. Conclusion Proximal colon cancer survival

  2. Colon and rectal cancer survival by tumor location and microsatellite instability: the Colon Cancer Family Registry.

    PubMed

    Phipps, Amanda I; Lindor, Noralane M; Jenkins, Mark A; Baron, John A; Win, Aung Ko; Gallinger, Steven; Gryfe, Robert; Newcomb, Polly A

    2013-08-01

    Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability. We assessed the differences in survival by colon or rectal cancer site, considering the contribution of microsatellite instability to such differences. This is a population-based prospective cohort study for cancer survival. This study was conducted within the Colon Cancer Family Registry, an international consortium. Participants were identified from population-based cancer registries in the United States, Canada, and Australia. Information on tumor site, microsatellite instability, and survival after diagnosis was available for 3284 men and women diagnosed with incident invasive colon or rectal cancer between 1997 and 2002, with ages at diagnosis ranging from 18 to 74. Cox regression was used to calculate hazard ratios for the association between all-cause mortality and tumor location, overall and by microsatellite instability status. Distal colon (HR, 0.59; 95% CI, 0.49-0.71) and rectal cancers (HR, 0.68; 95% CI, 0.57-0.81) were associated with lower mortality than proximal colon cancer overall. Compared specifically with patients with proximal colon cancer exhibiting no/low microsatellite instability, patients with distal colon and rectal cancers experienced lower mortality, regardless of microsatellite instability status; patients with proximal colon cancer exhibiting high microsatellite instability had the lowest mortality. Study limitations include the absence of stage at diagnosis and cause-of-death information for all but a subset of study participants. Some patient groups defined jointly by tumor site and microsatellite instability status are subject to small numbers. Proximal colon cancer survival differs from survival for distal colon and rectal cancer in a manner apparently dependent on microsatellite instability status. These

  3. [Evaluation of knowledge about colon cancer prevention versus other tumors].

    PubMed

    Sanguinetti, José María; Henry, Nicolás; Ocaña, Domingo; Polesel, Julio Lotero

    2015-06-01

    In Argentina almost 7% of deaths are due to different cancers with screening strategies. Evaluate knowledge about cancer prevention compared with other tumors. Materials. A descriptive and comparative study. A survey between April and June 2013 in Salta City, province of Salta, Argentina. Correct answers were considered. Statistical analysis: Descriptive (mean and percentage), comparative Chi square Test (significance level P<0,05). 100 surveys. Correct answers: 36% Colon (CI 0,27-0,45), 46% Prostate (CI 0,33-0,52) and 69 (CI 0,59-0,77) and 58 (CI 0,48-0,67)for mama and cervix. 20% (CI 0,13-0,28) knew that colon cancer has a genetic predisposition and 58% (CI 0,48-0,67) about mama. 73% (CI 0,63-0,8) received information about cancer prevention. The main source of information was the physician. 46% (CI 0,36-0,55) received medical care in private institutions. Those who had social security, higher educational levels and medical care in private institutions had better knowledge about cancer prevention except in colon cancer. The global results showed levels below 70% in general but extremely low in colon cancer. Not having social security, receiving medical care in public institutions and having a low educational level are related with poor knowledge about cancer prevention except for colon and prostate cancer.

  4. Spread of tumor microenvironment contributes to colonic obstruction through subperitoneal fibroblast activation in colon cancer

    PubMed Central

    Yokota, Mitsuru; Kojima, Motohiro; Higuchi, Youichi; Nishizawa, Yuji; Kobayashi, Akihiro; Ito, Masaaki; Saito, Norio; Ochiai, Atsushi

    2015-01-01

    We evaluated the influence of the cancer microenvironment formed by peritoneal invasion (CMPI) on clinical findings in colon cancer patients. In addition to the association with poor prognosis, we discovered a relationship with bowel obstruction. Detailed analysis revealed that clinical findings related to bowel obstruction occurred more frequently in patients with an elevated type tumor, which had peritoneal elastic laminal elevation to the tumor surface, compared to those with non-elevated type tumors among those with elastic laminal invasion (ELI). Lateral tumor spread and increase of tumor annularity rate in ELI-positive elevated type cases suggested the morphological progression from ELI-positive non-elevated type to elevated type. In addition, α-smooth muscle actin expression was the highest in ELI-positive elevated type, and prominent expressions were found not only in the deep tumor area but also in the shallow tumor area. Furthermore, contraction assays revealed the robust contractile ability of subperitoneal fibroblasts stimulated by cancer cell-conditioned medium. Our findings suggest that CMPI spread into the luminal side of the colonic wall along with tumor progression, which caused bowel obstruction through the activation of subperitoneal fibroblasts. However, although the clinical outcome was not different between the two types, the clinical findings were affected by the spread of CMPI. We are the first to explore how the alteration of the tumor-promoting microenvironment, along with tumor progression, contributes to the development of clinical findings. PMID:25613547

  5. Intussusception of Rectosigmoid Colon Cancer Mimicking a Pedunculated Tumor

    PubMed Central

    Saigusa, Susumu; Ohi, Masaki; Imaoka, Hiroki; Shimura, Tadanobu; Inoue, Yasuhiro; Kusunoki, Masato

    2014-01-01

    Intussusception in adults is a rare phenomenon involving the colon in approximately 20% of cases. A 65-year-old man was hospitalized with anorexia, anemia, dehydration, and melena. Digital rectal examination revealed a palpable mass approximately 5 cm from the anal verge. The mass moved between the rectosigmoid colon and the rectum below the peritoneal reflection during radiographic examinations and during sigmoidoscopy. We strongly suspected a rectosigmoid pedunculated tumor and performed a low anterior resection. Intraoperatively we observed intussusception of the rectosigmoid colon with easy manual reduction. The tumor was palpable in the rectosigmoid colon. The postoperative course was uneventful. This case illustrates intussusception of a rectosigmoid type 1 colon adenocarcinoma mimicking a pedunculated tumor. PMID:24963434

  6. Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer

    PubMed Central

    Wen, Yang-An; Xing, Xiaopeng; Harris, Jennifer W; Zaytseva, Yekaterina Y; Mitov, Mihail I; Napier, Dana L; Weiss, Heidi L; Mark Evers, B; Gao, Tianyan

    2017-01-01

    Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism by which adipocytes regulate the metabolism of colon cancer cells remains elusive. In this study, we showed that adipocytes isolated from adipose tissues of colon cancer patients have an important role in modulating cellular metabolism to support tumor growth and survival. Abundant adipocytes were found in close association with invasive tumor cells in colon cancer patients. Co-culture of adipocytes with colon cancer cells led to a transfer of free fatty acids that released from the adipocytes to the cancer cells. Uptake of fatty acids allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid β-oxidation. Mechanistically, co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize fatty acids and blocked the growth-promoting effect of adipocytes. In addition, we found that adipocytes stimulated the expression of genes associated with cancer stem cells and downregulated genes associated with intestinal epithelial cell differentiation in primary colon cancer cells and mouse tumor organoids. Importantly, the presence of adipocytes promoted the growth of xenograft tumors in vivo. Taken together, our results show that adipocytes in the tumor microenvironment serve as an energy provider and a metabolic regulator to promote the growth and survival of colon cancer cells. PMID:28151470

  7. DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells

    PubMed Central

    Karamitopoulou, Eva; Dawson, Heather; Koelzer, Viktor Hendrik; Agaimy, Abbas; Garreis, Fabian; Söder, Stephan; Laqua, William; Lugli, Alessandro; Hartmann, Arndt; Rau, Tilman T.; Schneider-Stock, Regine

    2015-01-01

    Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK's catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation. PMID:26405175

  8. Association of symptoms of colon cancer patients with tumor location and TNM tumor stage.

    PubMed

    Alexiusdottir, Kristin K; Möller, Pall Helgi; Snaebjornsson, Petur; Jonasson, Larus; Olafsdottir, Elinborg J; Björnsson, Einar Stefan; Tryggvadottir, Laufey; Jonasson, Jon G

    2012-07-01

    Colon cancer is the second most common cause of cancer death in Iceland and accounts for 8% of malignancies. We related information on symptoms of colon cancer patients with information on tumor location and pTNM-stage. The study is retrospective and population-based. Information on all patients diagnosed with colon cancer in Iceland in 1995-2004 was obtained. Information on symptoms of patients and blood hemoglobin was collected from patients' files. The pathological parameters were derived from a previously performed study. A total of 768 patients (422 males, 346 females) participated in this study. Median age was 73 years. Nearly 60% had anemia at the time of diagnosis, 53% had visible blood in stools, and 65% had changes in bowel habits. Around 84% had visible blood in stools and/or anemia. Of those with right-sided tumors, 75% had anemia and were more likely to be diagnosed incidentally (40%) than those with left-sided tumors (20%). Left-sided tumors were associated with blood in stools (68% compared to 41%, p < 0.05) and changes in bowel habits (74% compared to 57%, p < 0.05). Multivariate analysis indicated that blood in stools was strongly associated with a lower TNM-stage (OR = 0.75, p < 0.05). Anemia was strongly associated with a higher TNM-stage (OR = 1.84, p < 0.05). Right-sided tumors were associated with anemia and incidental diagnosis; left-sided tumors were associated with visible blood in stools and changes in bowel habits. Visible blood in stools was significantly associated with lower TNM-stage, whereas abdominal pain, general and acute symptoms were associated with higher TNM-stage.

  9. [Cytometric study of colonic tumors in a model of experimental colonic cancer. Impact of the diet].

    PubMed

    Afonso Rodríguez, J J; Medina Arana, V; Alvarez Argüelles, H; Hernández Calzadilla, C; González Hermoso, F

    1995-01-01

    Butyrate is a short chain fatty acid, made up of four carbon atoms. Along with acetate and propionate, they are the main volatile fatty acids formed by the microbial fermentation of the carbohydrates of dietary fibre in the colon, mainly in the caecum. Additionally, they acidify the intracolonic pH, and they play an important role in the regulation of the absorption of water and sodium. On the other hand, they are, especially butyrate, preferred by the colon cell, as sources of energy alternative to glucose. Besides this, butyrate, in cellular cultures, is a known antineoplasic agent which is characterized by doubling the cellular duplication time for cells in the G1 phase, it increases the activity of certain enzymes, it stimulates the effects of interferon, it modifies the morphology of the cells, which in some cases leads to the reversion of the characteristic transformations of the cancerous cells, and it produces alterations in the chromatin, the nucleoli, elements of the cytoskeleton and the Golgi apparatus. Even though it is not known how it causes these actions, it is thought that the acetylization of histones which it produces, may be an important mechanism. We analyzed the effect of this substance in a colonic carcinogenesis model in Sprague-Dawley rats, in which the tumors were induced with the alkylating agent 1,2-dimethylhydrazide, observing the cytometric pattern of the tumors, and the possible differences between both groups. In one of them, sodium butyrate was continuously infused by means of a intrathecal catheter at a rhythm of 1.5 ml/hour during the tumoral induction which lasted four weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Interactions between colon cancer cells and tumor-infiltrated macrophages depending on cancer cell-derived colony stimulating factor 1.

    PubMed

    Wang, Huayang; Shao, Qianqian; Sun, Jintang; Ma, Chao; Gao, Wenjuan; Wang, Qingjie; Zhao, Lei; Qu, Xun

    2016-04-01

    Tumor-infiltrated macrophages were potential targets of the immune therapy for patients with colon cancer. Colony stimulating factor 1 (CSF1) is a primary chemoattractant and functional regulator for macrophages, and therefore would be a feasible intervention for the macrophage-targeting therapeutics. However, the expression of CSF1 in colon cancer microenvironment and its roles in cancer development is largely unknown. In the present study, we found that CSF1 was over-expressed exclusively in colon cancer cells and was correlated with macrophages infiltration. The high CSF1 expression and macrophages infiltration were related to the tumor-node-metastasis (TNM) stage of colon cancer, and suggested to be positively associated with survival of colon cancer patients. In the in vitro studies based on an indirect Transwell system, we found that co-culture with macrophage promoted CSF1 production in colon cancer cells. Further investigation on regulatory mechanisms suggested that CSF1 production in colon cancer cells was dependent on PKC pathway, which was activated by IL-8, mainly produced by macrophages. Moreover, colon cancer cell-derived CSF1 drove the recruitment of macrophages and re-educated their secretion profile, including the augment of IL-8 production. The mice tumor xenografts study also found that over-expression of CSF1 in colon cancer cells promoted intratumoral infiltration of macrophages, and partially suppressed tumor growth. In all, our results demonstrated that CSF1 was an important factor in the colon cancer microenvironment, involving in the interactions between colon cancer cells and tumor-infiltrated macrophages.

  11. Interactions between colon cancer cells and tumor-infiltrated macrophages depending on cancer cell-derived colony stimulating factor 1

    PubMed Central

    Wang, Huayang; Shao, Qianqian; Sun, Jintang; Ma, Chao; Gao, Wenjuan; Wang, Qingjie; Zhao, Lei; Qu, Xun

    2016-01-01

    ABSTRACT Tumor-infiltrated macrophages were potential targets of the immune therapy for patients with colon cancer. Colony stimulating factor 1 (CSF1) is a primary chemoattractant and functional regulator for macrophages, and therefore would be a feasible intervention for the macrophage-targeting therapeutics. However, the expression of CSF1 in colon cancer microenvironment and its roles in cancer development is largely unknown. In the present study, we found that CSF1 was over-expressed exclusively in colon cancer cells and was correlated with macrophages infiltration. The high CSF1 expression and macrophages infiltration were related to the tumor–node-metastasis (TNM) stage of colon cancer, and suggested to be positively associated with survival of colon cancer patients. In the in vitro studies based on an indirect Transwell system, we found that co-culture with macrophage promoted CSF1 production in colon cancer cells. Further investigation on regulatory mechanisms suggested that CSF1 production in colon cancer cells was dependent on PKC pathway, which was activated by IL-8, mainly produced by macrophages. Moreover, colon cancer cell-derived CSF1 drove the recruitment of macrophages and re-educated their secretion profile, including the augment of IL-8 production. The mice tumor xenografts study also found that over-expression of CSF1 in colon cancer cells promoted intratumoral infiltration of macrophages, and partially suppressed tumor growth. In all, our results demonstrated that CSF1 was an important factor in the colon cancer microenvironment, involving in the interactions between colon cancer cells and tumor-infiltrated macrophages. PMID:27141406

  12. Stage dependent expression and tumor suppressive function of FAM134B (JK1) in colon cancer.

    PubMed

    Islam, Farhadul; Gopalan, Vinod; Wahab, Riajul; Smith, Robert A; Qiao, Bin; Lam, Alfred King-Yin

    2017-01-01

    The aims of the present study are to investigate sub-cellular location, differential expression in different cancer stages and functional role of FAM134B in colon cancer development. FAM134B expression was studied and quantified at protein and mRNA levels in cell lines using immunocytochemistry, Western blot and real-time PCR. In vitro functional assays and an in vivo xenotransplantation mouse models were used to investigate the molecular role of FAM134B in cancer cell biology in response to FAM134B silencing with shRNA lentiviral particles. FAM134B protein was noted in both cytoplasm and nuclei of cancer cells. In cancer cells derived from stage IV colon cancer, FAM134B expression was remarkably reduced when compared to non-cancer colon cells and cancer cells derived from stage II colon cancer. FAM134B knockdown significantly (P < 0.05) increased the proliferation of colon cancer cells following lentiviral transfection. Furthermore, FAM134B suppression significantly increased (34-52%; P < 0.05) the clonogenic capacity, wound healing potential of and increases the proportion of cells performing DNA synthesis (P < 0.01). Xenotransplantation model showed that larger and higher-grade tumors were formed in mice receiving FAM134B knockdown cells. To conclude, expression analysis, in vitro and in vivo indicated that FAM134B acts as a cancer suppressor gene in colon cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells.

    PubMed

    Zhang, Weina; Chen, Lechuang; Ma, Kai; Zhao, Yahui; Liu, Xianghe; Wang, Yu; Liu, Mei; Liang, Shufang; Zhu, Hongxia; Xu, Ningzhi

    2016-11-15

    Epidermal growth factor receptor (EGFR) is a target of colon cancer therapy, but the effects of this therapy on the tumor microenvironment remain poorly understood. Our in vivo studies showed that cetuximab, an anti-EGFR monoclonal antibody, effectively inhibited AOM/DSS-induced, colitis-associated tumorigenesis, downregulated M2-related markers, and decreased F4/80+/CD206+ macrophage populations. Treatment with conditioned medium of colon cancer cells increased macrophage expression of the M2-related markers arginase-1 (Arg1), CCL17, CCL22, IL-10 and IL-4. By contrast, conditioned medium of EGFR knockout colon cancer cells inhibited expression of these M2-related markers and induced macrophage expression of the M1-related markers inducible nitric oxide synthase (iNOS), IL-12, TNF-α and CCR7. EGFR knockout in colon cancer cells inhibited macrophage-induced promotion of xenograft tumor growth. Moreover, colon cancer-derived insulin-like growth factor-1 (IGF-1) increased Arg1 expression, and treatment with the IGF1R inhibitor AG1024 inhibited that increase. These results suggest that inhibition of EGFR signaling in colon cancer cells modulates cytokine secretion (e.g. IGF-1) and prevents M1-to-M2 macrophage polarization, thereby inhibiting cancer cell growth.

  14. Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells

    PubMed Central

    Zhang, Weina; Chen, Lechuang; Ma, Kai; Zhao, Yahui; Liu, Xianghe; Wang, Yu; Liu, Mei; Liang, Shufang; Zhu, Hongxia; Xu, Ningzhi

    2016-01-01

    Epidermal growth factor receptor (EGFR) is a target of colon cancer therapy, but the effects of this therapy on the tumor microenvironment remain poorly understood. Our in vivo studies showed that cetuximab, an anti-EGFR monoclonal antibody, effectively inhibited AOM/DSS-induced, colitis-associated tumorigenesis, downregulated M2-related markers, and decreased F4/80+/CD206+ macrophage populations. Treatment with conditioned medium of colon cancer cells increased macrophage expression of the M2-related markers arginase-1 (Arg1), CCL17, CCL22, IL-10 and IL-4. By contrast, conditioned medium of EGFR knockout colon cancer cells inhibited expression of these M2-related markers and induced macrophage expression of the M1-related markers inducible nitric oxide synthase (iNOS), IL-12, TNF-α and CCR7. EGFR knockout in colon cancer cells inhibited macrophage-induced promotion of xenograft tumor growth. Moreover, colon cancer-derived insulin-like growth factor-1 (IGF-1) increased Arg1 expression, and treatment with the IGF1R inhibitor AG1024 inhibited that increase. These results suggest that inhibition of EGFR signaling in colon cancer cells modulates cytokine secretion (e.g. IGF-1) and prevents M1-to-M2 macrophage polarization, thereby inhibiting cancer cell growth. PMID:27683110

  15. Exosomes from human colorectal cancer induce a tumor-like behavior in colonic mesenchymal stromal cells

    PubMed Central

    Lugini, Luana; Valtieri, Mauro; Federici, Cristina; Cecchetti, Serena; Meschini, Stefania; Condello, Maria; Signore, Michele; Fais, Stefano

    2016-01-01

    Background Cancer cells, including colorectal cancer ones (CRC), release high amounts of nanovesicles (exosomes), delivering biochemical messages for paracrine or systemic crosstalk. Mesenchymal stromal cells (MSCs) have been shown to play contradicting roles in tumor progression. Results CRC exosomes induce in cMSCs: i) atypical morphology, higher proliferation, migration and invasion; ii) formation of spheroids; iii) an acidic extracellular environment associated with iv) a plasma membrane redistribution of vacuolar H+-ATPase and increased expression of CEA. Colon cancer derived MSCs, which were isolated from tumor masses, produce umbilicated spheroids, a future frequently observed in the inner core of rapidly growing tumors and recapitulate the changes observed in normal colonic MSCs exposed to CRC exosomes. Materials and Methods Tissue specific colonic (c)MSCs were exposed to primary or metastatic CRC exosomes and analysed by light and electron microscopy, proliferation in 2D and 3D cultures, migration and invasion assays, Western blot and confocal microscopy for vacuolar H+-ATPase expression. Conclusions CRC exosomes are able to induce morphological and functional changes in colonic MSCs, which may favour tumor growth and its malignant progression. Our results suggest that exosomes are actively involved in cancer progression and that inhibiting tumor exosome release may represent a way to interfere with cancer. PMID:27418137

  16. Tumor LINE-1 Methylation Level in Association with Survival of Patients with Stage II Colon Cancer

    PubMed Central

    Swets, Marloes; Zaalberg, Anniek; Boot, Arnoud; van Wezel, Tom; Frouws, Martine A.; Bastiaannet, Esther; Gelderblom, Hans; van de Velde, Cornelis J. H.; Kuppen, Peter J. K.

    2016-01-01

    Genome-wide DNA hypomethylation is associated with a worse prognosis in early-stage colorectal cancer. To measure genome-wide DNA methylation levels, long interspersed nucleotide element (LINE-1) repeats are used as a surrogate marker. Cohort studies on the clinical impact of genome-wide DNA methylation level in patients with only early-stage colon cancer, are currently lacking. This study aimed to investigate the prognostic value of LINE-1 methylation in a stage II colon cancer cohort (n = 164). Manual needle microdissection of tumor areas was performed on formalin-fixed paraffin-embedded tumor tissue sections followed by DNA extraction. Bisulfite converted DNA was used to assess tumor LINE-1 methylation level by qPCR. Patients with LINE-1 hypomethylated tumors had a significantly worse overall survival compared to patients with a higher level of LINE-1 tumor DNA methylation (HR 1.68, 95% CI 1.03–2.75; p = 0.04). This effect was more prominent in patients aged over 65 years (HR 2.00, 95% CI 1.13–3.52; p = 0.02), although the test for age interaction was not significant. No significant effect on recurrence-free survival was observed. Based on these results, tumor LINE-1 hypomethylation is associated with a worse overall survival in stage II colon cancer. Whether the origin of this causation is cancer-specific or age-related can be debated. PMID:28035987

  17. Tumor LINE-1 Methylation Level in Association with Survival of Patients with Stage II Colon Cancer.

    PubMed

    Swets, Marloes; Zaalberg, Anniek; Boot, Arnoud; van Wezel, Tom; Frouws, Martine A; Bastiaannet, Esther; Gelderblom, Hans; van de Velde, Cornelis J H; Kuppen, Peter J K

    2016-12-27

    Genome-wide DNA hypomethylation is associated with a worse prognosis in early-stage colorectal cancer. To measure genome-wide DNA methylation levels, long interspersed nucleotide element (LINE-1) repeats are used as a surrogate marker. Cohort studies on the clinical impact of genome-wide DNA methylation level in patients with only early-stage colon cancer, are currently lacking. This study aimed to investigate the prognostic value of LINE-1 methylation in a stage II colon cancer cohort (n = 164). Manual needle microdissection of tumor areas was performed on formalin-fixed paraffin-embedded tumor tissue sections followed by DNA extraction. Bisulfite converted DNA was used to assess tumor LINE-1 methylation level by qPCR. Patients with LINE-1 hypomethylated tumors had a significantly worse overall survival compared to patients with a higher level of LINE-1 tumor DNA methylation (HR 1.68, 95% CI 1.03-2.75; p = 0.04). This effect was more prominent in patients aged over 65 years (HR 2.00, 95% CI 1.13-3.52; p = 0.02), although the test for age interaction was not significant. No significant effect on recurrence-free survival was observed. Based on these results, tumor LINE-1 hypomethylation is associated with a worse overall survival in stage II colon cancer. Whether the origin of this causation is cancer-specific or age-related can be debated.

  18. Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer.

    PubMed

    Kang, Chiao-Wen; Dutta, Avijit; Chang, Li-Yuan; Mahalingam, Jayashri; Lin, Yung-Chang; Chiang, Jy-Ming; Hsu, Chen-Yu; Huang, Ching-Tai; Su, Wan-Ting; Chu, Yu-Yi; Lin, Chun-Yen

    2015-10-23

    TIM-3 functions to enforce CD8+ T cell exhaustion, a dysfunctional state associated with the tolerization of tumor microenvironment. Here we report apoptosis of IFN-γ competent TIM-3+ population of tumor-infiltrating CD8+ T cells in colon cancer. In humans suffering from colorectal cancer, TIM-3+ population is higher in cancer tissue-resident relative to peripheral blood CD8+ T cells. Both the TIM-3+ and TIM-3- cancer tissue-resident CD8+ T cells secrete IFN-γ of comparable levels, although apoptotic cells are more in TIM-3+ compared to TIM-3- population. In mouse CT26 colon tumor model, majority of tumor-infiltrating CD8+ T cells express TIM-3 and execute cytolysis function with higher effector cytokine secretion and apoptosis in TIM-3+ compared to TIM-3- population. The tumor cells secrete galectin-9, which increases apoptosis of tumor-infiltrating CD8+ T cells. Galectin-9/TIM-3 signaling blockade with anti-TIM-3 antibody reduces the apoptosis and in addition, inhibits tumor growth in mice. The blockade increases therapeutic efficacy of cyclophosphamide to treat tumor in mice as well. These results reveal a previously unexplored role of TIM-3 on tumor-infiltrating CD8+ T cells in vivo.

  19. Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer.

    PubMed

    Drescher, Kristen M; Sharma, Poonam; Watson, Patrice; Gatalica, Zoran; Thibodeau, Stephen N; Lynch, Henry T

    2009-01-01

    The ability of the host to mount an appropriate immune response to aberrant cells is one factor that determines prognosis in cancer patients. Naturally occurring regulatory T cells (T regs; CD4+ CD25+ cells) are key regulators of peripheral tolerance. It has been suggested that high levels of T regs are detrimental to the patient in some forms of cancer, but the role of these antigen-specific cells in individuals with colorectal cancers with high levels of microsatellite instability is unknown. Herein, we examined the ability of individuals with MSI-H or microsatellite stable colon cancer to recruit lymphocytes to the tumor site. Immunohistochemical staining was performed on archived paraffin-embedded specimens from a total of 38 individuals with MSI-H (n = 25) or MSS (n = 13) colon cancers to determine the proportion of CD3+, CD8+ and CD25+ cells infiltrating the tumor site. Patients with MSI-H colon cancers had increased percentages of CD8+ TILs (cytotoxic T cells) as compared to individuals with MSS colon cancer (47.3 vs. 24.04% of the infiltrate CD8+, respectively). No differences in the levels of CD25+ T cells were observed between individuals with MSI-H colon cancers and MSS colon cancers (0.53 vs. 0.54% CD25+, respectively). Together, these data suggest that the survival advantage enjoyed by patients with MSI-H colorectal cancer may, in part, be attributed to the increased cytolytic response, but not to an antigen-specific immunosuppressive response in MSS patients.

  20. Gene expression in colon cancer: A focus on tumor site and molecular phenotype.

    PubMed

    Slattery, Martha L; Pellatt, Daniel F; Mullany, Lila E; Wolff, Roger K; Herrick, Jennifer S

    2015-09-01

    Hundreds to thousands of genes are differentially expressed in tumors when compared to nontumor colonic tissue samples. We evaluated gene expression patterns to better understand differences in colon cancer by tumor site and tumor molecular phenotype. We analyzed RNA-seq data from tumor/normal paired samples from 175 colon cancer patients. We implemented a cross validation strategy with nonparametric tests to identify genes which displayed varying expression characteristics related to paired tumor/nontumor tissue across proximal and distal colon sites and by tumor molecular phenotypes, that is, TP53, KRAS, CpG Island Methylator Phenotype (CIMP), and microsatellite instability (MSI). We used Ingenuity Pathway Analysis (IPA) to determine networks associated with deregulated genes in our data. Genes showed significant differences in expression characteristics at the 0.01 level in both validation groups between tumor subsite (116 genes), CIMP high versus CIMP low (79 genes), MSI versus microsatellite stable (MSS) (49 genes), TP53-mutated versus not mutated (17genes), and KRAS-mutated versus not mutated (1 gene). Deregulated genes for CIMP high and MSI tumors were often down-regulated. In contrast to CIMP high and MSI tumors, genes that were deregulated in TP53 were likely to be up-regulated. ERK1, WNT, growth factors and inflammation-related factors were focal points of both CIMP and MSI IPA networks. The MUC family of genes was up-regulated MSI networks. Numerous genes showed differences in expression between proximal and distal tumors, nontumor proximal and distal tissue, and tumor molecular phenotype. Deregulated mucin genes appear to play an important role in MSI tumors. © 2015 Wiley Periodicals, Inc.

  1. Colon cancer

    MedlinePlus

    ... THERAPY Targeted treatment zeroes in on specific targets (molecules) in cancer cells. These targets play a role ... colon cancer. Some studies have reported that NSAIDs (aspirin, ibuprofen, naproxen, and celecoxib) may help reduce the ...

  2. Comparative Study of Carcinoembryonic Antigen Tumor Marker in Stomach and Colon Cancer Patients in Khyber Pakhtunkhwa.

    PubMed

    Ahmad, Bashir; Gul, Bushra; Ali, Sajid; Bashir, Shumaila; Mahmood, Nourin; Ahmad, Jamshed; Nawaz, Seema

    2015-01-01

    Due to the increase in morbidity and mortality rate, cancer has become an alarming threat to the human population worldwide. Since cancer is a progressive disorder, timely diagnosis would be helpful to prevent/stop cancer from progressing to severe stage. In Khyber Pakhtunkhwa, Pakistan, most of the time, tumors are diagnosed with endoscopy and biopsy; therefore rare studies exist regarding the diagnosis of gastrointestinal (GIT) carcinomas based on tumor markers, especially CEA. This study made a comparative analysis of CEA in admitted hospitalized stomach and colon cancer patients diagnosed as GIT with biopsy. In this study, a total of 66 cases were included. The level of CEA was determined in the blood of these patients using ELISA technique. Out of 66 patients, the level of CEA was high in 59.1% of the total, 60.7% in colon cancer patients and 57.9 % in stomach cancer patients. Moreover, the incidence of colorectal and stomach cancer was greater in males as compared to females. Patients were more of the age group of 40- 60 and the level of CEA was comparatively higher in patients (51.5%) with histology which was moderately differentiated, than patients with well differentiated and poorly differentiated tumor histology. CEA level was high in more than 50% of the total patients. Moreover, CEA exhibited higher sensitivity for colon than stomach cancer.

  3. DAC can restore expression of NALP1 to suppress tumor growth in colon cancer.

    PubMed

    Chen, C; Wang, B; Sun, J; Na, H; Chen, Z; Zhu, Z; Yan, L; Ren, S; Zuo, Y

    2015-01-22

    Despite recent progress in the identification of genetic and molecular alternations in colorectal carcinoma, the precise molecular pathogenesis remains unclear. NALP1 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 1) is a member of the nucleotide-binding oligomerization domain-like receptor family of proteins that are key organization proteins in the inflammasome. It is reported that NALP1 plays a central role in cell apoptosis, pyroptosis, inflammatory reactions and autoimmune diseases. DAC (5-aza-2-deoxycytidine) is an antitumor drug useful to lung cancer, myelodysplastic disorders, myelodysplasia and acute myeloid leukemia. In this study, we examined the expression of NALP1 in human normal and cancerous colon tissues using tissue microarray, western blot and quantitative real-time PCR and we measured the expression of NALP1 in three kinds of colon cancer cell lines and animal models before and after treatment with DAC. Furthermore, we examined the treatment effects of DAC on colon cancer in our animal model. Our data indicate that NALP1 is expressed low in human colorectal tumoral tissues relative to paratumoral tissues and was associated with the survival and tumor metastasis of patients. The expression of NALP1 increased after treatment with DAC both in vitro and in vivo. Furthermore, DAC suppressed the growth of colon cancer and increased lifespan in mouse model. Therefore, we conclude that NALP1 is expressed low in colon cancer and associated with the survival and tumor metastasis of patients, and treatment with DAC can restore NALP1 levels to suppress the growth of colon cancer.

  4. Microarray Analysis of Gene Expression at the Tumor Front of Colon Cancer.

    PubMed

    Kobayashi, Takaaki; Masaki, Tadahiko; Nozaki, Eriko; Sugiyama, Masanori; Nagashima, Fumio; Furuse, Junji; Onishi, Hiroaki; Watanabe, Takashi; Ohkura, Yasuo

    2015-12-01

    Budding or the presence poorly differentiated clusters at the boundary of cancer tissue is a pathologically important finding and serves as a prognostic factor in colorectal cancer. However, few studies have examined the cancer tissue boundary in clinical samples. The purpose of the present study was to examine gene expression at the tumor front of colon cancer in surgically resected samples. Cancer tissues were obtained by laser microdissection of 20 surgically resected specimens. Genes with significantly different microarray signals between the tumor front and the tumor center were identified. Among genes showing significant up-regulation at the tumor front were six chemokines [chemokine c-c motif ligand (CCL)2 and -18, chemokine (C-X-C motif) ligand (CXCL)9-11, and interleukin 8 (IL8)], and two apoptosis-related molecules [ubiquitin D (UBD) and baculoviral iap repeat-containing 3 (BIRC3)]. Expression of laminin gamma 2 (LAMC2), matrix metallopeptidase 7 (MMP7) and epithelial-mesenchymal transition (EMT)-related molecules were elevated in the tumor front, but their fold changes were smaller than those of the aforementioned genes. These results suggest that chemokines, in addition to EMT-related molecules, may play important roles in invasion of colon cancer.

  5. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    PubMed

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (P<0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P<0.01) and reduced vessel size (P<0.05) were also observed, the latter only in the ZM198,615-pretreatment group. Furthermore, we performed a series of in vitro studies using the colon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  6. CysLT1R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer

    PubMed Central

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21WAF/Cip1 (P<0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P<0.01) and reduced vessel size (P<0.05) were also observed, the latter only in the ZM198,615-pretreatment group. Furthermore, we performed a series of in vitro studies using the colon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells. PMID:24039952

  7. Expression of pim-1 in tumors, tumor stroma and tumor-adjacent mucosa co-determines the prognosis of colon cancer patients.

    PubMed

    Peng, Yong-hai; Li, Jian-jun; Xie, Fang-wei; Chen, Jian-fang; Yu, Ying-hao; Ouyang, Xue-nong; Liang, Hou-jie

    2013-01-01

    Provirus integration site for Moloney murine leukemia virus (pim-1) is a proto-oncogene that is linked to the development and progression of several cancers. In this study, we evaluated pim-1 expression in tumors, tumor stroma and tumor-adjacent mucosa together as an independent prognostic factor for colon cancer patients. The study included 343 colon cancer patients. Immunohistochemical staining was used to detect pim-1. Multivariate cox regression for disease-free survival (DFS) were used to identify independent prognostic factors. Analytic hierarchy process (AHP) was used to calculate the weight of pim-1 in tumors, tumor stroma and tumor-adjacent mucosa in order to obtain a Pim-1 total score (PTS) for recurrence and survival. Kaplan-Meier DFS curves and OS curves for patients with different pim-1 expression levels were compared using the log-rank test. In this study, four independent prognostic factors were identified for colon cancer patients: pim-1 expression in tumors, tumor stroma, tumor-adjacent mucosa, as well as tumor stage. It has been established that clinical stage is an important prognostic factor for colon cancer patients. However, PTS can identify the patients who are likely to recur not only in the whole radical excision group but also within each stage of this group. Based on the results of this study we can conclude that the PTS combined with clinical staging system may be a better predictor of colon cancer patients' prognosis than using the clinical stage system alone. ClinicalTrials.gov Number: ChiCTR-PRCH-12002842.

  8. Expression of pim-1 in Tumors, Tumor Stroma and Tumor-Adjacent Mucosa Co-Determines the Prognosis of Colon Cancer Patients

    PubMed Central

    Chen, Jian-fang; Yu, Ying-hao; Ouyang, Xue-nong; Liang, Hou-jie

    2013-01-01

    Provirus integration site for Moloney murine leukemia virus (pim-1) is a proto-oncogene that is linked to the development and progression of several cancers. In this study, we evaluated pim-1 expression in tumors, tumor stroma and tumor-adjacent mucosa together as an independent prognostic factor for colon cancer patients. The study included 343 colon cancer patients. Immunohistochemical staining was used to detect pim-1. Multivariate cox regression for disease-free survival (DFS) were used to identify independent prognostic factors. Analytic hierarchy process (AHP) was used to calculate the weight of pim-1 in tumors, tumor stroma and tumor-adjacent mucosa in order to obtain a Pim-1 total score (PTS) for recurrence and survival. Kaplan–Meier DFS curves and OS curves for patients with different pim-1 expression levels were compared using the log-rank test. In this study, four independent prognostic factors were identified for colon cancer patients: pim-1 expression in tumors, tumor stroma, tumor-adjacent mucosa, as well as tumor stage. It has been established that clinical stage is an important prognostic factor for colon cancer patients. However, PTS can identify the patients who are likely to recur not only in the whole radical excision group but also within each stage of this group. Based on the results of this study we can conclude that the PTS combined with clinical staging system may be a better predictor of colon cancer patients’ prognosis than using the clinical stage system alone. Clinical Trials Gov. Number: ChiCTR-PRCH-12002842 PMID:24116137

  9. Apigenin sensitizes colon cancer cells to anti-tumor activity of ABT-263

    PubMed Central

    Shao, Huanjie; Jing, Kai; Mahmoud, Esraa; Huang, Haihong; Fang, Xianjun; Yu, Chunrong

    2013-01-01

    Apigenin is an edible plant-derived flavonoid that shows modest anti-tumor activities in vitro and in vivo. Apigenin treatment resulted in cell growth arrest and apoptosis in various types of tumors by modulating several signaling pathways. In the present study, we evaluated interactions between apigenin and ABT-263 in colon cancer cells. We observed a synergistic effect between apigenin and ABT-263 on apoptosis of colon cancer cells. ABT-263 alone induced limited cell death while upregulating expression of Mcl-1, a potential mechanism for the acquired resistance to ABT-263. The presence of apigenin antagonized ABT-263-induced Mcl-1 upregulation and dramatically enhanced ABT-263-induced cell death. Meanwhile, apigenin suppressed AKT and ERK activation. Inactivation of either AKT or ERK by lentivirus-transduced shRNA or treatment with specific small molecule inhibitors of these pathways enhanced ABT-263-induced cell death, mirroring the effect of apigenin. Moreover, the combination response was associated with upregulation of Bim and activation of Bax. Downregulation of Bax eliminated the synergistic effect of apigenin and ABT-263 on cell death. Xenograft studies in SCID mice showed that the combined treatment with apigenin and ABT-263 inhibited tumor growth by up to 70% without obvious adverse effects, while either agent only inhibited around 30%. Our results demonstrate a novel strategy to enhance ABT-263 induced anti-tumor activity in human colon cancer cells by apigenin via inhibition of the Mcl-1, AKT and ERK pro-survival regulators. PMID:24126433

  10. Contribution of Soft Substrates to Malignancy and Tumor Suppression during Colon Cancer Cell Division

    PubMed Central

    Rabineau, Morgane; Kocgozlu, Leyla; Dujardin, Denis; Senger, Bernard; Haikel, Youssef; Voegel, Jean-Claude; Freund, Jean-Noel; Schaaf, Pierre; Lavalle, Philippe; Vautier, Dominique

    2013-01-01

    In colon cancer, a highly aggressive disease, progression through the malignant sequence is accompanied by increasingly numerous chromosomal rearrangements. To colonize target organs, invasive cells cross several tissues of various elastic moduli. Whether soft tissue increases malignancy or in contrast limits invasive colon cell spreading remains an open question. Using polyelectrolyte multilayer films mimicking microenvironments of various elastic moduli, we revealed that human SW480 colon cancer cells displayed increasing frequency in chromosomal segregation abnormalities when cultured on substrates with decreasing stiffness. Our results show that, although decreasing stiffness correlates with increased cell lethality, a significant proportion of SW480 cancer cells did escape from the very soft substrates, even when bearing abnormal chromosome segregation, achieve mitosis and undergo a new cycle of replication in contrast to human colonic HCoEpiC cells which died on soft substrates. This observation opens the possibility that the ability of cancer cells to overcome defects in chromosome segregation on very soft substrates could contribute to increasing chromosomal rearrangements and tumor cell aggressiveness. PMID:24167628

  11. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells

    PubMed Central

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O’Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  12. [Clinical significance of tumor budding detection in stage II colon cancer].

    PubMed

    Liu, Shao-jie; Yang, Xiao-hong; Ren, Jing-qing; Zhu, Xuan-jin

    2013-08-01

    To investigate the association of tumor budding with recurrence and survival of patients with stage II colon cancer, in order to identify patients with high-risk recurrence who may benefit from adjuvant therapy. Clinical data of 112 stage II colon cancer patients in Guangzhou Red Cross Hospital between 1998 and 2007 were analyzed retrospectively. The degree of tumor budding was assessed by two observers and classified according to the number of tumor buds in the area with the greatest budding intensity on HE stain slides, as high-grade budding (≥10, n=30) and low-grade budding (≤9, n=82). Progression-free and cancer-specific survival were analyzed using the Kaplan-Meier method and Cox regression. All the patients were followed up and the median follow-up was 78 months. The 5-year progression-free survival rates for patients with high-grade and low-grade budding were 65.3% and 90.7% respectively (P=0.008). The 5-year cancer-specific survival rates were 72.1% and 93.8% respectively (P=0.001). Cox regression analysis demonstrated tumor budding was an independent predictor of disease progression (RR=4.572, 95%CI:2.218-11.746, P=0.002) and cancer-related death (RR=4.116, 95%CI:1.657-10.384, P=0.012). Tumor budding is a strong prognostic index for adverse outcome in stage II colon cancer patients,which may serve as a prognostic marker to identify patients with high risk of recurrence who may benefit from adjuvant therapy.

  13. KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers.

    PubMed

    Chen, Evan C; Karl, Taylor A; Kalisky, Tomer; Gupta, Santosh K; O'Brien, Catherine A; Longacre, Teri A; van de Rijn, Matt; Quake, Stephen R; Clarke, Michael F; Rothenberg, Michael E

    2015-09-01

    Receptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. We investigated the role of the RTK KIT in development of human colon cancer. An array of 137 patient-derived colon tumors and their associated xenografts were analyzed by immunohistochemistry to measure levels of KIT and its ligand KITLG. KIT and/or KITLG was stably knocked down by expression of small hairpin RNAs from lentiviral vectors in DLD1, HT29, LS174T, and COLO320 DM colon cancer cell lines, and in UM-COLON#8 and POP77 xenografts; cells transduced with only vector were used as controls. Cells were analyzed by real-time quantitative reverse transcription polymerase chain reaction, single-cell gene expression analysis, flow cytometry, and immunohistochemical, immunoblot, and functional assays. Xenograft tumors were grown from control and KIT-knockdown DLD1 and UM-COLON#8 cells in immunocompromised mice and compared. Some mice were given the RTK inhibitor imatinib after injection of cancer cells; tumor growth was measured based on bioluminescence. We assessed tumorigenicity using limiting dilution analysis. KIT and KITLG were expressed heterogeneously by a subset of human colon tumors. Knockdown of KIT decreased proliferation of colon cancer cell lines and growth of xenograft tumors in mice compared with control cells. KIT knockdown cells had increased expression of enterocyte markers, decreased expression of cycling genes, and, unexpectedly, increased expression of LGR5 associated genes. No activating mutations in KIT were detected in DLD1, POP77, or UM-COLON#8 cells. However, KITLG-knockdown DLD1 cells formed smaller xenograft tumors than control cells. Gene expression analysis of single CD44(+) cells indicated that KIT can promote growth via KITLG autocrine and/or paracrine signaling. Imatinib inhibited growth of KIT(+) colon cancer organoids in culture and growth of xenograft tumors in mice. Cancer cells with endogenous KIT expression were more tumorigenic in mice. KIT and

  14. Tumor size predicts long-term survival in colon cancer: an analysis of the National Cancer Data Base.

    PubMed

    Saha, Sukamal; Shaik, Mohammed; Johnston, Gregory; Saha, Supriya Kumar; Berbiglia, Lindsay; Hicks, Micheal; Gernand, Jill; Grewal, Sandeep; Arora, Madan; Wiese, David

    2015-03-01

    American Joint Committee on Cancer uses tumor size for "T" staging of many solid tumors for its effect on prognosis. However, tumor size has not been incorporated in tumor (T), nodal status (N), metastasis (M) staging for colon cancer. Hence, the National Cancer Data Base was used to determine whether tumor size correlates with TNM staging and survival. For the 300,386 patients, tumor size was divided into S1 (0 to 2 cm), S2 (>2 to 4 cm), S3 (>4 to 6 cm), and S4 (>6 cm). Statistical comparison was done for TNM stage, grade, and nodal status with tumor size. Kaplan-Meier survival analysis was done for each "S" stage. Of the 300,386 patients, 13% were classified as S1, 39% S2, 30% S3 and 18% as S4. Right colon was the most common site (48%). Tumor size positively correlated with grade, T stage, and nodal stage. Tumor size was inversely associated with survival. Tumor size is positively correlated with important prognostic factors and negatively impacted survival. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. MicroRNA-302a Functions as a Putative Tumor Suppressor in Colon Cancer by Targeting Akt

    PubMed Central

    Sun, Shengjie; Zhang, Guoqing; Wu, Zhiyong; Shi, Weiwei; Yang, Bo; Li, Ying

    2014-01-01

    Micro RNAs (miRNAs) are important regulators involved in various physical and pathological processes, including cancer. The miRNA-302 family has been documented as playing a critical role in carcinogenesis. In this study, we investigated the role of miRNA-302a in colon cancer. MiRNA-302a expression was detected in 44 colon cancer tissues and 10 normal colon tissues, and their clinicopathological significance was analyzed. Cell proliferation and cell cycle analysis were performed on colon cancer cells that stably expressed miRNA-302a. The target gene of miRNA-302a and the downstream pathway were further investigated. Compared with normal colon tissues, miRNA-302a expression was downregulated in colon cancer tissues. Overexpression of miRNA-302a induced G1/S cell cycle arrest in colon cancer cells, and suppressed colon cancer cell proliferation both in vitro and in vivo. Furthermore, miRNA-302a inhibited AKT expression by directly binding to its 3′ untranslated region, resulting in subsequent alterations of the AKT-GSK3β-cyclin D1 pathway. These results reveal miRNA-302a as a tumor suppressor in colon cancer, suggesting that miRNA-302a may be used as a potential target for therapeutic intervention in colon cancer. PMID:25542007

  16. Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling.

    PubMed

    Chung, Woonbok; Kwabi-Addo, Bernard; Ittmann, Michael; Jelinek, Jaroslav; Shen, Lanlan; Yu, Yinhua; Issa, Jean-Pierre J

    2008-04-30

    DNA hypermethylation is a common epigenetic abnormality in cancer and may serve as a useful marker to clone cancer-related genes as well as a marker of clinical disease activity. To identify CpG islands methylated in prostate cancer, we used methylated CpG island amplification (MCA) coupled with representational difference analysis (RDA) on prostate cancer cell lines. We isolated 34 clones that corresponded to promoter CpG islands, including 5 reported targets of hypermethylation in cancer. We confirmed the data for 17 CpG islands by COBRA and/or pyrosequencing. All 17 genes were methylated in at least 2 cell lines of a 21-cancer cell line panel containing prostate cancer, colon cancer, leukemia, and breast cancer. Based on methylation in primary tumors compared to normal adjacent tissues, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS and NSE1 are candidate biomarkers for prostate cancer (methylation range 50%-85%). The combination of NSE1 or SPOCK2 hypermethylation showed a sensitivity of 80% and specificity of 95% in differentiating cancer from normal. Similarly NKX2-5, SPOCK2, SLC16A12, DPYS and GALR2 are candidate biomarkers for colon cancer (methylation range 60%-95%) and GALR2 hypermethylation showed a sensitivity of 85% and specificity of 95%. Finally, SLC16A12, GALR2, TOX, SPOCK2, EGFR5 and DPYS are candidate biomarkers for breast cancer (methylation range 33%-79%) with the combination of EGFR5 or TOX hypermethylation showing a sensitivity of 92% and specificity of 92%. Expression analysis for eight genes that had the most hypermethylation confirmed the methylation associated silencing and reactivation with 5-aza-2'-deoxycytidine treatment. Our data identify new targets of transcriptional silencing in cancer, and provide new biomarkers that could be useful in screening for prostate cancer and other cancers.

  17. Comparative effectiveness of primary tumor resection in patients with stage IV colon cancer.

    PubMed

    Alawadi, Zeinab; Phatak, Uma R; Hu, Chung-Yuan; Bailey, Christina E; You, Y Nancy; Kao, Lillian S; Massarweh, Nader N; Feig, Barry W; Rodriguez-Bigas, Miguel A; Skibber, John M; Chang, George J

    2017-04-01

    Although the safety of combination chemotherapy without primary tumor resection (PTR) in patients with stage IV colon cancer has been established, questions remain regarding a potential survival benefit with PTR. The objective of this study was to compare mortality rates in patients who had colon cancer with unresectable metastases who did and did not undergo PTR. An observational cohort study was conducted among patients with unresectable metastatic colon cancer identified from the National Cancer Data Base (2003-2005). Multivariate Cox regression analyses with and without propensity score weighting (PSW) were performed to compare survival outcomes. Instrumental variable analysis, using the annual hospital-level PTR rate as the instrument, was used to account for treatment selection bias. To account for survivor treatment bias, in situations in which patients might die soon after diagnosis from different reasons, a landmark method was used. In the total cohort, 8641 of 15,154 patients (57%) underwent PTR, and 73.8% of those procedures (4972 of 6735) were at landmark. PTR was associated with a significant reduction in mortality using Cox regression (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.44-0.47) or PSW (HR, 0.46; 95% CI, 0. 44-0.49). However, instrumental variable analysis revealed a much smaller effect (relative mortality rate, 0.91; 95% CI, 0.87-0.96). Although a smaller benefit was observed with the landmark method using Cox regression (HR, 0.6; 95% CI, 0.55-0.64) and PSW (HR, 0.59; 95% CI, 0.54-0.64), instrumental variable analysis revealed no survival benefit (relative mortality rate, 0.97; 95% CI, 0.87-1.06). Among patients with unresectable metastatic colon cancer, after adjustment for confounder effects, PTR was not associated with improved survival compared with systemic chemotherapy; therefore, routine noncurative PTR is not recommended. Cancer 2017;123:1124-1133. © 2016 American Cancer Society. © 2016 American Cancer Society.

  18. Colon cancer - resources

    MedlinePlus

    Resources - colon cancer ... The following organizations are good resources for information on colon cancer : American Cancer Society -- www.cancer.org/cancer/colonandrectumcancer/index Colon Cancer Alliance -- www.ccalliance.org National ...

  19. Use of a combination of CEA and tumor budding to identify high-risk patients with stage II colon cancer.

    PubMed

    Du, Changzheng; Xue, Weicheng; Dou, Fangyuan; Peng, Yifan; Yao, Yunfeng; Zhao, Jun; Gu, Jin

    2017-07-24

    High-risk patients with stage II colon cancer may benefit from adjuvant chemotherapy, but identifying this patient population can be difficult. We assessed the prognosis value for predicting tumor progression in patients with stage II colon cancer, of a panel of 2 biomarkers for colon cancer: tumor budding and preoperative carcinoembryonic antigen (CEA). Consecutive patients (N = 134) with stage II colon cancer who underwent curative surgery from 2000 to 2007 were included. Multivariate analysis was used to evaluate the association of CEA and tumor budding grade with 5-year disease-free survival (DFS). The prognostic accuracy of CEA, tumor budding grade and the combination of both (CEA-budding panel) was determined. The study found that both CEA and tumor budding grade were associated with 5-year DFS. The prognostic accuracy for disease progression was higher for the CEA-budding panel (82.1%) than either CEA (70.9%) or tumor budding grade (72.4%) alone. The findings indicate that the combination of CEA levels and tumor budding grade has greater prognostic value for identifying patients with stage II colon cancer who are at high-risk for disease progression, than either marker alone.

  20. Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer

    PubMed Central

    Szabo, Csaba; Coletta, Ciro; Chao, Celia; Módis, Katalin; Szczesny, Bartosz; Papapetropoulos, Andreas; Hellmich, Mark R.

    2013-01-01

    The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H2S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H2S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capacity), as well as glycolysis. Treatment of nude mice with aminooxyacetic acid attenuated the growth of patient-derived colon cancer xenografts and reduced tumor blood flow. Similarly, CBS silencing of the tumor cells decreased xenograft growth and suppressed neovessel density, suggesting a role for endogenous H2S in tumor angiogenesis. In contrast to CBS, silencing of cystathionine-γ-lyase (the expression of which was unchanged in colon cancer) did not affect tumor growth or bioenergetics. In conclusion, H2S produced from CBS serves to (i) maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and (ii) promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients. The current findings identify CBS-derived H2S as a tumor growth factor and anticancer drug target. PMID:23836652

  1. Application of in vitro soft agar techniques for growth of tumor cells to the study of colon cancer.

    PubMed

    Buick, R N; Fry, S E; Salmon, S E

    1980-03-15

    An in vitro assay to measure the clonogenic or colony-forming capability of cancer cells present in biopsy samples has recently been applied to study the biology and drug-sensitivity of a variety of human neoplasms. This approach appears to be suitable for study of the tumor stem or progenitor cells present in malignant effusions from patients with colonic carcinoma. In our preliminary studies, morphology of the tumor colonies by inverted microscopy and with Papanicolaou staining of dried agar plating layers as well as immunofluorescent localization with a specific antiserum to human carcinoembrionic antigen have been used as markers of the neoplastic origin of colon tumor colony-forming cells. Successful application of this assay to colonic solid tumors will require improvement in techniques for disaggregation of viable clonogenic cells. We anticipate that short term clonal assays will have increasing use for clinical and biological studies of human colon cancer.

  2. Early stage colon cancer.

    PubMed

    Freeman, Hugh James

    2013-12-14

    Evidence has now accumulated that colonoscopy and removal of polyps, especially during screening and surveillance programs, is effective in overall risk reduction for colon cancer. After resection of malignant pedunculated colon polyps or early stage colon cancers, long-term repeated surveillance programs can also lead to detection and removal of asymptomatic high risk advanced adenomas and new early stage metachronous cancers. Early stage colon cancer can be defined as disease that appears to have been completely resected with no subsequent evidence of involvement of adjacent organs, lymph nodes or distant sites. This differs from the clinical setting of an apparent "curative" resection later pathologically upstaged following detection of malignant cells extending into adjacent organs, peritoneum, lymph nodes or other distant sites, including liver. This highly selected early stage colon cancer group remains at high risk for subsequent colon polyps and metachronous colon cancer. Precise staging is important, not only for assessing the need for adjuvant chemotherapy, but also for patient selection for continued surveillance. With advanced stages of colon cancer and a more guarded outlook, repeated surveillance should be limited. In future, novel imaging technologies (e.g., confocal endomicroscopy), coupled with increased pathological recognition of high risk markers for lymph node involvement (e.g., "tumor budding") should lead to improved staging and clinical care.

  3. Antitumor effect of pretreatment for colon cancer cells with hyperthermia plus geranylgeranylacetone in experimental metastasis models and a subcutaneous tumor model of colon cancer in mice.

    PubMed

    Okayama, Tetsuya; Kokura, Satoshi; Ishikawa, Takeshi; Adachi, Satoko; Hattori, Takeshi; Takagi, Tomohisa; Handa, Osamu; Naito, Yuji; Yoshikawa, Toshikazu

    2009-03-01

    We examined whether hyperthermia attenuated the metastatic potential of colon cancer through the induction of heat shock protein 70 (Hsp70). Colon26 cells were separated into four groups: (1) no pretreatment, (2) hyperthermia at 42 degrees C for 1 hour, (3) pretreatment with geranylgeranylacetone (GGA) 10(-6) M for 2 hours, and (4) hyperthermia after GGA treatment. We measured cell viabilities and the contents of Hsp70. We assessed nuclear factor-kappa-B (NF-kappa-B) status with and without tumor necrosis factor-alpha (TNF-alpha) stimulation. For in vivo study, colon26 cells were injected via the tail vein or into a subcutaneous area of mice and the numbers of lung metastatic nodules or the volumes of subcutaneous tumors were assessed. Untreated cells were incubated with PKH26. Experimental metastasis models were then generated and used to assess the fixed cancer cells. Tumor development in the subcutaneous tumor models and cell viabilities were similar among the four groups. However, the GGA plus hyperthermia group had fewer lung metastatic nodules in the experimental lung metastasis model and higher Hsp70 induction than the other cell groups. The GGA plus hyperthermia pretreatment group also showed a lower number of fixed cells in lungs and lower activation of NF-kappa-B by TNF-alpha than the other cell groups. It is suggested the metastatic potential but not the proliferation potency of cancer cells is inhibited by the transient induction of Hsp70.

  4. Noninvasive magnetic resonance imaging of the development of individual colon cancer tumors in rat liver.

    PubMed

    Mook, Olaf R F; Jonker, Ard; Strang, Aart C; Veltien, Andor; Gambarota, Giulio; Frederiks, Wilma M; Heerschap, Arend; Van Noorden, Cornelis J F

    2008-04-01

    Monitoring tumor development is essential for the understanding of mechanisms involved in tumor progression and to determine efficacy of therapy. One of the evolving approaches is longitudinal noninvasive magnetic resonance imaging (MRI) of tumors in experimental models. We applied high-resolution MRI at 7 Tesla to study the development of colon cancer tumors in rat liver. MRI acquisition was triggered to the respiratory cycle to minimize motion artifacts. A special radio frequency (RF) coil was designed to acquire detailed T1-weighted and T2-weighted images of the liver. T2-weighted images identified hyperintense lesions representing tumors with a minimum diameter of 2 mm, enabling the determination of growth rates and morphological aspects of individual tumors. It is concluded that high-resolution MRI using a dedicated RF coil and triggering to the respiratory cycle is an excellent tool for quantitative and morphological analysis of individual diffusely distributed tumors throughout the liver. However, at present, MRI requires expensive equipment and expertise and is a time-consuming methodology. Therefore, it should preferably be used for dedicated applications rather than for high-throughput assessment of total tumor load in animals.

  5. Perspectives on current tumor-node-metastasis (TNM) staging of cancers of the colon and rectum.

    PubMed

    Hu, Huankai; Krasinskas, Alyssa; Willis, Joseph

    2011-08-01

    Improvements in classifications of cancers based on discovery and validation of important histopathological parameters and new molecular markers continue unabated. Though still not perfect, recent updates of classification schemes in gastrointestinal oncology by the American Joint Commission on Cancer (tumor-node-metastasis [TNM] staging) and the World Health Organization further stratify patients and guide optimization of treatment strategies and better predict patient outcomes. These updates recognize the heterogeneity of patient populations with significant subgrouping of each tumor stage and use of tumor deposits to significantly "up-stage" some cancers; change staging parameters for subsets of IIIB and IIIC cancers; and introduce of several new subtypes of colon carcinomas. By the nature of the process, recent discoveries that are important to improving even routine standards of patient care, especially new advances in molecular medicine, are not incorporated into these systems. Nonetheless, these classifications significantly advance clinical standards and are welcome enhancements to our current methods of cancer reporting. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. O-1602, an atypical cannabinoid, inhibits tumor growth in colitis-associated colon cancer through multiple mechanisms.

    PubMed

    Kargl, Julia; Haybaeck, Johannes; Stančić, Angela; Andersen, Liisa; Marsche, Gunther; Heinemann, Akos; Schicho, Rudolf

    2013-04-01

    Cannabinoids have antiinflammatory and antitumorigenic properties. Some cannabinoids, such as O-1602, have no or only little affinity to classical cannabinoid receptors but exert cannabinoid-like antiinflammatory effects during experimental colitis. Here, we investigated whether O-1602 shows antitumorigenic effects in colon cancer cells and whether it could reduce tumorigenesis in the colon in vivo. The colon cancer cell lines HT-29 and SW480 were used to study the effect of O-1602 on viability and apoptosis. The effect of O-1602 on tumor growth in vivo was studied in a colitis-associated colon cancer mouse model. O-1602 decreased viability and induced apoptosis in colon cancer cells in a concentration-dependent manner (0.1-10 μM). In the mouse model, treatment with O-1602 (3 mg/kg, i.p., 12×) reduced tumor area by 50 % and tumor incidence by 30 %. Histological scoring revealed a significant decrease in tumor load. In tumor tissue, O-1602 decreased levels of proliferating cell nuclear antigen (PCNA), activation of oncogenic transcription factors STAT3 and NFκB p65, and expression of TNF-α while levels for proapoptotic markers, such as p53 and BAX, increased. The in vivo effects of O-1602 on PCNA, BAX, and p53 were also observed in colon cancer cells. The data provide a novel insight into antitumorigenic mechanisms of atypical cannabinoids. O-1602 exerts antitumorigenic effects by targeting colon cancer cells as well as proinflammatory pathways known to promote colitis-associated tumorigenesis. Due to its lack of central sedation, O-1602 could be an interesting compound for the treatment of colon and possibly other cancers.

  7. Human Colon Tumors Express a Dominant-negative Form of SIGIRR That Promotes Inflammation and Colitis-associated Colon Cancer in Mice

    PubMed Central

    Zhao, Junjie; Bulek, Katarzyna; Gulen, Muhammet Fatih; Zepp, Jarod A.; Karagkounis, Georgio; Martin, Bradley N; Zhou, Hao; Yu, Minjia; Liu, Xiuli; Huang, Emina; Fox, Paul L.; Kalady, Matthew F.; Markowitz, Sanford D.; Li, Xiaoxia

    2016-01-01

    Background & Aims Single immunoglobulin and toll-interleukin 1 receptor (SIGIRR), a negative regulator of the Toll-like and interleukin-1 receptor (IL1R) signaling pathways, controls intestinal inflammation and suppresses colon tumorigenesis in mice. However, the importance of SIGIRR in human colorectal cancer development has not been determined. We investigated the role of SIGIRR in development of human colorectal cancer. Methods We performed RNA sequence analyses of pairs of colon tumor and non-tumor tissues, each collected from 68 patients. Immunoblot and immunofluorescence analyses were used to determine levels of SIGIRR protein in primary human colonic epithelial cells, tumor tissues, and colon cancer cell lines. We expressed SIGIRR and mutant forms of the protein in Vaco cell lines. We created and analyzed mice that expressed full-length (control) or a mutant form of Sigirr (encoding SIGIRRN86/102S, which is not glycosylated) specifically in the intestinal epithelium. Some mice were given azoxymethane and dextran sulfate sodium to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by immunohistochemical and gene expression profile analyses. Results RNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRRΔE8, in colorectal cancer tissues compared to paired non-tumor tissues. SIGIRRΔE8 is not modified by complex glycans and is therefore retained in the cytoplasm—it cannot localize to the cell membrane or reduce IL1R signaling. SIGIRRΔE8 interacts with and has a dominant-negative effect on SIGIRR, reducing its glycosylation, localization to the cell surface, and function. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in non-tumor tissues it was found at the cell membrane. Mice that expressed SIGIRRN86/102S developed more inflammation and formed larger tumors after administration of azoxymethane and dextran sulfate sodium than control mice; colon tissues from these mutant

  8. MiR-9, -31, and -182 deregulation promote proliferation and tumor cell survival in colon cancer.

    PubMed

    Cekaite, Lina; Rantala, Juha K; Bruun, Jarle; Guriby, Marianne; Agesen, Trude H; Danielsen, Stine A; Lind, Guro E; Nesbakken, Arild; Kallioniemi, Olli; Lothe, Ragnhild A; Skotheim, Rolf I

    2012-09-01

    Several microRNAs (miRNAs) are known to be deregulated in colon cancer, but the mechanisms behind their potential involvement on proliferation and tumor cell survival are unclear. The present study aimed to identify miRNAs with functional implications for development of colon cancer. The cell proliferation and apoptosis were examined following perturbations of miRNA levels by employing a comprehensive miRNA library screen. miRNAs nominated for relevance to colon cancer were validated on expression and functional levels. By integrating the effect of miRNA up-regulation with the endogenous miRNA expression levels within the HT29, HCT116, and SW480 colon cancer cell lines, we identified miRNAs controlling cell proliferation (n = 53) and apoptosis (n = 93). From these functionally nominated miRNAs, we narrowed the list to 10 oncogene- and 20 tumor suppressor-like miRNAs that were also differentially expressed between colon cancer (n = 80) and normal colonic mucosa (n = 20). The differential expressions of miR-9, miR-31, and miR-182 were successfully validated in a series of colon carcinomas (n = 30) and polyps (n = 10) versus normal colonic mucosa (n = 10), whereas the functional effect was confirmed in an in-depth validation using different cell viability and apoptotic markers. Several transcription factors and genes regulating cell proliferation were identified as putative target genes by integrative miRNA/mRNA expression analysis obtained from the same colon cancer patient samples. This study suggests that deregulated expression of miR-9, miR-31, and miR-182 during carcinogenesis plays a significant role in the development of colon cancer by promoting proliferation and tumor cell survival.

  9. MicroRNA-506 suppresses tumor proliferation and metastasis in colon cancer by directly targeting the oncogene EZH2.

    PubMed

    Zhang, Yi; Lin, Changwei; Liao, Guoqing; Liu, Sheng; Ding, Jie; Tang, Fang; Wang, Zhenran; Liang, Xingsi; Li, Bo; Wei, Yangchao; Huang, Qi; Li, Xuan; Tang, Bo

    2015-10-20

    Increasing evidence reveals that aberrant expression of microRNA contributes to the development and progression of colon cancer, but the roles of microRNA-506 (miR-506) in colon cancer remain elusive. Here, we demonstrated that miR-506 was down-regulated in colon cancer tissue and cells and that miR-506 expression was inversely correlated with EZH2 expression, tumor size, lymph node invasion, TNM stage and metastasis. A high level of miR-506 identified patients with a favorable prognosis. In vitro and in vivo experiments confirmed that miR-506 inhibits the proliferation and metastasis of colon cancer, and a luciferase reporter assay confirmed that EZH2 is a direct and functional target of miR-506 via the 3'UTR of EZH2. The restoration of EZH2 expression partially reversed the proliferation and invasion of miR-506-overexpressing colon cancer cells. Moreover, we confirmed that the miR-506-EZH2 axis inhibits proliferation and metastasis by activating/suppressing specific downstream tumor-associated genes and the Wnt/β-catenin signaling pathway. Taking together, our study sheds light on the role of miR-506 as a suppressor for tumor growth and metastasis and raises the intriguing possibility that miR-506 may serve as a new potential marker for monitoring and treating colon cancer.

  10. Intratumoral Heterogeneity for Expression of Tyrosine Kinase Growth Factor Receptors in Human Colon Cancer Surgical Specimens and Orthotopic Tumors

    PubMed Central

    Kuwai, Toshio; Nakamura, Toru; Kim, Sun-Jin; Sasaki, Takamitsu; Kitadai, Yasuhiko; Langley, Robert R.; Fan, Dominic; Hamilton, Stanley R.; Fidler, Isaiah J.

    2008-01-01

    The design of targeted therapy, particularly patient-specific targeted therapy, requires knowledge of the presence and intratumoral distribution of tyrosine kinase receptors. To determine whether the expression of such receptors is constant or varies between and within individual colon cancer neoplasms, we examined the pattern of expression of the ligands, epidermal growth factor, vascular endothelial growth factor, and platelet-derived growth factor-B as well as their respective receptors in human colon cancer surgical specimens and orthotopic human colon cancers growing in the cecal wall of nude mice. The expression of the epidermal growth factor receptor and the vascular endothelial growth factor receptor on tumor cells and stromal cells, including tumor-associated endothelial cells, was heterogeneous in surgical specimens and orthotopic tumors. In some tumors, the receptor was expressed on both tumor cells and stromal cells, and in other tumors the receptor was expressed only on tumor cells or only on stromal cells. In contrast, the platelet-derived growth factor receptor was expressed only on stromal cells in both surgical specimens and orthotopic tumors. Examination of receptor expression in both individual surgical specimens and orthotopic tumors revealed that the platelet-derived growth factor receptor was expressed only on stromal cells and that the patterns of epidermal growth factor receptor and vascular endothelial growth factor receptor 2 expression differed between tumor cells. This heterogeneity in receptor expression among different tumor cells suggests that targeting a single tyrosine kinase may not yield eradication of the disease. PMID:18202197

  11. Vasohibin-1 suppresses colon cancer

    PubMed Central

    Liu, Shuai; Han, Bing; Zhang, Qunyuan; Dou, Jie; Wang, Fang; Lin, Wenli; Sun, Yuping; Peng, Guangyong

    2015-01-01

    Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor. However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo. PMID:25797264

  12. Positive detection of exfoliated colon cancer cells on linear stapler cartridges was associated with depth of tumor invasion and preoperative bowel preparation in colon cancer.

    PubMed

    Ikehara, Kishiko; Endo, Shungo; Kumamoto, Kensuke; Hidaka, Eiji; Ishida, Fumio; Tanaka, Jun-Ichi; Kudo, Shin-Ei

    2016-08-31

    The aim of this study was to investigate exfoliated cancer cells (ECCs) on linear stapler cartridges used for anastomotic sites in colon cancer. We prospectively analyzed ECCs on linear stapler cartridges used for anastomosis in 100 colon cancer patients who underwent colectomy. Having completed the functional end-to-end anastomosis, the linear stapler cartridges were irrigated with saline, which was collected for cytological examination and cytological diagnoses were made by board-certified pathologists based on Papanicolaou staining. The detection rate of ECCs on the linear stapler cartridges was 20 %. Positive detection of ECCs was significantly associated with depth of tumor invasion (p = 0.012) and preoperative bowel preparation (p = 0.003). There were no marked differences between ECC-positive and ECC-negative groups in terms of the operation methods, tumor location, histopathological classification, and surgical margins. Since ECCs were identified on the cartridge of the linear stapler used for anastomosis, preoperative mechanical bowel preparation using polyethylene glycol solution and cleansing at anastomotic sites using tumoricidal agents before anastomosis may be necessary to decrease ECCs in advanced colon cancer.

  13. Tart cherry anthocyanins inhibit tumor development in Apc(Min) mice and reduce proliferation of human colon cancer cells.

    PubMed

    Kang, Soo-Young; Seeram, Navindra P; Nair, Muraleedharan G; Bourquin, Leslie D

    2003-05-08

    Anthocyanins, which are bioactive phytochemicals, are widely distributed in plants and especially enriched in tart cherries. Based on previous observations that tart cherry anthocyanins and their respective aglycone, cyanidin, can inhibit cyclooxygenase enzymes, we conducted experiments to test the potential of anthocyanins to inhibit intestinal tumor development in Apc(Min) mice and growth of human colon cancer cell lines. Mice consuming the cherry diet, anthocyanins, or cyanidin had significantly fewer and smaller cecal adenomas than mice consuming the control diet or sulindac. Colonic tumor numbers and volume were not significantly influenced by treatment. Anthocyanins and cyanidin also reduced cell growth of human colon cancer cell lines HT 29 and HCT 116. The IC(50) of anthocyanins and cyanidin was 780 and 63 microM for HT 29 cells, respectively and 285 and 85 microM for HCT 116 cells, respectively. These results suggest that tart cherry anthocyanins and cyanidin may reduce the risk of colon cancer.

  14. High-fat Western diet-induced obesity contributes to increased tumor growth in mouse models of human colon cancer.

    PubMed

    O'Neill, Ann Marie; Burrington, Christine M; Gillaspie, Erin A; Lynch, Darin T; Horsman, Melissa J; Greene, Michael W

    2016-12-01

    Strong epidemiologic evidence links colon cancer to obesity. The increasing worldwide incidence of colon cancer has been linked to the spread of the Western lifestyle, and in particular consumption of a high-fat Western diet. In this study, our objectives were to establish mouse models to examine the effects of high-fat Western diet-induced obesity on the growth of human colon cancer tumor xenografts, and to examine potential mechanisms driving obesity-linked human colon cancer tumor growth. We hypothesize that mice rendered insulin resistant due to consumption of a high-fat Western diet will show increased and accelerated tumor growth. Homozygous Rag1(tm1Mom) mice were fed either a low-fat Western diet or a high-fat Western diet (HFWD), then human colon cancer xenografts were implanted subcutaneously or orthotopically. Tumors were analyzed to detect changes in receptor tyrosine kinase-mediated signaling and expression of inflammatory-associated genes in epididymal white adipose tissue. In both models, mice fed an HFWD weighed more and had increased intra-abdominal fat, and tumor weight was greater compared with in the low-fat Western diet-fed mice. They also displayed significantly higher levels of leptin; however, there was a negative correlation between leptin levels and tumor size. In the orthotopic model, tumors and adipose tissue from the HFWD group displayed significant increases in both c-Jun N-terminal kinase activation and monocyte chemoattractant protein 1 expression, respectively. In conclusion, this study suggests that human colon cancer growth is accelerated in animals that are obese and insulin resistant due to the consumption of an HFWD. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Carnitines slow down tumor development of colon cancer in the DMH-chemical carcinogenesis mouse model.

    PubMed

    Roscilli, Giuseppe; Marra, Emanuele; Mori, Federica; Di Napoli, Arianna; Mancini, Rita; Serlupi-Crescenzi, Ottaviano; Virmani, Ashraf; Aurisicchio, Luigi; Ciliberto, Gennaro

    2013-07-01

    Dietary agents are receiving much attention for the chemoprevention of cancer. While curcumin is known to influence several pathways and affect tumor growth in vivo, carnitin and its congeners play a variety of important metabolic functions: are involved in the oxydation of long-chain fatty acids, regulate acyl-CoA levels and influence protein activity and stability by modifying the extent of protein acetylation. In this study we evaluated the efficacy of carnitines in the prevention of cancer development using the 1,2,-dimethylhydrazine (DMH)-induced colon carcinogenesis model. We also assessed whether their combination was able to give rise to increased protection from cancer development. Mice treated with DMH were dosed orally with curcumin and/or carnitine and acylcarnitines for 20 weeks. At the end of the treatment colon samples were collected, and scored for multiple ACF and adenomas. We observed that carnitine and acyl-carnitines had same, if not higher, efficacy than curcumin alone in inhibiting the formation of neoplastic lesions induced by DMH treatment. Interestingly, the combination of curcumin and acetyl-L-carnitine was able to fully inhibit the development of advanced adenoma lesions. Our data unveil the antitumor effects of carnitines and warrant additional studies to further support the adoption of carnitines as cancer chemopreventative agents.

  16. Increased expression of TRPS1 affects tumor progression and correlates with patients' prognosis of colon cancer.

    PubMed

    Hong, Jun; Sun, Jie; Huang, Tao

    2013-01-01

    To detect the expression pattern of tricho-rhino-phalangeal syndrome-1 (TRPS1) in human colon cancer and to analyze its correlation with prognosis of patients with this disease. The expressions of TRPS1 in human colon cancer and its corresponding noncancerous colon tissues were detected at both mRNA and protein levels. The mRNA and protein expression levels of TRPS1 were both significantly higher in colon cancer than in corresponding noncancerous colon tissues (both P < 0.001). The protein level of TRPS1 in colon cancer tissues was significantly correlated with the mRNA level (r = 0.9, P < 0.001). Additionally, immunohistochemistry analysis also found increased TRPS1 expression in 63.0% (63/100) of colon cancer tissues. High TRPS1 expression was significantly associated with positive lymph node metastasis (P = 0.006) and higher pathological stage (P = 0.008) of patients with colon cancer. Multivariate Cox regression analysis further suggested that the increased expression of TRPS1 was an independent poor prognostic factor for this disease. Our data offer the convincing evidence for the first time that the increased expression of TRPS1 may be involved in the pathogenesis and progression of colon cancer. TRPS1 might be a potential marker to predict the prognosis in colon cancer.

  17. Direct contacts with colon cancer cells regulate the differentiation of bone marrow mesenchymal stem cells into tumor associated fibroblasts.

    PubMed

    Peng, Yanan; Li, Zongwei; Yang, Peng; Newton, Ian P; Ren, Hua; Zhang, Lichao; Wu, Haili; Li, Zhuoyu

    2014-08-15

    Tumor-stroma interactions are referred to as essential events in tumor progression. There has been growing attention that bone marrow-derived mesenchymal stem cells (BMSCs) can travel to tumor stroma, where they differentiate into tumor-associated fibroblast (TAF)-like cells, a predominant tumor-promoting stromal cell. However, little is definitively known about the contributors for this transition. Here, using an in vitro direct co-culture model of colon cancer cells and BMSCs, we identify that colon cancer cells can induce adjoining BMSCs to exhibit the typical characteristic of TAFs, with increased expression of α-smooth muscle actin (α-SMA). Importantly, the present data also reveals that activated Notch signaling mediates transformation of BMSCs to TAFs through the downstream TGF-β/Smad signaling pathway.

  18. Study shows colon and rectal tumors constitute a single type of cancer

    Cancer.gov

    The pattern of genomic alterations in colon and rectal tissues is the same regardless of anatomic location or origin within the colon or the rectum, leading researchers to conclude that these two cancer types can be grouped as one, according to The Cancer

  19. Pharmacological inhibition of Mdm2 triggers growth arrest and promotes DNA breakage in mouse colon tumors and human colon cancer cells

    PubMed Central

    Rigatti, Marc J.; Verma, Rajeev; Belinsky, Glenn S.; Rosenberg, Daniel W.; Giardina, Charles

    2011-01-01

    The p53 tumor suppressor protein performs a number of cellular functions, ranging from the induction of cell cycle arrest and apoptosis to effects on DNA repair. Modulating p53 activity with Mdm2 inhibitors is a promising approach for treating cancer; however, it is presently unclear how the in vivo application of Mdm2 inhibitors impact the myriad processes orchestrated by p53. Since approximately half of all colon cancers (predominately cancers with microsatellite instability) are p53-normal, we assessed the anticancer activity of the Mdm2 inhibitor Nutlin-3 in the mouse azoxymethane (AOM) colon cancer model, in which p53 remains wild type. Using a cell line derived from an AOM-induced tumor, we found that four daily exposures to Nutlin-3 induced persistent p53 stabilization and cell cycle arrest without significant apoptosis. A four day dosing schedule in vivo generated a similar response in colon tumors; growth arrest without significantly increased apoptosis. In adjacent normal colon tissue, Nutlin-3 treatment reduced both cell proliferation and apoptosis. Surprisingly, Nutlin-3 induced a transient DNA damage response in tumors but not in adjacent normal tissue. Nutlin-3 likewise induced a transient DNA damage response in human colon cancer cells in a p53-dependent manner, and enhanced DNA strand breakage and cell death induced by doxorubicin. Our findings indicate that Mdm2 inhibitors not only trigger growth arrest, but may also stimulate p53’s reported ability to slow homologous recombination repair. The potential impact of Nutlin-3 on DNA repair in tumors suggests that Mdm2 inhibitors may significantly accentuate the tumoricidal actions of certain therapeutic modalities. PMID:21557332

  20. Quantitative secretome analysis reveals the interactions between epithelia and tumor cells by in vitro modulating colon cancer microenvironment.

    PubMed

    Zeng, Xiao; Yang, Pengbo; Chen, Bing; Jin, Xuewen; Liu, Yuling; Zhao, Xia; Liang, Shufang

    2013-08-26

    In tumor microenvironment, interactions among multiple cell types are critical for cancer progression. Secreted proteins are responsible for crosstalk among these cells within tumor microenvironment. To elucidate the interactions of tumor and epithelia, we co-cultured colon cancer cell line HT29 with normal human colon mucosal epithelial cell line NCM460 to mimic tumor microenvironment in vitro and investigated the differential expression pattern of secretome. A quantitative proteomics approach based on stable isotope labeling by amino acids in cell culture (SILAC) and LC-mass spectrometry was used for secretome analysis. Totally 45 proteins were altered over 2-fold in co-cultured cellular supernatants between equal amounts of NCM460 and HT29 cells, compared with mono-cultured conditions. These differential secreted proteins involve in multiple tumor-associated biological functions. The secretion level and acting pattern of acrogranin, IGFBP6 and vimentin were changed along with different co-cultured cell number ratios between NCM460 and HT29 cells, simulating early, middle or advanced stage of colon cancer. Therefore, a quantitative secretome profiling based on a co-culture system can track secreted protein changes and their associated biological roles between tumor and epithelia, which gives a new insight on communications between tumor and epithelia as well as cancer biotherapy by inhibiting cell interactions. Tumor microenvironment is a complex system and comprised of cancer cells and host stromal cells. The growth and progression of tumor have been recognized were affected by multidirectional interactions of secreted proteins (secretome), which were produced by the cells within tumor microenvironment. Focus on general secreted molecules of living cells via proteomic tools, is promising for investigating cell communication. Stable isotope labeling by amino acids in cell culture (SILAC) is a metabolic labeling strategy for quantitative analysis, which is gaining

  1. Carotenoids and colon cancer.

    PubMed

    Slattery, M L; Benson, J; Curtin, K; Ma, K N; Schaeffer, D; Potter, J D

    2000-02-01

    Carotenoids have numerous biological properties that may underpin a role for them as chemopreventive agents. However, except for beta-carotene, little is known about how dietary carotenoids are associated with common cancers, including colon cancer. The objective of this study was to evaluate associations between dietary alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, and beta-cryptoxanthin and the risk of colon cancer. Data were collected from 1993 case subjects with first primary incident adenocarcinoma of the colon and from 2410 population-based control subjects. Dietary data were collected from a detailed diet-history questionnaire and nutrient values for dietary carotenoids were obtained from the US Department of Agriculture-Nutrition Coordinating Center carotenoid database (1998 updated version). Lutein was inversely associated with colon cancer in both men and women [odds ratio (OR) for upper quintile of intake relative to lowest quintile of intake: 0.83; 95% CI: 0.66, 1.04; P = 0.04 for linear trend]. The greatest inverse association was observed among subjects in whom colon cancer was diagnosed when they were young (OR: 0.66; 95% CI: 0.48, 0.92; P = 0.02 for linear trend) and among those with tumors located in the proximal segment of the colon (OR: 0.65; 95% CI: 0.51, 0.91; P < 0.01 for linear trend). The associations with other carotenoids were unremarkable. The major dietary sources of lutein in subjects with colon cancer and in control subjects were spinach, broccoli, lettuce, tomatoes, oranges and orange juice, carrots, celery, and greens. These data suggest that incorporating these foods into the diet may help reduce the risk of developing colon cancer.

  2. Histone hypoacetylation contributes to CXCL12 downregulation in colon cancer: impact on tumor growth and cell migration.

    PubMed

    Romain, Benoît; Benbrika-Nehmar, Radhia; Marisa, Laetitia; Legrain, Michèle; Lobstein, Viviane; Oravecz, Attila; Poidevin, Laetitia; Bour, Cyril; Freund, Jean-Noël; Duluc, Isabelle; Guenot, Dominique; Pencreach, Erwan

    2017-06-13

    CXCL12 has been shown to be involved in colon cancer metastasis, but its expression level and molecular mechanisms regulating its expression remain controversial. We thus evaluated CXCL12 expression in a large cohort of colon adenomas and carcinomas, investigated for an epigenetic mechanism controlling its expression and evaluated the impact of CXCL12 levels on cell migration and tumor growth. CXCL12 expression was measured in human colon adenomas and carcinomas with transcriptome array and RT-qPCR. The promoter methylation was analyzed with whole-genome DNA methylation chips and protein expression by immunohistochemistry. We confirm a reduced expression of CXCL12 in 75% of MSS carcinomas and show that the decrease is an early event as already present in adenomas. The methylome analysis shows that the CXCL12 promoter is methylated in only 30% of microsatellite-stable tumors. In vitro, treatments with HDAC inhibitors, butyrate and valproate restored CXCL12 expression in three colon cell lines, increased acetylation of histone H3 within the CXCL12 promoter and inhibited cell migration. In vivo, valproate diminished (65%) the number of intestinal tumors in APC mutant mice, slowed down xenograft tumor growth concomitant to restored CXCL12 expression. Finally we identified loss of PCAF expression in tumor samples and showed that forced expression of PCAF in colon cancer cell lines restored CXCL12 expression. Thus, reduced PCAF expression may participate to CXCL12 promoter hypoacetylation and its subsequent loss of expression. Our study is of potential clinical interest because agents that promote or maintain histone acetylation through HDAC inhibition and/or HAT stimulation, may help to lower colon adenoma/carcinoma incidence, especially in high-risk families, or could be included in therapeutic protocols to treat advanced colon cancer.

  3. Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts.

    PubMed

    Griffin, Carly; Karnik, Aditya; McNulty, James; Pandey, Siyaram

    2011-01-01

    The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (ρ(0)) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth.

  4. [Right Hemi-Colectomy for a Metastatic Transverse Colon Tumor from Breast Cancer Following Bilateral Breast Cancer Resection - A Case Report].

    PubMed

    Okamura, Shu; Yanagisawa, Tetsu; Ohishi, Kazuhito; Murata, Kohei; Nushijima, Yoichiro; Hamano, Rie; Fukuchi, Nariaki; Ebisui, Chikara; Yokouchi, Hideoki; Kinuta, Masakatsu

    2016-11-01

    We herein report the case of a 75-year-old female patient who underwent 4 surgeries for bilateral breast cancer and its recurrence. When she presented at a clinic with an irritable colon, a fist-sized tumor was palpated in the right upper abdomen at her first medical examination. Abdominal CT scan at the clinic revealed a tumor with a maximum diameter of 10 cm on the right side of the transverse colon and multiple swollen mesenteric lymph nodes. Therefore, the patient was referred to our hospital for surgery. Colonoscopy revealed stenosis of the same lesion with an edematous mucosa and sclerosis. Using immunohistochemistry, a biopsy specimen from the lesion tested positive for CK AE1+AE3, and negative for CD20(-)and CD3 (-). As a result, the tumor was diagnosed as a poorly differentiated adenocarcinoma. We performed right hemicolectomy to avoid her intestinal obstruction. Tumor cells were mainly present at the subserosa, according to HEstaining. Using immunostaining, the cells were tested for the following markers: CDX2(-), GCDFP15(weakly positive), CK7(strongly positive), CD20(partially positive), E R(+), PgR(-), and HER2(1+), characterizing the tumor as metastasis of breast cancer. Although gastro-intestinal metastasis from breast cancer is rare, and colon metastasis is even rarer, it might be necessary to rule out the possibility of a metastatic colon tumor from breast cancer when treating patients with a colon tumor who have undergone surgery for breast cancer.

  5. MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

    PubMed Central

    Mukherjee, P.; Pathangey, L.B.; Bradley, J.B.; Tinder, T.L.; Basu, G.D.; Akporiaye, E.T.; Gendler, S.J.

    2007-01-01

    A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan helper peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-γ-producing CD4+ helper and CD8+ cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced. PMID:17166639

  6. MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model.

    PubMed

    Mukherjee, P; Pathangey, L B; Bradley, J B; Tinder, T L; Basu, G D; Akporiaye, E T; Gendler, S J

    2007-02-19

    A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan-helper-peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-gamma-producing CD4(+) helper and CD8(+) cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

  7. [Colon cancer in pregnancy].

    PubMed

    Mathonnet, M; Fermeaux, V

    2003-09-01

    Colon cancers arise only rarely in the course of a pregnancy. Yet colon obstruction, perforation and metastatic spread seem to occur more frequently in this setting than with the average colon cancer. Perhaps this is due to the immunotolerance which accompanies pregnancy. No case of epidermoid (squamous cell) cancer of the colon has been previously described in a pregnant woman. This conjunction has a catastrophic prognosis: the diagnosis of colon tumor is delayed since symptoms are masked by the pregnancy, and epidermoid colon cancer is a particularly aggressive lesion. A major sub-diaphragmatic surgical procedure can be performed with reasonable safety to mother and fetus. Radiotherapy is contraindicated. Neo-adjuvant chemotherapy can be administered although the risks to the fetus are not well known. During the first trimester, a therapeutic abortion can be proposed to optimise the treatment of the mother. During the second and third trimesters, treatment of the mother exposes the fetus to the risk of malformations or premature delivery; delay in maternal treatment in hopes of prolonging the pregnancy in order to obtain a viable neonate diminish the chances of maternal survival.

  8. Stages of Colon Cancer

    MedlinePlus

    ... for information about colorectal cancer in children. Health history affects the risk of developing colon cancer. Anything ... colorectal cancer include the following: Having a family history of colon or rectal cancer in a first- ...

  9. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.

    PubMed

    Desnoyers, L R; Pai, R; Ferrando, R E; Hötzel, K; Le, T; Ross, J; Carano, R; D'Souza, A; Qing, J; Mohtashemi, I; Ashkenazi, A; French, D M

    2008-01-03

    Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.

  10. [Synchronous Double Cancer Involving Gastric Cancer Resembling a Submucosal Tumor with Stenosis in the Pylorus and Ascending Colon Cancer - A Case Report].

    PubMed

    Miyauchi, Tatsuomi; Miyaki, Akira; Ida, Arika; Kishibe, Saki; Yamaguchi, Kentaro; Shiozawa, Shunichi; Usui, Takebumi; Kuhara, Kotaro; Kono, Teppei; Naritaka, Yoshihiko

    2016-11-01

    An 82-year-old woman presented to our hospital with a complaint of frequent vomiting. She was admitted for intensive examination and treatment. Abdominal computed tomography revealed that her stomach was severely expanded, and the wall of the ascending colon was thickened throughout its circumference. Upper gastrointestinal endoscopy uncovered severe stenosis in the pylorus and an elevated lesion resembling a submucosal tumor on the posterior wall of the pylorus. Biopsies of the lesion revealed that it was of Group 1. On colonoscopy, type 2 cancer was found in the ascending colon throughout the circumference, and the biopsies revealed that it was of Group 5. Upper gastrointestinal endoscopy was repeated, and the same result was obtained. The possibility of malignancy could not be excluded; therefore, distal gastrectomy and right colectomy were performed. In terms of histopathology, both resected specimens displayed poorly differentiated adenocarcinoma; however, immunohistochemical studies revealed differences in staining at the two sites. The case was diagnosed as synchronous double cancer involving gastric cancer resembling a submucosal tumor with stenosis in the pylorus and ascending colon cancer. Gastric cancer resembling a submucosal tumor is usually difficult to diagnose on biopsy. If the endoscopic findings reveal an elevated lesion resembling a submucosal tumor with stenosis, then the possibility of carcinoma should be considered, and the most suitable treatment should be selected.

  11. Interleukin-22 promotes aerobic glycolysis associated with tumor progression via targeting hexokinase-2 in human colon cancer cells.

    PubMed

    Liu, Yulin; Xiang, Fan; Huang, Yongming; Shi, Liang; Hu, Chaojie; Yang, Yiming; Wang, Di; He, Nan; Tao, Kaixiong; Wu, Ke; Wang, Guobin

    2017-04-11

    Interleukin-22 has been explored extensively in human cancer, but its functions and underlying mechanisms are incompletely understood. Here, we show that aberrant interleukin-22 expression facilitates aerobic glycolysis in colon cancer cells. Elevated interleukin-22 mRNA expression was observed and positively correlated with hexokinase-2 in colon cancer tissues. In vitro, interleukin-22 enhanced glucose consumption and lactate production via targeting hexokinase-2 in colon cancer cells. Moreover, the transcriptional factor c-Myc and signal transducer and activator of transcription 3 were involved in interleukin-22-induced up-regulation of hexokinase-2. We further demonstrated that hexokinase-2 partly accounted for interleukin-22-mediated cellular proliferation in DLD-1 cells. In vivo, our data demonstrated that interleukin-22 significantly promoted tumor growth along with elevated expression of c-Myc and hexokinase-2 in mice. In summary, our findings provide a new perspective on the pro-inflammatory cytokine interleukin-22 in promoting aerobic glycolysis associated with tumor progression in human colon cancer cells.

  12. Tumor response assessment in locally advanced colon cancer after neoadjuvant chemotherapy

    PubMed Central

    González, Ignacio; Baixauli, Jorge; Martínez, Patricia; Rodríguez, Javier; Pastor, Carlos; Ribelles, María Jesús; Sola, Jesús Javier; Hernández-Lizoain, José Luís

    2014-01-01

    Background Preoperative chemotherapy followed by radical surgery is a novel therapeutic approach for locally advanced colon cancer (LACC). Neoadjuvant strategies require highly accurate diagnostic tests for a proper selection of candidate patients, allowing a low risk of overtreatment. This paper assesses the radiological, metabolic and pathological findings induced by preoperative oxaliplatin and fluoropyrimidines-based chemotherapy in LACC. Methods Forty-four consecutive patients with a confirmed diagnosis of LACC who received neoadjuvant chemotherapy and colon surgery were included. All patients were staged at baseline and before surgery. Clinical diagnosis consisted of physical examination, endoscopy with biopsy and computed tomography (CT) scan. In selected cases, a positron emission tomography/CT (PET/CT) scan was also performed. Accuracy and correlations between CT scan findings and pathologic report was assayed for T stage, N stage and TN stage. This study is retrospective in design. Results After chemotherapy, a statistical significant tumor volume reduction of 62.5% was achieved by CT-scan (P<0.001; Wilcoxon test) and a 38.9% decrease of standard uptake value (SUVmax) was observed on PET/CT (P=0.004). No progressive disease was reported during neoadjuvant treatment. Accuracy for T and N classification was 62% and 87%, respectively. Accuracy for TN stage was 77%, with 13.6% and 9.1% of the patients being under or overstaged, respectively. Pathologic stage II and III disease was observed in 29/44 (65.9%) and 15/44 (34.1%) of the patients, respectively. Pathologic complete response was achieved in three patients. Conclusions Oxaliplatin/fluorpyrimidine neoadjuvant chemotherapy induces major tumour shrinkage at both the pathological and radiological levels. The CT scan shows a high accuracy and a low overstaged rate in LACC patients treated by means of a neoadjuvant approach. PMID:24772338

  13. Human Colon Tumors Express a Dominant-Negative Form of SIGIRR That Promotes Inflammation and Colitis-Associated Colon Cancer in Mice.

    PubMed

    Zhao, Junjie; Bulek, Katarzyna; Gulen, Muhammet F; Zepp, Jarod A; Karagkounis, Georgio; Martin, Bradley N; Zhou, Hao; Yu, Minjia; Liu, Xiuli; Huang, Emina; Fox, Paul L; Kalady, Matthew F; Markowitz, Sanford D; Li, Xiaoxia

    2015-12-01

    Single immunoglobulin and toll-interleukin 1 receptor (SIGIRR), a negative regulator of the Toll-like and interleukin-1 receptor (IL-1R) signaling pathways, controls intestinal inflammation and suppresses colon tumorigenesis in mice. However, the importance of SIGIRR in human colorectal cancer development has not been determined. We investigated the role of SIGIRR in development of human colorectal cancer. We performed RNA sequence analyses of pairs of colon tumor and nontumor tissues, each collected from 68 patients. Immunoblot and immunofluorescence analyses were used to determine levels of SIGIRR protein in primary human colonic epithelial cells, tumor tissues, and colon cancer cell lines. We expressed SIGIRR and mutant forms of the protein in Vaco cell lines. We created and analyzed mice that expressed full-length (control) or a mutant form of Sigirr (encoding SIGIRR(N86/102S), which is not glycosylated) specifically in the intestinal epithelium. Some mice were given azoxymethane (AOM) and dextran sulfate sodium to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by immunohistochemical and gene expression profile analyses. RNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRR(ΔE8), in colorectal cancer tissues compared to paired nontumor tissues. SIGIRR(ΔE8) is not modified by complex glycans and is therefore retained in the cytoplasm-it cannot localize to the cell membrane or reduce IL1R signaling. SIGIRR(ΔE8) interacts with and has a dominant-negative effect on SIGIRR, reducing its glycosylation, localization to the cell surface, and function. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in nontumor tissues it was found at the cell membrane. Mice that expressed SIGIRR(N86/102S) developed more inflammation and formed larger tumors after administration of azoxymethane and dextran sulfate sodium than control mice; colon tissues from these mutant mice expressed

  14. Transition from colitis to cancer: high Wnt activity sustains the tumor-initiating potential of colon cancer stem cell precursors.

    PubMed

    Shenoy, Anitha K; Fisher, Robert C; Butterworth, Elizabeth A; Pi, Liya; Chang, Lung-Ji; Appelman, Henry D; Chang, Myron; Scott, Edward W; Huang, Emina H

    2012-10-01

    Ulcerative colitis (UC) increases the risk of colorectal cancer (CRC), but the mechanisms involved in colitis-to-cancer transition (CCT) are not well understood. CCT may involve a inflammation-dysplasia-carcinoma progression sequence compared with the better characterized adenoma-carcinoma progression sequence associated with sporadic CRC. One common thread may be activating mutations in components of the Wnt/β-catenin signaling pathway, which occur commonly as early events in sporadic CRC. To examine this hypothesis, we evaluated possible associations between Wnt/β-catenin signaling and CCT based on the cancer stem cell (CSC) model. Wnt/β-catenin immunostaining indicated that UC patients have a level of Wnt-pathway-active cells that is intermediate between normal colon and CRC. These UC cells exhibiting activation of the Wnt pathway constituted a major subpopulation (52% + 7.21) of the colonic epithelial cells positive for aldehyde dehydrogenase (ALDH), a putative marker of precursor colon CSC (pCCSC). We further fractionated this subpopulation of pCCSC using a Wnt pathway reporter assay. Over successive passages, pCCSCs with the highest Wnt activity exhibited higher clonogenic and tumorigenic potential than pCCSCs with the lowest Wnt activity, thereby establishing the key role of Wnt activity in driving CSC-like properties in these cells. Notably, 5/20 single cell injections of high-Wnt pCCSC resulted in tumor formation, suggesting a correlation with CCT. Attenuation of Wnt/β-catenin in high-Wnt pCCSC by shRNA-mediated downregulation or pharmacological inhibition significantly reduced tumor growth rates. Overall, the results of our study indicates (i) that early activation of Wnt/β-catenin signaling is critical for CCT and (ii) that high levels of Wnt/β-catenin signaling can further demarcate high-ALDH tumor-initiating cells in the nondysplastic epithelium of UC patients. As such, our findings offer plausible diagnostic markers and therapeutic target in the

  15. Anti-tumor efficacy of ultrasonic cavitation is potentiated by concurrent delivery of anti-angiogenic drug in colon cancer.

    PubMed

    Zhang, Chao; Huang, Pintong; Zhang, Ying; Chen, Jian; Shentu, Weihui; Sun, Yu; Yang, Zhijian; Chen, Shuyuan

    2014-05-28

    This study investigated the efficacy of concurrent delivery of an anti-angiogenic drug and ultrasonic cavitation therapy in a mouse model of human colon cancer. A biotinylated form of the anti-angiogenic drug Endostar was conjugated to a streptavidin-coated microbubble (MB). Mice bearing subcutaneous tumors (HT29) were divided into 4 groups. Group 1 served as an untreated control. Group 2 served as a cavitation control and received naked microbubbles and sham ultrasonic cavitation (MB+sham cavitation). Group 3 received naked microbubbles and ultrasonic cavitation (MB+cavitation). Group 4 received Endostar loaded microbubbles and ultrasonic cavitation (Endostar-MB+cavitation). Ultrasonic cavitation was performed using a high-power custom built sonicator. Contrast-enhanced ultrasound imaging (CEUS) was used to measure tumor blood flow before and after ultrasonic cavitation. In vivo fluorescence imaging was performed to monitor changes in tumor volume. Immunohistochemistry was performed to assess CD31, VEGFR-2 and alpha-v beta-3 integrin expression within the tumor. Apoptosis of the tumor cells was determined by TUNEL assay, and ultrastructural changes within the tumor were examined by electron microcopy. Ultrasonic cavitation with Endostar-MB demonstrated a significantly greater inhibition of tumor blood flow on day 7 and tumor growth on day 16 compared with naked MB and control groups. The Endostar-MB treated mice showed significantly decreased expression VEGFR-2 and alpha-v beta-3 integrin, and increased apoptosis of tumor cells and degradation of the tumor ultrastructure. Our findings indicated that the anti-vascular and anti-tumor effects of ultrasonic cavitation could be potentiated by simultaneously delivering an anti-angiogenic drug in colon cancer.

  16. Learning about Colon Cancer

    MedlinePlus

    ... Top of page Is there a test for hereditary colon cancer? Gene testing can identify individuals who ... Top of page Current NHGRI Clinical Research on Hereditary Colon Cancer Currently, NHGRI is not conducting clinical ...

  17. Overexpression of forkhead Box C2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial-mesenchymal transition.

    PubMed

    Li, Qingguo; Wu, Jitao; Wei, Ping; Xu, Ye; Zhuo, Changhua; Wang, Yuwei; Li, Dawei; Cai, Sanjun

    2015-01-01

    Forkhead box protein C2 (FOXC2) plays a vital role in carcinogenesis; however, its significance and prognostic value in colon cancer remain unclear. In this study, FOXC2 expression was analyzed in a tissue microarray (TMA) containing 185 samples of primary colon cancer tumor samples and in human colon cancer cell lines. The effect of FOXC2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo. FOXC2 was overexpressed in human colon cancer cells and tissues, and correlated with colon cancer progression and patient survival. Functional study demonstrated that FOXC2 promoted cell growth, cell migration, and tumor formation in nude mice, whereas knockdown of FOXC2 by short hairpin RNA (shRNAs) significantly suppressed cell growth, cell migration and tumor formation. Further study found that FOXC2 enhanced AKT activity with subsequent GSK-3β phosphorylation and Snail stabilization, and then induced epithelial-mesenchymal transition (EMT) and promoted tumor invasion and metastasis. Collectively, FOXC2 promotes colon cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in colon cancer.

  18. Colon cancer screening

    MedlinePlus

    Screening for colon cancer; Colonoscopy - screening; Sigmoidoscopy - screening; Virtual colonoscopy - screening; Fecal immunochemical test; Stool DNA test; sDNA test; Colorectal cancer - screening; Rectal ...

  19. Daikenchuto (TU-100) Suppresses Tumor Development in the Azoxymethane and APC(min/+) Mouse Models of Experimental Colon Cancer.

    PubMed

    Hasebe, Takumu; Matsukawa, Jun; Ringus, Daina; Miyoshi, Jun; Hart, John; Kaneko, Atsushi; Yamamoto, Masahiro; Kono, Toru; Fujiya, Mikihiro; Kohgo, Yutaka; Wang, Chong-Zi; Yuan, Chun-Su; Bissonnette, Marc; Musch, Mark W; Chang, Eugene B

    2017-01-01

    Chemopreventative properties of traditional medicines and underlying mechanisms of action are incompletely investigated. This study demonstrates that dietary daikenchuto (TU-100), comprised of ginger, ginseng, and Japanese pepper effectively suppresses intestinal tumor development and progression in the azoxymethane (AOM) and APC(min/+) mouse models. For the AOM model, TU-100 was provided after the first of six biweekly AOM injections. Mice were sacrificed at 30 weeks. APC(min/+) mice were fed diet without or with TU-100 starting at 6 weeks, and sacrificed at 24 weeks. In both models, dietary TU-100 decreased tumor size. In APC (min/+) mice, the number of small intestinal tumors was significantly decreased. In the AOM model, both TU-100 and Japanese ginseng decreased colon tumor numbers. Decreased Ki-67 and β-catenin immunostaining and activation of numerous transduction pathways involved in tumor initiation and progression were observed. EGF receptor expression and stimulation/phosphorylation in vitro were investigated in C2BBe1 cells. TU-100, ginger, and 6-gingerol suppressed EGF receptor induced Akt activation. TU-100 and ginseng and to a lesser extent ginger or 6-gingerol inhibited EGF ERK1/2 activation. TU-100 and some of its components and metabolites of these components inhibit tumor progression in two mouse models of colon cancer by blocking downstream pathways of EGF receptor activation. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Hypofractionated Irradiation Has Immune Stimulatory Potential and Induces a Timely Restricted Infiltration of Immune Cells in Colon Cancer Tumors

    PubMed Central

    Frey, Benjamin; Rückert, Michael; Weber, Julia; Mayr, Xaver; Derer, Anja; Lotter, Michael; Bert, Christoph; Rödel, Franz; Fietkau, Rainer; Gaipl, Udo S.

    2017-01-01

    In addition to locally controlling the tumor, hypofractionated radiotherapy (RT) particularly aims to activate immune cells in the RT-modified microenvironment. Therefore, we examined whether hypofractionated RT can activate dendritic cells (DCs), induce immune cell infiltration in tumors, and how the chronology of immune cell migration into tumors occurs to gain knowledge for future definition of radiation breaks and inclusion of immunotherapy. Colorectal cancer treatments offer only limited survival benefit, and immunobiological principles for additional therapies need to be explored with preclinical models. The impact of hypofractionated RT on CT26 colon cancer tumor cell death, migration of DCs toward supernatants (SN) of tumor cells, and activation of DCs by SN were analyzed. The subcutaneous tumor of a BALB/c-CT26 mouse model was locally irradiated with 2 × 5 Gy, the tumor volume was monitored, and the infiltration of immune cells in the tumor was determined by flow cytometry daily. Hypofractionated RT induced a mixture of apoptotic and necrotic CT26 cells, which is known to be in particular immunogenic. DCs that migrated toward SN of CT26 cells particularly upregulated the activation markers CD80 and CD86 when in contact with SN of irradiated tumor cells. After hypofractionated RT, the tumor outgrowth was significantly retarded and in the irradiated tumors an increased infiltration of macrophages (CD11bhigh/F4-80+) and DCs (MHC-II+), but only between day 5 and 10 after the first irradiation, takes place. While CD4+ T cells migrated into non-irradiated and irradiated tumors, CD8+ T cells were only found in tumors that had been irradiated and they were highly increased at day 8 after the first irradiation. Myeloid-derived suppressor cells and regulatory T cells show regular turnover in irradiated and non-irradiated tumors. Tumor cell-specific anti-IgM antibodies were enhanced in the serum of animals with irradiated tumors. We conclude that

  1. Hypofractionated Irradiation Has Immune Stimulatory Potential and Induces a Timely Restricted Infiltration of Immune Cells in Colon Cancer Tumors.

    PubMed

    Frey, Benjamin; Rückert, Michael; Weber, Julia; Mayr, Xaver; Derer, Anja; Lotter, Michael; Bert, Christoph; Rödel, Franz; Fietkau, Rainer; Gaipl, Udo S

    2017-01-01

    In addition to locally controlling the tumor, hypofractionated radiotherapy (RT) particularly aims to activate immune cells in the RT-modified microenvironment. Therefore, we examined whether hypofractionated RT can activate dendritic cells (DCs), induce immune cell infiltration in tumors, and how the chronology of immune cell migration into tumors occurs to gain knowledge for future definition of radiation breaks and inclusion of immunotherapy. Colorectal cancer treatments offer only limited survival benefit, and immunobiological principles for additional therapies need to be explored with preclinical models. The impact of hypofractionated RT on CT26 colon cancer tumor cell death, migration of DCs toward supernatants (SN) of tumor cells, and activation of DCs by SN were analyzed. The subcutaneous tumor of a BALB/c-CT26 mouse model was locally irradiated with 2 × 5 Gy, the tumor volume was monitored, and the infiltration of immune cells in the tumor was determined by flow cytometry daily. Hypofractionated RT induced a mixture of apoptotic and necrotic CT26 cells, which is known to be in particular immunogenic. DCs that migrated toward SN of CT26 cells particularly upregulated the activation markers CD80 and CD86 when in contact with SN of irradiated tumor cells. After hypofractionated RT, the tumor outgrowth was significantly retarded and in the irradiated tumors an increased infiltration of macrophages (CD11b(high)/F4-80(+)) and DCs (MHC-II(+)), but only between day 5 and 10 after the first irradiation, takes place. While CD4(+) T cells migrated into non-irradiated and irradiated tumors, CD8(+) T cells were only found in tumors that had been irradiated and they were highly increased at day 8 after the first irradiation. Myeloid-derived suppressor cells and regulatory T cells show regular turnover in irradiated and non-irradiated tumors. Tumor cell-specific anti-IgM antibodies were enhanced in the serum of animals with irradiated tumors. We conclude that

  2. Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer.

    PubMed

    Bohanes, P; Yang, D; Loupakis, F; LaBonte, M J; Gerger, A; Ning, Y; Lenz, C; Lenz, F; Wakatsuki, T; Zhang, W; Benhaim, L; El-Khoueiry, A; El-Khoueiry, R; Lenz, H-J

    2015-06-01

    Integrins (ITGs) are key elements in cancer biology, regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Moving from the hypothesis that ITGs could have different effects in stage II and III colon cancer, we tested whether a comprehensive panel of germline single-nucleotide polymorphisms (SNPs) in ITG genes could predict stage-specific time to tumor recurrence (TTR). A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole-blood samples were analyzed for germline SNPs in ITG genes using PCR-restriction fragment length polymorphism or direct DNA sequencing. In the multivariable analysis, stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (hazard ratio (HR)=4.027, 95% confidence interval (95% CI) 1.556-10.421, P=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, 95% CI 1.194-3.269, P=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases the combined analysis of ITGB1 rs2298141 and ITGA4 rs7562325 allowed to identify three distinct prognostic subgroups (P=0.009). The interaction between stage and the combined ITGB1 rs2298141 and ITGA4 rs7562325 on TTR was significant (P=0.025). This study identifies germline polymorphisms in ITG genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data may help to select subgroups of patients who may benefit from ITG-targeted treatments.

  3. Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

    PubMed Central

    Bae, Jooeun; Samur, Mehmet; Munshi, Aditya; Hideshima, Teru; Keskin, Derin; Kimmelman, Alec; Lee, Ann-Hwee; Dranoff, Glen; Anderson, Kenneth C; Munshi, Nikhil C

    2015-01-01

    XBP1 is a critical transcriptional activator of the unfolded protein response (UPR), which increases tumor cell survival under prolonged endoplasmic reticulum (ER) stress and hypoxic conditions.This study was designed to evaluate the immunogenicity of heteroclitic XBP1 unspliced (US)184–192 (YISPWILAV) and heteroclictic XBP1 spliced (SP)367–375 (YLFPQLISV) HLA-A2 peptides, and to characterize the specific activities of XBP1 peptides-specific cytotoxic T lymphocytes (XBP1-CTL) against breast cancer, colon cancer, and pancreatic cancer cells.The XBP1-CTL had upregulated expression of critical T cell markers and displayed HLA-A2-restricted and antigen-specific activities against breast cancer, colon cancer and pancreatic cancer cells. XBP1-CTL were enriched withCD45RO+ memory CTL, which showed high expression of critical T cell markers (CD28, ICOS, CD69, CD40L), cell proliferation and antitumor activities as compared to CD45RO− non-memory CTL. The effector memory (EM: CD45RO+CCR7−) subset had the highest level of cell proliferation while the central memory (CM: CD45RO+CCR7+) subset demonstrated enhanced functional activities (CD107a degranulation, IFNγ/IL-2 production) upon recognition of the respective tumor cells. Furthermore, both the EM and CM XBP1-CTL subsets expressed high levels of Th1 transcription regulators Tbet and Eomes. The highest frequencies of IFNγ or granzyme B producing cells were detected within CM XBP1-CTL subset that were either Tbet+ or Eomes+ in responding to the tumor cells.These results demonstrate the immunotherapeutic potential of a cocktail of immunogenic HLA-A2 specific heteroclitic XBP1 US184–192 and heteroclictic XBP1 SP367–375 peptides to induce CD3+CD8+ CTL enriched for CM and EM cells with specific antitumor activities against a variety of solid tumors. PMID:25941601

  4. Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer.

    PubMed

    Newmark, Harold L; Yang, Kan; Kurihara, Naoto; Fan, Kunhua; Augenlicht, Leonard H; Lipkin, Martin

    2009-01-01

    We reported previously that a new Western-style diet (NWD) for 18 months, consisting of elevated lipids and decreased calcium, vitamin D and methyl-donor nutrients, induced colonic tumors in normal C57Bl/6 mice [Newmark, H.L. et al. (2001) A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis, 22, 1871-1875], suggesting a new mouse model for human sporadic colon cancer. Here, we have extended this study during a longer feeding period of 2 years wherein tumor formation, tumor inhibition by addition of dietary calcium and vitamin D and their effects on gene expression were determined. We also similarly tested individual supplements of methyl donor (transfer) nutrients (folic acid, choline, methionine and dietary fiber), but these had no significant effect on colonic tumor incidence or multiplicity, whereas supplementation with combined calcium and vitamin D produced significant decrease in both colon tumor incidence and multiplicity, during 2 years of feeding. No visible colonic tumors were found at 6 months, very few at 12 months, more at 18 months and significantly at 24 months. In a related study of gene changes of the mouse colonic mucosa at 6 months of feeding taken from this study, long before any tumors were visibly detectable, indicated altered profiles of gene expression linked to later risk of dietary initiation of colon tumor formation. This type of early genetic altered profile, an indication of increased risk of later colonic tumor development, may become a useful tool for prediction of colon tumor risk while the colon grossly still appears histologically and physiologically normal.

  5. Alterations of lymph nodes evaluation after colon cancer resection: patient and tumor heterogeneity should be taken into consideration

    PubMed Central

    Guan, Xu; Chen, Wei; Li, Shuai; Jiang, Zheng; Liu, Zheng; Zhao, Zhixun; Wang, Song; Yang, Ming; Wang, Xishan

    2016-01-01

    Despite the adequacy of nodal evaluation was gradually improved for colon cancer (CC), rare attention has been paid for the effect of patient and tumor heterogeneity on nodal evaluation. We identified 109902 CC patients in stage I-III from Surveillance, Epidemiology, and End-Results (SEER) database during 2004-2013. The lymph nodes evaluations were separately assessed in different patient- and tumor-related features, including gender, age, T stage, histology, tumor differentiation, tumor size and tumor location. The 5-year cancer specific survival (CSS) was calculated with Kaplan-Meier method, log-rank tests were used to compare the differences of CSS in patients with ≥12 and <12 lymph nodes examined. Here, we identified features including gender, age, T stage, tumor differentiation, tumor size and location were independently associated with the median number of lymph node, the rate of ≥12 lymph nodes and the rate of node positivity of CC patients. We then divided CC patients into 29 subgroups according to different patient- and tumor-related features. The median number of lymph node presented a large variance from 12 to 24, the rate of ≥12 lymph nodes increased from 53.2% to 91.2% under the combined effect of patient and tumor heterogeneity. Furthermore, the positive association between increased lymph nodes count and improved survival couldn't be observed in 8261 CC patients with the effect of this heterogeneity. In conclusion, the tumor and patient heterogeneity lead to large alterations of nodal evaluation; we should pay more attention to this effect in clinical practice. PMID:27577077

  6. Blood circulating tumor DNA for non-invasive genotyping of colon cancer patients.

    PubMed

    Siravegna, Giulia; Bardelli, Alberto

    2016-03-01

    Most solid tumors, including colorectal cancers, shed cell-free DNA (ctDNA) in the blood. ctDNA can be analyzed to generate molecular profiles which capture the heterogeneity of the disease more comprehensively then tumor tissue biopsies. This approach commonly called 'liquid biopsy' can be applied to monitor response to therapy, to assess minimal residual disease and to uncover the emergence of drug resistance. This review will discuss current and future developments of ctDNA analysis in the clinical management of colorectal cancer patients.

  7. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

    PubMed Central

    Tie, Jeanne; Wang, Yuxuan; Tomasetti, Cristian; Li, Lu; Springer, Simeon; Kinde, Isaac; Silliman, Natalie; Tacey, Mark; Wong, Hui-Li; Christie, Michael; Kosmider, Suzanne; Skinner, Iain; Wong, Rachel; Steel, Malcolm; Tran, Ben; Desai, Jayesh; Jones, Ian; Haydon, Andrew; Hayes, Theresa; Price, Tim J.; Strausberg, Robert L.; Diaz, Luis A.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Gibbs, Peter

    2017-01-01

    Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence. PMID:27384348

  8. Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147.

    PubMed

    Gonsalves, Wilson I; Mahoney, Michelle R; Sargent, Daniel J; Nelson, Garth D; Alberts, Steven R; Sinicrope, Frank A; Goldberg, Richard M; Limburg, Paul J; Thibodeau, Stephen N; Grothey, Axel; Hubbard, Joleen M; Chan, Emily; Nair, Suresh; Berenberg, Jeffrey L; McWilliams, Robert R

    2014-07-01

    KRAS and BRAF (V600E) mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them. Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF (V600E) mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided. KRAS (35%) and BRAF (V600E) (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF (V600E) mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men. Tumors with BRAF (V600E) mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR. Specific patient and tumor characteristics are associated with KRAS and BRAF (V600E) mutations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. Patient and Tumor Characteristics and BRAF and KRAS Mutations in Colon Cancer, NCCTG/Alliance N0147

    PubMed Central

    Gonsalves, Wilson I.; Mahoney, Michelle R.; Sargent, Daniel J.; Nelson, Garth D.; Alberts, Steven R.; Sinicrope, Frank A.; Goldberg, Richard M.; Limburg, Paul J.; Thibodeau, Stephen N.; Grothey, Axel; Hubbard, Joleen M.; Chan, Emily; Nair, Suresh; Berenberg, Jeffrey L.

    2014-01-01

    Background KRAS and BRAF V600E mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them. Methods Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF V600E mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided. Results KRAS (35%) and BRAF V600E (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF V600E mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men. Tumors with BRAF V600E mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR. Conclusions Specific patient and tumor characteristics are associated with KRAS and BRAF V600E mutations. PMID:24925349

  10. Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells.

    PubMed

    Gouyer, V; Fontaine, D; Dumont, P; de Wever, O; Fontayne-Devaud, H; Leteurtre, E; Truant, S; Delacour, D; Drobecq, H; Kerckaert, J-P; de Launoit, Y; Bracke, M; Gespach, C; Desseyn, J-L; Huet, G

    2008-07-03

    From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.

  11. Dystroglycan Expression Is Frequently Reduced in Human Breast and Colon Cancers and Is Associated with Tumor Progression

    PubMed Central

    Sgambato, Alessandro; Migaldi, Mario; Montanari, Micaela; Camerini, Andrea; Brancaccio, Andrea; Rossi, Giulio; Cangiano, Rodolfo; Losasso, Carmen; Capelli, Giovanni; Trentini, Gian Paolo; Cittadini, Achille

    2003-01-01

    Dystroglycan (DG) is an adhesion molecule responsible for crucial interactions between extracellular matrix and cytoplasmic compartment. It is formed by two subunits, α-DG (extracellular) and β-DG (transmembrane), that bind to laminin in the matrix and dystrophin in the cytoskeleton, respectively. In this study we evaluated by Western blot analysis the expression of DG in a series of human cancer cell lines of various histogenetic origin and in a series of human primary colon and breast cancers. Decreased expression of DG was observed in most of the cell lines and in both types of tumors and correlated with higher tumor grade and stage. Analysis of the mRNA levels suggested that expression of DG protein is likely regulated at a posttranscriptional level. Evaluation of α-DG expression by immunostaining in a series of archival cases of primary breast carcinomas confirmed that α-DG expression is lost in a significant fraction of tumors (66%). Loss of DG staining correlated with higher tumor stage (P = 0.022), positivity for p53 (P = 0.033), and high proliferation index (P = 0.045). A significant correlation was also observed between loss of α-DG and overall survival (P = 0.013 by log-rank test) in an univariate analysis. These data indicate that DG expression is frequently lost in human malignancies and suggest that this glycoprotein might play an important role in human tumor development and progression. PMID:12598319

  12. FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP-7.

    PubMed

    Bai, Yu-Pan; Shang, Kun; Chen, Huan; Ding, Fei; Wang, Zhen; Liang, Chen; Xu, Ye; Sun, Meng-Hong; Li, Ying-Yi

    2015-10-01

    Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in the tumor stroma, are important modifiers of tumour progression. In the present study, we observed that azoxymethane and dextran sodium sulfate treatments induced increasingly severe colorectal mucosal inflammation and the intratumoural accumulation of CAFs. Fibroblast growth factor (FGF)-1 and FGF-3 were detected in infiltrating cells, and FGFR4, the specific receptor for FGF-1 and FGF-3, was detected in colon cancer tissues. The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)-7 and mitogen-activated protein kinase kinase (Mek)/extracellular signal-regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation. Moreover, we separated CAFs, pericarcinoma fibroblasts (PFs), and normal fibroblasts (NFs) from human colon tissue specimens to characterize the function of CAFs. We observed that CAFs secrete more FGF-1/-3 than NFs and PFs and promote cancer cell growth and angiogenesis through the activation of FGFR4, which is followed by the activation of Mek/Erk and the modulation of MMP-7 expression. The administration of FGF-1/-3-neutralizing antibodies or the treatment of cells with FGFR4 siRNA or the FGFR4 inhibitor PD173074 markedly suppressed colon cancer cell proliferation and neovascularization. These observations suggest a crucial role for CAFs and FGF signaling in the initiation and progression of colorectal cancer. The inhibition of the FGF signaling pathway may be a useful strategy for the treatment of colon cancer.

  13. FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP-7

    PubMed Central

    Bai, Yu-Pan; Shang, Kun; Chen, Huan; Ding, Fei; Wang, Zhen; Liang, Chen; Xu, Ye; Sun, Meng-Hong; LI, Ying-Yi

    2015-01-01

    Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in the tumor stroma, are important modifiers of tumour progression. In the present study, we observed that azoxymethane and dextran sodium sulfate treatments induced increasingly severe colorectal mucosal inflammation and the intratumoural accumulation of CAFs. Fibroblast growth factor (FGF)-1 and FGF-3 were detected in infiltrating cells, and FGFR4, the specific receptor for FGF-1 and FGF-3, was detected in colon cancer tissues. The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)-7 and mitogen-activated protein kinase kinase (Mek)/extracellular signal-regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation. Moreover, we separated CAFs, pericarcinoma fibroblasts (PFs), and normal fibroblasts (NFs) from human colon tissue specimens to characterize the function of CAFs. We observed that CAFs secrete more FGF-1/-3 than NFs and PFs and promote cancer cell growth and angiogenesis through the activation of FGFR4, which is followed by the activation of Mek/Erk and the modulation of MMP-7 expression. The administration of FGF-1/-3-neutralizing antibodies or the treatment of cells with FGFR4 siRNA or the FGFR4 inhibitor PD173074 markedly suppressed colon cancer cell proliferation and neovascularization. These observations suggest a crucial role for CAFs and FGF signaling in the initiation and progression of colorectal cancer. The inhibition of the FGF signaling pathway may be a useful strategy for the treatment of colon cancer. PMID:26183471

  14. Secreted clusterin in colon tumor cell models and its potential as diagnostic marker for colorectal cancer.

    PubMed

    Rodríguez-Piñeiro, A M; García-Lorenzo, A; Blanco-Prieto, S; Alvarez-Chaver, P; Rodríguez-Berrocal, F J; Cadena, M Páez de la; Martínez-Zorzano, V S

    2012-01-01

    We studied the specific changes of the secreted protein clusterin and its cytoplasmic precursor regarding colorectal tumorigenesis, using in vitro differentiation of Caco-2 cells. In tumor-like stage, we observed an overexpression of both precursor and secreted clusterin, corroborated in the cell line SW-480. Noticeably, SW-620 cells (from a tumoral node, thus with metastatic capacity) did not show overexpression of either precursor or secreted clusterin, suggesting a downregulation related to local metastasis. We further investigated clusterin in serum, finding a significant increase in colorectal cancer patients, with 81% sensitivity, 79% specificity, and an area under the ROC curve of 0.85.

  15. Understanding your colon cancer risk

    MedlinePlus

    Colon cancer - prevention; Colon cancer - screening ... We do not know what causes colon cancer, but we do know some of the things that may increase the risk of getting it, such as: Age. Your risk increases after ...

  16. Curcumin Suppresses Crosstalk between Colon Cancer Stem Cells and Stromal Fibroblasts in the Tumor Microenvironment: Potential Role of EMT

    PubMed Central

    Buhrmann, Constanze; Kraehe, Patricia; Lueders, Cora; Shayan, Parviz; Goel, Ajay; Shakibaei, Mehdi

    2014-01-01

    Objective Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment. Methods Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU. Results Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment. Conclusion Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by curcumin might be

  17. Negligible Colon Cancer Risk from Food-Borne Acrylamide Exposure in Male F344 Rats and Nude (nu/nu) Mice-Bearing Human Colon Tumor Xenografts

    PubMed Central

    Raju, Jayadev; Roberts, Jennifer; Sondagar, Chandni; Kapal, Kamla; Aziz, Syed A.; Caldwell, Don; Mehta, Rekha

    2013-01-01

    Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet) reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control) or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM) or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu) mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control) or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a “complete carcinogen”, but acts as a “co-carcinogen” by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters. PMID:24040114

  18. [A case report of the use of laparoscopic surgery to remove an adrenal tumor following resection of sigmoid colon cancer].

    PubMed

    Okano, Miho; Yasui, Masayoshi; Nishino, Masaya; Hosoda, Yohei; Nagai, Kenichi; Kim, Yongkook; Tsujinaka, Toshimasa

    2014-11-01

    A 58-year-old woman underwent sigmoidectomy and partial cystectomy for sigmoid colon cancer following colostomy. The final staging of the tumor was T3, N1, tub2, M0, fStage IIIa. She received 6 courses of CapeOX (oxaliplatin 130mg/m², capecitabine 200mg/m²) as adjuvant chemotherapy, which was discontinued because of severe general fatigue. At the same time, an increase in the levels of serum carcinoembryonic antigen (CEA) was detected and abdominal computed tomography (CT) revealed an expanded adrenal mass. Since whole-body ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) showed no evidence of multiple organ metastases except for the right adrenal tumor, a solitary adrenal metastasis from sigmoid colon cancer was strongly suspected. Hence, colostomy closure and laparoscopic adrenalectomy were concurrently performed. Histological examination revealed non-functional adrenal adenoma. Therefore, laparoscopic surgery was a reasonable choice even in this complex case.

  19. Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family

    PubMed Central

    Suliman, Mohammed A.; Zhang, Zhenxing; Na, Heya; Ribeiro, Ailton L.L.; Zhang, Yu; Niang, Bachir; Hamid, Abdu Salim; Zhang, Hua; Xu, Lijie; Zuo, Yunfei

    2016-01-01

    Colorectal cancer (CRC) is among the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for the development of new therapeutic approaches for the treatment of CRC. Accumulating evidence has revealed that niclosamide, an anthelminthic drug, exerts antitumor activity in several types of cancer, including colon cancer. However, the underlying molecular mechanisms responsible for the effects of this drug remain elusive. Previous studies have shown that the aberrant Notch signaling pathway contributes to the carcinogenesis of colon cancer. Herein, we examined the effects of niclosamide on the growth, migration and apoptosis of colon cancer cells, and the role of the Notch signaling pathway. By performing MTT, wound-healing and Transwell migration assays, we observed that niclosamide suppressed the growth and migration of colon cancer cells, and flow cytometry demonstrated that cell apoptosis was induced. This was associated with the decreased protein expression of Notch1, Notch2, Notch3 and Hey1, and the increased expression of the tumor suppressor microRNA (miR or miRNA)-200 family members (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) that are typically downregulated in colon cancer. Collectively, these findings demonstrate that niclosamide potentially inhibits the progression of colon cancer by downregulating Notch signaling and by upregulating the miR-200 family members. PMID:27460529

  20. Gene expression differences between colon and rectum tumors.

    PubMed

    Sanz-Pamplona, Rebeca; Cordero, David; Berenguer, Antonio; Lejbkowicz, Flavio; Rennert, Hedy; Salazar, Ramon; Biondo, Sebastiano; Sanjuan, Xavier; Pujana, Miguel A; Rozek, Laura; Giordano, Thomas J; Ben-Izhak, Ofer; Cohen, Hector I; Trougouboff, Philip; Bejhar, Jacob; Sova, Yanina; Rennert, Gad; Gruber, Stephen B; Moreno, Victor

    2011-12-01

    Colorectal cancer studies typically include both colon and rectum tumors as a common entity, though this assumption is controversial and only minor differences have been reported at the molecular and epidemiologic level. We conducted a molecular study based on gene expression data of tumors from colon and rectum to assess the degree of similarity between these cancer sites at transcriptomic level. A pooled analysis of 460 colon tumors and 100 rectum tumors from four data sets belonging to three independent studies was conducted. Microsatellite instable tumors were excluded as these are known to have a different expression profile and have a preferential proximal colon location. Expression differences were assessed with linear models, and significant genes were identified using adjustment for multiple comparisons. Minor differences at a gene expression level were found between tumors arising in the proximal colon, distal colon, or rectum. Only several HOX genes were found to be associated with tumor location. More differences were found between proximal and distal colon than between distal colon and rectum. Microsatellite stable colorectal cancers do not show major transcriptomic differences for tumors arising in the colon or rectum. The small but consistent differences observed are largely driven by the HOX genes. These results may have important implications in the design and interpretation of studies in colorectal cancer. ©2011 AACR.

  1. Carcinoma obstruction of the proximal colon cancer and long-term prognosis--obstruction is a predictor of worse outcome in TNM stage II tumor.

    PubMed

    Chin, Chih-Chien; Wang, Jeng-Yi; Changchien, Chung-Rong; Huang, Wen-Shih; Tang, Reiping

    2010-07-01

    Colon obstruction is suggested to be a predictor of poor outcome in colon cancer. However, the effect of obstruction on outcome in patients with different tumor-nodes-metastases (TNM) stage cancer has not been fully addressed. The aim of this study is to determine whether colon obstruction predicts surgical and long-term oncologic outcomes in patients with proximal colon cancer. A total of 1,492 consecutive patients underwent open resection of primary adenocarcinoma of right colon in a single institution between January 1995 and December 2005. Clinical and follow-up data were extracted from a prospective colorectal cancer database. Univariate and multivariate analyses were performed to identify colon obstruction and other predictors of surgical and oncologic outcomes. Among 1,492 patients, 306 (20.5%) patients presented with colon obstruction. The rates of surgical morbidity and mortality were greater in patients with an obstruction as compared to patients without an obstruction (22.2% and 3.9% vs. 14.1% and 1.9%; p = 0.0005 and 0.041, respectively). Obstruction predicted a worse long-term disease-free survival (DFS) among patients with stage II-III disease (log-rank test, p = 0.0003). The data were stratified by TNM stage. Obstruction predicted a worse DFS among patients with TNM stage II cancer (598 patients; log-rank test, p = 0.001; Cox regression, p = 0.012), but it was not a predictor in TNM stage III cancer patients (424 patients; p = 0.116; p = 0.108). Colon obstruction was an independent predictor of long-term outcome only in TNM stage II but not in stage III proximal colon cancer. Patients with TNM stage II obstructive colon cancer could be included in future trials of adjuvant therapies.

  2. A polysaccharide from Lentinus edodes inhibits human colon cancer cell proliferation and suppresses tumor growth in athymic nude mice

    PubMed Central

    Wang, Jinglin; Li, Weiyong; Huang, Xiao; Liu, Ying; Li, Qiang; Zheng, Ziming; Wang, Kaiping

    2017-01-01

    The antitumor effect of Lentinan is thought rely on the activation of immune responses; however, little is known about whether Lentinan also directly attacks cancer cells. We therefore investigated the direct antitumor activity of SLNT (a water-extracted polysaccharide from Lentinus edodes) and its probable mechanism. We showed that SLNT significantly inhibited proliferation of HT-29 colon cancer cells and suppressed tumor growth in nude mice. Annxein V-FITC/PI, DAPI, AO/EB and H&E staining assays all showed that SLNT induced cell apoptosis both in vitro and in vivo. SLNT induced apoptosis by activating Caspase-3 via both intrinsic and extrinsic pathways, which presented as the activation of Caspases-9 and -8, upregulation of cytochrome c and the Bax/Bcl-2 ratio, downregulation of NF-κB, and overproduction of ROS and TNF-α in vitro and in vivo. Pretreatment with the caspase-3 inhibitor Ac-DEVD-CHO or antioxidant NAC blocked SLNT-induced apoptosis. These findings suggest that SLNT exerts direct antitumor effects by inducing cell apoptosis via ROS-mediated intrinsic and TNF-α-mediated extrinsic pathways. SLNT may thus represent a useful candidate for colon cancer prevention and treatment. PMID:27888812

  3. Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1#

    PubMed Central

    Zhang, Huabing; Ramakrishnan, Sadeesh K.; Triner, Daniel; Centofanti, Brook; Maitra, Dhiman; Győrffy, Balázs; Sebolt-Leopold, Judith S.; Dame, Michael K.; Varani, James; Brenner, Dean E.; Fearon, Eric R.; Omary, M. Bishr; Shah, Yatrik M.

    2016-01-01

    Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1- activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. Here, we found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetic or chemical-induced mouse models of CRC, in patient-derived xenografts and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viabilty of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells in hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death; whereas culturing cells in normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers. PMID:26443705

  4. Cholesterol metabolism and colon cancer.

    PubMed

    Broitman, S A; Cerda, S; Wilkinson, J

    1993-01-01

    While epidemiologic and concordant experimental data indicate a direct relationship between dietary fat (and presumably caloric) intake and the development of colon cancer, the effect of dietary cholesterol on this disease is still not clear. However, there appears to be a developing literature concerning an inverse relationship between serum and plasma cholesterol levels, and the risk for colon cancer. Findings that low serum cholesterol levels are apparent as early as ten years prior to the detection of colon cancer implies that sub clinical disease is probably not involved initially in this process. The possibility of low serum cholesterol as a bio-marker was considered in epidemiologic studies which focused upon obese men with lower than normal serum cholesterol levels who were found to be at increased risk to colon cancer. While the relationship between low serum cholesterol and colonic or intestinal cholesterol metabolism is presently not understood, current genetic studies provide a promising though as yet unexplored potential association. Alterations which occur during the developmental progression of colonic cancer include changes in chromosome 5, which also carries two genes vital to the biosynthesis and regulation of systemic and cellular cholesterol metabolism, 3-hydroxy-3-methylglutaryl coenzyme A synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA R). Regulation of cholesterol metabolism in intestinal cells in vivo and in vitro varies from that seen in normal fibroblasts or hepatocytes in terms of exogenous sources of cholesterol and how these sources regulate internal synthesis. Colonic cancer cells have been used to assess small bowel enterocyte cholesterol metabolism, which has been possible because of their ability to differentiate in culture, however information regarding true colonic enterocyte cholesterol metabolism is relatively scarce. Colonic cancer cells have been shown to possess a diminished or nonexistent ability to use

  5. Stroma-directed imatinib therapy impairs the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic transplantation model of colon cancer.

    PubMed

    Shinagawa, Kei; Kitadai, Yasuhiko; Tanaka, Miwako; Sumida, Tomonori; Onoyama, Mieko; Ohnishi, Mayu; Ohara, Eiji; Higashi, Yukihito; Tanaka, Shinji; Yasui, Wataru; Chayama, Kazuaki

    2013-02-15

    Bone marrow-derived mesenchymal stem cells (MSCs) are reported to contribute to formation of tumor-promoting stromal cells. We reported recently that, in an orthotopic nude mice model of colon cancer, MSCs traveled to tumor stroma, where they differentiated into carcinoma-associated fibroblast (CAF)-like cells. We also found that CAFs express platelet-derived growth factor receptor (PDGFR) at a high level and that imatinib therapy targeting PDGFR in CAFs inhibits growth and metastasis of human colon cancer. These findings led us to examine whether the tumor-promoting effect of MSCs is impaired by blockade of PDGFR signaling achieved with imatinib. Orthotopic transplantation and splenic injection of human MSCs along with KM12SM human colon cancer cells, in comparison with transplantation of KM12SM cells alone, resulted in significantly greater promotion of tumor growth and liver metastasis. The KM12SM + MSC xenograft enhanced cell proliferation and angiogenesis and inhibited tumor cell apoptosis. When tumor-bearing animals were treated with imatinib, there was no significant increase in primary tumor volume or total volume of liver metastases, despite the KM12SM+MSC xenograft, and survival in the mixed-cell group was prolonged by imatinib treatment. Moreover, the ability of MSCs to migrate to tumor stroma was impaired, and the number of MSCs surviving in the tumor microenvironment was significantly decreased. In in vitro experiments, treatment with imatinib inhibited migration of MSCs. Our data suggest that blockade of PDGF signaling pathways influences the interaction between bone marrow-derived MSCs and tumor cells in the tumor microenvironment and, hence, inhibits the progressive growth of colon cancer.

  6. Prognostic value of circulating tumor DNA in patients with colon cancer: Systematic review

    PubMed Central

    Fan, Gaowei; Zhang, Kuo; Yang, Xin; Ding, Jiansheng; Wang, Zujian; Li, Jinming

    2017-01-01

    The application of circulating tumor DNA(ctDNA) represents a non-invasive method for tumor detection. Its prognostic significance in patients with colorectal cancer is controversial. We performed a systematic review of data from published studies to assess the prognostic values of ctDNA in patients with colorectal cancer. We searched Medline, Embase, Web of Science, the Cochrane Library, and Scopus databases to identify eligible studies reporting disease-free survival (DFS) and overall survival (OS) stratified by ctDNA prior to December 6, 2016. We evaluated the quality and design of these studies. A total of 22 studies were eligible for systematic review. Among them, 11 studies investigated the prognostic value of ctDNA on disease-free survival (DFS). Seven of 11 studies showed that ctDNA was an independent variable to estimate the probability of DFS by multivariate analyses. Thirteen studies assessed the relationship between ctDNA and overall survival (OS). Eight of 13 studies showed that ctDNA was an independent predictor of worse OS through the use of multivariate analyses. This analysis provides evidence that ctDNA may be a prognostic biomarker, negatively correlated with the survival of patients with colorectal cancer. PMID:28187169

  7. Computer-assisted stereology and automated image analysis for quantification of tumor infiltrating lymphocytes in colon cancer.

    PubMed

    Eriksen, Ann C; Andersen, Johnnie B; Kristensson, Martin; dePont Christensen, René; Hansen, Torben F; Kjær-Frifeldt, Sanne; Sørensen, Flemming B

    2017-08-29

    Precise prognostic and predictive variables allowing improved post-operative treatment stratification are missing in patients treated for stage II colon cancer (CC). Investigation of tumor infiltrating lymphocytes (TILs) may be rewarding, but the lack of a standardized analytic technique is a major concern. Manual stereological counting is considered the gold standard, but digital pathology with image analysis is preferred due to time efficiency. The purpose of this study was to compare manual stereological estimates of TILs with automatic counts obtained by image analysis, and at the same time investigate the heterogeneity of TILs. From 43 patients treated for stage II CC in 2002 three paraffin embedded, tumor containing tissue blocks were selected one of them representing the deepest invasive tumor front. Serial sections from each of the 129 blocks were immunohistochemically stained for CD3 and CD8, and the slides were scanned. Stereological estimates of the numerical density and area fraction of TILs were obtained using the computer-assisted newCAST stereology system. For the image analysis approach an app-based algorithm was developed using Visiopharm Integrator System software. For both methods the tumor areas of interest (invasive front and central area) were manually delineated by the observer. Based on all sections, the Spearman's correlation coefficients for density estimates varied from 0.9457 to 0.9638 (p < 0.0001), whereas the coefficients for area fraction estimates ranged from 0.9400 to 0.9603 (P < 0.0001). Regarding heterogeneity, intra-class correlation coefficients (ICC) for CD3+ TILs varied from 0.615 to 0.746 in the central area, and from 0.686 to 0.746 in the invasive area. ICC for CD8+ TILs varied from 0.724 to 0.775 in the central area, and from 0.746 to 0.765 in the invasive area. Exact objective and time efficient estimates of numerical densities and area fractions of CD3+ and CD8+ TILs in stage II colon cancer can be obtained by image

  8. Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.

    PubMed

    Selmin, Ornella I; Fang, Changming; Lyon, Adam M; Doetschman, Tom C; Thompson, Patricia A; Martinez, Jesse D; Smith, Jeffrey W; Lance, Peter M; Romagnolo, Donato F

    2016-02-01

    The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention. We investigated how APC inactivation influences the regulation of FXR expression in colonic mucosal cells. We hypothesized that APC inactivation would epigenetically repress nuclear receptor subfamily 1, group H, member 4 (FXR gene name) expression through increased CpG methylation. Normal proximal colonic mucosa and normal-appearing adjacent colonic mucosa and colon tumors were collected from wild-type C57BL/6J and Apc-deficient (Apc(Min) (/+)) male mice, respectively. The expression of Fxr, ileal bile acid-binding protein (Ibabp), small heterodimer partner (Shp), and cyclooxygenase-2 (Cox-2) were determined by real-time polymerase chain reaction. In both normal and adjacent colonic mucosa and colon tumors, we measured CpG methylation of Fxr in bisulfonated genomic DNA. In vitro, we measured the impact of APC inactivation and deoxycholic acid (DCA) treatment on FXR expression in human colon cancer HCT-116 cells transfected with silencing RNA for APC and HT-29 cells carrying inactivated APC. In Apc(Min) (/+) mice, constitutive CpG methylation of the Fxrα3/4 promoter was linked to reduced (60-90%) baseline Fxr, Ibabp, and Shp and increased Cox-2 expression in apparently normal adjacent mucosa and colon tumors. Apc knockdown in HCT-116 cells increased cellular myelocytomatosis (c-MYC) and lowered (∼50%) FXR expression, which was further reduced (∼80%) by DCA. In human HCT-116 but not HT-29 colon cancer cells, DCA induced FXR expression and lowered CpG methylation of FXR. We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells

  9. Role of blood tumor markers in predicting metastasis and local recurrence after curative resection of colon cancer

    PubMed Central

    Peng, Yifan; Zhai, Zhiwei; Li, Zhongmin; Wang, Lin; Gu, Jin

    2015-01-01

    Aim: To investigate the prognostic value of carcinoembryonic antigen (CEA), CA199, CA724 and CA242 in peripheral blood and local draining venous blood in colon cancer patients after curative resection. Methods: 92 colon cancer patients who received curative resection were retrospectively analyzed. The CEA, CA199, CA724 and CA242 were detected in peripheral blood and local draining venous blood. Results: Metastasis or local recurrence was found in 29 (29/92, 31.5%) patients during follow-up period. 92 patients were divided into two groups: metastasis/local recurrence group (n = 29) and non-metastasis/local recurrence group (n = 63). Peripheral venous CEA, CA199, CA724 and CA242 (p-CEA, p-CA199, p-CA724 and p-CA242) were comparable between two groups (P > 0.05). The median draining venous CEA (d-CEA) in metastases/local recurrence group (23.7 ± 6.9 ng/ml) was significantly higher than that in non-metastases/local recurrence group (18.1 ± 6.3 ng/ml; P < 0.05), but marked differences were not observed in draining venous CA199, CA724 and CA242 (d-CA199, d-CA724 and d-CA242) between two groups (P > 0.05). The optimal cut-off value of d-CEA was 2.76 ng/ml, with the sensitivity and specificity of 90% and 40% in the prediction of metastasis or local recurrence, respectively. d-CEA correlated with tumor differentiation, T stage, TNM stage, metastasis and local recurrence. Subgroup analysis showed that, of 41 patients with stage II colon cancer, the optimal cut-off value of d-CEA was 8.78 ng/mL, and the sensitivity and specificity were 87.5% and 69.7% in the prediction of metastasis or local recurrence, respectively. Conclusion: d-CEA may be a prognostic factor for stage II colon cancer patients. PMID:25785084

  10. Surgical treatment of colon cancer

    PubMed Central

    Mastalier, B.; Tihon, C.; Ghita, B.; Botezatu, C.; Deaconescu, V.; Mandisodza, P.; Draghici, C.; Simion, S.

    2012-01-01

    Most patients with colon cancer are surgically treated, with postoperative association of chemotherapy and possibly immunotherapy in advanced cases. Surgical treatment is chosen depending on the evolution stage, tumor topography and the existence of complications, colonic surgery being dictated by colonic vascularization. The radical character of the surgical intervention can be assured only in the early stages of the tumor. Colostomy is rarely necessary in patients with colon cancer. In the period of the last 5 years (2007-2011), 307 patients with colon cancer were operated in “Colentina” Surgical Clinic, radical intervention being possible only in 219 cases. 48 cases were emergency interventions for occlusion or perforation with peritonitis. Every time the mechanical preparation of the bowel was not possible, the intraoperative washout technique was used. Postoperative complications were met in 27 cases, being represented by bleeding (3 cases), peritoneal abscess (5 cases), anastomotic fistula (7 cases), abdominal wound infection (12 cases). In 5 cases the operation was done laparoscopically. Preoperative mortality was of 13 cases. Postoperative chemotherapy was done in the great majority of cases. PMID:23144667

  11. Halocynthiaxanthin and peridinin sensitize colon cancer cell lines to tumor necrosis factor-related apoptosis-inducing ligand.

    PubMed

    Yoshida, Tatsushi; Maoka, Takashi; Das, Swadesh K; Kanazawa, Kazuki; Horinaka, Mano; Wakada, Miki; Satomi, Yoshiko; Nishino, Hoyoku; Sakai, Toshiyuki

    2007-06-01

    Carotenoids are compounds contained in foods and possess anticarcinogenic activity. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. However, some tumors remain tolerant to TRAIL-induced apoptosis. Therefore, it is important to develop agents that overcome this resistance. We show, for the first time, that certain carotenoids sensitize cancer cells to TRAIL-induced apoptosis. Combined treatment with halocynthiaxanthin, a dietary carotenoid contained in oysters and sea squirts, and TRAIL drastically induced apoptosis in colon cancer DLD-1 cells, whereas each agent alone only slightly induced apoptosis. The combination induced nuclear condensation and poly(ADP-ribose) polymerase cleavage, which are major features of apoptosis. Various caspase inhibitors could attenuate the apoptosis induced by this combination. Furthermore, the dominant-negative form of a TRAIL receptor could block the apoptosis, suggesting that halocynthiaxanthin specifically facilitated the TRAIL signaling pathway. To examine the molecular mechanism of the synergistic effect of the combined treatment, we did an RNase protection assay. Halocynthiaxanthin markedly up-regulated a TRAIL receptor, death receptor 5 (DR5), among the death receptor-related genes, suggesting a possible mechanism for the combined effects. Moreover, we examined whether other carotenoids also possess the same effects. Peridinin, but not alloxanthin, diadinochrome, and pyrrhoxanthin, induced DR5 expression and sensitized DLD-1 cells to TRAIL-induced apoptosis. These results indicate that the combination of certain carotenoids and TRAIL is a new strategy to overcome TRAIL resistance in cancer cells.

  12. Colon cancer - slideshow

    MedlinePlus

    ... ency/presentations/100157.htm Colon cancer - Series—Normal anatomy To use the sharing features on this page, ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

  13. Tumor microRNA-29a expression and the risk of recurrence in stage II colon cancer.

    PubMed

    Weissmann-Brenner, Alina; Kushnir, Michal; Lithwick Yanai, Gila; Aharonov, Ranit; Gibori, Hadas; Purim, Ofer; Kundel, Yulia; Morgenstern, Sara; Halperin, Marissa; Niv, Yaron; Brenner, Baruch

    2012-06-01

    There is emerging evidence for the prognostic role of various microRNA (miRNA) molecules in colon cancer. The aim of this study was therefore to compare the miRNA profiles in the primary tumor of patients with recurrent and non-recurrent colon cancer. The study population included 110 patients, 51 (46%) with stage I and 59 (54%) with stage II disease, who underwent curative colectomies between 1995 and 2005 without adjuvant therapy and for whom reliable miRNA expression data were available. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor samples. Initial profiling, using microarrays, was done in order to identify potential biomarkers of recurrence. The miRNA expression was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 months of surgery (bad prognosis group, n=23, 21%) and those who did not (good prognosis group, n=87, 79%) in the entire group and within each stage. The results showed that in stage I, none of the 903 miRNAs tested showed differential expression between patients with good prognosis compared with those with poor prognosis. In contrast, in stage II, one miRNA, miR-29a, showed a clear differential expression between the groups (p=0.028). High expression of miR-29a was associated with a longer disease-free survival (DFS), on both univariate and multivariate analyses. Using miR-29a, the positive predictive value for non-recurrence was 94% (2 recurrences among 31 patients). The differential expression of miR-29a was verified by qRT-PCR, showing a similar impact of this miR on DFS. In conclusion, this study demonstrated a significant impact of miR-29a on the risk of recurrence in patients with stage II but not in patients with stage I colon cancer. Based on these results, a validation study is planned.

  14. Overexpression of protein kinase C in HT29 colon cancer cells causes growth inhibition and tumor suppression.

    PubMed Central

    Choi, P M; Tchou-Wong, K M; Weinstein, I B

    1990-01-01

    By using a retrovirus-derived vector system, we generated derivatives of the human colon cancer cell line HT29 that stably overexpress a full-length cDNA encoding the beta 1 isoform of rat protein kinase C (PKC). Two of these cell lines, PKC6 and PKC7, displayed an 11- to 15-fold increase in PKC activity when compared with the C1 control cell line that carries the vector lacking the PKC cDNA insert. Both of the overexpresser cell lines exhibited striking alterations in morphology when exposed to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Following exposure to TPA, PKC6 and PKC7 cells displayed increased doubling time, decreased saturation density, and loss of anchorage-independent growth in soft agar; but these effects were not seen with the C1 cells. Also, in contrast to the control cells, the PKC-overproducing cells failed to display evidence of differentiation, as measured by alkaline phosphatase activity, when exposed to sodium butyrate. In addition, the PKC-overexpresser cells displayed decreased tumorigenicity in nude mice, even in the absence of treatment with TPA. These results provide the first direct evidence that PKC can inhibit tumor cell growth. Thus, in some tumors, PKC might act as a growth-suppressor gene. Images PMID:2388620

  15. Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression.

    PubMed

    He, Tiantian; Zhou, Huaibin; Li, Chunmei; Chen, Yuan; Chen, Xiaowan; Li, Chenli; Mao, Jiating; Lyu, Jianxin; Meng, Qing H

    2016-09-01

    Methylglyoxal (MG) is a highly reactive dicarbonyl compound exhibiting anti-tumor activity. The anti-tumor effects of MG have been demonstrated in some types of cancer, but its role in colon cancer and the mechanisms underlying this activity remain largely unknown. We investigated its role in human colon cancer and the underlying mechanism using human colon cancer cells and animal model. Viability, proliferation, and apoptosis were quantified in DLD-1 and SW480 colon cancer cells by using the Cell Counting Kit-8, plate colony formation assay, and flow cytometry, respectively. Cell migration and invasion were assessed by wound healing and transwell assays. Glucose consumption, lactate production, and intracellular ATP production also were assayed. The levels of c-Myc protein and mRNA were quantitated by western blot and qRT-PCR. The anti-tumor role of MG in vivo was investigated in a DLD-1 xenograft tumor model in nude mice. We demonstrated that MG inhibited viability, proliferation, migration, and invasion and induced apoptosis of DLD-1 and SW480 colon cancer cells. Treatment with MG reduced glucose consumption, lactate production, and ATP production and decreased c-Myc protein levels in these cells. Moreover, MG significantly suppressed tumor growth and c-Myc expression in vivo. Our findings suggest that MG plays an anti-tumor role in colon cancer. It inhibits cancer cell growth by altering the glycolytic pathway associated with downregulation of c-Myc protein. MG has therapeutic potential in colon cancer by interrupting cancer metabolism.

  16. Nuclear Matrix Proteins in Human Colon Cancer

    NASA Astrophysics Data System (ADS)

    Keesee, Susan K.; Meneghini, Marc D.; Szaro, Robert P.; Wu, Ying-Jye

    1994-03-01

    The nuclear matrix is the nonchromatin scaffolding of the nucleus. This structure confers nuclear shape, organizes chromatin, and appears to contain important regulatory proteins. Tissue specific nuclear matrix proteins have been found in the rat, mouse, and human. In this study we compared high-resolution two-dimensional gel electropherograms of nuclear matrix protein patterns found in human colon tumors with those from normal colon epithelia. Tumors were obtained from 18 patients undergoing partial colectomy for adenocarcinoma of the colon and compared with tissue from 10 normal colons. We have identified at least six proteins which were present in 18 of 18 colon tumors and 0 of 10 normal tissues, as well as four proteins present in 0 of 18 tumors and in 10 of 10 normal tissues. These data, which corroborate similar findings of cancer-specific nuclear matrix proteins in prostate and breast, suggest that nuclear matrix proteins may serve as important markers for at least some types of cancer.

  17. Inhibition of peritoneal dissemination of colon cancer by hyperthermic CO2 insufflation: A novel approach to prevent intraperitoneal tumor spread

    PubMed Central

    Zhou, Houming; Zheng, Minhua

    2017-01-01

    Background The increasing use of laparoscopic surgery for advanced gastrointestinal cancer raises concerns about intra-peritoneal tumor spread. Prevention of peritoneal dissemination is extremely important but a preventive modality is lacking. The aim of this study was to examine a novel approach (hyperthermic CO2 insufflation, HT-CO2) for preventing peritoneal dissemination during laparoscopic surgery. Methods A peritoneal dissemination model was established in Balb/c nu/nu mice by intraperitoneal injection of human colon cancer cells (SW1116, 1×106). The mice (n = 48) were subsequently randomized into two groups and subjected to hyperthermic CO2 (43°C, >95% humidity, HT-CO2 group) or standard normothermic CO2 (21°C, <1% relative humidity, NT-CO2 group) insufflation for 3 hours. The mice were sacrificed 28 days later. The peritoneal dissemination was quantitatively analyzed by counting and weighing the peritoneal nodules. The port sites and ascites volume were measured. The peritoneal damage of HT-CO2 was histologically examined with light microscopy and scanning electron microscopy. Intra-abdominal adhesions were evaluated 4 weeks later. Results The number of peritoneal nodules in the HT-CO2 group was significantly less than that in the NT-CO2 group (10.21±3.72 vs. 67.12±5.49, P<0.01). The mean weight of metastatic tumors in the HT-CO2 group was significantly lower than that in the NT-CO2 group (0.31±0.10g vs. 2.16±0.31g, P<0.01). Massive ascites were found in the NT-CO2 group while significantly less ascites developed in HT-CO2- treated mice (8.26±0.31ml vs. 1.27±0.28ml, P<0.01). No port-site metastases were detected in the HT-CO2 group while the incidence of the NT-CO2 group was 12.5% (3/24). HT-CO2 subjection resulted in slight peritoneal damage; the peritoneum returned to normal within five days. No adhesions formed after HT-CO2 treatment. Conclusions HT-CO2 can suppress peritoneal dissemination of colon cancer cells and only causes slight and

  18. Inflammation and colon cancer.

    PubMed

    Terzić, Janos; Grivennikov, Sergei; Karin, Eliad; Karin, Michael

    2010-06-01

    The connection between inflammation and tumorigenesis is well-established and in the last decade has received a great deal of supporting evidence from genetic, pharmacological, and epidemiological data. Inflammatory bowel disease is an important risk factor for the development of colon cancer. Inflammation is also likely to be involved with other forms of sporadic as well as heritable colon cancer. The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and could differ between colitis-associated and other forms of colorectal cancer. Recent work has elucidated the role of distinct immune cells, cytokines, and other immune mediators in virtually all steps of colon tumorigenesis, including initiation, promotion, progression, and metastasis. These mechanisms, as well as new approaches to prevention and therapy, are discussed in this review.

  19. Manganese superoxide dismutase (SOD2/MnSOD)/catalase and SOD2/GPx1 ratios as biomarkers for tumor progression and metastasis in prostate, colon, and lung cancer.

    PubMed

    Miar, Ana; Hevia, David; Muñoz-Cimadevilla, Henar; Astudillo, Aurora; Velasco, Julio; Sainz, Rosa M; Mayo, Juan C

    2015-08-01

    The role of manganese-dependent superoxide dismutase (SOD2/MnSOD) during tumor progression has been studied for several decades with controversial results. While SOD2 downregulation was initially associated with tumor initiation and was proposed as a tumor suppressor gene, recent studies have reported that SOD2 might favor tumor progression and dissemination. To our knowledge this is the first time that changes in SOD2 expression in three different types of tumors, i.e., prostate, lung, and colon cancer, are studied by analyzing both SOD2 mRNA and protein levels in a total of 246 patients' samples. In prostate samples, SOD2 protein levels were also increased, especially in middle stage tumors. In the case of colon and lung tumors both mRNA and protein SOD2 levels were increased in malignant tissues compared to those in nontumor samples. More importantly, all metastases analyzed showed increased levels of SOD2 when compared to those of normal primary tissue and healthy adjacent tissue. Together, these results suggest that a common redox imbalance in these three types of tumor occurs at intermediate stages which then might favor migration and invasion, leading to a more aggressive cancer type. Consequently, the ratios SOD2/catalase and SOD2/Gpx1 could be considered as potential markers during progression from tumor growth to metastasis.

  20. Anti-tumor activity of Sann-Joong-Kuey-Jian-Tang alone and in combination with 5-fluorouracil in a human colon cancer colo 205 cell xenograft model.

    PubMed

    Cheng, Chun-Yuan; Lin, Yi-Hsiang; Su, Chin-Cheng

    2010-01-01

    Malignant tumors are the leading cause of death in Taiwan; among these, colon cancer ranks third as a cause of cancer-related death. Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional Chinese medicinal prescription, has been used to treat lymph node diseases and infectious lesions, and exhibits cytotoxic activity in many cancer cell lines. Our previous studies demonstrated that SJKJT inhibits the proliferation of human colon cancer colo 205 cells in vitro. The aim of this study was to evaluate the anti-tumor activity of SJKJT alone and in combination with 5-fluorouracil (5-FU) in vivo. SCID mice bearing human colon cancer colo 205 cell xenografts were administered SJKJT alone (30 mg/kg daily, p.o.), SJKJT (30 mg/kg daily, p.o.) in combination with 5-FU (30 mg/kg weekly, i.p.), or vehicle alone. At the end of the 4-week dosing schedule, the tumor and animal body weights were individually measured. The SCID mice were sacrificed with CO2 inhalation, the xenograft tumors were dissected, and the protein expression of microtubule-associated protein light chain 3 (MAP-LC3-II) in colo 205 xenograft tumors was measured by Western blotting. In the control, SJKJT-, and SJKJT plus 5-FU-treated mice, the tumor weights were 6.37±2.57, 0.43±0.35 and 1.63±0.46 g, and the mice body weights were 29±0.55, 29±2.71 and 27±0.77 g, respectively. Treatment with SJKJT resulted in a reduction in tumor weight compared with the control group, indicating that SJKJT inhibits tumor growth in a colo 205 xenograft model. SJKJT also increased LC3-II protein expression as compared to the controls. The present study shows that SJKJT alone or in combination with 5-FU has a positive effect on the treatment of SCID mice bearing human colon cancer colo 205 cell xenografts. This suggests that SJKJT has therapeutic potential in the treatment of human colon cancer.

  1. Hinokitiol inhibits cell growth through induction of S-phase arrest and apoptosis in human colon cancer cells and suppresses tumor growth in a mouse xenograft experiment.

    PubMed

    Lee, Youn-Sun; Choi, Kyeong-Mi; Kim, Wonkyun; Jeon, Young-Soo; Lee, Yong-Moon; Hong, Jin-Tae; Yun, Yeo-Pyo; Yoo, Hwan-Soo

    2013-12-27

    Hinokitiol (1), a tropolone-related natural compound, induces apoptosis and has anti-inflammatory, antioxidant, and antitumor activities. In this study, the inhibitory effects of 1 were investigated on human colon cancer cell growth and tumor formation of xenograft mice. HCT-116 and SW-620 cells derived from human colon cancers were found to be similarly susceptible to 1, with IC50 values of 4.5 and 4.4 μM, respectively. Compound 1 induced S-phase arrest in the cell cycle progression and decreased the expression levels of cyclin A, cyclin E, and Cdk2. Conversely, 1 increased the expression of p21, a Cdk inhibitor. Compound 1 decreased Bcl-2 expression and increased the expression of Bax, and cleaved caspase-9 and -3. The effect of 1 on tumor formation when administered orally was evaluated in male BALB/c-nude mice implanted intradermally separately with HCT-116 and SW-620 cells. Tumor volumes and tumor weights in the mice treated with 1 (100 mg/kg) were decreased in both cases. These results suggest that the suppression of tumor formation by compound 1 in human colon cancer may occur through cell cycle arrest and apoptosis.

  2. Hypoxia-inducible factor-1α and semaphorin4D genes involved with tumor-associated macrophage-induced metastatic behavior and clinical significance in colon cancer.

    PubMed

    Mu, Linjun; Wang, Jinshen; Chen, Yuezhi; Li, Leping; Guo, Xiaobo; Zheng, Sheng; Jing, Changqing

    2014-01-01

    Hypoxia promotes tumor angiogenesis and hypoxia-inducible factor-1 alpha (HIF-1α) plays a pivotal role in this process. Recently identified pro-angiogenic factor, semaphorin4D (Sema4D) also promotes angiogenesis and enhances invasive proliferation in some tumors. Furthermore, tumor-associated macrophages (TAMs) can increase the expression of HIF-1α and Sema4D in cancer cells and thus influence tumor growth and progression. The purpose of this study was to evaluate the effect of TAMs on the expression of Sema4D and HIF-1α and the impact of biologic behavior in colon cancer cells. Immunohistochemistry was used to analyze HIF-1α and Sema4D expression in 86 curatively resected colon cancer samples and 52 normal colon tissues samples. The relationship between their expression and clinicopathological factors was analyzed. Furthermore, macrophage-tumor cell interactions, such as metastasis, angiogenesis, were also studied using in vitro co-culture systems. Statistical analysis was performed using SPSS 17.0 software (SPSS Inc., USA). Differences between two groups were analyzed with Student's t test. HIF-1α (58%) and Sema4D (60%) were expressed at a significantly higher level in tumors than in normal tissues (P < 0.01, for both). Furthermore, HIF-1α and Sema4D expression was significantly correlated with lymphatic metastasis, specific histological types and TNM stages (P < 0.05), but not with age and tumor size (P > 0.05). Sema4D expression was correlated with that of HIF-1α (r = 0.567, P < 0.01). TAMs markedly induced HIF-1α and Sema4D expression in colon cancer cells and subsequently increased their migration and invasion. HIF-1α and Sema4D expression are closely related to lymphatic metastasis, specific histological types and TNM stages in colon cancer. Furthermore, TAMs promote migration and invasion of colon cancer cells and endothelial tube formation, possibly through up-regulation of HIF-1α and Sema4D.

  3. Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts

    PubMed Central

    Cheng, Michelle; Ho, Samantha; Yoo, Jun Hwan; Tran, Deanna Hoang-Yen; Bakirtzi, Kyriaki; Su, Bowei; Tran, Diana Hoang-Ngoc; Kubota, Yuzu; Ichikawa, Ryan; Koon, Hon Wai

    2015-01-01

    Background Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-β1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation. Conclusion Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast

  4. Gene-expression signature of tumor recurrence in patients with stage II and III colon cancer treated with 5'fluoruracil-based adjuvant chemotherapy.

    PubMed

    Giráldez, María Dolores; Lozano, Juan José; Cuatrecasas, Míriam; Alonso-Espinaco, Virginia; Maurel, Joan; Mármol, Maribel; Hörndler, Carlos; Ortego, Javier; Alonso, Vicente; Escudero, Pilar; Ramírez, Gina; Petry, Christoph; Lasalvia, Luis; Bohmann, Kerstin; Wirtz, Ralph; Mira, Aurea; Castells, Antoni

    2013-03-01

    Although receiving adjuvant chemotherapy after radical surgery, a disappointing proportion of patients with colorectal cancer will develop tumor recurrence. Probability of relapse is currently predicted from pathological staging, there being a need for additional markers to further select high-risk patients. This study was aimed to identify a gene-expression signature to predict tumor recurrence in patients with Stages II and III colon cancer treated with 5'fluoruracil (5FU)-based adjuvant chemotherapy. Two-hundred and twenty-eight patients diagnosed with Stages II-III colon cancer and treated with surgical resection and 5FU-based adjuvant chemotherapy were included. RNA was extracted from formalin-fixed, paraffin-embedded tissue samples and expression of 27 selected candidate genes was analyzed by RT-qPCR. A tumor recurrence predicting model, including clinico-pathological variables and gene-expression profiling, was developed by Cox regression analysis and validated by bootstrapping. The regression analysis identified tumor stage and S100A2 and S100A10 gene expression as independently associated with tumor recurrence. The risk score derived from this model was able to discriminate two groups with a highly significant different probability of tumor recurrence (HR, 2.75; 95%CI, 1.71-4.39; p = 0.0001), which it was maintained when patients were stratified according to tumor stage. The algorithm was also able to distinguish two groups with different overall survival (HR, 2.68; 95%CI, 1.12-6.42; p = 0.03). Identification of a new gene-expression signature associated with a high probability of tumor recurrence in patients with Stages II and III colon cancer receiving adjuvant 5FU-based chemotherapy, and its combination in a robust, easy-to-use and reliable algorithm may contribute to tailor treatment and surveillance strategies.

  5. [Using cancer case identification algorithms in medico-administrative databases: Literature review and first results from the REDSIAM Tumors group based on breast, colon, and lung cancer].

    PubMed

    Bousquet, P-J; Caillet, P; Coeuret-Pellicer, M; Goulard, H; Kudjawu, Y C; Le Bihan, C; Lecuyer, A I; Séguret, F

    2017-10-01

    The development and use of healthcare databases accentuates the need for dedicated tools, including validated selection algorithms of cancer diseased patients. As part of the development of the French National Health Insurance System data network REDSIAM, the tumor taskforce established an inventory of national and internal published algorithms in the field of cancer. This work aims to facilitate the choice of a best-suited algorithm. A non-systematic literature search was conducted for various cancers. Results are presented for lung, breast, colon, and rectum. Medline, Scopus, the French Database in Public Health, Google Scholar, and the summaries of the main French journals in oncology and public health were searched for publications until August 2016. An extraction grid adapted to oncology was constructed and used for the extraction process. A total of 18 publications were selected for lung cancer, 18 for breast cancer, and 12 for colorectal cancer. Validation studies of algorithms are scarce. When information is available, the performance and choice of an algorithm are dependent on the context, purpose, and location of the planned study. Accounting for cancer disease specificity, the proposed extraction chart is more detailed than the generic chart developed for other REDSIAM taskforces, but remains easily usable in practice. This study illustrates the complexity of cancer detection through sole reliance on healthcare databases and the lack of validated algorithms specifically designed for this purpose. Studies that standardize and facilitate validation of these algorithms should be developed and promoted. Copyright © 2017. Published by Elsevier Masson SAS.

  6. Translation initiation factor eIF3b expression in human cancer and its role in tumor growth and lung colonization.

    PubMed

    Wang, Hong; Ru, Yuanbin; Sanchez-Carbayo, Marta; Wang, Xuejiao; Kieft, Jeffrey S; Theodorescu, Dan

    2013-06-01

    Discovery transcriptomic analyses suggest eukaryotic initiation factor 3b (eIF3b) is elevated in human bladder and prostate cancer, yet its role as a prognostic factor or its requirement in the maintenance or progression of human cancer is not established. Here, we determine the therapeutic potential of eIF3b by examining the clinical relevance of its expression in human cancer tissues and its role in experimental tumor models. We examined mRNA expression of eIF3b in bladder (N = 317) and prostate (N = 566) tissue samples and protein expression by immunohistochemistry in 143 bladder tumor samples as a function of clinicopathologic features. The impact of eIF3b depletion by siRNA in human cancer lines was evaluated in regard to in vitro cell growth, cell cycle, migration, in vivo subcutaneous tumor growth, and lung colonization. eIF3b mRNA expression correlated to tumor grade, stage, and survival in human bladder and prostate cancer. eIF3b protein expression stratified survival in human bladder cancer. eIF3b depletion reduced in vitro cancer cell growth; inhibited G1-S cell-cycle transition by changing protein but not RNA expression of cyclin A, E, Rb, and p27Kip1; inhibited migration; and disrupted actin cytoskeleton and focal adhesions. These changes were associated with decreased protein expression of integrin α5. Integrin α5 depletion phenocopied effects observed with eIF3b. eIF3b-depleted bladder cancer cells formed fewer subcutaneous tumors that grew more slowly and had reduced lung colonization. eIF3b expression relates to human bladder and prostate cancer prognosis, is required for tumor growth, and thus a candidate therapeutic target. ©2013 AACR

  7. Protein phosphatase 2A is essential to maintain active Wnt signaling and its Aβ tumor suppressor subunit is not expressed in colon cancer cells.

    PubMed

    Carmen Figueroa-Aldariz, M; Castañeda-Patlán, M Cristina; Santoyo-Ramos, Paula; Zentella, Alejandro; Robles-Flores, Martha

    2015-11-01

    Canonical Wnt signaling is altered in most cases of colorectal cancer. Experimental evidence indicates that protein phosphatase 2A (PP2A) may play either positive or negative roles in Wnt signaling but its precise in vivo functions remain elusive. In this work, using colon cultured cell lines we showed that basal PP2A activity is markedly reduced in malignant cells compared to non-malignant counterparts. We found that whereas normal or cancer cells displaying not altered Wnt signaling express mRNAs coding for PP2A-A scaffold α and β isoforms, cancer cells which have altered Wnt signaling do not express the Aβ isoform mRNA. Remarkably, we found that the Aβ protein levels are lost in all colon cancer cells, and in patients' tumor biopsies. In addition, all cancer cells exhibit higher levels of RalA activity, compared to non-malignant cells. Rescue experiments to restore Aβ expression in malignant RKO cells, diminished the RalGTPase activation and cell proliferation, indicating that the Aβ isoform acts as tumor suppressor in colon cancer cells. Reciprocal co-immunoprecipitation and immunofluorescence studies showed that the PP2A-C and -Aα subunits, expressed in all colon cells, interact in vivo with β-catenin only in malignant cells. Selective inhibition of PP2A did not significantly affect cellular apoptosis but induced dose-dependent negative effects in β-catenin-mediated transcriptional activity and in cell proliferation of malignant cells, indicating that the residual PP2A activity found in malignant cells, mediated by -C and Aα core subunits, is essential to maintain active Wnt signaling and cell proliferation in colon cancer cells. © 2014 Wiley Periodicals, Inc.

  8. Nef-M1, a peptide antagonist of CXCR4, inhibits tumor angiogenesis and epithelial‑to‑mesenchymal transition in colon and breast cancers.

    PubMed

    Katkoori, Venkat R; Basson, Marc D; Bond, Vincent C; Manne, Upender; Bumpers, Harvey L

    2015-09-29

    The Nef-M1 peptide competes effectively with the natural ligand of CXC chemokine receptor 4 (CXCR4), stromal cell-derived factor 1-alpha, to induce apoptosis and inhibit growth in colon cancer (CRC) and breast cancer (BC). Its role in tumor angiogenesis, and epithelial-to-mesenchymal transition (EMT) regulation, key steps involved in tumor growth and metastasis, are unknown. We evaluated the angioinhibitory effect of Nef-M1 peptide and examined its role in the inhibition of EMT in these cancers. Colon (HT29) and breast (MDA-MB231) cancer cells expressing CXCR4 were studied in vitro and in xenograft tumors propagated in severe combined immunodeficient mice. The mice were treated intraperitoneally with Nef-M1 or scrambled amino acid sequence of Nef-M1 (sNef-M1) peptide, a negative control, starting at the time of tumor implantation. Sections from tumors were evaluated for tumor angiogenesis, as measured by microvessel density (MVD) based on immunostaining of endothelial markers. In vitro tumor angiogenesis was assessed by treating human umbilical vein endothelial cells with conditioned media from the tumor cell lines. A BC cell line (MDA-MB 468) which does not express CXCR4 was used to study the actions of Nef-M1 peptide. Western blot and immunofluorescence analyses assessed the effect of Nef-M1 on tumor angiogenesis and EMT in both tumors and cancer cells. Metastatic lesions of CRC and BC expressed more CXCR4 than primary lesions. It was also found that tumors from mice treated with sNef-M1 had well established vascularity, while Nef-M1 treated tumors had very poor vascularization. Indeed, the mean MVD was lower in tumors from Nef-M1 treated mice than in sNef-M1 treated tumors. Nef-M1 treated tumor has poor morphology and loss of endothelial integrity. Although conditioned medium from CRC or BC cells supported HUVEC tube formation, the conditioned medium from Nef-M1 treated CRC or BC cells did not support tube formation. Western blot analyses revealed that Nef-M1

  9. Colon Cancer Metastatic to the Biliary Tree.

    PubMed

    Strauss, Alexandra T; Clayton, Steven B; Markow, Michael; Mamel, Jay

    2016-04-01

    Metastasis of colon adenocarcinoma is commonly found in the lung, liver, or peritoneum. Common bile duct (CBD) tumors related to adenomas from familial adenomatous polyposis metastasizing from outside of the gastrointestinal tract have been reported. We report a case of biliary colic due to metastatic colon adenocarcinoma to the CBD. Obstructive jaundice with signs of acalculous cholecystitis on imaging in a patient with a history of colon cancer should raise suspicion for metastasis to CBD.

  10. Keep Colon Cancer At Bay

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_164231.html Keep Colon Cancer at Bay Colonoscopy best way to detect disease ... 22, 2017 WEDNESDAY, March 22, 2017 (HealthDay News) -- Colon cancer can be treated and cured if it's diagnosed ...

  11. Serum exosomal miR-4772-3p is a predictor of tumor recurrence in stage II and III colon cancer

    PubMed Central

    Liu, Chang; Eng, Cathy; Shen, Jianjun; Lu, Yue; Takata, Yoko; Mehdizadeh, Amir; Chang, George J.; Rodriguez-Bigas, Miguel A.; Li, Yanan; Chang, Ping; Mao, Yixiang; Hassan, Manal M.; Wang, Fangyu; Li, Donghui

    2016-01-01

    Purpose The study was aimed to evaluate the prognostic or predictive value of serum exosomal microRNAs (miRNAs) for tumor recurrence and response to adjuvant therapy in stage II and stage III colon cancer. Results 145 differentially expressed mature miRNAs were identified (P<0.05) and 10 top hits were carried forward in validation test. MiR-4772-3p was significantly under-expressed in 27 patients with recurrence compared to in 57 patients without recurrence (P=0.002). The reduced expression was significantly related to increased risk of tumor recurrence and risk of death. As a predictor for tumor recurrence, ROC analysis revealed the AUC (95% CI) was 0.72 (0.59-0.85, P=0.001) for lower level of miR-4772-3p compared to 0.63 (0.51-0.75, P=0.062) for tumor site and 0.65 (0.51-0.78,P=0.034) for lymph node status. Among 66/84 patients who received FOLFOX adjuvant therapy, 9/10 (90%) patients with a lower level and 10/56 (18%) patients with a higher level of miR-4772-3p had tumor recurrence (P<0.001). Materials and Methods Blood samples were prospectively collected from84 patients with stage II/III colon cancer after tumor resection and before adjuvant therapy. Serum exosomal miRNA profiles were determined by RNA sequencing. Differentially expressed mature miRNAs were identified between patients with or without tumor recurrence. The top hits were validated in individual RNA samples using quantitative real-time reverse transcription PCR. Conclusions Reduced expression of serum exosomal miR-4772-3p is a prognostic biomarker for tumor recurrence in stage II and stage III colon cancer patients. The predictive value of this marker for response to FOLFOX adjuvant therapy needs further investigation. PMID:27788488

  12. LGR5-positive colon cancer stem cells interconvert with drug-resistant LGR5-negative cells and are capable of tumor reconstitution.

    PubMed

    Kobayashi, Shinta; Yamada-Okabe, Hisafumi; Suzuki, Masami; Natori, Osamu; Kato, Atsuhiko; Matsubara, Koichi; Jau Chen, Yu; Yamazaki, Masaki; Funahashi, Shinichi; Yoshida, Kenji; Hashimoto, Eri; Watanabe, Yoshinori; Mutoh, Hironori; Ashihara, Motooki; Kato, Chie; Watanabe, Takeshi; Yoshikubo, Takashi; Tamaoki, Norikazu; Ochiya, Takahiro; Kuroda, Masahiko; Levine, Arnold J; Yamazaki, Tatsumi

    2012-12-01

    The cancer stem cell (CSC) concept has been proposed as an attractive theory to explain cancer development, and CSCs themselves have been considered as targets for the development of diagnostics and therapeutics. However, many unanswered questions concerning the existence of slow cycling/quiescent, drug-resistant CSCs remain. Here we report the establishment of colon cancer CSC lines, interconversion of the CSCs between a proliferating and a drug-resistant state, and reconstitution of tumor hierarchy from the CSCs. Stable cell lines having CSC properties were established from human colon cancer after serial passages in NOD/Shi-scid, IL-2Rγ(null) (NOG) mice and subsequent adherent cell culture of these tumors. By generating specific antibodies against LGR5, we demonstrated that these cells expressed LGR5 and underwent self-renewal using symmetrical divisions. Upon exposure to irinotecan, the LGR5(+) cells transitioned into an LGR5(-) drug-resistant state. The LGR5(-) cells converted to an LGR5(+) state in the absence of the drug. DNA microarray analysis and immunohistochemistry demonstrated that HLA-DMA was specifically expressed in drug-resistant LGR5(-) cells, and epiregulin was expressed in both LGR5(+) and drug-resistant LGR5(-) cells. Both cells sustained tumor initiating activity in NOG mice, giving rise to a tumor tissue hierarchy. In addition, anti-epiregulin antibody was found to be efficacious in a metastatic model. Both LGR5(+) and LGR5(-) cells were detected in the tumor tissues of colon cancer patients. The results provide new biological insights into drug resistance of CSCs and new therapeutic options for cancer treatment. Copyright © 2012 AlphaMed Press.

  13. [Colonic amoebiasis simulating a cecal tumor: case report].

    PubMed

    Ayari, H; Rebii, S; Ghariani, W; Daghfous, A; Hasni, R; Rehaiem, R; Rezgui-Marhoul, L; Zoghlami, A

    2013-01-01

    Colonic ameboma is a rare inflammatory pseudo-tumor of the colon that can mimic cancer development. This case was located in the cecum and appeared malignant from a macroscopic view. Accordingly a right hemicolectomy was performed, followed by an end-to-side ileocolic anastomosis. The pathology study enabled us to correct the diagnosis and affirm its amebic origin.

  14. Colon cancer stem cells: implications in carcinogenesis

    PubMed Central

    Sanders, Matthew A.; Majumdar, Adhip P. N.

    2014-01-01

    The cancer stem cell model was described for hematologic malignancies in 1997 and since then evidence has emerged to support it for many solid tumors as well, including colon cancer. This model proposes that certain cells within the tumor mass are pluripotent and capable of self-renewal and have an enhanced ability to initiate distant metastasis. The cancer stem cell model has important implications for cancer treatment, since most current therapies target actively proliferating cells and may not be effective against the cancer stem cells that are responsible for recurrence. In recent years great progress has been made in identifying markers of both normal and malignant colon stem cells. Proteins proposed as colon cancer stem cell markers include CD133, CD44, CD166, ALDH1A1, Lgr5, and several others. In this review we consider the evidence for these proteins as colon cancer stem cell markers and as prognostic indicators of colon cancer survival. Additionally, we discuss potential functions of these proteins and the implications this may have for development of therapies that target colon cancer stem cells. PMID:21196254

  15. Irinotecan and Alisertib in Treating Patients With Advanced Solid Tumors or Colorectal Cancer

    ClinicalTrials.gov

    2016-12-20

    Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Stage IIIA Colon Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  16. Silibinin modulates caudal-type homeobox transcription factor (CDX2), an intestine specific tumor suppressor to abrogate colon cancer in experimental rats.

    PubMed

    Sangeetha, N; Nalini, N

    2015-01-01

    To authenticate the colon cancer preventive potential of silibinin, the efficacy of silibinin needs to be tested by evaluating an organ-specific biomarker. The aim of this study was to evaluate the impact of silibinin on the colonic expression of the caudal-type homeobox transcription factor (CDX2) an intestine specific tumor suppressor gene and its downstream targets in the colon of rats challenged with 1,2 dimethyl hydrazine (DMH). Rats of groups 1 and 2 were treated as control and silibinin control. Rats under groups 3 and 4 were given DMH (20 mg/kg body weight (b.w.) subcutaneously) once a week for 15 consecutive weeks from the 4th week of the experimental period. In addition, group 4 rats alone were treated with silibinin (50 mg/kg b.w. per os) everyday throughout the study period of 32 weeks. Histological investigation and messenger RNA and protein expression studies were performed in the colonic tissues of experimental rats. Findings of the study revealed that DMH administration significantly decreased the expression of CDX2 and Guanylyl cyclase C (GCC) in the colon of experimental rats. Further the decreased levels of CDX2 protein, colonic mucin content, and increased number of mast cells in the colon of DMH alone-administered rats reflects the onset of carcinogenesis. The pathological changes caused due to CDX2 suppression were attenuated by silibinin supplementation.

  17. Colon and pancreas tumors enhance coagulation: role of hemeoxygenase-1.

    PubMed

    Nielsen, Vance G; Nfonsam, Valentine N; Matika, Ryan W; Ong, Evan S; Jie, Tun; Warneke, James A; Steinbrenner, Evangelina B

    2014-07-01

    Colon and pancreatic cancer are associated with significant thrombophilia. Colon and pancreas tumor cells have an increase in hemeoxygenase-1 (HO-1) activity, the endogenous enzyme responsible for carbon monoxide production. Given that carbon monoxide enhances plasmatic coagulation, we determined if patients undergoing resection of colon and pancreatic tumors had an increase in endogenous carbon monoxide and plasmatic hypercoagulability. Patients with colon (n = 17) and pancreatic (n = 10) tumors were studied. Carbon monoxide was determined by the measurement of carboxyhemoglobin (COHb). A thrombelastographic method to assess plasma coagulation kinetics and formation of carboxyhemefibrinogen (COHF) was utilized. Nonsmoking patients with colon and pancreatic tumors had abnormally increased COHb concentrations of 1.4 ± 0.9 and 1.9 ± 0.7%, respectively, indicative of HO-1 upregulation. Coagulation analyses comparing both tumor groups demonstrated no significant differences in any parameter; thus the data were combined for the tumor groups for comparison with 95% confidence interval values obtained from normal individuals (n = 30) plasma. Seventy percent of tumor patients had a velocity of clot formation greater than the 95% confidence interval value of normal individuals, with 53% of this hypercoagulable group also having COHF formation. Further, 67% of tumor patients had clot strength that exceeded the normal 95% confidence interval value, and 56% of this subgroup had COHF formation. Finally, 63% of all tumor patients had COHF formation. Future investigation of HO-1-derived carbon monoxide in the pathogenesis of colon and pancreatic tumor-related thrombophilia is warranted.

  18. Advances in colon cancer.

    PubMed

    Levin, Mark

    2003-06-01

    From May 29 to June 5, 2003, the American Society of Clinical Oncology held its 39th Annual Meeting in Chicago, Illinois, U.S.A. The meeting was devoted to the presentation of advances in clinical sciences, diagnosis, prevention and management of malignant disorders, and brings together investigators, clinicians, policy makers and other professionals interested in the science and impact of cancer worldwide. This report will be presented in two parts, the first focusing of colon cancer, and the second on breast cancer will be published in the next issue of Drug News & Perspectives.

  19. Role of metformin in suppressing 1,2-dimethylhydrazine-induced colon cancer in diabetic and non-diabetic mice: effect on tumor angiogenesis and cell proliferation.

    PubMed

    Zaafar, Dalia K; Zaitone, Sawsan A; Moustafa, Yasser M

    2014-01-01

    Several studies indicated that type 2 diabetes mellitus and insulin resistance are associated with increased colon cancer risk. Recently, studies suggest that metformin can reduce cancer risk in diabetic or non-diabetic patients with unclear mechanisms. This work aimed to determine the effect of metformin on chemically-induced colon cancer in mice. Colon cancer was induced using 1,2-dimethylhydrazine (DMH, 20 mg/kg/week, s.c.) for fifteen weeks. Experiment I: healthy mice were fed with basal diet for four weeks and then allocated into seven groups, (i) saline, (ii) DMH, (iii) oxaliplatin, (iv-v): metformin (100 or 200 mg/kg) and (vi-vii): oxaliplatin+metformin (100 or 200 mg/kg), respectively. Experiment II: type 2 diabetes mellitus was induced by injection of STZ (30 mg/kg) after four weeks of high-fat feeding and then mice were allocated into seven groups similar to those reported in experiment I. Examination of the colonic tissue at the end of the experiment highlighted an increase in angiogenic markers and cell proliferation and showed a greater immunostaining for insulin growth factor I receptors and CD34 in the colon of diabetic mice compared to non-diabetics. In general, metformin downregulated tumor angiogenesis and augmented the antitumor effect of oxaliplatin. Overall, the current results showed that metformin protected against DMH-induced colon cancer in non-diabetic and diabetic mice. This therapeutic effect was, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.

  20. Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells.

    PubMed

    Mehdawi, Lubna M; Prasad, Chandra Prakash; Ehrnström, Roy; Andersson, Tommy; Sjölander, Anita

    2016-11-01

    The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme in prostaglandin E2 catabolism and is down-regulated in colorectal cancer (CRC) tissue. Canonical Wnt signaling is frequently elevated in colon cancers and has been shown to down-regulate 15-PGDH expression. Therefore, we have in the current study investigated if the non-canonical ligand WNT5A relates to increased expression of 15-PGDH in colon cancer cells. In the same cohort of patients, we demonstrated a parallel and significant loss of 15-PGDH and WNT5A protein expression in CRC tissues compared with matched normal colon tissues. Furthermore, patients with low 15-PGDH/WNT5A expression in their tumors showed reduced survival compared with patients with high 15-PGDH/WNT5A expression. To investigate if WNT5A signaling directly affects 15-PGDH expression, we performed in vitro analyses of colon cancer cells (HT-29 and Caco-2). Both cell lines, when treated with recombinant WNT5A (rWNT5A) or Foxy-5, a WNT5A-mimicking peptide, responded by increasing their expression of 15-PGDH mRNA and protein. Our investigations showed that rWNT5A and Foxy-5 induced this increased expression of 15-PGDH through reduced β-catenin signaling as well as increased JNK/AP-1 signaling in colon cancer cells. WNT5A signaling also induced increased 15-PGDH expression in a breast cancer cell line both in vitro and in vivo. In agreement, WNT5A signaling also increased the expression of the differentiation markers sucrose-isomaltase and mucin-2 in colon cancer cells. Our results show that WNT5A signaling regulates 15-PGDH expression, thus uncovering a novel mechanism by which WNT5A acts as a tumor suppressor and suggests that increased 15-PGDH expression could be used as an indicator of a positive response to Foxy-5 in patients treated with this WNT5A agonist.

  1. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism

    PubMed Central

    Chattopadhyay, Nibedita; Berger, Allison J.; Koenig, Erik; Bannerman, Bret; Garnsey, James; Bernard, Hugues; Hales, Paul; Maldonado Lopez, Angel; Yang, Yu; Donelan, Jill; Jordan, Kristen; Tirrell, Stephen; Stringer, Bradley; Xia, Cindy; Hather, Greg; Galvin, Katherine; Manfredi, Mark; Rhodes, Nelson; Amidon, Ben

    2015-01-01

    In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition. PMID:26709701

  2. Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation.

    PubMed

    Tawfik, Mona K; Mohamed, Magda I

    2016-08-01

    Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20mg/kg/week,s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20μg/kg) group: mice received exenatide (10 or 20μg/kg/day,s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD34) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20μg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.

  3. Concomitant consumption of lycopene and fish oil inhibits tumor growth and progression in a mouse xenograft model of colon cancer

    USDA-ARS?s Scientific Manuscript database

    Our previous report showed that concomitant supplementation of lycopene and eicosa-pentaenoic acid synergistically inhibited the proliferation of human colon cancer HT-29 cells in vitro. To validate our findings, the present study investigated whether consumption of lycopene and fish oil would help ...

  4. A new method for detection of tumor driver-dependent changes of protein sialylation in a colon cancer cell line reveals nectin-3 as TGFBR2 target

    PubMed Central

    Lee, Jennifer; Warnken, Uwe; Schnölzer, Martina; Gebert, Johannes; Kopitz, Jürgen

    2015-01-01

    Protein-linked glycans play key roles in cell differentiation, cell–cell interactions, cell growth, adhesion and immune response. Aberrant glycosylation is a characteristic feature of tumor cells and is involved in tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. It can serve as cancer biomarker and treatment target. To enable comprehensive screening for the impact of tumor driving mutations in colorectal cancer cells we present a method for specific analysis of tumor driver-induced glycome changes. The strategy is based on a combination of three technologies, that is recombinase-mediated cassette exchange (RMCE), Click-It chemistry and mass spectrometry. The new method is exemplified by the analysis of the impact of inactivating mutations of the TGF-ß-receptor type II (TGFBR2) on sialic acid incorporation into protein-linked glycans of the colon cancer cell line HCT116. Overall, 70 proteins were found to show de novo sialic acid incorporation exclusively upon TGFBR2 expression whereas 7 proteins lost sialylation upon TGFBR2 reconstitution. Validation of detected candidate glycoproteins is demonstrated with the cell surface glycoprotein nectin-3 known to be involved in metastasis, invasion and prognosis of various cancers. Altogether, our new approach can help to systematically puzzle out the influence of tumor-specific mutations in a major signaling pathway, as exemplified by the TGFBR2 tumor suppressor, on the tumor glycome. It facilitates the identification of glycan-based tumor markers that could be used for diagnostic and therapeutic applications. In principle the outlined strategy can be adapted to any cancer cell line, tumor driver mutation and several glycan-building blocks. PMID:26177744

  5. A new method for detection of tumor driver-dependent changes of protein sialylation in a colon cancer cell line reveals nectin-3 as TGFBR2 target.

    PubMed

    Lee, Jennifer; Warnken, Uwe; Schnölzer, Martina; Gebert, Johannes; Kopitz, Jürgen

    2015-10-01

    Protein-linked glycans play key roles in cell differentiation, cell-cell interactions, cell growth, adhesion and immune response. Aberrant glycosylation is a characteristic feature of tumor cells and is involved in tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. It can serve as cancer biomarker and treatment target. To enable comprehensive screening for the impact of tumor driving mutations in colorectal cancer cells we present a method for specific analysis of tumor driver-induced glycome changes. The strategy is based on a combination of three technologies, that is recombinase-mediated cassette exchange (RMCE), Click-It chemistry and mass spectrometry. The new method is exemplified by the analysis of the impact of inactivating mutations of the TGF-ß-receptor type II (TGFBR2) on sialic acid incorporation into protein-linked glycans of the colon cancer cell line HCT116. Overall, 70 proteins were found to show de novo sialic acid incorporation exclusively upon TGFBR2 expression whereas 7 proteins lost sialylation upon TGFBR2 reconstitution. Validation of detected candidate glycoproteins is demonstrated with the cell surface glycoprotein nectin-3 known to be involved in metastasis, invasion and prognosis of various cancers. Altogether, our new approach can help to systematically puzzle out the influence of tumor-specific mutations in a major signaling pathway, as exemplified by the TGFBR2 tumor suppressor, on the tumor glycome. It facilitates the identification of glycan-based tumor markers that could be used for diagnostic and therapeutic applications. In principle the outlined strategy can be adapted to any cancer cell line, tumor driver mutation and several glycan-building blocks.

  6. COTA (colon-ovarian tumor antigen). An immunohistochemical study.

    PubMed

    Pant, K D; Fenoglio-Preiser, C M; Berry, C O; Zamora, P O; Ram, M D; Fulks, R M; Rhodes, B A

    1986-07-01

    A goat anti-serum was prepared against mucinous ovarian cyst fluid and absorbed with normal colon and a variety of normal tissues until the only residual immunoreactivity was directed against colon cancer and ovarian tumor mucin. The set of antigenic determinants defined by this anti-serum has been called COTA, standing for colon-ovarian-tumor-antigen. This highly absorbed anti-serum (anti-COTA) was used for immunohistochemical staining of 42 different tissues in parallel with staining with a goat anti-CEA, which was also highly absorbed. The results suggest that COTA is a highly sensitive and specific antigen for colon carcinoma and may have potential for the early detection of malignant changes predictive of cancer of the colon.

  7. Exposure to ACEI/ARB and β-Blockers Is Associated with Improved Survival and Decreased Tumor Progression and Hospitalizations in Patients with Advanced Colon Cancer.

    PubMed

    Engineer, Diana R; Burney, Basil O; Hayes, Teresa G; Garcia, Jose M

    2013-01-01

    Advanced colon cancer is associated with weight loss and decreased survival. Studies suggest that angiotensin and β-adrenergic blockade decrease colon cancer progression and ameliorate weight loss. This study aims to determine whether exposure to β-adrenoceptor blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) is associated with decreased mortality, tumor progression, number of hospitalizations, or weight loss in colorectal cancer. Retrospective chart review included patients with advanced colorectal cancer. Survival, stage, hospitalization, cancer progression, cancer treatment, and body weight history were collected. Two hundred sixty-two of 425 new stage III to IV colorectal cancer cases reviewed met the study criteria. Those exposed to ACEI/ARB, BB, or both were more likely to have diabetes, hypertension, and stage III colorectal cancer. Adjusting for age, presence of hypertension and diabetes, and stage, ACEI/ARB + BB exposure was associated with decreased mortality compared to unexposed individuals [hazard ratio (HR) = 0.5, confidence interval (CI) = 0.29-0.85; Cox regression, P = .01]. Fewer total and cancer-related hospitalizations and decreased cancer progression in the ACEI/ARB + BB group versus the unexposed group (HR = 0.59, CI = 0.36-0.99, P = .047) were seen. Exposure did not affect weight changes; furthermore, body weight changes from both prediagnosis and at diagnosis to 6, 12, 18, and 24 months postdiagnosis predicted survival. We have observed an association between exposure to a combination of ACEI/ARB + BB and increased survival, decreased hospitalizations, and decreased tumor progression in advanced colorectal cancer. Future studies will be needed to replicate these results and generalize them to broader populations. Determination of causality will require a randomized controlled trial.

  8. Monitoring of Tumor Promotion and Progression in a Mouse Model of Inflammation-Induced Colon Cancer with Magnetic Resonance Colonography1

    PubMed Central

    Young, Matthew R; Ileva, Lilia V; Bernardo, Marcelino; Riffle, Lisa A; Jones, Yava L; Kim, Young S; Colburn, Nancy H; Choyke, Peter L

    2009-01-01

    Early detection of precancerous tissue has significantly improved survival of most cancers including colorectal cancer (CRC). Animal models designed to study the early stages of cancer are valuable for identifying molecular events and response indicators that correlate with the onset of disease. The goal of this work was to investigate magnetic resonance (MR) colonography in a mouse model of CRC on a clinical MR imager. Mice treated with azoxymethane and dextran sulfate sodium were imaged by serial MR colonography (MRC) from initiation to euthanasia. Magnetic resonance colonography was obtained with both T1- and T2-weighted images after administration of a Fluorinert enema to remove residual luminal signal and intravenous contrast to enhance the colon wall. Individual tumor volumes were calculated and validated ex vivo. The Fluorinert enema provided a clear differentiation of the lumen of the colon from the mucosal lining. Inflammation was detected 3 days after dextran sulfate sodium exposure and subsided during the next week. Tumors as small as 1.2 mm3 were detected and as early as 29 days after initiation. Individual tumor growths were followed over time, and tumor volumes were measured by MR imaging correlated with volumes measured ex vivo. The use of a Fluorinert enema during MRC in mice is critical for differentiating mural processes from intraluminal debris. Magnetic resonance colonography with Fluorinert enema and intravenous contrast enhancement will be useful in the study of the initial stages of colon cancer and will reduce the number of animals needed for preclinical trials of prevention or intervention. PMID:19242605

  9. "Cancer tumor".

    NASA Astrophysics Data System (ADS)

    Bronshtehn, V. A.

    The title is a phrase borrowed from a speech by a Leningrad pressman, V. E. Lvov, who called upon those attending a theoretical conference on ideological issues in astronomy held by the Leningrad Branch of the All-Union Astronomic and Geodetic Society (13 - 4 December 1948), "to make a more radical emphasis on the negative role of relativistic cosmology which is a cancer tumor disintegrating the contemporary astronomy theory, and a major ideological enemy of a materialist astronomy".

  10. Multi-Target Approaches in Colon Cancer Chemoprevention Based on Systems Biology of Tumor Cell-Signaling

    PubMed Central

    Guruswamy, Suresh; Rao, Chinthalapally V.

    2008-01-01

    Colorectal cancer is the leading cause of cancer related deaths in the United States. Although it is preventable, thousands of lives are lost each year in the U.S. to colorectal cancer than to breast cancer and AIDS combined. In colon cancer, the formation and progression of precancerous lesions like aberrant crypt foci and polyps is associated with the up-regulation of cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and hydroxy methyl glutaryl CoA reductase (HMG-CoA reductase). The current review will focus on the signaling pathway involving COX-2 and HMG-CoA reductase enzymes and their downstream effectors in signaling mechanism. Cancer cells need huge pools of both cholesterol and isoprenoids to sustain their unlimited growth potential. Cholesterol by modulating caveolae formation regulates several signaling molecules like AKT, IGFR, EGFR and Rho which are involved in cell growth and survival. Cholesterol is also essential for lipid body formation which serves as storage sites for COX-2, eicosanoids and caveolin-1. Experimental studies have identified important mechanisms showing that COX-2, caveolin-1, lipid bodies and prenylated proteins is involved in carcinogenesis. Therefore multi-target, multi-drug approach is the ideal choice for effective colon cancer chemoprevention. This review will give an overview of the two pathways, their signaling networks, and the interactions between the components of the two networks in the activation and regulation of cell signaling involving growth/survival and explain the rationale for colon cancer chemoprevention using COX-2 inhibitors and statins. PMID:19763245

  11. Genetic variants within obesity-related genes are associated with tumor recurrence in patients with stages II/III colon cancer.

    PubMed

    Sebio, Ana; Gerger, Armin; Matsusaka, Satoshi; Yang, Dongyun; Zhang, Wu; Stremitzer, Stefan; Stintzing, Sebastian; Sunakawa, Yu; Yamauchi, Shinichi; Ning, Yan; Fujimoto, Yoshiya; Ueno, Masashi; Lenz, Heinz-Josef

    2015-01-01

    Obesity is an established risk factor for colorectal cancer (CRC) incidence and it is also linked to CRC recurrence and survival. Polymorphisms located in obesity-related genes are associated with an increased risk of developing several cancer types including CRC. We evaluated whether single-nucleotide polymorphisms in obesity-related genes may predict tumor recurrence in colon cancer patients. Genotypes were obtained from germline DNA from 207 patients with stage II or III colon cancer at the Norris Comprehensive Cancer Center. Nine polymorphisms in eight obesity-related genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA, and DSCR1) were evaluated. The primary endpoint of the study was the 3-year recurrence rate. Positive associations were also tested in an independent Japanese cohort of 350 stage III CRC patients. In univariate analysis, for PPARrs1801282, patients with a CC genotype had significantly lower recurrence probability (29 ± 4% SE) compared with patients with a CG genotype (48 ± 8% SE) [hazard ratio (HR): 1.77; 95% confidence interval (CI), 1.01-3.10; P = 0.040]. For DSCR1rs6517239, patients with an AA genotype had higher recurrence probability than patients carrying at least one allele G (37 ± 4% SE vs. 15 ± 6% SE) (HR: 0.51; 95% CI, 0.27-0.94; P = 0.027). This association was stronger in the patients bearing a left-sided tumor (HR: 0.34; 95% CI, 0.13-0.88; P = 0.018). In the Japanese cohort, no associations were found. This hypothesis-generating study suggests a potential influence of polymorphisms within obesity-related genes in the recurrence probability of colon cancer. These interesting results should be evaluated further.

  12. A high-fat diet increases angiogenesis, solid tumor growth, and lung metastasis of CT26 colon cancer cells in obesity-resistant BALB/c mice.

    PubMed

    Park, Heesook; Kim, Minhee; Kwon, Gyoo Taik; Lim, Do Young; Yu, Rina; Sung, Mi-Kyung; Lee, Ki Won; Daily, James W; Park, Jung Han Yoon

    2012-11-01

    We evaluated whether high-fat diet (HFD), in the absence of increased calorie intake, increases colon cancer growth and metastasis. Four-week-old male BALB/c mice were fed on an HFD (60 kcal% fat) or control diet (10 kcal% fat) for 16 wk, after which CT26 colon cancer cells were subcutaneously injected into the right flank. Solid tumor growth and the number and volume of tumor nodules in the lung were increased markedly in the HFD group with only a slight increase in body weight (5.9%). HFD feeding increased tumor tissue levels of Ki67, cyclin A, cyclin D1, CDK2, Bcl-xL, and Bcl-2; reduced p53 levels and TUNEL-positive apoptotic cells; increased the levels of CD45, CD68, CD31, VEGF, P-VEGF receptor-2, iNOS, and COX-2 as well as hemoglobin content; and increased the levels of HIF-1α, P-STAT3-Y705, P-STAT3-S727, P-IκB-α, P-p65, p65, P-c-Jun, P-Akt, P-ERK1/2, P-p38, and P-SAPK/JNK. HFD feeding increased the serum levels of EGF, insulin, IGF-I, IFN-γ, leptin, RANTES, MCP-1, IL-1ra, and SDF-1α and media conditioned by epididymal fat tissue explants from HFD-fed mice caused an increase in microvessel outgrowth from the mouse aorta and tube formation of human umbilical vein endothelial cells. These results indicate that the chronic consumption of an HFD increases colon cancer cell proliferation, tumor angiogenesis, and lung metastasis in mice in the absence of discernible weight gain. HFD feeding increases the levels of growth factors which activate transcription factors, thereby inducing the expression of many genes involved in the stimulation of inflammation, angiogenesis, and cellular proliferation. Copyright © 2011 Wiley Periodicals, Inc.

  13. Extravirgin olive oil up-regulates CB₁ tumor suppressor gene in human colon cancer cells and in rat colon via epigenetic mechanisms.

    PubMed

    Di Francesco, Andrea; Falconi, Anastasia; Di Germanio, Clara; Micioni Di Bonaventura, Maria Vittoria; Costa, Antonio; Caramuta, Stefano; Del Carlo, Michele; Compagnone, Dario; Dainese, Enrico; Cifani, Carlo; Maccarrone, Mauro; D'Addario, Claudio

    2015-03-01

    Extravirgin olive oil (EVOO) represents the typical lipid source of the Mediterranean diet, an eating habit pattern that has been associated with a significant reduction of cancer risk. Diet is the more studied environmental factor in epigenetics, and many evidences suggest dysregulation of epigenetic pathways in cancer. The aim of our study was to investigate the effects of EVOO and its phenolic compounds on endocannabinoid system (ECS) gene expression via epigenetic regulation in both human colon cancer cells (Caco-2) and rats exposed to short- and long-term dietary EVOO. We observed a selective and transient up-regulation of CNR1 gene - encoding for type 1 cannabinoid receptor (CB₁) - that was evoked by exposure of Caco-2 cells to EVOO (100 ppm), its phenolic extracts (OPE, 50 μM) or authentic hydroxytyrosol (HT, 50 μM) for 24 h. None of the other major elements of the ECS (i.e., CB₂; GPR55 and TRPV1 receptors; and NAPE-PLD, DAGL, FAAH and MAGL enzymes) was affected at any time point. The stimulatory effect of OPE and HT on CB₁ expression was inversely correlated to DNA methylation at CNR1 promoter and was associated with reduced proliferation of Caco-2 cells. Interestingly, CNR1 gene was less expressed in Caco-2 cells when compared to normal colon mucosa cells, and again this effect was associated with higher level of DNA methylation at CNR1. Moreover, in agreement with the in vitro studies, we also observed a remarkable (~4-fold) and selective increase in CB₁ expression in the colon of rats receiving dietary EVOO supplementation for 10 days. Consistently, CpG methylation of rat Cnr1 promoter, miR23a and miR-301a, previously shown to be involved in the pathogenesis of colorectal cancer and predicted to target CB₁ mRNA, was reduced after EVOO administration down to ~50% of controls. Taken together, our findings demonstrating CB₁ gene expression modulation by EVOO or its phenolic compounds via epigenetic mechanism, both in vitro and in vivo, may

  14. Protein-bound polysaccharide from Phellinus linteus inhibits tumor growth, invasion, and angiogenesis and alters Wnt/β-catenin in SW480 human colon cancer cells.

    PubMed

    Song, Kyoung-Sub; Li, Ge; Kim, Jong-Seok; Jing, Kaipeng; Kim, Tae-Dong; Kim, Jin-Pyo; Seo, Seung-Bo; Yoo, Jae-Kuk; Park, Hae-Duck; Hwang, Byung-Doo; Lim, Kyu; Yoon, Wan-Hee

    2011-07-22

    Polysaccharides extracted from the Phellinus linteus (PL) mushroom are known to possess anti-tumor effects. However, the molecular mechanisms responsible for the anti-tumor properties of PL remain to be explored. Experiments were carried out to unravel the anticancer effects of PL. The anti-cancer effects of PL were examined in SW480 colon cancer cells by evaluating cell proliferation, invasion and matrix metallo-proteinase (MMP) activity. The anti-angiogenic effects of PL were examined by assessing human umbilical vein endothelial cell (HUVEC) proliferation and capillary tube formation. The in vivo effect of PL was evaluated in an athymic nude mouse SW480 tumor engraft model. PL (125-1000 μg/mL) significantly inhibited cell proliferation and decreased β-catenin expression in SW480 cells. Expression of cyclin D1, one of the downstream-regulated genes of β-catenin, and T-cell factor/lymphocyte enhancer binding factor (TCF/LEF) transcription activity were also significantly reduced by PL treatment. PL inhibited in vitro invasion and motility as well as the activity of MMP-9. In addition, PL treatment inhibited HUVEC proliferation and capillary tube formation. Tumor growth of SW480 cells implanted into nude mice was significantly decreased as a consequence of PL treatment, and tumor tissues from treated animals showed an increase in the apoptotic index and a decrease in β-catenin expression. Moreover, the proliferation index and microvessel density were significantly decreased. These data suggest that PL suppresses tumor growth, invasion, and angiogenesis through the inhibition of Wnt/β-catenin signaling in certain colon cancer cells.

  15. Protein-bound polysaccharide from Phellinus linteus inhibits tumor growth, invasion, and angiogenesis and alters Wnt/β-catenin in SW480 human colon cancer cells

    PubMed Central

    2011-01-01

    Background Polysaccharides extracted from the Phellinus linteus (PL) mushroom are known to possess anti-tumor effects. However, the molecular mechanisms responsible for the anti-tumor properties of PL remain to be explored. Experiments were carried out to unravel the anticancer effects of PL. Methods The anti-cancer effects of PL were examined in SW480 colon cancer cells by evaluating cell proliferation, invasion and matrix metallo-proteinase (MMP) activity. The anti-angiogenic effects of PL were examined by assessing human umbilical vein endothelial cell (HUVEC) proliferation and capillary tube formation. The in vivo effect of PL was evaluated in an athymic nude mouse SW480 tumor engraft model. Results PL (125-1000 μg/mL) significantly inhibited cell proliferation and decreased β-catenin expression in SW480 cells. Expression of cyclin D1, one of the downstream-regulated genes of β-catenin, and T-cell factor/lymphocyte enhancer binding factor (TCF/LEF) transcription activity were also significantly reduced by PL treatment. PL inhibited in vitro invasion and motility as well as the activity of MMP-9. In addition, PL treatment inhibited HUVEC proliferation and capillary tube formation. Tumor growth of SW480 cells implanted into nude mice was significantly decreased as a consequence of PL treatment, and tumor tissues from treated animals showed an increase in the apoptotic index and a decrease in β-catenin expression. Moreover, the proliferation index and microvessel density were significantly decreased. Conclusions These data suggest that PL suppresses tumor growth, invasion, and angiogenesis through the inhibition of Wnt/β-catenin signaling in certain colon cancer cells. PMID:21781302

  16. MicroRNA-100 functions as a tumor suppressor by inhibiting Lgr5 expression in colon cancer cells.

    PubMed

    Zhou, Ming-Kai; Liu, Xiao-Jun; Zhao, Zhi-Guo; Cheng, Yi-Meng

    2015-04-01

    Previous studies have demonstrated that microRNAs (miRNAs), a class of single‑stranded RNA molecules that are 18‑27 nucleotides in length, serve a critical function in tumorigenesis, including in the development of colon cancer. In the current study, miR‑100 levels were demonstrated to be reduced in colon cancer tissues compared with the levels in matched adjacent normal tissues. Forced overexpression of miR‑100 by transfection with miR‑100 mimics substantially inhibited the proliferation, migration and invasion of SW480 and HCT116 cells, whereas reduced expression, resulting from transfection of antisense oligonucleotides, promoted these processes. At the molecular level, miR‑100 was observed to reduce the levels of leucine‑rich repeat‑containing G protein‑coupled receptor 5 (Lgr5), by binding to its 3'‑untranslated region. As a result of this, Wnt/β‑catenin signaling was affected by fluctuations in the level of miR‑100 mimics or antisense. Collectively, the results of the current study elucidate a novel regulatory pathway involving miR‑100 and Lgr5 in colon cancer cells, which may present a potential therapeutic target.

  17. Colon cancer stem cells: controversies and perspectives.

    PubMed

    Puglisi, Maria Ausiliatrice; Tesori, Valentina; Lattanzi, Wanda; Gasbarrini, Giovanni Battista; Gasbarrini, Antonio

    2013-05-28

    Tumors have long been viewed as a population in which all cells have the equal propensity to form new tumors, the so called conventional stochastic model. The cutting-edge theory on tumor origin and progression, tends to consider cancer as a stem cell disease. Stem cells are actively involved in the onset and maintenance of colon cancer. This review is intended to examine the state of the art on colon cancer stem cells (CSCs), with regard to the recent achievements of basic research and to the corresponding translational consequences. Specific prominence is given to the hypothesized origin of CSCs and to the methods for their identification. The growing understanding of CSC biology is driving the optimization of novel anti-cancer targeted drugs.

  18. New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells

    PubMed Central

    2010-01-01

    Background Growing evidence suggests that the majority of tumors are organized hierarchically, comprising a population of tumor-initiating, or cancer stem cells (CSCs) responsible for tumor development, maintenance and resistance to drugs. Previously we have shown that the CD133high/CD44high fraction of colon cancer cells is different from their bulk counterparts at the functional, morphological and genomic levels. In contrast to the majority of colon cancer cells expressing moderate levels of CD133, CD44 and CD166, cells with a high combined expression of CD133 and CD44 possessed several characteristic stem cell features, including profound self-renewal capacity in vivo and in vitro, and the ability to give rise to different cell phenotypes. The present study was undertaken for two aims: a) to determine stem cell-related genomic characteristics of floating 3D multicellular spheroids induced by CD133high/CD44high colon cancer cells; and b) to evaluate CSC-specific alterations induced by new-generation taxoid SB-T-1214. Results Selected CSC phenotype was isolated from three independent invasive colon cancer cell lines, HCT116, HT29 and DLD-1. A stem cell-specific PCR array assay (SABiosciences) revealed that colonospheres induced by purified CD133high/CD44high expressing cells display profound up-regulation of stem cell-related genes in comparison with their bulk counterparts. The FACS analysis has shown that the 3D colonospheres contained some minority cell populations with high levels of expression of Oct4, Sox2, Nanog and c-Myc, which are essential for stem cell pluripotency and self-renewal. Single administration of the SB-T-1214 at concentration 100 nM-1 μM for 48 hr not only induced growth inhibition and apoptotic cell death in these three types of colon cancer spheroids in 3D culture, but also mediated massive inhibition of the stem cell-related genes and significant down-regulation of the pluripotency gene expression. PCR array and FACS data were confirmed

  19. Right colon cancer: Left behind.

    PubMed

    Gervaz, P; Usel, M; Rapiti, E; Chappuis, P; Neyroud-Kaspar, I; Bouchardy, C

    2016-09-01

    Prognosis of colon cancer (CC) has steadily improved during the past three decades. This trend, however, may vary according to proximal (right) or distal (left) tumor location. We studied if improvement in survival was greater for left than for right CC. We included all CC recorded at the Geneva population-based registry between 1980 and 2006. We compared patients, tumor and treatment characteristics between left and right CC by logistic regression and compared CC specific survival by Cox models taking into account putative confounders. We also compared changes in survival between CC location in early and late years of observation. Among the 3396 CC patients, 1334 (39%) had right-sided and 2062 (61%) left-sided tumors. In the early 1980s, 5-year specific survival was identical for right and left CCs (49% vs. 48%). During the study period, a dramatic improvement in survival was observed for patients with left-sided cancers (Hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.29-0.62, p < 0.001) but not for right CC patients (HR: 0.76, 95% CI: 0.50-1.14, p = 0.69). As a consequence, patients with distal CC have a better outcome than patients with proximal CC (HR for left vs. right CC: 0.81, 95% CI: 0.72-0.90, p < 0.001). Our data indicate that, contrary to left CC, survival of patients with right CC did not improve since 1980. Of all colon cancer patients, those with right-sided lesions have by far the worse prognosis. Change of strategic management in this subgroup is warranted. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Id1 Deficiency Protects against Tumor Formation in Apc(Min/+) Mice but Not in a Mouse Model of Colitis-Associated Colon Cancer.

    PubMed

    Zhang, Ning; Subbaramaiah, Kotha; Yantiss, Rhonda K; Zhou, Xi Kathy; Chin, Yvette; Benezra, Robert; Dannenberg, Andrew J

    2015-04-01

    Different mechanisms contribute to the development of sporadic, hereditary and colitis-associated colorectal cancer. Inhibitor of DNA binding/differentiation (Id) proteins act as dominant-negative antagonists of basic helix-loop-helix transcription factors. Id1 is a promising target for cancer therapy, but little is known about its role in the development of colon cancer. We used immunohistochemistry to demonstrate that Id1 is overexpressed in human colorectal adenomas and carcinomas, whether sporadic or syndromic. Furthermore, elevated Id1 levels were found in dysplasia and colon cancer arising in patients with inflammatory bowel disease. Because levels of PGE2 are also elevated in both colitis and colorectal neoplasia, we determined whether PGE2 could induce Id1. PGE2 via EP4 stimulated protein kinase A activity resulting in enhanced pCREB-mediated Id1 transcription in human colonocytes. To determine the role of Id1 in carcinogenesis, two mouse models were used. Consistent with the findings in humans, Id1 was overexpressed in tumors arising in both Apc(Min) (/+) mice, a model of familial adenomatous polyposis, and in experimental colitis-associated colorectal neoplasia. Id1 deficiency led to significant decrease in the number of intestinal tumors in Apc(Min) (/+) mice and prolonged survival. In contrast, Id1 deficiency did not affect the number or size of tumors in the model of colitis-associated colorectal neoplasia, likely due to exacerbation of colitis associated with Id1 loss. Collectively, these results suggest that Id1 plays a role in gastrointestinal carcinogenesis. Our findings also highlight the need for different strategies to reduce the risk of colitis-associated colorectal cancer compared with sporadic or hereditary colorectal cancer.

  1. CT Findings of Colonic Complications Associated with Colon Cancer

    PubMed Central

    Shin, Hyeong Cheol; Kim, Il Young; Kim, Young Tong; Kim, Chang-Jin

    2010-01-01

    A broad spectrum of colonic complications can occur in patients with colon cancer. Clinically, some of these complications can obscure the presence of underlying malignancies in the colon and these complications may require emergency surgical management. The complications of the colon that can be associated with colon cancer include obstruction, perforation, abscess formation, acute appendicitis, ischemic colitis and intussusception. Although the majority of these complications only rarely occur, familiarity with the various manifestations of colon cancer complications will facilitate making an accurate diagnosis and administering prompt management in these situations. The purpose of this pictorial essay is to review the CT appearance of the colonic complications associated with colon cancer. PMID:20191069

  2. CT findings of colonic complications associated with colon cancer.

    PubMed

    Kim, Sang Won; Shin, Hyeong Cheol; Kim, Il Young; Kim, Young Tong; Kim, Chang-Jin

    2010-01-01

    A broad spectrum of colonic complications can occur in patients with colon cancer. Clinically, some of these complications can obscure the presence of underlying malignancies in the colon and these complications may require emergency surgical management. The complications of the colon that can be associated with colon cancer include obstruction, perforation, abscess formation, acute appendicitis, ischemic colitis and intussusception. Although the majority of these complications only rarely occur, familiarity with the various manifestations of colon cancer complications will facilitate making an accurate diagnosis and administering prompt management in these situations. The purpose of this pictorial essay is to review the CT appearance of the colonic complications associated with colon cancer.

  3. Neuropilin-1 in Human Colon Cancer

    PubMed Central

    Parikh, Alexander A.; Fan, Fan; Liu, Wen Biao; Ahmad, Syed A.; Stoeltzing, Oliver; Reinmuth, Niels; Bielenberg, Diane; Bucana, Corazon D.; Klagsbrun, Michael; Ellis, Lee M.

    2004-01-01

    Neuropilin-1 (NRP-1), a recently identified co-receptor for vascular endothelial growth factor, is expressed by several nongastrointestinal tumor types and enhances prostate cancer angiogenesis and growth in preclinical models. We investigated the expression and regulation of NRP-1 and the effect of NRP-1 overexpression on angiogenesis and growth of human colon adenocarcinoma by immunohistochemistry and in situ hybridization. NRP-1 was expressed in 20 of 20 human colon adenocarcinoma specimens but not in the adjacent nonmalignant colonic mucosa. By reverse transcriptase-polymerase chain reaction analysis, NRP-1 mRNA was expressed in seven of seven colon adenocarcinoma cell lines. Subcutaneous xenografts of stably transfected KM12SM/LM2 human colon cancer cells overexpressing NRP-1 led to increased tumor growth and angiogenesis in nude mice. In in vitro assays, conditioned medium from NRP-1-transfected cell lines led to an increase in endothelial cell migration, but did not affect endothelial cell growth. Epidermal growth factor (EGF) led to induction of NRP-1 in human colon adenocarcinoma cells and selective blockade of the epidermal growth factor receptor (EGFR) decreased constitutive and EGF-induced NRP-1 expression. Blockade of the Erk 1/2 and P38 mitogen-activated protein kinase signaling pathways also led to a decrease in constitutive and EGF-induced NRP-1 expression. These findings demonstrate the ubiquitous expression of NRP-1 in human colon cancer and suggest that NRP-1 may contribute to colon cancer angiogenesis and growth. This study also suggests that EGF and mitogen-activated protein kinase signaling pathways play an important role in NRP-1 regulation in colon cancer cells. PMID:15161648

  4. Colon tumor cells grown in NASA Bioreactor

    NASA Technical Reports Server (NTRS)

    2001-01-01

    These photos compare the results of colon carcinoma cells grown in a NASA Bioreactor flown on the STS-70 Space Shuttle in 1995 flight and ground control experiments. The cells grown in microgravity (left) have aggregated to form masses that are larger and more similar to tissue found in the body than the cells cultured on the ground (right). The principal investigator is Milburn Jessup of the University of Texas M. D. Anderson Cancer Center. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Cell constructs grown in a rotating bioreactor on Earth (left) eventually become too large to stay suspended in the nutrient media. In the microgravity of orbit, the cells stay suspended. Rotation then is needed for gentle stirring to replenish the media around the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). Credit: NASA and University of Texas M. D. Anderson Cancer Center.

  5. Colon tumor cells grown in NASA Bioreactor

    NASA Technical Reports Server (NTRS)

    2001-01-01

    These photos compare the results of colon carcinoma cells grown in a NASA Bioreactor flown on the STS-70 Space Shuttle in 1995 flight and ground control experiments. The cells grown in microgravity (left) have aggregated to form masses that are larger and more similar to tissue found in the body than the cells cultured on the ground (right). The principal investigator is Milburn Jessup of the University of Texas M. D. Anderson Cancer Center. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Cell constructs grown in a rotating bioreactor on Earth (left) eventually become too large to stay suspended in the nutrient media. In the microgravity of orbit, the cells stay suspended. Rotation then is needed for gentle stirring to replenish the media around the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). Credit: NASA and University of Texas M. D. Anderson Cancer Center.

  6. Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression.

    PubMed

    Zakraoui, Ons; Marcinkiewicz, Cezary; Aloui, Zohra; Othman, Houcemeddine; Grépin, Renaud; Haoues, Meriam; Essafi, Makram; Srairi-Abid, Najet; Gasmi, Ammar; Karoui, Habib; Pagès, Gilles; Essafi-Benkhadir, Khadija

    2017-01-01

    Lebein, is an heterodimeric disintegrin isolated from Macrovipera lebetina snake venom that was previously characterized as an inhibitor of ADP-induced platelet aggregation. In this study, we investigated the effect of Lebein on the p53-dependent growth of human colon adenocarcinoma cell lines. We found that Lebein significantly inhibited LS174 (p53wt), HCT116 (p53wt), and HT29 (p53mut) colon cancer cell viability by inducing cell cycle arrest through the modulation of expression levels of the tumor suppression factor p53, cell cycle regulating proteins cyclin D1, CDK2, CDK4, retinoblastoma (Rb), CDK1, and cyclin-dependent kinase inhibitors p21 and p27. Interestingly, Lebein-induced apoptosis of colon cancer cells was dependent on their p53 status. Thus, in LS174 cells, cell death was associated with PARP cleavage and the activation of caspases 3 and 8 while in HCT116 cells, Lebein induced caspase-independent apoptosis through increased expression of apoptosis inducing factor (AIF). In LS174 cells, Lebein triggers the activation of the MAPK ERK1/2 pathway through induction of reactive oxygen species (ROS). It also decreased cell adhesion and migration to fibronectin through down regulation of α5β1 integrin. Moreover, Lebein significantly reduced the expression of two angiogenesis stimulators, Vascular Endothelial Growth Factor (VEGF) and Neuropilin 1 (NRP1). It inhibited the VEGF-induced neovascularization process in the quail embryonic CAM system and blocked the development of human colon adenocarcinoma in nude mice. Overall, our work indicates that Lebein may be useful to design a new therapy against colon cancer. © 2016 Wiley Periodicals, Inc.

  7. Mebendazole and a non-steroidal anti-inflammatory combine to reduce tumor initiation in a colon cancer preclinical model

    PubMed Central

    Williamson, Tara; Bai, Ren-Yuan; Staedtke, Verena; Huso, David; Riggins, Gregory J.

    2016-01-01

    Inheritance of a gene mutation leads to the initiation of 5 to 10% of most cancers, including colon cancer cases. We developed a chemoprevention strategy using a novel combination of the non-steroidal anti-inflammatory (NSAID) sulindac plus the anthelminthic benzimidazole, mebendazole. This oral drug combination was effective in the ApcMin/+ mouse model of Familial Adenomatous Polyposis (FAP). Treatment with 35 mg/kg daily mebendazole reduced the number of intestinal adenomas by 56% (P = 0.0002), 160 ppm sulindac by 74% (P < 0.0001), and the combination by 90% (P < 0.0001). The combination significantly reduced microadenomas, polyp number and size in both the small intestines and colon when compared to untreated controls or sulindac alone. Mebendazole as a single agent decreased COX2 expression, blood vessel formation, VEGFR2 phosphorylation, and worked synergistically with sulindac to reduce overexpression of MYC, BCL2, and various pro-inflammatory cytokines. Given the low toxicity of mebendazole, these preclinical findings support the consideration of clinical trials for high risk cancer patients using mebendazole either alone or in combination. The findings have implications for populations with moderate and above risk for developing cancer. PMID:27612418

  8. Novel diet-related mouse model of colon cancer parallels human colon cancer

    PubMed Central

    Prasad, Anil R; Prasad, Shilpa; Nguyen, Huy; Facista, Alexander; Lewis, Cristy; Zaitlin, Beryl; Bernstein, Harris; Bernstein, Carol

    2014-01-01

    AIM: To investigate the close parallels between our novel diet-related mouse model of colon cancer and human colon cancer. METHODS: Twenty-two wild-type female mice (ages 6-8 wk) were fed the standard control diet (AIN-93G) and an additional 22 female mice (ages 6-8 wk) were fed the control diet supplemented with 0.2% deoxycholic acid [diet + deoxycholic acid (DOC)] for 10 mo. Tumors occurred in the colons of mice fed diet + DOC and showed progression to colon cancer [adenocarcinoma (AC)]. This progression is through the stages of tubular adenoma (TA), TA with high grade dysplasia or adenoma with sessile serrated morphology, intramucosal AC, AC stage T1, and AC stage T2. The mouse tumors were compared to human tumors at the same stages by histopathological analysis. Sections of the small and large intestines of mice and humans were evaluated for glandular architecture, cellular and nuclear morphology including cellular orientation, cellular and nuclear atypia, pleomorphism, mitotic activity, frequency of goblet cells, crypt architecture, ulceration, penetration of crypts through the muscularis mucosa and presence of malignant crypts in the muscularis propria. In addition, preserved colonic tissues from genetically similar male mice, obtained from a prior experiment, were analyzed by immunohistochemistry. The male mice had been fed the control diet or diet + DOC. Four molecular markers were evaluated: 8-OH-dG, DNA repair protein ERCC1, autophagy protein beclin-1 and the nuclear location of beta-catenin in the stem cell region of crypts. Also, male mice fed diet + DOC plus 0.007% chlorogenic acid (diet + DOC + CGA) were evaluated for ERCC1, beclin-1 and nuclear location of beta-catenin. RESULTS: Humans with high levels of diet-related DOC in their colons are at a substantially increased risk of developing colon cancer. The mice fed diet + DOC had levels of DOC in their colons comparable to that of humans on a high fat diet. The 22 mice without added DOC in their diet

  9. Augmentation of apoptosis and tumor regression by flavopiridol in the presence of CPT-11 in Hct116 colon cancer monolayers and xenografts.

    PubMed

    Motwani, M; Jung, C; Sirotnak, F M; She, Y; Shah, M A; Gonen, M; Schwartz, G K

    2001-12-01

    CPT-11, a DNA topoisomerase I inhibitor, has demonstrated clinical activity in colorectal cancer. Flavopiridol, a cyclin-dependent kinase inhibitor, is rapidly emerging as a chemotherapy modulator. To enhance the therapeutic index of CPT-11 in colon cancer, we studied the combination of these two drugs in relatively resistant human colon cancer cells, Hct116. Exposure of parental Hct116 cells to clinically achievable concentrations of SN-38 (the active metabolite of CPT-11) induces p21 and a G(2) arrest. However, these conditions fail to induce apoptosis. In contrast, Hct116 cells that are p21 deficient (p21-/- Hct116) readily undergo apoptosis after treatment with SN-38. In this study we show that the parental Hct116 cells can be sensitized to undergo apoptosis by the addition of flavopiridol after SN-38 treatment. The induction of apoptosis was greatest with sequential therapy consisting of SN-38 followed by flavopiridol. Clonogenic assays also showed greatest inhibition with this sequence. Sequential treatment with SN-38 followed by flavopiridol was associated with higher activation of caspase-3 and greater cleavage of both p21 and XIAP, an inhibitor of apoptosis, compared with other treatment schedules. CPT-11 induced some tumor regressions but no complete responses in the p21-intact Hct116 xenografts. CPT-11 with flavopiridol more than doubled tumor regression, compared with CPT-11 alone, and produced a 30% complete response rate. Our studies indicate that CPT-11 induces cell cycle arrest rather than cell death and that flavopiridol, by activating the caspase cascade, cleaves the inhibitors of apoptosis and sensitizes the cells to undergo cell death. Thus, flavopiridol combined with CPT-11 may provide a completely new therapeutic approach in the treatment of colon cancer.

  10. Sclareol induces apoptosis in human HCT116 colon cancer cells in vitro and suppression of HCT116 tumor growth in immunodeficient mice.

    PubMed

    Dimas, Konstantinos; Hatziantoniou, Sophia; Tseleni, Sophia; Khan, Humaira; Georgopoulos, Aristidis; Alevizopoulos, Konstantinos; Wyche, James H; Pantazis, Panayotis; Demetzos, Costas

    2007-04-01

    Labd-14-ene-8, 13-diol (sclareol) is a labdane-type diterpene, which has demonstrated significant cytotoxic activity against human leukemic cell lines, but its effect on solid tumor-derived cells is uknown. Here, we demonstrate that addition of sclareol to cultures of human colon cancer HCT116 cells results in inhibition of DNA synthesis, arrest of cells at the G(1) phase of the cell cycle, activation of caspases-8, -9, PARP degradation, and DNA fragmentation, events characteristic of induction of apoptosis. Intraperitoneal (ip) administration of sclareol alone, at the maximum tolerated dose, was unable to induce suppression of growth of HCT116 tumors established as xenografts in immunodeficient SCID mice. In contrast, ip administration of liposome-encapsulated sclareol, following a specific schedule, induced suppression of tumor growth by arresting tumor cell proliferation as assessed by detecting the presence of the cell proliferation-associated nuclear protein, Ki67, in thin tumor sections. These findings suggest that sclareol incorporated into liposomes may possess chemotherapeutic potential for the treatment of colorectal and other types of human cancer.

  11. Ethanol Enhances Tumor Angiogenesis In Vitro Induced by Low-Dose Arsenic in Colon Cancer Cells Through Hypoxia-Inducible Factor 1 Alpha Pathway

    PubMed Central

    Shi, Xianglin

    2012-01-01

    Health effects due to environmental exposure to arsenic are a major global health concern. Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. Ethanol is also a well-established risk factor for many malignancies. However, little is known about the effects of coexposure to arsenic and ethanol in tumor development. In this study, we investigate the signaling and angiogenic effect of coexposure of arsenic and ethanol on different colon cancer cell lines. Results show that ethanol markedly enhanced arsenic-induced tumor angiogenesis in vitro. These responses are related to intracellular reactive oxygen species (ROS) generation, NADPH oxidase activation, and upregulation of PI3K/Akt and hypoxia-inducible factor 1 alpha (HIF-1α) signaling. We have also found that ethanol increases the arsenic-induced expression and secretion of angiogenic signaling molecules such as vascular endothelial growth factor, which further confirmed the above observation. Antioxidant enzymes inhibited arsenic/ethanol-induced tumor angiogenesis, demonstrating that the responsive signaling pathways of coexposure to arsenic and ethanol are related to ROS generation. We conclude that ethanol is able to enhance arsenic-induced tumor angiogenesis in colorectal cancer cells via the HIF-1α pathway. These results indicate that alcohol consumption should be taken into consideration in the investigation of arsenic-induced carcinogenesis in arsenic-exposed populations. PMID:22872060

  12. Ethanol enhances tumor angiogenesis in vitro induced by low-dose arsenic in colon cancer cells through hypoxia-inducible factor 1 alpha pathway.

    PubMed

    Wang, Lei; Son, Young-Ok; Ding, Songze; Wang, Xin; Hitron, John Andrew; Budhraja, Amit; Lee, Jeong-Chae; Lin, Qinchen; Poyil, Pratheeshkumar; Zhang, Zhuo; Luo, Jia; Shi, Xianglin

    2012-12-01

    Health effects due to environmental exposure to arsenic are a major global health concern. Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. Ethanol is also a well-established risk factor for many malignancies. However, little is known about the effects of coexposure to arsenic and ethanol in tumor development. In this study, we investigate the signaling and angiogenic effect of coexposure of arsenic and ethanol on different colon cancer cell lines. Results show that ethanol markedly enhanced arsenic-induced tumor angiogenesis in vitro. These responses are related to intracellular reactive oxygen species (ROS) generation, NADPH oxidase activation, and upregulation of PI3K/Akt and hypoxia-inducible factor 1 alpha (HIF-1α) signaling. We have also found that ethanol increases the arsenic-induced expression and secretion of angiogenic signaling molecules such as vascular endothelial growth factor, which further confirmed the above observation. Antioxidant enzymes inhibited arsenic/ethanol-induced tumor angiogenesis, demonstrating that the responsive signaling pathways of coexposure to arsenic and ethanol are related to ROS generation. We conclude that ethanol is able to enhance arsenic-induced tumor angiogenesis in colorectal cancer cells via the HIF-1α pathway. These results indicate that alcohol consumption should be taken into consideration in the investigation of arsenic-induced carcinogenesis in arsenic-exposed populations.

  13. Quantitative Assessment of Tumor Responses after Radiation Therapy in a DLD-1 Colon Cancer Mouse Model Using Serial Dynamic Contrast-Enhanced Magnetic Resonance Imaging

    PubMed Central

    Ahn, Sung Jun; Koom, Woong Sub; An, Chan Sik; Lim, Joon Seok; Lee, Seung-Koo; Suh, Jin-Suck

    2012-01-01

    Purpose The purpose of this study was to investigate the predictability of pretreatment values including Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) derived parameters (Ktrans, Kep and Ve), early changes in parameters (Ktrans, tumor volume), and heterogeneity (standard deviation of Ktrans) for radiation therapy responses via a human colorectal cancer xenograft model. Materials and Methods A human colorectal cancer xenograft model with DLD-1 cancer cells was produced in the right hind limbs of five mice. Tumors were irradiated with 3 fractions of 3 Gy each for 3 weeks. Baseline and follow up DCE-MRI were performed. Quantitative parameters (Ktrans, Kep and Ve) were calculated based on the Tofts model. Early changes in Ktrans, standard deviation (SD) of Ktrans, and tumor volume were also calculated. Tumor responses were evaluated based on histology. With a cut-off value of 0.4 for necrotic factor, a comparison between good and poor responses was conducted. Results The good response group (mice #1 and 2) exhibited higher pretreatment Ktrans than the poor response group (mice #3, 4, and 5). The good response group tended to show lower pretreatment Kep, higher pretreatment Ve, and larger baseline tumor volume than the poor response group. All the mice in the good response group demonstrated marked reductions in Ktrans and SD value after the first radiation. All tumors showed increased volume after the first radiation therapy. Conclusion The good response after radiation therapy group in the DLD-1 colon cancer xenograft nude mouse model exhibited a higher pretreatment Ktrans and showed an early reduction in Ktrans, demonstrating a more homogenous distribution. PMID:23074115

  14. Quantification of β-Catenin Signaling Components in Colon Cancer Cell Lines, Tissue Sections, and Microdissected Tumor Cells using Reaction Monitoring Mass Spectrometry

    PubMed Central

    Chen, Yi; Gruidl, Mike; Remily-Wood, Elizabeth; Liu, Richard Z.; Eschrich, Steven; Lloyd, Mark; Nasir, Aejaz; Bui, Marilyn M.; Huang, Emina; Shibata, David; Yeatman, Timothy; Koomen, John M.

    2010-01-01

    Reaction monitoring mass spectrometry has emerged as a powerful tool for targeted detection and quantification of proteins in clinical samples. Here, we report the use of gel electrophoresis for protein fractionation and liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM) screening for quantitative analysis of components from the Wnt/β-catenin signaling pathway, which contributes to colon tumor formation and progression. In silico tools are used to design LC-MRM screens for each target protein. Following successful peptide detection, stable isotope labeled peptides are synthesized and developed as internal standards. Then, the assays are implemented in colon cancer cell lines to achieve detection in minimal amounts of cells, compatible with direct translation to clinical specimens. Selected assays are compared with qualitative results from immunoblotting (Westerns) and translated to individual frozen colon tissue sections and laser capture microdissected tumor cells. This LC-MRM platform has been translated from in vitro models to clinical specimens, forming the basis for future experiments in patient assessment. PMID:20590165

  15. Nuclear matrix proteins in human colon cancer.

    PubMed Central

    Keesee, S K; Meneghini, M D; Szaro, R P; Wu, Y J

    1994-01-01

    The nuclear matrix is the nonchromatin scaffolding of the nucleus. This structure confers nuclear shape, organizes chromatin, and appears to contain important regulatory proteins. Tissue specific nuclear matrix proteins have been found in the rat, mouse, and human. In this study we compared high-resolution two-dimensional gel electropherograms of nuclear matrix protein patterns found in human colon tumors with those from normal colon epithelia. Tumors were obtained from 18 patients undergoing partial colectomy for adenocarcinoma of the colon and compared with tissue from 10 normal colons. We have identified at least six proteins which were present in 18 of 18 colon tumors and 0 of 10 normal tissues, as well as four proteins present in 0 of 18 tumors and in 10 of 10 normal tissues. These data, which corroborate similar findings of cancer-specific nuclear matrix proteins in prostate and breast, suggest that nuclear matrix proteins may serve as important markers for at least some types of cancer. Images PMID:8127905

  16. ARMc8 indicates aggressive colon cancers and promotes invasiveness and migration of colon cancer cells.

    PubMed

    Jiang, Guiyang; Zhang, Yong; Zhang, Xiupeng; Fan, Chuifeng; Wang, Liang; Xu, Hongtao; Yu, Juanhan; Wang, Enhua

    2015-11-01

    Recent studies have implicated ARMc8 in promoting tumor formation in non-small cell lung cancer and breast cancer; however, so far, no studies have revealed the expression pattern or cellular function of ARMc8 in colon cancer. In this study, we used immunohistochemical staining to measure ARMc8 expression in 206 cases of colon cancer and matched adjacent normal colon tissue. Clinically important behaviors of cells, including invasiveness and migration, were evaluated after upregulation of ARMc8 expression in HT29 cells through gene transfection or downregulation of expression in LoVo cells using RNAi. We found that ARMc8 was primarily located in the membrane and cytoplasm of tumor cells, and its expression level was significantly higher in colon cancer in comparison to that in the adjacent normal colon tissues (p < 0.001). ARMc8 expression was closely related to TNM stage (p = 0.006), lymph node metastasis (p = 0.001), and poor prognosis (p = 0.002) of colon cancer. The invasiveness and migration capacity of HT29 cells transfected with ARMc8 were significantly greater than those of control cells (p < 0.001), while ARMc8 siRNA treatment significantly reduced cell invasion and migration in LoVo cells (p < 0.001). Furthermore, we demonstrated that ARMc8 could upregulate the expression of MMP7 and snail and downregulate the expression of p120ctn and α-catenin. Therefore, ARMc8 probably enhanced invasiveness and metastatic capacity by affecting these tumor-associated factors, thereby playing a role in enhancing the tumorigenicity of colon cancer cells. ARMc8 is likely to become a potential therapeutic target for colon cancer.

  17. Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection

    SciTech Connect

    Ahmed, Kamran A.; Fulp, William J.; Berglund, Anders E.; Hoffe, Sarah E.; Dilling, Thomas J.; Eschrich, Steven A.; Shridhar, Ravi; Torres-Roca, Javier F.

    2015-07-15

    Purpose: We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases. Methods and Materials: Patients were identified from our institutional review board–approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation. Results: The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026). Conclusions: Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger

  18. Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection.

    PubMed

    Ahmed, Kamran A; Fulp, William J; Berglund, Anders E; Hoffe, Sarah E; Dilling, Thomas J; Eschrich, Steven A; Shridhar, Ravi; Torres-Roca, Javier F

    2015-07-15

    We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases. Patients were identified from our institutional review board-approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation. The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026). Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort. Copyright © 2015 Elsevier Inc. All rights

  19. Differences between colon cancer primaries and metastases utilizing a molecular assay for tumor radiosensitivity suggest implications for potential oligometastatic SBRT patient selection

    PubMed Central

    Ahmed, Kamran A.; Fulp, William J.; Berglund, Anders E.; Hoffe, Sarah E.; Dilling, Thomas J.; Eschrich, Steven A.; Shridhar, Ravi; Torres-Roca, Javier F.

    2015-01-01

    Purpose/Objectives We have previously developed a multigene expression model of tumor radiosensitivity (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck). The purpose of this study was to assess differences in RSI scores between primary colon cancer and metastases. Methods and Materials Patients were identified from our institutional IRB approved prospective observational protocol. A total of 704 metastatic and 1,362 primary lesions were obtained from a de-identified meta-data pool. RSI was calculated using the previously published ranked based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiotherapy (SBRT) was used for validation. Results The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors compared with 54% of primaries were in the RSI-radioresistant (RSI-RR) peak, suggesting that, metastatic tumors may be slightly more radioresistant than primaries (p=0.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radioresistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31), p<0.0001. These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control (LC) rate over patients with liver metastases (2 yr LC 100% vs. 73.0%, p=0.026). Conclusions Assessment of radiosensitivity between primary and metastatic tissues of colon cancer histology, reveals significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort. PMID:25838188

  20. Infrared imaging as a cancer diagnostic tool: introducing a new concept of spectral barcodes for identifying molecular changes in colon tumors.

    PubMed

    Nallala, Jayakrupakar; Piot, Olivier; Diebold, Marie-Danièle; Gobinet, Cyril; Bouché, Olivier; Manfait, Michel; Sockalingum, Ganesh D

    2013-03-01

    Complementary diagnostic methods to conventional histopathology are under scrutiny for various types of cancers for rapid and molecular level diagnostics. In this perspective, a biophotonic approach based on infrared spectral micro-imaging combined with multivariate statistical analysis has been implemented on colon tissues. The ability of infrared imaging to investigate the intrinsic biochemical features of cells and tissues has been exploited to develop a new concept of spectral bar coding. To implement this concept, 10 frozen colon tissue samples (five nontumoral and tumoral pairs from five patients) were imaged using infrared spectral micro-imaging in a nondestructive manner. The spectral images were processed by a multivariate clustering method to identify the histological organization in a label-free manner. Spectral information from the epithelial components was then automatically recovered on the basis of their intrinsic biochemical composition, and compared using a statistical method (Mann-Whitney U-test) to construct spectral barcodes specific to each patient. The spectral barcodes representing the discriminant infrared spectral wavenumbers (900-1,800 cm(-1) ) enabled characterization of some of the malignancy-associated biochemical alterations associated with mucin, nucleotides, carbohydrates, and protein regions. This approach not only allowed the identification of common biochemical alterations among all the colon cancer patients, but also revealed a difference of gradient within individual patients. This new concept of spectral bar coding gives insight into the potential of infrared spectral micro-imaging as a complementary diagnostic tool to conventional histopathology, for biochemical level understanding of malignancy in colon cancers in an objective and label-free manner.

  1. Melanosis coli in patients with colon cancer

    PubMed Central

    Biernacka-Wawrzonek, Dorota; Stępka, Michał; Tomaszewska, Alicja; Ehrmann-Jóśko, Agnieszka; Chojnowska, Natalia; Muszyński, Jacek

    2016-01-01

    Introduction Melanosis coli is a benign lesion affecting the mucosa of the large intestine. There is a relationship between the presence of melanosis and anthraquinone laxative use. Melanosis coli is also observed in patients with colon cancer, but there is doubt whether these two conditions are related. Aim To analyze the correlation between melanosis and colon cancer. Material and methods We analyzed retrospectively 436 patients undergoing colon cancer surgery. There were 246 women and 190 men. Patients were divided into three age groups: under 50 years, between 51 and 65 years, and over 66 years. We analyzed sections of the cancer and intestinal mucosa from the tumor’s proximal (2–5 cm) and distal (8–10 cm) zone. Results Melanosis coli was present in 52 patients, which represents 11.9% of patients with colon cancer. More often it was present in women. The most common location of melanosis and colon cancer was the terminal part of the large intestine. In patients below 50 years of age in both sexes melanosis coli did not occur. In men, melanosis was more common in the age group over 66 years. Intensity of pigmentation was higher in the tumor’s distal zone. Conclusions The incidence of melanosis coli increases with age, similar to that of colon cancer. Melanosis was not present inside tumors, in almost half of the cases it was not present in the proximal zone, and the degree of pigmentation increased in distal zone. The cause-effect relationship between melanosis coli and colon cancer remains uncertain. PMID:28337232

  2. Long-lasting complete response status of advanced stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine: two case reports.

    PubMed

    Imaoka, Yuki; Kuranishi, Fumito; Miyazaki, Tsubasa; Yasuda, Hiroko; Ohno, Tadao

    2017-09-11

    The prognosis of advanced (stage IV) cancer of the digestive organs is very poor. We have previously reported a case of advanced breast cancer with bone metastasis that was successfully treated with combined treatments including autologous formalin-fixed tumor vaccine (AFTV). Herein, we report the success of this approach in advanced stage IV (heavily metastasized) cases of gall bladder cancer and colon cancer. Case 1: A 61-year-old woman with stage IV gall bladder cancer (liver metastasis and lymph node metastasis) underwent surgery in May 2011, including partial resection of the liver. She was treated with AFTV as the first-line adjuvant therapy, followed by conventional chemotherapy. This patient is still alive without any recurrence, as confirmed with computed tomography, for more than 5 years. Case 2: A 64-year-old man with stage IV colon cancer (multiple para-aortic lymph node metastases and direct abdominal wall invasion) underwent non-curative surgery in May 2006. Following conventional chemotherapy, two courses of AFTV and radiation therapy were administered sequentially. This patient has had no recurrence for more than 5 years. We report the success of combination therapy including AFTV in cases of liver-metastasized gall bladder cancer and abdominal wall-metastasized colon cancer. Both patients experienced long-lasting, complete remission. Therefore, combination therapies including AFTV should be considered in patients with advanced cancer of the digestive organs.

  3. DIFFERENTIATION OF BENIGN PERIABLATIONAL ENHANCEMENT FROM RESIDUAL TUMOR FOLLOWING RADIOFREQUENCY ABLATION USING CONTRAST-ENHANCED ULTRASONOGRAPHY IN A RAT SUBCUTANEOUS COLON CANCER MODEL

    PubMed Central

    Wu, Hanping; Patel, Ravi; Zheng, Yuanyi; Solorio, Luis; Krupka, Tianyi M.; Ziats, Nicholas P.; Hagga, John R.; Exner, Agata A.

    2012-01-01

    Benign periablational enhancement (BPE) response to thermal injury is a barrier to early detection of residual tumor in contrast enhanced imaging after radiofrequency (RF) ablation. The objective of this study was to evaluate the role of quantitative of contrast-enhanced ultrasound (CEUS) in early differentiation of BPE from residual tumor in a BD-IX rat subcutaneous colon cancer model. A phantom study was first performed to test the validity of the perfusion parameters in predicting blood flow of two US contrast imaging modes – contrast harmonic imaging (CHI) and microflow imaging (MFI). To create a simple model of BPE, a peripheral portion of the tumor was ablated along with surrounding normal tissue, leaving part of the tumor untreated. First-pass dynamic enhancement (FPDE) and MFI scans of CEUS were performed before ablation and immediately, 1, 4, and 7 days after ablation. Time-intensity-curves in regions of BPE and residual tumor were fitted to the function y=A(1−exp(−β(t−t0))+C, in which A, β, t0 and C represent blood volume, flow speed, time to start and baseline intensity, respectively. In the phantom study, positive linear correlations were noted between A, β, Aβ and contrast concentration, speed, and flow rate, respectively, in both CHI and MFI. On CEUS images of the in vivo study, the unenhanced ablated zone was surrounded by BPE and irregular peripheral enhancement consistent with residual tumor. On days 0, 4 and 7, blood volume (A) in BPE was significantly higher than that in residual tumor in both FPDE imaging and MFI. Significantly greater blood flow (Aβ) was seen in BPE compared to residual tumor tissue in FPDE on day 7 and in MFI on day 4. The results of this study demonstrate that qualitative CEUS can be potentially used for early detection of viable tumor in post-ablation assessment. PMID:22266229

  4. Sulindac reversal of 15-PGDH-mediated resistance to colon tumor chemoprevention with NSAIDs

    PubMed Central

    Fink, Stephen P.; Dawson, Dawn M.; Zhang, Yongyou; Kresak, Adam; Lawrence, Earl G.; Yang, Peiying; Chen, Yanwen; Barnholtz-Sloan, Jill S.; Willis, Joseph E.; Kopelovich, Levy; Markowitz, Sanford D.

    2015-01-01

    Non-steroidal anti-inflammatory drugs prevent colorectal cancer by inhibiting cyclooxygenase (COX) enzymes that synthesize tumor-promoting prostaglandins. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a tumor suppressor that degrades tumor-promoting prostaglandins. Murine knockout of 15-PGDH increases susceptibility to azoxymethane-induced colon tumors. It also renders these mice resistant to celecoxib, a selective inhibitor of inducible COX-2 during colon neoplasia. Similarly, humans with low colonic 15-PGDH are also resistant to colon adenoma prevention with celecoxib. Here, we used aspirin and sulindac, which inhibit both COX-1 and COX-2, in order to determine if these broader COX inhibitors can prevent colon tumors in 15-PGDH knockout (KO) mice. Unlike celecoxib, sulindac proved highly effective in colon tumor prevention of 15-PGDH KO mice. Significantly, however, aspirin demonstrated no effect on colon tumor incidence in either 15-PGDH wild-type or KO mice, despite a comparable reduction in colonic mucosal Prostaglandin E2 (PGE2) levels by both sulindac and aspirin. Notably, colon tumor prevention activity by sulindac was accompanied by a marked induction of lymphoid aggregates and proximal colonic inflammatory mass lesions, a side effect seen to a lesser degree with celecoxib, but not with aspirin. These findings suggest that sulindac may be the most effective agent for colon cancer prevention in humans with low 15-PGDH, but its use may also be associated with inflammatory lesions in the colon. PMID:25503930

  5. [The role of NF-kappaB in colon cancer].

    PubMed

    Seo, Geom Seog

    2011-01-01

    Colon cancer is the 3rd common malignancy and 4th common cause of cancer death in Korea. Recent studies have shown that abnormal inflammatory response plays a critical role in colon carcinogenesis. A striking example of connection between inflammation and cancer is NF-kappaB, in which key regulator of inflammation and immune response is associated with target for colon cancer treatment. Constitutive NF-kappaB expression in colon cancer is 40-80% in vivo as well as in vitro, and the inactivation of IKKbeta subunit can reduce tumor multiplicity. The possible mechanisms by which NF-kappaB can contribute to colon carcinogenesis include the activator of antiapoptotic gene expression, enhanced cell survival and proliferation, regulation of angiogenesis and promotion of metastasis of cancer cells. Recent insights into the role of NF-kappaB involved in colon cancer development as well as their relevance as therapeutic targets are herein discussed.

  6. Breast and Colon Cancer Family Registries

    Cancer.gov

    The Breast Cancer Family Registry and the Colon Cancer Family Registry were established by the National Cancer Institute as a resource for investigators to use in conducting studies on the genetics and molecular epidemiology of breast and colon cancer.

  7. Colon resection for ovarian cancer: intraoperative decisions.

    PubMed

    Hoffman, Mitchel S; Zervose, Emmanuel

    2008-11-01

    To discuss the benefits and morbidity of and indications for colon resection during cytoreductive operations for ovarian cancer. The history of cytoreductive surgery for ovarian cancer is discussed, with special attention to the incorporation of colon resection. Literature regarding cytoreductive surgery for ovarian cancer is then reviewed, again with attention to the role of colon resection. The focus of the review is directed at broad technical considerations and rationales, for both primary and secondary cytoreduction. Over the past 15 to 20 years the standard cytoreductive operation for ovarian cancer has shifted from an abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy to an en bloc radical resection of the pelvic tumor and an omentectomy, and more recently to include increasing use of extensive upper abdominal surgery. En bloc pelvic resection frequently includes rectosigmoid resection, almost always accompanied by a primary anastomosis. Other portions of the colon are at risk for metastatic involvement and sometimes require resection in order to achieve optimal cytoreduction. The data regarding colon resection for the purpose of surgical cytoreduction of ovarian cancer are conflicting (in terms of benefit) and all retrospective. However, the preponderance of information supports a benefit in terms of survival when cytoreduction is clearly optimal. Similar to primary surgery, benefit from secondary cytoreduction of ovarian cancer occurs when only a small volume of disease is left behind. The preponderance of data suggests that colon resection to achieve optimal cytoreduction has a positive impact on survival. In order to better understand the role of colon resection as well as other extensive cytoreductive procedures for ovarian cancer, it will be important to continue to improve our understanding of prognostic variables such as the nuances of metastatic bowel involvement in order to better guide appropriate surgical management.

  8. Colon cancer associated transcripts in human cancers.

    PubMed

    Chen, Yincong; Xie, Haibiao; Gao, Qunjun; Zhan, Hengji; Xiao, Huizhong; Zou, Yifan; Zhang, Fuyou; Liu, Yuchen; Li, Jianfa

    2017-08-02

    Long non-coding RNAs serve as important regulators in complicated cellular activities, including cell differentiation, proliferation and death. Dysregulation of long non-coding RNAs occurs in the formation and progression of cancers. The family of colon cancer associated transcripts, long non-coding RNAs colon cancer associated transcript-1 and colon cancer associated transcript-2 are known as oncogenes involved in various cancers. Colon cancer associated transcript-1 is a novel lncRNA located in 8q24.2, and colon cancer associated transcript-2 maps to the 8q24.21 region encompassing rs6983267. Colon cancer associated transcripts have close associations with clinical characteristics, such as lymph node metastasis, high TNM stage and short overall survival. Knockdown of them can reverse the malignant phenotypes of cancer cells, including proliferation, migration, invasion and apoptosis. Moreover, they can increase the expression level of c-MYC and oncogenic microRNAs via activating a series of complex mechanisms. In brief, the family of colon cancer associated transcripts may serve as potential biomarkers or therapeutic targets for human cancers. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Discovery of Fully Human Anti-MET Monoclonal Antibodies with Antitumor Activity against Colon Cancer Tumor Models In Vivo1

    PubMed Central

    van der Horst, Edward Htun; Chinn, Lawrence; Wang, Min; Velilla, Timothy; Tran, Hoang; Madrona, Yarrow; Lam, Andrew; Ji, May; Hoey, Timothy C; Sato, Aaron K

    2009-01-01

    The receptor tyrosine kinase MET is a major component controlling the invasive growth program in embryonic development and in invasive malignancies. The discovery of therapeutic antibodies against MET has been difficult, and antibodies that compete with hepatocyte growth factor (HGF) act as agonists. By applying phage technology and cell-based panning strategies, we discovered two fully human antibodies against MET (R13 and R28), which synergistically inhibit HGF binding to MET and elicit antibody-dependent cellular cytotoxicity. Cell-based phosphorylation assays demonstrate that R13 and R28 abrogate HGF-induced activation of MET, AKT1, ERK1/2, and HGF-induced migration and proliferation. FACS experiments suggest that the inhibitory effect is mediated by “locking” MET receptor in a state with R13, which then increases avidity of R28 for the extracellular domain of MET, thus blocking HGF binding without activating the receptor. In vivo studies demonstrate that the combination of R13/28 significantly inhibited tumor growth in various colon tumor xenograft models. Inhibition of tumor growth was associated with induction of hypoxia. Global gene expression analysis shows that inhibition of HGF/MET pathway significantly upregulated the tumor suppressors KLF6, CEACAM1, and BMP2, the negative regulator of phosphatidylinositol-3-OH-kinase PIK3IP1, and significantly suppressed SCF and SERPINE2, both enhancers of proliferation and invasiveness. Moreover, in an experimental metastasis model, R13/28 increased survival by preventing the recurrence of otherwise lethal lung metastases. Taken together, these results underscore the utility of a dual-antibody approach for targeting MET and possibly other receptor tyrosine kinases. Our approach could be expanded to drug discovery efforts against other cell surface proteins. PMID:19308290

  10. LIGHT Elevation Enhances Immune Eradication of Colon Cancer Metastases.

    PubMed

    Qiao, Guilin; Qin, Jianzhong; Kunda, Nicholas; Calata, Jed F; Mahmud, Dolores L; Gann, Peter; Fu, Yang-Xin; Rosenberg, Steven A; Prabhakar, Bellur S; Maker, Ajay V

    2017-04-15

    The majority of patients with colon cancer will develop advanced disease, with the liver being the most common site of metastatic disease. Patients with increased numbers of tumor-infiltrating lymphocytes in primary colon tumors and liver metastases have improved outcomes. However, the molecular factors that could empower antitumor immune responses in this setting remain to be elucidated. We reported that the immunostimulatory cytokine LIGHT (TNFSF14) in the microenvironment of colon cancer metastases associates with improved patient survival, and here we demonstrate in an immunocompetent murine model that colon tumors expressing LIGHT stimulate lymphocyte proliferation and tumor cell-specific antitumor immune responses. In this model, increasing LIGHT expression in the microenvironment of either primary tumors or liver metastases triggered regression of established tumors and slowed the growth of liver metastases, driven by cytotoxic T-lymphocyte-mediated antitumor immunity. These responses corresponded with significant increases in tumor-infiltrating lymphocytes and increased expression of lymphocyte-homing signals in the metastatic tumors. Furthermore, we demonstrated evidence of durable tumor-specific antitumor immunity. In conclusion, increasing LIGHT expression increased T-cell proliferation, activation, and infiltration, resulting in enhanced tumor-specific immune-mediated tumor regressions in primary tumors and colorectal liver metastases. Mechanisms to increase LIGHT in the colon cancer microenvironment warrant further investigation and hold promise as an immunotherapeutic strategy. Cancer Res; 77(8); 1880-91. ©2017 AACR.

  11. Selenium, Folate, and Colon Cancer

    PubMed Central

    Connelly-Frost, Alexandra; Poole, Charles; Satia, Jessie A.; Kupper, Lawrence L.; Millikan, Robert C.; Sandler, Robert S.

    2009-01-01

    Background Selenium is an essential trace element which has been implicated in cancer risk; however, study results have been inconsistent with regard to colon cancer. Our objectives were to 1) investigate the association between selenium and colon cancer 2) evaluate possible effect measure modifiers and 3) evaluate potential biases associated with the use of post-diagnostic serum selenium measures Methods The North Carolina Colon Cancer Study is a large population-based, case-control study of colon cancer in North Carolina between 1996 and 2000 (n=1,691). Nurses interviewed patients about diet and lifestyle and drew blood specimens which were used to measure serum selenium. Results Individuals who had both high serum selenium (>140 mcg/L) and high reported folate (>354 mcg/day), had a reduced relative risk of colon cancer (OR=0.5, 95% CI=0.4,0.8). The risk of colon cancer for those with high selenium and low folate was approximately equal to the risk among those with low selenium and low folate (OR=1.1, 95% CI=0.7,1.5) as was the risk for those with low selenium and high folate (OR=0.9, 95% CI=0.7–1.2). We did not find evidence of bias due to weight loss, stage at diagnosis, or time from diagnosis to selenium measurement. Conclusion High levels of serum selenium and reported folate jointly were associated with a substantially reduced risk of colon cancer. Folate status should be taken into account when evaluating the relation between selenium and colon cancer in future studies. Importantly, weight loss, stage at diagnosis, or time from diagnosis to blood draw did not appear to produce strong bias in our study. PMID:19235033

  12. Colorectal Cancers Mimic Structural Organization of Normal Colonic Crypts

    PubMed Central

    Cernat, Laura; Blaj, Cristina; Jackstadt, Rene; Brandl, Lydia; Engel, Jutta; Hermeking, Heiko; Jung, Andreas; Kirchner, Thomas; Horst, David

    2014-01-01

    Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments. Colorectal cancers derive from colonic crypt epithelia but, in contrast, form morphologically disarrayed glands. In this study, we investigated to which extent colorectal cancers phenocopy colonic crypt architecture and thus preserve structural organization of the normal intestinal epithelium. A subset of colon cancers showed crypt-like compartments with high WNT activity and nuclear β-Catenin at the leading tumor edge, adjacent proliferation, and enhanced Cytokeratin 20 expression in most differentiated tumor epithelia of the tumor center. This architecture strongly depended on growth conditions, and was fully reproducible in mouse xenografts of cultured and primary colon cancer cells. Full crypt-like organization was associated with low tumor grade and was an independent prognostic marker of better survival in a collection of 221 colorectal cancers. Our findings suggest that full activation of preserved intestinal morphogenetic programs in colon cancer requires in vivo growth environments. Furthermore, crypt-like architecture was linked with less aggressive tumor biology, and may be useful to improve current colon cancer grading schemes. PMID:25111606

  13. Margin Size is an Independent Predictor of Local Tumor Progression After Ablation of Colon Cancer Liver Metastases

    SciTech Connect

    Wang Xiaodong; Sofocleous, Constantinos T. Erinjeri, Joseph P.; Petre, Elena N.; Gonen, Mithat; Do, Kinh G.; Brown, Karen T.; Covey, Anne M.; Brody, Lynn A.; Alago, William; Thornton, Raymond H.; Kemeny, Nancy E.; Solomon, Stephen B.

    2013-02-15

    This study was designed to evaluate the relationship between the minimal margin size and local tumor progression (LTP) following CT-guided radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLM). An institutional review board-approved, HIPPA-compliant review identified 73 patients with 94 previously untreated CLM that underwent RFA between March 2003 and May 2010, resulting in an ablation zone completely covering the tumor 4-8 weeks after RFA dynamic CT. Comparing the pre- with the post-RFA CT, the minimal margin size was categorized to 0, 1-5, 6-10, and 11-15 mm. Follow-up included CT every 2-4 months. Kaplan-Meier methodology and Cox regression analysis were used to evaluate the effect of the minimal margin size, tumor location, size, and proximity to a vessel on LTP. Forty-five of 94 (47.9 %) CLM progressed locally. Median LTP-free survival (LPFS) was 16 months. Two-year LPFS rates for ablated CLM with minimal margin of 0, 1-5 mm, 6-10 mm, 11-15 mm were 26, 46, 74, and 80 % (p < 0.011). Minimal margin (p = 0.002) and tumor size (p = 0.028) were independent risk factors for LTP. The risk for LTP decreased by 46 % for each 5-mm increase in minimal margin size, whereas each additional 5-mm increase in tumor size increased the risk of LTP by 22 %. An ablation zone with a minimal margin uniformly larger than 5 mm 4-8 weeks postablation CT is associated with the best local tumor control.

  14. Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumor suppressor in colon that protects against colitis and colon cancer under low-fiber dietary conditions

    PubMed Central

    Gurav, Ashish; Sivaprakasam, Sathish; Bhutia, Yangzom D.; Boettger, Thomas; Singh, Nagendra; Ganapathy, Vadivel

    2016-01-01

    Summary Mammalian colon harbors trillions of bacteria under physiologic conditions; this symbiosis is made possible because of a tolerized response from the mucosal immune system. The mechanisms underlying this tolerogenic phenomenon remain poorly understood. Here we show that Slc5a8, a Na+-coupled high-affinity transporter in colon for the bacterial fermentation product butyrate, plays a critical role in this process. Among various immune cells in colon, dendritic cells (DCs) are unique not only in their accessibility to luminal contents but also in their ability to induce tolerogenic phenotype in T cells. We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naïve T cells into immunosuppressive FoxP3+ Tregs, and suppress conversion of naïve T cells into pro-inflammatory IFN-γ-producing cells. Slc5a8-null DCs do not induce IDO1 and Aldh1A2 and do not generate Tregs or suppress IFN-γ-producing T cells in response to butyrate. We also provide in vivo evidence for an obligatory role for Slc5a8 in suppression of IFN-γ-producing T cells. Furthermore, Slc5a8 protects against colitis and colon cancer under conditions of low-fiber intake but not when dietary fiber intake is optimal. This agrees with the high-affinity nature of the transporter to mediate butyrate entry into cells. We conclude that Slc5a8 is an obligatory link between dietary fiber and mucosal immune system via the bacterial metabolite butyrate, and that this transporter is a conditional tumor suppressor in colon linked to dietary fiber content. PMID:25984582

  15. The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia

    PubMed Central

    Bonetto, Andrea; Rupert, Joseph E.; Barreto, Rafael; Zimmers, Teresa A.

    2017-01-01

    Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality1. Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma2–4. Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength3–5. Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6)3, which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism2. Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification. PMID:27929469

  16. Most effective colon cancer chemopreventive agents in rats: a systematic review of aberrant crypt foci and tumor data, ranked by potency

    PubMed Central

    Corpet, Denis E.; Taché, Sylviane

    2002-01-01

    Potential chemopreventive agents for colorectal cancer are assessed in rodents. We speculated that the magnitude of the effect is meaningful, and ranked all published agents according to their potency. Data were gathered systematically from 137 articles with the aberrant crypt foci (ACF) endpoint, and 146 articles with the tumor endpoint. A table was built containing potency of each agent to reduce the number of ACF. Another table was built with potency of each agent to reduce the tumor incidence. Both tables are shown in the present paper, and on a website with sorting abilities (http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html). Potency was estimated by the ratio of value in control rats divided by value in treated rats. From each article, only the most potent agent was kept, except from articles reporting the effect of more than 7 agents. Among the 186 agents in the ACF table, the median agent halved the number of ACF. The most potent agents to reduce azoxymethane-induced ACF were pluronic, polyethylene glycol, perilla oil with beta-carotene, and sulindac sulfide. Among the 160 agents in the tumor table, the median agent halved the tumor incidence in rats. The most potent agents to reduce the incidence of azoxymethane-induced tumors were celecoxib, a protease inhibitor from soy, difluoromethylornithine with piroxicam, polyethylene glycol, and a thiosulfonate. For the 57 agents present in both tables, a significant correlation was found between the potencies against ACF and tumors (r=0.45, p<0.001). Without celecoxib, a major outlying point in the correlation, it reached r=0.68 (p<0.001, N=56). In conclusion, this review gathers almost all known chemopreventive agents, ranks the most promising ones against colon carcinogenesis in rats or mice, and further supports the use of ACF as surrogate endpoint for tumors in rats. PMID:12467130

  17. Two initiation sites of early detection of colon cancer revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of the tumor cells.

    PubMed

    Amsterdam, Abraham; Shezen, Elias; Raanan, Calanit; Schreiber, Letizia; Slilat, Yasmin; Fabrikant, Yakov; Melzer, Ehud; Seger, Rony

    2013-07-01

    We have used human specimens and antibodies to pERK1/2 to detect early development of colon cancer using indirect immunocytochemistry. Two distinct sites were stained; one at the tip of the colon crypts and the other in the stromal tissue associated with the colonic tissue. These foci represent early stages of colon cancer initiation sites as established by enhanced Kirsten Rat Sarcoma Virus (KRAS) and the lack of p53 staining. The enhanced KRAS coincides with the initiation of tumor growth revealed by pERK1/2, both in the tip of the colon crypts, as well as in the stromal initiation site of the colon tumors. Foci of pERK1/2 staining were also detected in 50% of stromal tissue and tips of colon crypts, which were classified as normal tissues, adjacent to the malignant tissue according to general morphology. However, in colon specimens, where no malignancy was observed, no accumulation of pERK1/2 was observed. The staining of pERK1/2 at the stromal foci of the apparently non-malignant tissue appeared as aggregates in the perinuclear region, while in the colon epithelium it appeared in the cell nuclei. In low-grade colon cancer that was still free of induced mutated p53, staining of pERK1/2 was prominent in the cell nuclei, both in the stroma tissue and the tip of the colon crypts. In the intermediate stage, that exhibited significant p53 staining, only a fraction of p53-free tumor cells was labeled with pERK1/2 antibody, while in high-grade tumors, all cells of tumors were labeled with antibodies to p53, but not with antibodies to pERK1/2. We suggest that the down regulation in pERK1/2 labeling is due to the mitogenic capacity of the tumor cells, which are shifted from being driven by nuclear pERK1/2 to mutated p53 expression. We also found that the cytoplasm of low grade tumors was positive for epiregulin, while this labeling decreased in high-grade tumors. We found that the tumors arising from the stroma demonstrated poor structural differentiation, while the

  18. Ornithine decarboxylase, mitogen-activated protein kinase and matrix metalloproteinase-2 expressions in human colon tumors

    PubMed Central

    Nemoto, Takahiro; Kubota, Shunichiro; Ishida, Hideyuki; Murata, Nobuo; Hashimoto, Daijo

    2005-01-01

    AIM: To investigate the expressions of ornithine decarboxylase (ODC), MMP-2, and Erk, and their relationship in human colon tumors. METHODS: ODC activity, MMP-2 expression, and mitogen-activated protein (MAP) kinase activity (Erk phosphorylation) were determined in 58 surgically removed human colon tumors and their adjacent normal tissues, using [1-14C]-ornithine as a substrate, ELISA assay, and Western blotting, respectively. RESULTS: ODC activity, MMP-2 expression, and Erk phosphorylation were significantly elevated in colon tumors, compared to those in adjacent normal tissues. A significant correlation was observed between ODC activities and MMP-2 levels. CONCLUSION: This is the first report showing a significant correlation between ODC activities and MMP-2 levels in human colon tumors. As MMP-2 is involved in cancer invasion and metastasis, and colon cancer overexpresses ODC, suppression of ODC expression may be a rational approach to treat colon cancer which overexpresses ODC. PMID:15918191

  19. Proteins and an Inflammatory Network Expressed in Colon Tumors

    PubMed Central

    Zhu, Wenhong; Fang, Changming; Gramatikoff, Kosi; Niemeyer, Christina C.; Smith, Jeffrey W.

    2011-01-01

    The adenomatous polyposis coli (APC) protein is crucial to homeostasis of normal intestinal epithelia because it suppresses the β-catenin/TCF pathway. Consequently, loss or mutation of the APC gene causes colorectal tumors in humans and mice. Here, we describe our use of Multidimensional Protein Identification Technology (MudPIT) to compare protein expression in colon tumors to that of adjacent healthy colon tissue from ApcMin/+ mice. Twenty-seven proteins were found to be up-regulated in colon tumors and twenty-five down-regulated. As an extension of the proteomic analysis, the differentially expressed proteins were used as “seeds” to search for co-expressed genes. This approach revealed a co-expression network of 45 genes that is up-regulated in colon tumors. Members of the network include the antibacterial peptide cathelicidin (CAMP), Toll-like receptors (TLRs), IL-8, and triggering receptor expressed on myeloid cells 1 (TREM1). The co-expression network is associated with innate immunity and inflammation, and there is significant concordance between its connectivity in humans versus mice (Friedman: p value = 0.0056). This study provides new insights into the proteins and networks that are likely to drive the onset and progression of colon cancer. PMID:21366352

  20. VEGF and colon cancer growth beyond angiogenesis: does VEGF directly mediate colon cancer growth via a non-angiogenic mechanism?

    PubMed

    Ahluwalia, Amrita; Jones, Michael K; Matysiak-Budnik, Tamara; Tarnawski, Andrzej S

    2014-01-01

    In this article we review the role of vascular endothelial growth factor (VEGF) in colon cancer growth and the underlying mechanisms. Angiogenesis, the growth of new capillary blood vessels in the body, is critical for tissue injury healing and cancer growth. In 1971, Judah Folkman proposed the concept that tumor growth beyond 2 mm is critically dependent on angiogenesis. Tumors including colon cancers release angiogenic growth factors that stimulate blood vessels to grow into the tumors thus providing oxygen and nutrients that enable exponential growth. VEGF is the most potent angiogenic growth factor. Several studies have highlighted the role of VEGF in colon cancer, specifically in the stimulation of angiogenesis. This role of VEGF is strongly supported by studies showing that inhibition of VEGF using the blocking antibody, bevacizumab, results in decreased angiogenesis and abrogation of cancer growth. In the United States, bevacizumab in combination with chemotherapy is FDA approved for the treatment of metastatic colon cancer. However, the source of VEGF in colon cancer tissue, the mechanisms of VEGF generation in colon cancer cells and the molecular pathways involved in VEGF mediated angiogenesis in colon cancer are not fully known. The possibility that VEGF directly stimulates cancer cell growth in an autocrine manner has not been explored in depth.

  1. A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites.

    PubMed

    Zhang, Yan; Ma, Junli; Zhang, Sai; Deng, Ganlu; Wu, Xiaoling; He, Jingxuan; Pei, Haiping; Shen, Hong; Zeng, Shan

    2015-09-01

    Stage III colon cancer is currently treated as an entity with a unified therapeutic principle. The aim of the retrospective study is to explore the clinicopathological characteristics and outcomes of site-specific stage III colon cancers and the influences of tumor location on prognosis. Eight hundred ninety-five patients with stage III colon cancer treated with radical operation and subsequent adjuvant chemotherapy (5-fluorouracil/oxaliplatin) were divided into seven groups according to colon segment (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon). Expression of excision repair cross-complementing group 1 (ERCC1) and thymidylate synthase (TS) was examined by immunohistochemistry. We assessed if differences exist in patient characteristics and clinic outcomes between the seven groups. There were significant differences in tumor differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage (P < 0.001), metachronous liver metastasis (P < 0.001), metachronous lung metastasis (P < 0.001), and ERCCI expression (P < 0.001) between the seven groups. Both 5-year recurrence-free survival (RFS) and 5-year overall survival (OS) exhibited significant differences (both P < 0.001) with survival gradually decreasing from cecum to sigmoid colon. Cox regression analyses identified that tumor location was an independent prognostic factor for RFS and OS. Stage III colon cancer located proximally carried a poorer survival than that located distally. Different efficacies of FOLFOX adjuvant chemotherapy may be an important factor affecting survival of site-specific stage III colon cancers.

  2. Epithelial Hypoxia-Inducible Factor 2α Facilitates the Progression of Colon Tumors through Recruiting Neutrophils

    PubMed Central

    Triner, Daniel; Xue, Xiang; Schwartz, Andrew J.; Jung, Inkyung; Colacino, Justin A.

    2016-01-01

    ABSTRACT Inflammation is a significant risk factor for colon cancer. Recent work has demonstrated essential roles for several infiltrating immune populations in the metaplastic progression following inflammation. Hypoxia and stabilization of hypoxia-inducible factors (HIFs) are hallmark features of inflammation and solid tumors. Previously, we demonstrated an important role for tumor epithelial HIF-2α in colon tumors; however, the function of epithelial HIF-2α as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2α was essential in tumor growth. Concurrently, epithelial disruption of HIF-2α significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2α-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2α signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2α-overexpressing mice in conjunction with data mining from the Cancer Genome Atlas showed that the neutrophil chemokine CXCL1 gene was highly upregulated in colon tumor epithelium in a HIF-2α-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2α-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2α is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer. PMID:27956697

  3. Characterization of azoxymethane-induced colon tumor metastasis to lung in a mouse model relevant to human sporadic colorectal cancer and evaluation of grape seed extract efficacy.

    PubMed

    Derry, Molly M; Raina, Komal; Agarwal, Rajesh; Agarwal, Chapla

    2014-08-01

    The second leading cause of cancer-related deaths (both genders combined) in the United States is colorectal cancer (CRC). This emphasizes the need to develop both effective therapies for CRC patients and pre-clinical models mimicking human disease that carry translational potential in drug-development. Notably, at present there are no in situ models of CRC metastasis to lung. In our azoxymethane-induced colon tumorigenesis study in A/J mice assessing grape seed extract (GSE) efficacy, during necropsy we also found multiple lung nodules suggestive of colon tumor metastasis to lung that were significantly inhibited in GSE fed group. Both histopathological and molecular studies were performed to characterize and establish the origin of these lesions in lung. Histologically these nodules were determined as adenocarcinoma of mucin origin. Molecular analyses by immunohistochemistry (IHC) and RT-PCR revealed strong protein and transcript levels of colon specific markers CDX2 and CK20 in these lung nodules compared to uninvolved control lung tissue. Vis-à-vis, these nodules also showed minimally expressed lung specific biomarkers, specifically surfactant D and TTF-1, in IHC analysis. Additionally, 0.25% GSE supplementation in diet (w/w) decreased the incidence of these lung nodules by 53% and their total number by 66%. Together, the characterization of this unique in situ mouse model of CRC metastasis to lung provides translational opportunities in developing effective therapies to clinically manage and treat CRC at the advanced stage. Moreover, GSE efficacy in inhibiting CRC metastasis to lung in this model further supports its translational potential in controlling CRC growth, progression and metastasis in patients.

  4. Colon cancer mesenchymal stem cells modulate the tumorigenicity of colon cancer through interleukin 6.

    PubMed

    Lin, Jen-Tsun; Wang, Jeng-Yi; Chen, Mu-Kuan; Chen, Hong-Chang; Chang, Tung-Hao; Su, Bi-Wen; Chang, Pey-Jium

    2013-08-15

    Multipotent mesenchymal stem cells (MSCs) have been isolated from several tumors and are implicated to play critical roles to increase malignant cell growth, invasion and metastasis. Here, we show that the MSC-like cells were isolated from human colon cancer tissues. These isolated hCC-MSCs (human colon cancer-derived mesenchymal stem cells) shared similar characteristic features with bone marrow-derived MSCs, which include cell morphology, surface antigens and specific gene expression. Additionally, the hCC-MSCs could differentiate into osteocytes or adipocytes under appropriate culture conditions. The conditioned medium collected from the cultured hCC-MSCs was shown to enhance the migration and invasive activity of HCT-116 colon cancer cells in vitro. Besides, transplantation of HCT-116 cells along with hCC-MSCs in nude mice increased the tumor growth and metastasis. Further study revealed that IL-6 present in the hCC-MSC-conditioned medium sufficiently induced the levels of Notch-1 and CD44 in HCT-116 and HT-29 cells, which contribute to enhance tumorigenic activity of HCT-116 and HT-29 cells. By using immunohistochemical staining, the intense co-expression of IL-6, Notch-1 and CD44 was predominantly detected in human colon cancer tissues. Taken together, our findings suggest the importance of the IL-6/Notch-1/CD44 signaling axis in the interaction between hCC-MSCs and colon cancer cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Human Colon Cancer Cells Cultivated in Space

    NASA Technical Reports Server (NTRS)

    1995-01-01

    Within five days, bioreactor cultivated human colon cancer cells (shown) grown in Microgravity on the STS-70 mission in 1995, had grown 30 times the volume of the control specimens on Earth. The samples grown in space had a higher level of cellular organization and specialization. Because they more closely resemble tumors found in the body, microgravity grown cell cultures are ideal for research purposes.

  6. Human Colon Cancer Cells Cultivated in Space

    NASA Technical Reports Server (NTRS)

    1995-01-01

    Within five days, bioreactor cultivated human colon cancer cells (shown) grown in Microgravity on the STS-70 mission in 1995, had grown 30 times the volume of the control specimens on Earth. The samples grown in space had a higher level of cellular organization and specialization. Because they more closely resemble tumors found in the body, microgravity grown cell cultures are ideal for research purposes.

  7. Sporadic colon cancer murine models demonstrate the value of autoantibody detection for preclinical cancer diagnosis.

    PubMed

    Barderas, Rodrigo; Villar-Vázquez, Roi; Fernández-Aceñero, María Jesús; Babel, Ingrid; Peláez-García, Alberto; Torres, Sofía; Casal, J Ignacio

    2013-10-15

    Although autoantibody detection has been proposed for diagnosis of colorectal cancer, little is known about their initial production and development correlation with cancer progression. Azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice developed colon adenocarcinoma in the distal colon similar to human sporadic colon cancer. We assessed this model together with AOM and DSS-only models for their applicability to early detection of cancer. All AOM/DSS-treated mice produced autoantibodies to tumor-associated antigens analogous to those observed in human colon cancer patients. Autoantibody response was related to tumor antigen overexpression. Cancer autoantibodies were detected 21 days after starting treatment, when no malignant histopathological features were detectable, and they increased according to tumor progression. When carcinogenesis was induced separately by AOM or DSS, only those mice that developed malignant lesions produced significant levels of autoantibodies. These findings demonstrate that autoantibody development is an early event in tumorigenesis and validates its use for preclinical colon cancer diagnosis.

  8. Endoscopic Localization of Colon Cancer Is Frequently Inaccurate.

    PubMed

    Nayor, Jennifer; Rotman, Stephen R; Chan, Walter W; Goldberg, Joel E; Saltzman, John R

    2017-08-01

    Colonoscopic location of a tumor can influence both the surgical procedure choice and overall treatment strategy. To determine the accuracy of colonoscopy in determining the location of colon cancer compared to surgical localization and to elucidate factors that predict discordant colon cancer localization. We conducted a retrospective cross-sectional study of colon cancers diagnosed on colonoscopy at two academic tertiary-care hospitals and two affiliated community hospitals from 2012 to 2014. Colon cancer location was obtained from the endoscopic and surgical pathology reports and characterized by colon segment. We collected data on patient demographics, tumor characteristics, endoscopic procedure characteristics, surgery planned, and surgery performed. Univariate analyses using Chi-squared test and multivariate analysis using forward stepwise logistic regression were performed to determine factors that predict discordant colon cancer localization. There were 110 colon cancer cases identified during the study period. Inaccurate endoscopic colon cancer localization was found in 29% (32/110) of cases. These included 14 cases (12.7%) that were discordant by more than one colonic segment and three cases where the presurgical planned procedure was significantly changed at the time of surgery. On univariate analyses, right-sided colon lesions were associated with increased inaccuracy (43.8 vs 24.4%, p = 0.04). On multivariate analysis, right-sided colon lesions remained independently associated with inaccuracy (OR 1.74, 95% CI 1.03-2.93, p = 0.04). Colon cancer location as determined by colonoscopy is often inaccurate, which can result in intraoperative changes to surgical management, particularly in the right colon.

  9. Myeloid heme oxygenase-1 promotes metastatic tumor colonization in mice.

    PubMed

    Lin, Heng-Huei; Chiang, Ming-Tsai; Chang, Po-Chiao; Chau, Lee-Young

    2015-03-01

    Heme oxygenase-1 (HO-1) is a heme degradation enzyme with antioxidant and immune-modulatory functions. HO-1 promotes tumorigenesis by enhancing tumor cell proliferation and invasion. Whether HO-1 has an effect on cancer progression through stromal compartments is less clear. Here we show that the growth of tumor engrafted subcutaneously in syngeneic mice was not affected by host HO-1 expression. However, lung metastasis arisen from subcutaneous tumor or circulating tumor cells was significantly reduced in HO-1(+/-) mice comparing to wild type (WT) mice. The reduced lung metastasis was also observed in B6 mice bearing HO-1(+/-) bone marrow as comparing to WT chimeras, indicating that HO-1 expression in hematopoietic cells impacts tumor colonization at the metastatic site. Further experiments demonstrated that the numbers of myeloid cells recruited to pulmonary premetastatic niches and metastatic loci were significantly lower in HO-1(+/-) mice than in WT mice. Likewise, the extents of tumor cell extravasation and colonization at the metastatic loci in the early phase of metastasis were significantly lower in HO-1(+/-) mice. Mechanistic studies revealed that HO-1 impacted chemoattractant-induced myeloid cell migration by modulating p38 kinase signaling. Moreover, myeloid HO-1-induced expressions of vascular endothelial growth factor and interleukin-10 promoted tumor cell transendothelial migration and STAT3 activation in vitro. These data support a pathological role of myeloid HO-1 in metastasis and suggest a possibility of targeting myeloid HO-1 for cancer treatment.

  10. Terahertz polarization imaging for colon cancer detection

    NASA Astrophysics Data System (ADS)

    Doradla, Pallavi; Alavi, Karim; Joseph, Cecil S.; Giles, Robert H.

    2014-03-01

    Continuous wave terahertz (THz) imaging has the potential to offer a safe, noninvasive medical imaging modality for delineating colorectal cancer. The terahertz reflectance measurements of fresh 3 - 5 mm thick human colonic excisions were acquired using a continuous-wave polarization imaging technique. A CO2 optically pumped Far- Infrared molecular gas laser operating at 584 GHz was used to illuminate the colon tissue, while the reflected signals were detected using a liquid Helium cooled silicon bolometer. Both co-polarized and cross-polarized remittance from the samples was collected using wire grid polarizers in the experiment. The experimental analysis of 2D images obtained from THz reflection polarization imaging techniques showed intrinsic contrast between cancerous and normal regions based on increased reflection from the tumor. Also, the study demonstrates that the cross-polarized terahertz images not only correlates better with the histology, but also provide consistent relative reflectance difference values between normal and cancerous regions for all the measured specimens.

  11. Comparative Analysis of Tumor Cell Dissemination to the Sentinel Lymph Nodes and to the Bone Marrow in Patients With Nonmetastasized Colon Cancer: A Prospective Multicenter Study.

    PubMed

    Weixler, Benjamin; Viehl, Carsten T; Warschkow, Rene; Guller, Ulrich; Ramser, Michaela; Sauter, Guido; Zuber, Markus

    2017-06-07

    Small nodal tumor infiltrates (SNTI; isolated tumor cells and micrometastases) in sentinel lymph nodes and bone marrow micrometastases (BMM) were independently described as prognostic factors in patients with colon cancer. To examine the association between the occurrence of SNTI and BMM as well as their prognostic relevance. This prospective study was conducted at 3 university-affiliated institutions in Switzerland between May 2000 and December 2006. Statistical analyses were performed in October 2016. A total of 122 patients with stage I to III colon cancer were included. Follow-up time exceeded 6 years, with no patients lost to follow-up. Bone marrow aspiration from the iliac crests and in vivo sentinel lymph node mapping were performed during open standard oncological resection. Bone marrow aspirates were stained with the pancytokeratin marker A45-B/B3. All sentinel lymph nodes underwent multilevel sectioning and were stained with hematoxylin-eosin and the pancytokeratin marker AE1/AE3. Association of SNTI in sentinel lymph nodes and BMM in patients with stage I to III colon cancer and the prognostic effect on disease-free survival (DFS) and overall survival (OS). Of the 122 patients, 63 (51.6%) were female, with a mean (SD) age of 71.2 (11.7) years. Small nodal tumor infiltrates and BMM were found in a total of 21 patients (17.2%) and 46 patients (37.7%), respectively. The occurrence of BMM was not associated with the presence of SNTI by standard correlation (κ, -0.07; 95% CI, -0.29 to 0.14; P = .49) nor by univariate logistic regression analysis (odds ratio, 0.64; 95% CI, 0.22-1.67; P = .37) or multivariate logistic regression analysis (odds ratio, 1.09; 95% CI, 0.34-3.28; P = .88). The presence of SNTI was an independent negative prognostic factor for DFS (hazard ratio [HR], 2.93; 95% CI, 1.24-6.93; P = .02) and OS (HR, 4.04; 95% CI, 1.56-10.45; P = .005), as was BMM (HR, 2.07; 95% CI, 1.06-4.06; P = .04; and HR, 2.68; 95% CI, 1

  12. Preventing Second Cancers in Colon Cancer Survivors

    Cancer.gov

    In this phase III trial, people who have had curative surgery for colon cancer will be randomly assigned to take sulindac and a placebo, eflornithine and a placebo, both sulindac and eflornithine, or two placebo pills for 36 months.

  13. [Effect of chemotherapy in primary tumor of MSI-H colon cancer aged 50 years or younger].

    PubMed

    Chika, Noriyasu; Ishibashi, Keiichiro; Kumamoto, Kensuke; Okada, Norimichi; Suzuki, Okihide; Hatano, Satoshi; Amano, Kunihiko; Matsuzawa, Takeaki; Kuwabara, Kouki; Sobajima, Jun; Kumagai, Yoichi; Baba, Hiroyuki; Haga, Norihiro; Iwama, Takeo; Ishida, Hideyuki; Inokuma, Shigehisa; Takeuchi, Ikuya

    2013-11-01

    Microsatellite instability( MSI) in colorectal carcinoma is reportedly associated with resistance to 5-fluorouracil-based chemotherapy. Moreover, colorectal cancer patients aged ≤ 50 years could potentially have Lynch syndrome. In the present study, we examined 11 colorectal cancer patients with unresectable Stage IV disease who underwent resection of the primary tumor between January 2006 and December 2012. The relationship between the MSI status and the efficacy of first- line oxaliplatin-based chemotherapy was retrospectively examined. The MSI status included MSI-H in 1 patient, MSS-L in 2 patients, and MSS in 8 patients. The MSI-H in 1 patient was associated with familial adenomatous polyposis. Following chemotherapy, among 8 MSS patients, 3 showed stable disease (SD) and 1 showed partial response (PR). Moreover 2 MSH-L patients and 1 MSI-H patient showed progressive disease (PD) after chemotherapy. However, additional data collection is required to determine the effect of oxaliplatin-based chemotherapy for MSS-H or MSS-L colorectal patients aged ≤ 59 years.

  14. Colonic Laterally Spreading Tumor Diagnosed as an Early Cancer and Treated with Endoscopic Mucosal Resection: A Case Report and Review of Literature

    PubMed Central

    Abdelaziz, Mohamad; Sayed, Motaz

    2017-01-01

    Laterally spreading tumors (LSTs) are generally defined as superficial lesions ≥10 mm in diameter that typically extend laterally rather than vertically along the colonic wall. Such lesions are now increasingly reported because of increased awareness and the introduction of chromo and magnifying colonoscopy. Although the clinicopathological characteristics and the efficacy of endoscopic management of LSTs have been defined in Japanese cohorts, reports from the Middle East are lacking where surgical resection is the mainstay of treatment. We report a case with an LST about 20 cm from anal verge removed by endoscopic mucosal resection. After histopathological evaluation of the removed specimen, we categorized the patient as having high risk early colon cancer. The intensive follow-up as an additional treatment strategy was chosen for the patient. This review addresses the management of early carcinoma in colorectal polyp with reference to proper preoperative assessment, treatment selection with special attention to role of biomarkers, the need for additional treatment on the basis of the presence of risk factors and endoscopic follow-up after treatment. PMID:28316766

  15. Estrogen in obesity-associated colon cancer: friend or foe? Protecting postmenopausal women but promoting late-stage colon cancer.

    PubMed

    Chen, Jiezhong; Iverson, Don

    2012-11-01

    Obesity is associated with the increased incidence of colon cancer. Many cancer risk factors have been identified including increased blood levels of insulin, leptin, interleukin-6, interleukin-17, tumor necrosis factor-alpha, and decreased blood levels of adiponectin. However, the role of blood levels of estrogen in obesity-associated colon cancer is controversial. Evidence showed that obesity affected men more strongly than women in the carcinogenesis of colon cancer, indicating protective effect of estrogen which is increased in obesity. However, an epidemiological study has also shown that endogenous estradiol level is an independent risk factor for colon cancer, positively associated with colon cancer after normalizing insulin, IGF-1. The controversial opinions may be caused by different effects of ER-alpha and ER-beta. ER-alpha can increase colon cancer cell proliferation and increase cancer incidence. ER-beta has the opposite effect to ER-alpha, and it causes apoptosis of colon cancer cells. The normal colonocytes mainly express ER-beta. Therefore, increased estrogen in obesity may have protective effect via ER-beta in obesity-associated colon cancer. However, with the development of colon cancer, ER-alpha is increased and ER-beta is decreased. In the late stage of colon cancer, estrogen may promote cancer development via ER-alpha. The different effects and expression of ER-alpha and ER-beta may explain the different results observed in several epidemiological studies as well as several animal experiments. Therefore, manipulation of estrogen-caused signal pathways to inhibit ER-alpha and stimulate ER-beta may have preventive and therapeutic effect for obesity-associated colon cancer.

  16. Inhibitory effect of phytoglycoprotein on tumor necrosis factor-{alpha} and interleukin-6 at initiation stage of colon cancer in 1,2-dimethylhydrazine-treated ICR mice

    SciTech Connect

    Lee, Sei-Jung; Lim, Kye-Taek

    2007-12-01

    This study was carried out to investigate the chemopreventive potentials of plant originated glycoprotein (UDN glycoprotein, 116 kDa) isolated from the stems of Ulmus davidiana Nakai (UDN) on aberrant crypt foci (ACF) formation in 1,2-dimethylhydrazine (DMH)-treated ICR mice. UDN glycoprotein was administered to mice at 0.01% and 0.02% levels for 5 weeks. The mice were treated with 20 mg/kg DMH twice a week for 2 weeks in presence of UDN glycoprotein and killed at week 6. We found that UDN glycoprotein has inhibitory effects on the frequency of colonic aberrant crypt foci (ACF), activation of colonic proliferating cell nuclear antigen (PCNA), and release of plasma lactate dehydrogenase (LDH) in DMH-treated mice. In addition, UDN glycoprotein has anti-oxidative effects on the formation of plasma thiobarbituric acid reactive substances (TBARS) and the production of plasma inducible nitric oxide (NO) in DMH-treated mouse. Also, 0.02% UDN glycoprotein suppressed the DNA binding activities of nuclear factor-kappa B (NF-{kappa}B) and activator protein-1 (AP-1), accompanying the inhibitions of its subunits (p50, p65, c-Jun, and c-Fos), pro-inflammatory proteins [inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)], and pro-inflammatory cytokines [tumor necrosis factor (TNF)-{alpha} and interleukin (IL)-6] on DMH-stimulated ACF formation. On the basis of these results, we assume that UDN glycoprotein may be useful for colon cancer prevention at initiation stage.

  17. [Molecular targets in colon cancer].

    PubMed

    Borner, M M

    2006-04-01

    Colorectal cancer is the second leading cause of cancer death in Switzerland. The nihilism that dominated the treatment of these patients for decades has been replaced by a measure of enthusiasm, given recent therapeutic advances. New anticancer drugs such as irinotecan and oxaliplatin have changed the standard chemotherapy treatment of metastatic colorectal cancer. However, the real hype has come from molecular targeted therapy. Identification of cellular processes characteristic of colon cancer has permitted therapeutic targeting with favorable therapeutic index. Inhibition of the epidermal growth factor receptor in the clinic has provided proof of principle that interruption of signal transduction cascades in patients has therapeutic potential. Angiogenesis, especially the vascular endothelial growth factor pathway, has been proven to be another highly successful molecular target. In this article, we will review molecular targets, which are under active clinical investigation in colon cancer.

  18. En bloc pancreaticoduodenectomy for right colon cancer invading adjacent organs.

    PubMed

    Berrospi, Francisco; Celis, Juan; Ruiz, Eloy; Payet, Eduardo

    2002-03-01

    Surgical treatment of colorectal cancer needs an extended resection of the tumor en block with invaded organs. There is little information about the surgical treatment of right-sided colon carcinoma directly involving duodenum and pancreas. Our objective is to report our experience with three patients who underwent en bloc pancreaticoduodenectomy and hemicolectomy for locally advanced right colon cancer. Retrospective review of clinical records of patients with colon cancer. Three patients with right colon cancer adherent to adjacent organs underwent en block surgery. No operative deaths occurred. All patients are alive without evidence of disease at 10, 30, 113 months of follow-up, respectively. Locally advanced right-sided colon cancer can be safely treated with en bloc pancreaticoduodenectomy and colectomy with excellent long-term results. Copyright 2002 Wiley--Liss, Inc.

  19. Oxaliplatin and Infliximab Combination Synergizes in Inducing Colon Cancer Regression

    PubMed Central

    Li, Wenya; Xu, Jian; Zhao, Jian; Zhang, Rui

    2017-01-01

    Background Colon cancer is one of the most common malignant cancers and causes millions of deaths each year. There are still no effective treatments for colon cancer patients who are at advanced stage. Tumor necrosis factor-alpha (TNF-α) might be a good therapy target due to its widely-accepted roles in regulating multiple important biological processes, especially in promoting inflammation. Material/Methods We evaluated the expression of TNF-α in 108 human colon cancer tissue samples and 2 colon cancer cell lines (CT26 and HCT116), and analyzed its prognostic values. Further, we explored the roles and mechanism of anti-TNF-α treatment in combination with chemotherapy in vitro and in vivo. Results We found that TNF-α was highly expressed in colon cancer cell lines. The survival analysis and Cox regression analysis indicated that high TNF-α was an independent adverse prognosticator of colon cancer. In addition, anti-TNF-α treatment enhanced the effects of chemotherapy in the xenograft mouse model through inducing ADCC and CDC effects. Conclusions We conclude that TNF-α is an independent adverse prognosticator of colon cancer, and anti-TNF-α might benefit colon cancer patients. PMID:28190020

  20. Exo70 is an independent prognostic factor in colon cancer.

    PubMed

    Xiao, Li; Zheng, Kaifeng; Lv, Xia; Hou, Jihuan; Xu, Liang; Zhao, Yujie; Song, Fei; Fan, Yaqiong; Cao, Hanwei; Zhang, Wenqing; Hong, Xiaoting; Zhan, Yan-Yan; Hu, Tianhui

    2017-07-11

    Exo70, a key component of the Exocyst complex, plays important roles in human cancer progression beyond exocytosis. However, the expression of Exo70 and its prognostic value for patients with colon cancer has not been well investigated to date. In this study, we observed that the mRNA and protein levels of Exo70 were upregulated in 11 of 13 colon cancer tissues, compared with their normal counterparts, which was validated by immunohistochemical analysis in a tissue microarray containing 89 pairs of colon cancer tissues and the matched adjacent normal tissues. Statistical analysis revealed that Exo70 expression is positively correlated with tumor size, invasion depth, TNM stage and distant metastasis. Kaplan-Meier survival analysis showed that colon cancer patients with higher Exo70 expression have a poorer clinical outcome than those with lower Exo70 expression. Multivariate Cox regression analysis revealed that Exo70, age and distant metastasis were there independent prognostic factors for overall survival rate of colon cancer patients. Through gain- and loss of Exo70 in colon cancer cells, we found that Exo70 could enhance the migration ability of colon cancer cells. Taken together, our studies revealed that Exo70 might be a promising negative prognostic factor and a potential therapeutic target for colon cancer.

  1. Cholesterol excretion and colon cancer.

    PubMed

    Broitman, S A

    1981-09-01

    Populations consuming diets high in fat and cholesterol exhibit a greater incidence of colon cancer than those consuming less fat and cholesterol. Lowering elevated serum cholesterol levels experimentally or clinically is associated with increased large-bowel tumorigenesis. Thus, cholesterol lost to the gut, either dietary or endogenously synthesized, appears to have a role in large-bowel cancer. Whether the effect(s) is mediated by increases in fecal bile acid excretion or some other mechanism is not clear.

  2. SRPK2 promotes the growth and migration of the colon cancer cells.

    PubMed

    Wang, Jian; Wu, Hai-Feng; Shen, Wei; Xu, Dong-Yan; Ruan, Ting-Yan; Tao, Guo-Qing; Lu, Pei-Hua

    2016-07-15

    Colon cancer is one of the major causes of cancer-related death in the world. Understanding the molecular mechanism underlying this malignancy will facilitate the diagnosis and treatment. Serine-arginine protein kinase 2 (SRPK2) has been reported to be upregulated in several cancer types. However, its expression and functions in colon cancer remains unknown. In this study, it was found that the expression of SRPK2 was up-regulated in the clinical colon cancer samples. Overexpression of SRPK2 promoted the growth and migration of colon cancer cells, while knocking down the expression of SRPK2 inhibited the growth, migration and tumorigenecity of colon cancer cells. Molecular mechanism studies revealed that SRPK2 activated ERK signaling in colon cancer cells. Taken together, our study demonstrated the tumor promoting roles of SRPK2 in colon cancer cells and SRPK2 might be a promising therapeutic target for colon cancer.

  3. DNA testing and molecular screening for colon cancer.

    PubMed

    Carethers, John M

    2014-03-01

    Colon cancer develops and progresses as a consequence of abnormal cellular molecular changes, many of which result in mutant DNA. Modern molecular techniques allow examination of individual patient genetic data that ascribe risk, predict outcome, and/or modify an approach to therapy. DNA testing and molecular screening are in use today and are becoming a critical and necessary part of routine patient care. Assessing at-risk patients for hereditary colon cancer is predicted to move from individual gene testing that is commonly performed today to whole exome or whole genome sequencing, providing additional vast information of the patient's genome that might not be related to the colon cancer syndrome. Detecting mutant DNA from shed tumor cells in fecal material for colon cancer screening will increase in diagnostic accuracy over time, with improvements in the panel of mutant DNA being examined and through clinical testing. DNA mutations and other molecular changes detected directly from within the colon cancer help to inform and guide the physician for the best approach for optimal patient care and outcome. The use of epidermal growth factor receptor-targeted therapy in advanced colon cancer patients requires knowledge of the mutation status for KRAS and BRAF genes, and knowing the mutational status of PIK3CA may predict how patients respond to aspirin to prevent colon cancer recurrence. Biologically driven decision-making, or precision medicine, is becoming increasingly adopted for optimal care and outcome for colon cancer patients. Gastroenterologists will need to be increasingly aware.

  4. Aberrant DNA methylation occurs in colon neoplasms arising in the azoxymethane colon cancer model

    PubMed Central

    Borinstein, Scott C.; Conerly, Melissa; Dzieciatkowski, Slavomir; Biswas, Swati; Washington, M. Kay; Trobridge, Patty; Henikoff, Steve; Grady, William M.

    2010-01-01

    Mouse models of intestinal tumors have advanced our understanding of the role of gene mutations in colorectal malignancy. However, the utility of these systems for studying the role of epigenetic alterations in intestinal neoplasms remains to be defined. Consequently, we assessed the role of aberrant DNA methylation in the azoxymethane (AOM) rodent model of colon cancer. AOM induced tumors display global DNA hypomethylation, which is similar to human colorectal cancer. We next assessed the methylation status of a panel of candidate genes previously shown to be aberrantly methylated in human cancer or in mouse models of malignant neoplasms. This analysis revealed different patterns of DNA methylation that were gene specific. Zik1 and Gja9 demonstrated cancer-specific aberrant DNA methylation, whereas, Cdkn2a/p16, Igfbp3, Mgmt, Id4, and Cxcr4 were methylated in both the AOM tumors and normal colon mucosa. No aberrant methylation of Dapk1 or Mlt1 was detected in the neoplasms, but normal colon mucosa samples displayed methylation of these genes. Finally, p19Arf, Tslc1, Hltf, and Mlh1 were unmethylated in both the AOM tumors and normal colon mucosa. Thus, aberrant DNA methylation does occur in AOM tumors, although the frequency of aberrantly methylated genes appears to be less common than in human colorectal cancer. Additional studies are necessary to further characterize the patterns of aberrantly methylated genes in AOM tumors. PMID:19777566

  5. Phytoestrogens regulate vitamin D metabolism in the mouse colon: relevance for colon tumor prevention and therapy.

    PubMed

    Kállay, Enikö; Adlercreutz, Herman; Farhan, Hesso; Lechner, Daniel; Bajna, Erika; Gerdenitsch, Waltraud; Campbell, Moray; Cross, Heide S

    2002-11-01

    Soybean products are highly represented in the traditional Asian diet. Major components of soy proteins are phytoestrogens, such as isoflavones. They may be responsible for the extremely low incidence of prostate and mammary tumors and possibly also of colon cancer in countries such as China and Japan. Serum 1,25-dihydroxyvitamin D3 level is inversely related to incidence of some cancers. Levels are determined by skin exposure to ultraviolet light or, to a minor extent, nutritional uptake and by subsequent conversion of the precursor vitamin D to the active hormone by the cytochrome P450 hydroxylases CYP27A1, CYP27B1 (responsible for synthesis) and CYP24 (responsible for catabolism) in liver and kidney. However, vitamin D synthesis is also found in colonocytes and is enhanced during incipient malignancy. This may indicate an autocrine/paracrine role for this differentiation-inducing hormone in defense against progression. We were able to demonstrate that either a single large oral dose of genistein or feeding soy protein for 4 mo elevated CYP27B1 and decreased CYP24 expression in the mouse colon. Our data therefore suggest that an inverse correlation of soy product consumption with colon tumor incidence may be consequent to enhanced colonic synthesis of the antimitotic hormone 1,25-dihydroxyvitamin D3.

  6. Polyamines and colon cancer.

    PubMed

    Wallace, H M; Caslake, R

    2001-09-01

    Colorectal cancer is a major health problem in the western world and is associated with significant morbidity and mortality. Diet makes a significant contribution to the disease, with high fat, low fibre diets correlating positively with a high incidence of colorectal cancer. Intracellular polyamine concentrations and ornithine decarboxylase activity are both increased in colorectal cancer tissue and in premalignant polyps. Measurement of the polyamine content of serum and urine of individuals has been proposed as a diagnostic marker of malignancy but a number of false positives make this idea untenable. There may, however, still be a role for the measurement of urinary polyamine content as a means of monitoring the efficacy of therapy. Inhibition of polyamine metabolism by polyamine analogues or by non-steroidal anti-inflammatory drugs may be useful in the chemotherapy and/or chemoprevention of colorectal cancer. Preliminary results suggest that a low polyamine diet might be helpful as part of a health care plan for cancer patients.

  7. Sulindac reversal of 15-PGDH-mediated resistance to colon tumor chemoprevention with NSAIDs.

    PubMed

    Fink, Stephen P; Dawson, Dawn M; Zhang, Yongyou; Kresak, Adam; Lawrence, Earl G; Yang, Peiying; Chen, Yanwen; Barnholtz-Sloan, Jill S; Willis, Joseph E; Kopelovich, Levy; Markowitz, Sanford D

    2015-02-01

    Non-steroidal anti-inflammatory drugs prevent colorectal cancer by inhibiting cyclooxygenase (COX) enzymes that synthesize tumor-promoting prostaglandins. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a tumor suppressor that degrades tumor-promoting prostaglandins. Murine knockout of 15-PGDH increases susceptibility to azoxymethane-induced colon tumors. It also renders these mice resistant to celecoxib, a selective inhibitor of inducible COX-2 during colon neoplasia. Similarly, humans with low colonic 15-PGDH are also resistant to colon adenoma prevention with celecoxib. Here, we used aspirin and sulindac, which inhibit both COX-1 and COX-2, in order to determine if these broader COX inhibitors can prevent colon tumors in 15-PGDH knockout (KO) mice. Unlike celecoxib, sulindac proved highly effective in colon tumor prevention of 15-PGDH KO mice. Significantly, however, aspirin demonstrated no effect on colon tumor incidence in either 15-PGDH wild-type or KO mice, despite a comparable reduction in colonic mucosal Prostaglandin E₂ (PGE₂) levels by both sulindac and aspirin. Notably, colon tumor prevention activity by sulindac was accompanied by a marked induction of lymphoid aggregates and proximal colonic inflammatory mass lesions, a side effect seen to a lesser degree with celecoxib, but not with aspirin. These findings suggest that sulindac may be the most effective agent for colon cancer prevention in humans with low 15-PGDH, but its use may also be associated with inflammatory lesions in the colon. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway.

    PubMed

    Vasconcelos-Dos-Santos, A; Loponte, H F B R; Mantuano, N R; Oliveira, I A; de Paula, I F; Teixeira, L K; de-Freitas-Junior, J C M; Gondim, K C; Heise, N; Mohana-Borges, R; Morgado-Díaz, J A; Dias, W B; Todeschini, A R

    2017-03-20

    Hyperglycemia is a common feature of diabetes mellitus, considered as a risk factor for cancer. However, its direct effects in cancer cell behavior are relatively unexplored. Herein we show that high glucose concentration induces aberrant glycosylation, increased cell proliferation, invasion and tumor progression of colon cancer. By modulating the activity of the rate-limiting enzyme, glutamine-fructose-6-phosphate amidotransferase (GFAT), we demonstrate that hexosamine biosynthetic pathway (HBP) is involved in those processes. Biopsies from patients with colon carcinoma show increased levels of GFAT and consequently aberrant glycans' expression suggesting an increase of HBP flow in human colon cancer. All together, our results open the possibility that HBP links hyperglycemia, aberrant glycosylation and tumor malignancy, and suggest this pathway as a potential therapeutic target for colorectal cancer.

  9. Clinical significance of urothelial carcinoma associated 1 in colon cancer.

    PubMed

    Tao, Kun; Yang, Jing; Hu, Yuemei; Sun, Yaohua; Tan, Zhenyu; Duan, Jinglin; Zhang, Feng; Yan, Hongli; Deng, Anmei

    2015-01-01

    This study aimed to investigate the expression levels of urothelial carcinoma associated 1 (UCA1) in cancer tissues and plasma of colon cancer patients, and evaluate its clinical significance. Quantitative real-time PCR was used to determine the expression levels of UCA1 in 80 pairs of colon cancer and adjacent normal tissues, plasma samples from 20 healthy controls, 20 colon cancer patients before and after tumor removal. The relationships between UCA1 expression and clinical features and overall survival were analyzed. Compared with adjacent normal tissues, UCA1 was significantly upregulated in colon cancer tissues, especially in cases with LNM and advanced TNM stages (P < 0.05). High UCA1 expression was associated with LMN, higher pT category, and advanced TNM stages (P < 0.05). Patients with high UCA1 expression had worse survival time than those with low UCA1 expression (adjusted HR = 2.002, 95% CI 1.007-3.981, P = 0.048). Furthermore, plasma levels of UCA1 in colon cancer patients were significantly higher than those of controls (P = 0.016). There was significant difference in plasma level of UCA1 between samples taken before and after surgery (P = 0.048). In conclusion, tissue expression of UCA1 is related to prognosis in colon cancer. Plasma UCA1 may serve as a potential biomarker for early diagnosis and disease monitoring of colon cancer patients.

  10. Ferritin content in human cancerous and noncancerous colonic tissue.

    PubMed

    Vaughn, C B; Weinstein, R; Bond, B; Rice, R; Vaughn, R W; McKendrick, A; Ayad, G; Rockwell, M A; Rocchio, R

    1987-01-01

    Tumor tissue samples from 25 patients with adenocarcinoma of the colon, twelve related samples of normal colons as well as five serum specimens from the same patients were analyzed for ferritin. The average ferritin content of the tumor tissue was 788 ng/mcp with a range of 47-1,745 ng/mcp. The average ferritin content of normal colon mucosa was 115 ng/mcp with a range of 32-230 ng/mcp. Two specimens of metastatic colon cancer taken from the retroperitoneal space and liver, respectively, contained 3,867 and 2,827 ng/mcp of ferritin. The ferritin content of the tumor tissue was higher than that of the normal colon in 8 of 9 patients who had specimens obtained from both sites. The amount of ferritin found in tumor tissue was independent of sex, age, and the site of the original tumor. This study shows that the ferritin content of colon neoplasms is elevated and indicates that the tumor tissue may be the direct source of elevated serum levels of ferritin previously observed in cancer patients.

  11. Epsin is required for Dishevelled stability and Wnt signaling activation in colon cancer development

    PubMed Central

    Chang, Baojun; Tessneer, Kandice L.; McManus, John; Liu, Xiaolei; Hahn, Scott; Pasula, Satish; Wu, Hao; Song, Hoogeun; Chen, Yiyuan; Cai, Xiaofeng; Dong, Yunzhou; Brophy, Megan L.; Rahman, Ruby; Ma, Jian-Xing; Xia, Lijun; Chen, Hong

    2015-01-01

    Uncontrolled canonical Wnt signaling supports colon epithelial tumor expansion and malignant transformation. Understanding the regulatory mechanisms involved is crucial for elucidating the pathogenesis of and will provide new therapeutic targets for colon cancer. Epsins are ubiquitin-binding adaptor proteins upregulated in several human cancers; however, epsins’ involvement in colon cancer is unknown. Here we show that loss of intestinal epithelial epsins protects against colon cancer by significantly reducing the stability of the crucial Wnt signaling effector, dishevelled (Dvl2), and impairing Wnt signaling. Consistently, epsins and Dvl2 are correspondingly upregulated in colon cancer. Mechanistically, epsin binds Dvl2 via its epsin N-terminal homology domain and ubiquitin-interacting motifs and prohibits Dvl2 polyubiquitination and degradation. Our findings reveal an unconventional role for epsins in stabilizing Dvl2 and potentiating Wnt signaling in colon cancer cells to ensure robust colon cancer progression. Epsins’ pro-carcinogenic role suggests they are potential therapeutic targets to combat colon cancer. PMID:25871009

  12. Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment.

    PubMed

    Hung, Kenneth E; Maricevich, Marco A; Richard, Larissa Georgeon; Chen, Wei Y; Richardson, Michael P; Kunin, Alexandra; Bronson, Roderick T; Mahmood, Umar; Kucherlapati, Raju

    2010-01-26

    Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.

  13. Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation on Tumor-Associated Endothelial Cells Leads to Treatment of Orthotopic Human Colon Cancer in Nude Mice1

    PubMed Central

    Sasaki, Takamitsu; Kitadai, Yasuhiko; Nakamura, Toru; Kim, Jang-Seong; Tsan, Rachel Z; Kuwai, Toshio; Langley, Robert R; Fan, Dominic; Kim, Sun-Jin; Fidler, Isaiah J

    2007-01-01

    The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-α) and vascular endothelial growth factor (VEGF) but were negative for EGFR, human epidermal growth factor receptor 2 (HER2), and VEGFR. Double immunofluorescence staining revealed that tumor-associated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR), and phosphorylated VEGFR (pVEGFR). Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase) or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01); this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001). AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, and increased the level of apoptosis in both tumor-associated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer. PMID:18084614

  14. Developmental pathways in colon cancer

    PubMed Central

    Bertrand, Fred E.; Angus, C. William; Partis, William J.; Sigounas, George

    2012-01-01

    A hallmark of cancer is reactivation/alteration of pathways that control cellular differentiation during developmental processes. Evidence indicates that WNT, Notch, BMP and Hedgehog pathways have a role in normal epithelial cell differentiation, and that alterations in these pathways accompany establishment of the tumorigenic state. Interestingly, there is recent evidence that these pathways are intertwined at the molecular level, and these nodes of intersection may provide opportunities for effective targeted therapies. This review will highlight the role of the WNT, Notch, BMP and Hedgehog pathways in colon cancer. PMID:23032367

  15. Z-505 hydrochloride, an orally active ghrelin agonist, attenuates the progression of cancer cachexia via anabolic hormones in Colon 26 tumor-bearing mice.

    PubMed

    Yoshimura, Makoto; Shiomi, Yoshihiro; Ohira, Yuta; Takei, Mineo; Tanaka, Takao

    2017-09-15

    Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent for treatment of this syndrome. We investigated the anti-cachexia effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, using a mouse model of cancer cachexia. We performed a calcium flux assay in Chinese hamster ovary (CHO-K1) cells stably expressing human GHSR1a to quantify the agonistic activity of Z-505. In Colon 26 tumor-bearing mice, Z-505 (300mg/kg, p.o., twice daily) was administered for 7 days to assess its anti-cachexia effects. Body weight and food intake were monitored during the period, and the skeletal muscle and epididymal fat weights were measured. Serum levels of insulin, insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6), and corticosterone were measured to confirm the mechanism of the anti-cachexia action of Z-505. Z-505 showed strong agonistic activity similar to that of human ghrelin, with a half maximal effective concentration (EC50) value of 0.45nM. Z-505 treatment significantly increased food intake and inhibited the progression of weight loss. Z-505 also significantly attenuated muscle wasting and fat loss, and increased circulating levels of anabolic factors such as insulin and IGF-1, but not catabolic factors such as IL-6 and corticosterone. These findings suggest that Z-505 might be effective in the treatment of cachexia via the increased anabolic hormone levels stimulated by the activation of the ghrelin receptor, GHSR1a. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Drugs Approved for Colon and Rectal Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for use in colon cancer and rectal cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  17. PET-MRI in Diagnosing Patients With Colon or Rectal Cancer

    ClinicalTrials.gov

    2015-11-25

    Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IIA Colon Cancer; Stage IIA Rectal Cancer; Stage IIB Colon Cancer; Stage IIB Rectal Cancer; Stage IIC Colon Cancer; Stage IIC Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

  18. Outcomes of colon resection in patients with metastatic colon cancer.

    PubMed

    Moghadamyeghaneh, Zhobin; Hanna, Mark H; Hwang, Grace; Mills, Steven; Pigazzi, Alessio; Stamos, Michael J; Carmichael, Joseph C

    2016-08-01

    Patients with advanced colorectal cancer have a high incidence of postoperative complications. We sought to identify outcomes of patients who underwent resection for colon cancer by cancer stage. The National Surgical Quality Improvement Program database was used to evaluate all patients who underwent colon resection with a diagnosis of colon cancer from 2012 to 2014. Multivariate logistic regression analysis was performed to investigate patient outcomes by cancer stage. A total of 7,786 colon cancer patients who underwent colon resection were identified. Of these, 10.8% had metastasis at the time of operation. Patients with metastatic disease had significantly increased risks of perioperative morbidity (adjusted odds ratio [AOR]: 1.44, P = .01) and mortality (AOR: 3.72, P = .01). Patients with metastatic disease were significantly younger (AOR: .99, P < .01) had a higher American Society of Anesthesiologists score (AOR: 1.29, P < .2) and had a higher rate of emergent operation (AOR: 1.40, P < .01). Overall, 10.8% of patients undergoing colectomy for colon cancer have metastatic disease. Postoperative morbidity and mortality are significantly higher than in patients with localized disease. Published by Elsevier Inc.

  19. FRAT1 expression regulates proliferation in colon cancer cells.

    PubMed

    Zhu, Kongxi; Guo, Jianqiang; Wang, Hongjuan; Yu, Weihua

    2016-12-01

    Colorectal cancer is one of the most common gastric malignancies worldwide. However, the underlying mechanism of colon cancer development and valuable indicators of the disease remain unclear. In this study, the expression of frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) in colon cancer was investigated and the association between FRAT1 expression and biological properties of tumors was analyzed. A total of 147 colon cancer tissue samples and adjacent normal tissues were collected between January 2013 and June 2014. The FRAT1 gene and protein expression levels were analyzed in tissues with different TNM and pathological stages. Small hairpin RNAs (shRNAs) containing the human FRAT1 gene were constructed and transfected into colon cancer HT-29 cells. The proliferation and migration of the cells was also analyzed in relation to a reduction in FRAT1 expression. In colon cancer tissues, the expression of FRAT1 was significantly higher when compared with adjacent tissues. In addition, FRAT1 expression was found to positively correlate with the degree of tumor malignancy, and this difference was determined to be statistically significant (P<0.05). Following shRNA transfection in HT-29 cells to decrease the expression of FRAT1, the proliferation and migration of the HT-29 cells decreased (due to conversion of the shRNA into small interfering RNA). These results indicate that in colon cancer, FRAT1 may present a novel tool for analyzing the tumor progression and may be a novel therapeutic target for the treatment of colon cancer.

  20. Personalized Proteome Profiles of Healthy and Tumor Human Colon Organoids Reveal Both Individual Diversity and Basic Features of Colorectal Cancer.

    PubMed

    Cristobal, Alba; van den Toorn, Henk W P; van de Wetering, Marc; Clevers, Hans; Heck, Albert J R; Mohammed, Shabaz

    2017-01-03

    Diseases at the molecular level are complex and patient dependent, necessitating development of strategies that enable precision treatment to optimize clinical outcomes. Organoid technology has recently been shown to have the potential to recapitulate the in vivo characteristics of the original individual's tissue in a three-dimensional in vitro culture system. Here, we present a quantitative mass-spectrometry-based proteomic analysis and a comparative transcriptomic analysis of human colorectal tumor and healthy organoids derived, in parallel, from seven patients. Although gene and protein signatures can be derived to distinguish the tumor organoid population from healthy organoids, our data clearly reveal that each patient possesses a distinct organoid signature at the proteomic level. We demonstrate that a personalized patient-specific organoid proteome profile can be related to the diagnosis of a patient and with future development contribute to the generation of personalized therapies.

  1. Preoperative anemia in colon cancer: assessment of risk factors.

    PubMed

    Dunne, James R; Gannon, Christopher J; Osborn, Tiffany M; Taylor, Michelle D; Malone, Debra L; Napolitano, Lena M

    2002-06-01

    Anemia is common in cancer patients and is associated with reduced survival. Recent studies document that treatment of anemia with blood transfusion in cancer patients is associated with increased infection risk, tumor recurrence, and mortality. We therefore investigated the incidence of preoperative anemia in colorectal cancer and assessed risk factors for anemia. Prospective data were collected on 311 patients diagnosed with colorectal cancer over a 6-year period from 1994 through 1999. Patients were stratified by age, gender, presenting complaint, preoperative hematocrit, American Joint Committee on Cancer (AJCC) stage, and TNM classification. Discrete variables were compared using Pearson's Chi-square analysis. Continuous variables were compared using Student's t test. Differences were considered significant when P < 0.05. The mean age of the study cohort was 67 +/- 9.2 with 98 per cent of the study population being male. The mean AJCC stage was 2.2 +/- 1.2 and the mean preoperative hematocrit was 35 +/- 7.9 with an incidence of 46.1 per cent. The most common presenting complaints were hematochezia (n = 59), anemia (n = 51), heme-occult-positive stool (n = 33), bowel obstruction (n = 26), abdominal pain (n = 21), and palpable mass (n = 13). Preoperative anemia was most common in patients with right colon cancer with an incidence of 57.6 per cent followed by left colon cancer (42.2%) and rectal cancer (29.8%). Patients with right colon cancer had significantly lower preoperative hematocrits compared with left colon cancer (33 +/- 8.5 vs 36 +/- 7.4; P < 0.01) and rectal cancer (33 +/- 8.5 vs 38 +/- 6.0; P < 0.0001). Patients with right colon cancer also had significantly increased stage at presentation compared with left colon cancer (2.3 +/- 1.3 vs 2.1 +/- 1.2; P < 0.02). Age was not a significant risk factor for preoperative anemia in colorectal cancer. We conclude that there is a high incidence of anemia in patients with colon cancer. Patients with right colon

  2. Colon cancer modulation by a diabetic environment: A single institutional experience

    PubMed Central

    Gonzalez, Nieves; Portal-Nuñez, Sergio; Zazo, Sandra; Corton, Marta; Minguez, Pablo; Gomez-Guerrero, Carmen; Arce, Jose Miguel; Sanz, Ana Belen; Mas, Sebastian; Aguilera, Oscar; Alvarez-Llamas, Gloria; Esbrit, Pedro; Ortiz, Alberto; Ayuso, Carmen; Egido, Jesus; Rojo, Federico; Garcia-Foncillas, Jesus

    2017-01-01

    Background Multiple observational studies suggest an increased risk of colon cancer in patients with diabetes mellitus (DM). This can theoretically be the result of an influence of the diabetic environment on carcinogenesis or the tumor biologic behavior. Aim To gain insight into the influence of a diabetic environment on colon cancer characteristics and outcomes. Material and methods Retrospective analysis of clinical records in an academic tertiary care hospital with detailed analysis of 81 diabetic patients diagnosed of colon cancer matched with 79 non-diabetic colon cancer patients. The impact of streptozotocin-induced diabetes on the growth of colon cancer xenografts was studied in mice. Results The incidence of DM in 1,137 patients with colorectal cancer was 16%. The diabetic colon cancer cases and non-diabetic colon cancer controls were well matched for demographic and clinical variables. The ECOG Scale Performance Status was higher (worse) in diabetics (ECOG ≥1, 29.1% of controls vs 46.9% of diabetics, p = 0.02), but no significant differences were observed in tumor grade, adjuvant therapy, tumor site, lymphovascular invasion, stage, recurrence, death or cancer-related death. Moreover, no differences in tumor variables were observed between patients treated or not with metformin. In the xenograft model, tumor growth and histopathological characteristics did not differ between diabetic and nondiabetic animals. Conclusion Our findings point towards a mild or negligible effect of the diabetes environment on colon cancer behavior, once cancer has already developed. PMID:28253286

  3. Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice

    PubMed Central

    Ho, Desiree S.; Fu, S. Kristine; Forrest, Cynthia H.; Croft, Kevin D.; Olynyk, John K.; Lawrance, Ian C.; Trinder, Debbie

    2013-01-01

    Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk. PMID:24223168

  4. Mesenchymal stem cells enhance growth and metastasis of colon cancer.

    PubMed

    Shinagawa, Kei; Kitadai, Yasuhiko; Tanaka, Miwako; Sumida, Tomonori; Kodama, Michiyo; Higashi, Yukihito; Tanaka, Shinji; Yasui, Wataru; Chayama, Kazuaki

    2010-11-15

    Recently, mesenchymal stem cells (MSCs) were reported to migrate to tumor stroma as well as injured tissue. We examined the role of human MSCs in tumor stroma using an orthotopic nude mice model of KM12SM colon cancer. In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in greater tumor weight than did transplantation of KM12SM cells alone. The survival rate was significantly lower in the mixed-cell group, and liver metastasis was seen only in this group. Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index, significantly greater microvessel area and significantly lower apoptotic index. Splenic injection of KM12SM cells mixed with MSCs, in comparison to splenic injection of KM12SM cells alone, resulted in a significantly greater number of liver metastases. MSCs incorporated into the stroma of primary and metastatic tumors expressed α-smooth muscle actin and platelet-derived growth factor receptor-β as carcinoma-associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors. Collectively, MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration and invasion and by inhibiting apoptosis of tumor cells.

  5. Bitter Melon Component and Colon Cancer Prevention | Division of Cancer Prevention

    Cancer.gov

    DESCRIPTION (provided by applicant): Despite the best screening efforts to identify and remove colon polyps, colon cancer remains a leading cause of cancer related morbidity and mortality, both in the US and around the world. Also, current therapeutics while good in removing most cancer cells are not adequate because they leave some cells behind. This is because these cells can reemerge and develop a fresh tumor, which in many cases can manifest in a different organ due to metastasis. |

  6. Supplementation by vitamin D compounds does not affect colonic tumor development in vitamin D sufficient murine models

    PubMed Central

    Irving, Amy A.; Halberg, Richard B.; Albrecht, Dawn M.; Plum, Lori A.; Krentz, Kathleen J.; Clipson, Linda; Drinkwater, Norman; Amos-Landgraf, James M.; Dove, William F.; DeLuca, Hector F.

    2012-01-01

    Epidemiological studies indicate that sunlight exposure and vitamin D are each associated with a lower risk of colon cancer. The few controlled supplementation trials testing vitamin D in humans reported to date show conflicting results. We have used two genetic models of familial colon cancer, the ApcPirc/+ (Pirc) rat and the ApcMin/+ (Min) mouse, to investigate the effect of 25-hydroxyvitamin D3 [25(OH)D3] and two analogs of vitamin D hormone on colonic tumors. Longitudinal endoscopic monitoring allowed us to test the efficacy of these compounds in preventing newly arising colonic tumors and in affecting established colonic tumors. 25(OH)D3 and two analogs of vitamin D hormone each failed to reduce tumor multiplicities or alter the growth patterns of colonic tumors in the Pirc rat or the Min mouse. PMID:21907701

  7. Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival.

    PubMed

    Fink, Stephen P; Myeroff, Lois L; Kariv, Revital; Platzer, Petra; Xin, Baozhong; Mikkola, Debra; Lawrence, Earl; Morris, Nathan; Nosrati, Arman; Willson, James K V; Willis, Joseph; Veigl, Martina; Barnholtz-Sloan, Jill S; Wang, Zhenghe; Markowitz, Sanford D

    2015-10-13

    Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target.

  8. Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival

    PubMed Central

    Fink, Stephen P.; Myeroff, Lois L.; Kariv, Revital; Platzer, Petra; Xin, Baozhong; Mikkola, Debra; Lawrence, Earl; Morris, Nathan; Nosrati, Arman; Willson, James K. V.; Willis, Joseph; Veigl, Martina; Barnholtz-Sloan, Jill S.; Wang, Zhenghe; Markowitz, Sanford D.

    2015-01-01

    Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target. PMID:26437221

  9. Increased expression and aberrant localization of mucin 13 in metastatic colon cancer.

    PubMed

    Gupta, Brij K; Maher, Diane M; Ebeling, Mara C; Sundram, Vasudha; Koch, Michael D; Lynch, Douglas W; Bohlmeyer, Teresa; Watanabe, Akira; Aburatani, Hiroyuki; Puumala, Susan E; Jaggi, Meena; Chauhan, Subhash C

    2012-11-01

    MUC13 is a newly identified transmembrane mucin. Although MUC13 is known to be overexpressed in ovarian and gastric cancers, limited information is available regarding the expression of MUC13 in metastatic colon cancer. Herein, we investigated the expression profile of MUC13 in colon cancer using a novel anti-MUC13 monoclonal antibody (MAb, clone ppz0020) by immunohistochemical (IHC) analysis. A cohort of colon cancer samples and tissue microarrays containing adjacent normal, non-metastatic colon cancer, metastatic colon cancer, and liver metastasis tissues was used in this study to investigate the expression pattern of MUC13. IHC analysis revealed significantly higher (p<0.001) MUC13 expression in non-metastatic colon cancer samples compared with faint or very low expression in adjacent normal tissues. Interestingly, metastatic colon cancer and liver metastasis tissue samples demonstrated significantly (p<0.05) higher cytoplasmic and nuclear MUC13 expression compared with non-metastatic colon cancer and adjacent normal colon samples. Moreover, cytoplasmic and nuclear MUC13 expression correlated with larger and poorly differentiated tumors. Four of six tested colon cancer cell lines also expressed MUC13 at RNA and protein levels. These studies demonstrate a significant increase in MUC13 expression in metastatic colon cancer and suggest a correlation between aberrant MUC13 localization (cytoplasmic and nuclear expression) and metastatic colon cancer.

  10. Increased Expression and Aberrant Localization of Mucin 13 in Metastatic Colon Cancer

    PubMed Central

    Gupta, Brij K.; Maher, Diane M.; Ebeling, Mara C.; Sundram, Vasudha; Koch, Michael D.; Lynch, Douglas W.; Bohlmeyer, Teresa; Watanabe, Akira; Aburatani, Hiroyuki; Puumala, Susan E.; Jaggi, Meena

    2012-01-01

    MUC13 is a newly identified transmembrane mucin. Although MUC13 is known to be overexpressed in ovarian and gastric cancers, limited information is available regarding the expression of MUC13 in metastatic colon cancer. Herein, we investigated the expression profile of MUC13 in colon cancer using a novel anti-MUC13 monoclonal antibody (MAb, clone ppz0020) by immunohistochemical (IHC) analysis. A cohort of colon cancer samples and tissue microarrays containing adjacent normal, non-metastatic colon cancer, metastatic colon cancer, and liver metastasis tissues was used in this study to investigate the expression pattern of MUC13. IHC analysis revealed significantly higher (p<0.001) MUC13 expression in non-metastatic colon cancer samples compared with faint or very low expression in adjacent normal tissues. Interestingly, metastatic colon cancer and liver metastasis tissue samples demonstrated significantly (p<0.05) higher cytoplasmic and nuclear MUC13 expression compared with non-metastatic colon cancer and adjacent normal colon samples. Moreover, cytoplasmic and nuclear MUC13 expression correlated with larger and poorly differentiated tumors. Four of six tested colon cancer cell lines also expressed MUC13 at RNA and protein levels. These studies demonstrate a significant increase in MUC13 expression in metastatic colon cancer and suggest a correlation between aberrant MUC13 localization (cytoplasmic and nuclear expression) and metastatic colon cancer. PMID:22914648

  11. RET is a potential tumor suppressor gene in colorectal cancer

    PubMed Central

    Luo, Yanxin; Tsuchiya, Karen D.; Park, Dong Il; Fausel, Rebecca; Kanngurn, Samornmas; Welcsh, Piri; Dzieciatkowski, Slavomir; Wang, Jianping; Grady, William M.

    2012-01-01

    Cancer arises as the consequence of mutations and epigenetic alterations that activate oncogenes and inactivate tumor suppressor genes. Through a genome-wide screen for methylated genes in colon neoplasms, we identified aberrantly methylated RET in colorectal cancer. RET, a transmembrane receptor tyrosine kinase and a receptor for the GDNF-family ligands, was one of the first oncogenes to be identified and has been shown to be an oncogene in thyroid cancer and pheochromocytoma. However, unexpectedly, we found RET is methylated in 27% of colon adenomas and in 63% of colorectal cancers, and now provide evidence that RET has tumor suppressor activity in colon cancer. The aberrant methylation of RET correlates with decreased RET expression, whereas the restoration of RET in colorectal cancer cell lines results in apoptosis. Furthermore, in support of a tumor suppressor function of RET, mutant RET has also been found in primary colorectal cancer. We now show that these mutations inactivate RET, which is consistent with RET being a tumor suppressor gene in the colon. These findings suggest that the aberrant methylation of RET and the mutational inactivation of RET promote colorectal cancer formation and that RET can serve as a tumor suppressor gene in the colon. Moreover, the increased frequency of methylated RET in colon cancers compared to adenomas suggests RET inactivation is involved in the progression of colon adenomas to cancer. PMID:22751117

  12. Patients with Acromegaly Presenting with Colon Cancer: A Case Series

    PubMed Central

    Nakhle, Samer; Ludlam, William H.

    2016-01-01

    Introduction. Frequent colonoscopy screenings are critical for early diagnosis of colon cancer in patients with acromegaly. Case Presentations. We performed a retrospective analysis of the incidental diagnoses of colon cancer from the ACCESS trial (ClinicalTrials.gov identifier: NCT01995734). Colon cancer was identified in 2 patients (4.5%). Case  1 patient was a 36-year-old male with acromegaly who underwent transsphenoidal surgery to remove the pituitary adenoma. After surgery, the patient underwent routine colonoscopy screening, which revealed a 40 mm tubular adenoma in the descending colon. A T1N1a carcinoma was surgically removed, and 1 of 22 lymph nodes was positive for metastatic disease, leading to a diagnosis of stage 3 colon cancer. Case  2 patient was a 50-year-old male with acromegaly who underwent transsphenoidal surgery to remove a 2 cm pituitary adenoma. The patient reported severe cramping and lower abdominal pain, and an invasive 8.1 cm3 grade 2 adenocarcinoma with signet rings was identified in the ascending colon and removed. Of the 37 lymph nodes, 34 were positive for the presence of tumor cells, and stage 3c colon cancer was confirmed. Conclusion. Current guidelines for colonoscopy screening at the time of diagnosis of acromegaly and at appropriate follow-up intervals should be followed. PMID:28025627

  13. High copy number of mitochondrial DNA predicts poor prognosis in patients with advanced stage colon cancer.

    PubMed

    Wang, Yun; He, Shuixiang; Zhu, Xingmei; Qiao, Wei; Zhang, Juan

    2016-12-23

    The aim of this investigation was to determine whether alterations in mitochondrial DNA (mtDNA) copy number in colon cancer were associated with clinicopathological parameters and postsurgical outcome. By quantitative real-time PCR assay, the mtDNA copy number was detected in a cohort of colon cancer and matched adjacent colon tissues (n = 162). The majority of patients had higher mtDNA content in colon cancer tissues than matched adjacent colon tissues. Moreover, high mtDNA content in tumor tissues was associated with larger tumor size, higher serum CEA level, advanced TNM stage, vascular emboli, and liver metastases. Further survival curve analysis showed that high mtDNA content was related to the worst survival in patients with colon cancer at advanced TNM stage. High mtDNA content is a potential effective factor of poor prognosis in patients with advanced stage colon cancer.

  14. [A case of metastatic gastric cancer originating from transverse colon cancer].

    PubMed

    Nushijima, Youichirou; Nakano, Katsutoshi; Sugimoto, Keishi; Nakaguchi, Kazunori; Kan, Kazuomi; Maruyama, Hirohide; Doi, Sadayuki; Okamura, Shu; Murata, Kohei

    2014-11-01

    Metastatic gastric cancer is uncommon, and metastasis of colorectal cancer to the stomach is extremely rare. We report a case of metastatic gastric cancer that originated from transverse colon cancer. A 52-year-old woman underwent a left hemicolectomy and D3 lymph node dissection based on a diagnosis of transverse colon cancer. The pathology results were as follows: mucinous adenocarcinoma, type 2, 6 × 11 cm, ss, ly1 v1, pm (-), dm (-), n1 (+), P0, H0, M0, Stage IIIa. The patient received XELOX as postoperative adjuvant therapy for 6 months. One year and 3 months after the left hemicolectomy, gastroscopy revealed a submucosal tumor in the lower body of the stomach and an incipient cancer in the cardia of the stomach, and a colonoscopy revealed an incipient cancer in the transverse colon. An endoscopic ultrasonography fine needle aspiration biopsy of the submucosal tumor in the lower body of the stomach was performed. Histology showed that this tumor was a mucinous adenocarcinoma similar to the primary transverse colon cancer, which led to a diagnosis of metastatic gastric cancer originating from transverse colon cancer. Distant metastasis was not detected. Endoscopic submucosal dissection of the incipient gastric cancer was performed, as were distal gastrectomy and partial colectomy. Peritoneal dissemination and para-aortic lymph node recurrence were detected 7 months after the second surgery.

  15. Comparison of the feasibility of laparoscopic resection of the primary tumor in patients with stage IV colon cancer with early and advanced disease: the short- and long-term outcomes at a single institution.

    PubMed

    Wang, Jui-Ho; King, Tai-Ming; Chang, Min-Chi; Hsu, Chao-Wen

    2013-10-01

    The role of resection of the primary tumor in patients with stage IV colorectal cancer (CRC) remains controversial. Laparoscopic resection has become an accepted therapeutic option for treating early stage I-III CRC; however, it has not been evaluated for use in patients with advanced stage disease. We conducted a retrospective observational study to evaluate the feasibility of laparoscopic resection of the primary tumor exclusively in patients with stage IV colon cancer compared to open resection in patients with stage IV colon cancer and laparoscopic resection in patients with stage I-III colon cancer in terms of operative results and short- and long-term outcomes. Laparoscopic resection was performed in 35 stage IV patients and open resection was performed in 40 stage IV patients. One hundred and eighteen stage I-III patients who underwent laparoscopic resection were evaluated. In the comparison between the laparoscopic group and the open group among patients with stage IV colon cancer, postoperative recovery appeared to be better in the laparoscopic group than in the open group, as reflected by shorter times to resumption of a regular diet (p = 0.049), shorter lengths of hospitalization (p = 0.083), increased feasibility of postoperative chemotherapy (p < 0.001), shorter time intervals from surgery to chemotherapy (p = 0.031) and longer median survival (p = 0.078) at the expense of longer operative times (p = 0.025). In the comparison between the laparoscopic resection in stage IV and stage I-III disease groups, no significant differences were observed in operative results and short- and long-term outcomes, except for the rate of ostomy creation (48.5 vs. 8.5%, p = 0.02). Laparoscopic resection of the primary tumor in patients with stage IV colon cancer achieves equivalent results to that performed in patients with stage I-III disease and that performed in patients with stage IV disease using open resection. The use of a minimally invasive approach in the

  16. Antibody-linked drug destroys tumor cells and tumor blood vessels in many types of cancer | Center for Cancer Research

    Cancer.gov

    A team led by Brad St. Croix, Ph.D., Senior Associate Scientist, Mouse Cancer Genetics Program, has developed an antibody-drug conjugate (ADC) that destroys both tumor cells and the blood vessels that nourish them. The drug significantly shrank breast tumors, colon tumors and several other types of cancer and prolonged survival. Learn more...  

  17. Microbes, Microbiota and Colon Cancer

    PubMed Central

    Sears, Cynthia L.; Garrett, Wendy S.

    2014-01-01

    Summary Colorectal cancer (CRC) presents a considerable disease burden worldwide. The human colon is also an anatomical location with the largest number of microbes. It is natural therefore to anticipate a role for microbes, particularly bacteria, in colorectal carcinogenesis. The increasing accessibility of microbial meta’omics is fueling a surge in our understanding of the role that microbes and the microbiota play in CRC. In this review, we will discuss recent insights into contributions of the microbiota to CRC and explore conceptual frameworks for evaluating the role of microbes in cancer causation. We also highlight new findings on candidate CRC-potentiating species and current knowledge gaps. Finally, we explore the roles of microbial metabolism as it relates to bile acids, xenobiotics, and diet in the etiology and therapeutics of CRC. PMID:24629338

  18. Colon Cancer Risk Assessment - Gauss Program

    Cancer.gov

    An executable file (in GAUSS) that projects absolute colon cancer risk (with confidence intervals) according to NCI’s Colorectal Cancer Risk Assessment Tool (CCRAT) algorithm. GAUSS is not needed to run the program.

  19. Synchronous Gastrointestinal Carcinoid Tumor and Colon Adenocarcinoma: Case Reports and Literature Review

    PubMed Central

    Winn, Jessica N.; Sathyamurthy, Anjana; Kneib, Jessica L.; Ibdah, Jamal A.; Tahan, Veysel

    2017-01-01

    Case series Patient: Male, 40; Male, 70 Final Diagnosis: Synchronous gastrointestinal carcinoid tumor and colon adenocarcinoma Symptoms: Weakness Medication: — Clinical Procedure: Colonoscopy Specialty: Gastroenterology and Hepatology Objective: Rare co-existance of disease or pathology Background: Coexistence of carcinoid tumor and colorectal adenocarcinoma is rare. In this report, we present two cases and review the current literature for synchronous carcinoid tumor and colorectal carcinoma occurrence. Case Reports: In both cases, the rectal carcinoid tumors and sigmoid colon adenocarcinomas were detected by colonoscopy. The colon adenocarcinomas were effectively treated with a laparoscopic sigmoidectomy and the carcinoids were successfully removed endoscopically. Our 40-year-old patient was the youngest among 17 reported patient cases. Conclusions: These two cases demonstrate that the diagnosis of gastrointestinal carcinoid requires a complete assessment of the remainder of the colon for another primary cancer to achieve a timely treatment management strategy. PMID:28579603

  20. Modeling Efficacy of Bevacizumab Treatment for Metastatic Colon Cancer

    PubMed Central

    Islam, Rezwan; Chyou, Po-Huang; Burmester, James K

    2013-01-01

    Purpose: Bevacizumab, an FDA-approved adjuvant treatment for metastatic colon cancer, has extended survival for many patients. However, factors predicting response to treatment remain undefined. Patients and Methods: Relevant clinical and environmental data were abstracted from medical records of 149 evaluable patients treated with bevacizumab for metastatic colon cancer at a multi-specialty clinic. Tumor response was calculated from radiologic reports using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and verified by oncologist review. Patients with at least one occurrence of complete or partial response or stable disease were classified as responders; those exhibiting progressive disease were classified as non-responders. Results: Univariate analysis demonstrated that blood in stool (P<0.05), unexplained weight loss (P<0.05), primary colon cancer site (P<0.05), chemotherapy treatment of primary tumor site (P<0.05), and adenocarcinoma versus adenoma subtype (P<0.05) was associated with tumor responsiveness. Factors remaining statistically significant following multivariate modeling included adenocarcinoma as tumor cell type versus other adenocarcinoma subtypes (OR=6.35, 95% CI: 1.08-37.18), chemotherapy treatment applied to primary tumor (OR= 0.07, 95% CI: 0.0-0.76,), tumor localization to cecal/ascending colon (OR=0.061, 95% CI: 0.006-0.588,), and unexplained weight loss (OR=0.1, 95% CI: 0.02-0.56,). Chemotherapy treatment of primary tumor, unexplained weight loss, and cecal/ascending localization of the tumor were associated with poorer outcomes. Adenocarcinoma as cell type compared to other adenocarcinoma subtypes was associated with better response to bevacizumab treatment. Conclusion: Results suggest that response to bevacizumab therapy may be predicted by modeling clinical factors including symptomology on presentation, tumor location and type, and initial response to chemotherapy. PMID:23678369

  1. Colon cancer releases alpha-tocopherol from its O-glycosides better than normal colon tissue.

    PubMed

    Knaś, Małgorzata; Szajda, Sławomir Dariusz; Snarska, Jadwiga; Zalewska-Szajda, Beata; Walejko, Piotr; Borzym-Kluczyk, Malgorzata; Knaś-Karaszewska, Katarzyna; Kepka, Alina; Chojnowska, Sylwia; Waszkiewicz, Napoleon; Zimnoch, Magdalena; Maj, Jadwiga; Hryniewicka, Agnieszka; Dudzik, Danuta; Witkowshi, Stanislaw; Puchalski, Zbigniew; Zwierz, Krzysztof

    2009-01-01

    Free radicals, in a colon, may damage DNA, make difficult DNA repair and change course of post-translational modifications of regulatory proteins, which promote tumor initiation and progression. Therefore risk of colon cancer is closely related to diet and other lifestyle factors. Dietary antioxidants, such as vitamin E, should reduce the levels of harmful oxidation products. However vitamin E is not soluble in water, which decreases its bioavailability. As O-glycosides of alpha-tocopherol are better soluble in water and penetrate to tissues easier than free alpha-tocopherol, the aim of our work was to investigate the rate of release the free tocopherol from its O-glycosides in colon cancer, in comparison to human healthy colon tissue. The activities of enzymes catalysing hydrolysis of alpha-tocopheryl glucoside (1a) and mannoside (1b) as well as p-nitrophenyl beta-glucoside (2a) and mannoside (2b) in cancer and healthy human colon tissues, were determined according to the modified method described by Zwierz et al. The alpha-tocopherol and p-nitrophenol were significantly better released from the respective glucosides and mannosides in cancer tissue than in "healthy" human colon tissues, with p = 0.000947 for la, p = 0.033024 for 1b; p = 0.0028 for 2a, and p = 0.0033 for 2b, respectively. Alpha-tocopherol and p-nitrophenol are released from the O-glycosides of glucose and mannose in significantly higher amount in colon cancer than in healthy tissues. The alpha-tocopherol O-glycosides can be considered as prodrugs in prevention and treatment of the colon cancer.

  2. ST6Gal-I protein expression is upregulated in human epithelial tumors and correlates with stem cell markers in normal tissues and colon cancer cell lines.

    PubMed

    Swindall, Amanda F; Londoño-Joshi, Angelina I; Schultz, Matthew J; Fineberg, Naomi; Buchsbaum, Donald J; Bellis, Susan L

    2013-04-01

    The ST6Gal-I sialyltransferase adds an α2-6-linked sialic acid to the N-glycans of certain receptors. ST6Gal-I mRNA has been reported to be upregulated in human cancer, but a prior lack of antibodies has limited immunochemical analysis of the ST6Gal-I protein. Here, we show upregulated ST6Gal-I protein in several epithelial cancers, including many colon carcinomas. In normal colon, ST6Gal-I localized selectively to the base of crypts, where stem/progenitor cells are found, and the tissue staining patterns were similar to the established stem cell marker ALDH1. Similarly, ST6Gal-I expression was restricted to basal epidermal layers in skin, another stem/progenitor cell compartment. ST6Gal-I was highly expressed in induced pluripotent stem (iPS) cells, with no detectable expression in the fibroblasts from which iPS cells were derived. On the basis of these observations, we investigated further an association of ST6Gal-I with cancer stem cells (CSC). Selection of irinotecan resistance in colon carcinoma cells led to a greater proportion of CSCs compared with parental cells, as measured by the CSC markers CD133 and ALDH1 activity (Aldefluor). These chemoresistant cells exhibited a corresponding upregulation of ST6Gal-I expression. Conversely, short hairpin RNA (shRNA)-mediated attenuation of ST6Gal-I in colon carcinoma cells with elevated endogenous expression decreased the number of CD133/ALDH1-positive cells present in the cell population. Collectively, our results suggest that ST6Gal-I promotes tumorigenesis and may serve as a regulator of the stem cell phenotype in both normal and cancer cell populations.

  3. ST6Gal-I protein expression is upregulated in human epithelial tumors and correlates with stem cell markers in normal tissues and colon cancer cell lines

    PubMed Central

    Swindall, Amanda F.; Londoño-Joshi, Angelina I.; Schultz, Matthew J.; Fineberg, Naomi; Buchsbaum, Donald J.; Bellis, Susan L.

    2014-01-01

    The ST6Gal-I sialyltransferase adds an α2–6-linked sialic acid to the N-glycans of certain receptors. ST6Gal-I mRNA has been reported to be upregulated in human cancer, but a prior lack of antibodies has limited immunochemical analysis of the ST6Gal-I protein. Here we show upregulated ST6Gal-I protein in several epithelial cancers, including many colon carcinomas. In normal colon, ST6Gal-I localized selectively to the base of crypts, where stem/progenitor cells are found, and the tissue staining patterns were similar to the established stem cell marker ALDH1. Similarly, ST6Gal-I expression was restricted to basal epidermal layers in skin, another stem/progenitor cell compartment. ST6Gal-I was highly expressed in induced pluripotent stem (iPS) cells, with no detectable expression in the fibroblasts from which iPS cells were derived. On the basis of these observations we investigated further an association of ST6Gal-I with cancer stem cells (CSCs). Selection of irinotecan resistance in colon carcinoma cells led to a greater proportion of CSCs compared with parental cells, as measured by the CSC markers CD133 and ALDH1 activity (Aldefluor). These chemoresistant cells exhibited a corresponding upregulation of ST6Gal-I expression. Conversely, shRNA-mediated attenuation of ST6Gal-I in colon carcinoma cells with elevated endogenous expression decreased the number of CD133/ALDH1-positive cells present in the cell population. Collectively, our results suggest that ST6Gal-I promotes tumorigenesis and may serve as a regulator of the stem cell phenotype in both normal and cancer cell populations. PMID:23358684

  4. Tumor evolution in space: the effects of competition colonization tradeoffs on tumor invasion dynamics.

    PubMed

    Orlando, Paul A; Gatenby, Robert A; Brown, Joel S

    2013-01-01

    We apply competition colonization tradeoff models to tumor growth and invasion dynamics to explore the hypothesis that varying selection forces will result in predictable phenotypic differences in cells at the tumor invasive front compared to those in the core. Spatially, ecologically, and evolutionarily explicit partial differential equation models of tumor growth confirm that spatial invasion produces selection pressure for motile phenotypes. The effects of the invasive phenotype on normal adjacent tissue determine the patterns of growth and phenotype distribution. If tumor cells do not destroy their environment, colonizer and competitive phenotypes coexist with the former localized at the invasion front and the latter, to the tumor interior. If tumors cells do destroy their environment, then cell motility is strongly selected resulting in accelerated invasion speed with time. Our results suggest that the widely observed genetic heterogeneity within cancers may not be the stochastic effect of random mutations. Rather, it may be the consequence of predictable variations in environmental selection forces and corresponding phenotypic adaptations.

  5. Variation in Positron Emission Tomography Use After Colon Cancer Resection

    PubMed Central

    Bailey, Christina E.; Hu, Chung-Yuan; You, Y. Nancy; Kaur, Harmeet; Ernst, Randy D.; Chang, George J.

    2015-01-01

    Purpose: Colon cancer surveillance guidelines do not routinely include positron emission tomography (PET) imaging; however, its use after surgical resection has been increasing. We evaluated the secular patterns of PET use after surgical resection of colon cancer among elderly patients and identified factors associated with its increasing use. Patients and Methods: We used the SEER-linked Medicare database (July 2001 through December 2009) to establish a retrospective cohort of patients age ≥ 66 years who had undergone surgical resection for colon cancer. Postoperative PET use was assessed with the test for trends. Patient, tumor, and treatment characteristics were analyzed using univariable and multivariable logistic regression analyses. Results: Of the 39,221 patients with colon cancer, 6,326 (16.1%) had undergone a PET scan within 2 years after surgery. The use rate steadily increased over time. The majority of PET scans had been performed within 2 months after surgery. Among patients who had undergone a PET scan, 3,644 (57.6%) had also undergone preoperative imaging, and 1,977 (54.3%) of these patients had undergone reimaging with PET within 2 months after surgery. Marriage, year of diagnosis, tumor stage, preoperative imaging, postoperative visit to a medical oncologist, and adjuvant chemotherapy were significantly associated with increased PET use. Conclusion: PET use after colon cancer resection is steadily increasing, and further study is needed to understand the clinical value and effectiveness of PET scans and the reasons for this departure from guideline-concordant care. PMID:25852143

  6. In colon cancer, normal colon tissue and blood cells have altered telomere lengths.

    PubMed

    Valls-Bautista, Cristina; Piñol-Felis, Carme; Reñé-Espinet, Josep M; Buenestado-García, Juan; Viñas-Salas, Joan

    2015-06-01

    Telomere length (TL) shortened occurs in colorectal carcinogenetic process. Our objective is to determine if it is only a local fact or there are alterations in normal colon cells and in other body cells. TL of tumoral and normal mucosa and leukocytes of 40 patients operated of colorectal cancer (CRC) and 40 control patients with normal colonoscopy were measured by Southern-blot. Groups were matched by the same localization as tumors, sex, and age. In CRC patients, TRFL (Telomere Repeat Factor Length) leukocytes mean was 8.84 kpb, normal colonic mucosa 7.97 kpb, and tumoral mucosa 7.33 kpb (P < 0.001). In the 40 normal control patients, mean TRFL of colonic mucosa was 7.76 kpb, while in blood cells was 7.01 kpb (P < 0.001). We observed an inverse correlation between leukocytes TRFL and age (r(2)  = 0.17, P = 0.008). Mucosa TRFL correlates significantly with patient's age (r(2)  = 0.138, P = 0.018). TRFL of controls colonic mucosa correlates with TRFL of their blood cells (r(2)  = 0.354, P < 0.001). Normal colonic mucosa and leukocytes in CCR patients presents telomere altered in respect to normal patients. Telomere length in normal leukocytes could be an initial marker for colorectal cancer. © 2015 Wiley Periodicals, Inc.

  7. Impact of Diabetes on Oncologic Outcome of Colorectal Cancer Patients: Colon vs. Rectal Cancer

    PubMed Central

    Park, Min Geun; Lee, Ji-Won; Chu, Sang Hui; Park, Ji-Hye; Lee, Mi Kyung; Sato, Kaori; Ligibel, Jennifer A.; Meyerhardt, Jeffrey A.; Kim, Nam Kyu

    2013-01-01

    Background To evaluate the impact of diabetes on outcomes in colorectal cancer patients and to examine whether this association varies by the location of tumor (colon vs. rectum). Patients and methods This study includes 4,131 stage I-III colorectal cancer patients, treated between 1995 and 2007 (12.5% diabetic, 53% colon, 47% rectal) in South Korea. Cox proportional hazards modeling was used to determine the prognostic influence of DM on survival endpoints. Results Colorectal cancer patients with DM had significantly worse disease-free survival (DFS) [hazard ratio (HR) 1.17, 95% confidence interval (CI): 1.00–1.37] compared with patients without DM. When considering colon and rectal cancer independently, DM was significantly associated with worse overall survival (OS) (HR: 1.46, 95% CI: 1.11–1.92), DFS (HR: 1.45, 95% CI: 1.15–1.84) and recurrence-free survival (RFS) (HR: 1.32, 95% CI: 0.98–1.76) in colon cancer patients. No association for OS, DFS or RFS was observed in rectal cancer patients. There was significant interaction of location of tumor (colon vs. rectal cancer) with DM on OS (P = 0.009) and DFS (P = 0.007). Conclusions This study suggests that DM negatively impacts survival outcomes of patients with colon cancer but not rectal cancer. PMID:23405123

  8. Metformin: A Potential Therapeutic Agent for Recurrent Colon Cancer

    PubMed Central

    Nangia-Makker, Pratima; Yu, Yingjie; Vasudevan, Anita; Farhana, Lulu; Rajendra, Sindhu G.; Levi, Edi; Majumdar, Adhip P. N.

    2014-01-01

    Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties. However, most of the studies to evaluate therapeutic efficacy of metformin have been on primary cancer. No information is available whether metformin could be effectively used for recurrent cancer, specifically colorectal cancer (CRC) that affects up to 50% of patients treated by conventional chemotherapies. Although the reasons for recurrence are not fully understood, it is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs). Therefore, development of non-toxic treatment strategies targeting CSCs would be of significant therapeutic benefit. In the current investigation, we have examined the effectiveness of metformin, in combination with 5-fluorouracil and oxaliplatin (FuOx), the mainstay of colon cancer therapeutics, on survival of chemo-resistant colon cancer cells that are highly enriched in CSCs/CSLCs. Our data show that metformin acts synergistically with FuOx to (a) induce cell death in chemo resistant (CR) HT-29 and HCT-116 colon cancer cells, (b) inhibit colonospheres formation and (c) enhance colonospheres disintegration. In vitro cell culture studies have further demonstrated that the combinatorial treatment inhibits migration of CR colon cancer cells. These changes were associated with increased miRNA 145 and reduction in miRNA 21. Wnt/β-catenin signaling pathway was also down-regulated indicating its pivotal role in regulating the growth of CR colon cancer cells. Data from SCID mice xenograft model of CR HCT-116 and CR HT-29 cells show that the combination of metformin and FuOX is highly effective in inhibiting the growth of colon tumors as evidenced by ∼50% inhibition in growth following 5 weeks of combination treatment, when compared with the vehicle treated controls. Our current data suggest that metformin together with conventional chemotherapy could be an effective treatment

  9. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden.

    PubMed

    Baxter, Nielson T; Zackular, Joseph P; Chen, Grace Y; Schloss, Patrick D

    2014-01-01

    A growing body of evidence indicates that the gut microbiome plays a role in the development of colorectal cancer (CRC). Patients with CRC harbor gut microbiomes that are structurally distinct from those of healthy individuals; however, without the ability to track individuals during disease progression, it has not been possible to observe changes in the microbiome over the course of tumorigenesis. Mouse models have demonstrated that these changes can further promote colonic tumorigenesis. However, these models have relied upon mouse-adapted bacterial populations and so it remains unclear which human-adapted bacterial populations are responsible for modulating tumorigenesis. We transplanted fecal microbiota from three CRC patients and three healthy individuals into germ-free mice, resulting in six structurally distinct microbial communities. Subjecting these mice to a chemically induced model of CRC resulted in different levels of tumorigenesis between mice. Differences in the number of tumors were strongly associated with the baseline microbiome structure in mice, but not with the cancer status of the human donors. Partitioning of baseline communities into enterotypes by Dirichlet multinomial mixture modeling resulted in three enterotypes that corresponded with tumor burden. The taxa most strongly positively correlated with increased tumor burden were members of the Bacteroides, Parabacteroides, Alistipes, and Akkermansia, all of which are Gram-negative. Members of the Gram-positive Clostridiales, including multiple members of Clostridium Group XIVa, were strongly negatively correlated with tumors. Analysis of the inferred metagenome of each community revealed a negative correlation between tumor count and the potential for butyrate production, and a positive correlation between tumor count and the capacity for host glycan degradation. Despite harboring distinct gut communities, all mice underwent conserved structural changes over the course of the model. The

  10. Colon cancer stem cells: promise of targeted therapy.

    PubMed

    Todaro, Matilde; Francipane, Maria Giovanna; Medema, Jan Paul; Stassi, Giorgio

    2010-06-01

    First developed for hematologic disorders, the concept of cancer stem cells (CSCs) was expanded to solid tumors, including colorectal cancer (CRC). The traditional model of colon carcinogenesis includes several steps that occur via mutational activation of oncogenes and inactivation of tumor suppressor genes. Intestinal epithelial cells exist for a shorter amount of time than that required to accumulate tumor-inducing genetic changes, so researchers have investigated the concept that CRC arises from the long-lived stem cells, rather than from the differentiated epithelial cells. Colon CSCs were originally identified through the expression of the CD133 glycoprotein using an antibody directed to its epitope AC133. It is not clear if CD133 is a marker of colon CSCs-other cell surface markers, such as epithelial-specific antigen, CD44, CD166, Musashi-1, CD29, CD24, leucine-rich repeat-containing G-protein-coupled receptor 5, and aldehyde dehydrogenase 1, have been proposed. In addition to initiating and sustaining tumor growth, CSCs are believed to mediate cancer relapse after chemotherapy. How can we identify and analyze colon CSCs and what agents are being designed to kill this chemotherapy-refractory population?

  11. Locally advanced colon cancer with cutaneous invasion: case report.

    PubMed

    Tenreiro, Nádia; Ferreira, Cátia; Silva, Silvia; Marques, Rita; Ribeiro, Artur; Sousa, Paulo Jorge; Luís, Fernando Próspero

    2017-03-01

    Locally advanced colon cancer with direct abdominal wall and skin invasion is an extremely rare finding with most data being derived from case reports, historical autopsy-based or single-center retrospective studies. We present a unique case of a colon cancer with direct cutaneous invasion and colocutaneous fistulization. Eighty-six year old Caucasian female with multiple comorbidities, referred to Surgical Consultation due to ulcerated skin lesion in the abdomen. She had a long-standing large umbilical hernia but with no previous episodes of incarceration or occlusive symptoms. She denied any digestive or constitutional symptoms. Physical examination showed a large non-reducible umbilical hernia, with an associated painless firm mass within the hernia sac and cutaneous ulcerated growth. Colonoscopy revealed transverse colon cancer (endoscopic biopsy of the tumor and skin punch biopsy confirmed adenocarcinoma of the colon). Computed tomography showed a tumoral mass within the umbilical hernia, with cutaneous infiltration and enlarged regional lymph nodes. Rapid local progression led to colocutaneous fistula with total fecal diversion. We performed an extended right hemicolectomy with en bloc excision of the hernia sac and infiltrating cutaneous mass. In the current era of widespread use of screening colonoscopies, initial diagnosis of locally advanced colon cancer is decreasing. However, this unique case presented an opportunity to recall the advantages of multivisceral resections.

  12. Curcumin inhibits tumor epithelial‑mesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in colon cancer cells.

    PubMed

    Zhang, Zewei; Chen, Haitao; Xu, Chao; Song, Lu; Huang, Lulu; Lai, Yuebiao; Wang, Yuqi; Chen, Hanlu; Gu, Danlin; Ren, Lili; Yao, Qinghua

    2016-05-01

    Tumor invasion and metastasis are closely associated with epithelial‑mesenchymal transition (EMT). EMT refers to epithelial cells under physiological and pathological conditions that are specific to mesenchymal transition. Curcumin inhibits EMT progression via Wnt signaling. The Wnt signaling pathway is a conservative EMT‑related signaling pathway that is involved in the development of various tumors. In the present study, MTS assays were employed to analyze the proliferation of curcumin‑treated cells. Naked cuticle homolog 2 (NKD2), chemokine receptor 4 (CXCR4) and antibodies associated with EMT were examined in SW620 colorectal cancer cell lines using western blot analysis and real‑time qPCR. NKD2 small‑interfering RNA (siRNA) and CXCR4 expression plasmid was synthesized and transfected into the colorectal cancer cell lines, and NKD2 and CXCR4 expression levels were detected. The results showed that curcumin significantly inhibited the proliferation of colorectal cancer cells and upregulated the expression of NKD2 in SW620 colorectal cancer cells and in the xenograft, resulting in the downregulation of key markers in the Wnt signaling. In addition, the progression of ETM was inhibited due to the overexpression of E‑cadherin as well as the downregulation of vimentin. Curcumin also inhibited tumor metastasis by downregulating the expression of CXCR4 significantly. The results suggested involvement of the NKD2‑Wnt‑CXCR4 signaling pathway in colorectal cancer cells. In addition, curcumin is inhibit this signaling and the development of colorectal cancer.

  13. Frequent mutation of Apc gene in rat colon tumors and mucin-depleted foci, preneoplastic lesions in experimental colon carcinogenesis.

    PubMed

    Femia, Angelo Pietro; Dolara, Piero; Giannini, Augusto; Salvadori, Maddalena; Biggeri, Annibale; Caderni, Giovanna

    2007-01-15

    Mucin-depleted foci (MDF) are microscopic dysplastic lesions induced in the colon of rodents by specific colon carcinogens. Most MDF show Wnt pathway activation, whereas only a subset shows mutations in the Ctnnb1 gene, coding for beta-catenin. Because Apc is a member of the Wnt pathway and the most frequent mutated gene in human colon cancer, we tested whether MDF harbor Apc mutations. F344 rats were treated twice with 150 mg/kg of 1,2-dimethylhydrazine. After 15 or 28 weeks, MDF, aberrant crypt foci (ACF), and tumors were collected. We screened a segment of the Apc gene comprising the region homologous to the mutation cluster region (MCR) of human APC, which frequently shows mutations in experimental colon tumors. Mutations were identified by PCR amplification and sequencing in 6:24 MDF (25%), 7:23 tumors (30%), 0:24 ACF (0%). Most of the mutations (92%) in MDF and tumors were localized in a region upstream from the MCR. All mutations were single-base substitutions and mainly formed by G:C-->A:T and C:G-->T:A transitions. The pattern of nucleotide changes was similar in MDF and tumors, and, interestingly, the same mutation in codon 1047 was found in two MDF and in three tumors. Four out of the six mutations found in MDF were nonsense mutations, and two were missense. All mutations in tumors determined a protein truncation. These results show that Apc mutations are present in MDF with a frequency similar to that of tumors, strengthening the evidence that they are precancerous lesions in colon carcinogenesis.

  14. Expression and clinical significance of tyrosine phosphatase SHP-2 in colon cancer.

    PubMed

    Cai, Peifen; Guo, Wenjie; Yuan, Huaqin; Li, Qian; Wang, Weicheng; Sun, Yang; Li, Xiaomin; Gu, Yanhong

    2014-04-01

    Protein-tyrosine phosphatase SHP-2, encoded by gene PTPN11, has been identified as a tumor-promoting factor in several types of leukemia and is hyper-activated by other mechanisms in some solid tumors including gastric cancer, breast cancer, non-small cell lung cancer (NSCLC), etc. But few were reported on the expression and significances of SHP-2 in colon cancer. Here, we detect SHP-2 expression in colon cancer cells, colon cancer-induced by AOM+DSS in mice and 232 human colon cancer specimens, including 58 groups of self-matched adjacent peritumor tissues and normal tissues. We found that compared to the normal colon tissues, SHP-2 significantly decreased in tumor tissues (P<0.001). The same results were got in colon tumor cells as well as mice colon tumors. And in humans samples, low SHP-2 expression showed a significantly correlation with poor tumor differentiation (P<0.05), late TNM stage (P=0.1666) and lymph node metastasis (P<0.05).

  15. Targeted Sequencing for Discovery and Validation of DNA Methylation Markers of Colon Cancer Metastasis — EDRN Public Portal

    Cancer.gov

    Colon cancer is the second leading cause of cancer death in the United States. A key issue in treating colon cancer patients is inability to accurately predict tumors that have metastatic potential and require adjuvant chemotherapy. This project will test the model that tumor metastases arise from intra-tumor heterogeneity generated by DNA methylation events, and that detecting these events can provide a predictve signature of tumors with poor outcome

  16. Relationship Between Tumor Gene Expression and Recurrence in Four Independent Studies of Patients With Stage II/III Colon Cancer Treated With Surgery Alone or Surgery Plus Adjuvant Fluorouracil Plus Leucovorin

    PubMed Central

    O'Connell, Michael J.; Lavery, Ian; Yothers, Greg; Paik, Soonmyung; Clark-Langone, Kim M.; Lopatin, Margarita; Watson, Drew; Baehner, Frederick L.; Shak, Steven; Baker, Joffre; Cowens, J. Wayne; Wolmark, Norman

    2010-01-01

    Purpose These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients. Patients and Methods We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06. Results A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV. Conclusion RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study. PMID:20679606

  17. Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T cells directed to a tumor-associated antigen are generated in vivo during GVHD.

    PubMed

    Carnevale-Schianca, Fabrizio; Cignetti, Alessandro; Capaldi, Antonio; Vitaggio, Katiuscia; Vallario, Antonella; Ricchiardi, Alberto; Sperti, Elisa; Ferraris, Renato; Gatti, Marco; Grignani, Giovanni; Rota-Scalabrini, Delia; Geuna, Massimo; Fizzotti, Marco; Sangiolo, Dario; Sottile, Antonino; De Rosa, Giovanni; Bucci, Anna Rosa; Lambertenghi-Deliliers, Giorgio; Benedetti, Edoardo; Nash, Richard; Aglietta, Massimo

    2006-05-01

    A pilot study was conducted to evaluate safety and activity of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in colorectal carcinoma (CRC) and to determine whether a T-cell response to a tumor-associated antigen (TAA) was induced. Fifteen patients with metastatic CRC underwent HCT from human leukocyte antigen (HLA)-matched siblings after a nonmyeloablative conditioning regimen. All patients engrafted with a median donor T-cell chimerism of 72% at day +56. Eight patients experienced grades II to IV acute graft-versus-host disease (GVHD). Despite progressive disease before HCT, partial remission and disease stabilization longer than 90 days were observed in 1 and 3 patients, respectively. Induction of TAA-specific T cells was evaluated with a carcinoembryonic antigen (CEA)-specific HLA-A(*)0201 pentamer in 6 patients with CRC. CEA-specific CD8(+) T cells were detected in 3 of 3 patients concomitant with GHVD onset, but not in 3 of 3 patients without GVHD. They were also not detected in 9 of 9 control patients with GVHD who received transplants for diagnoses other than CRC. Antitumor activity of CEA-specific T cells was also validated in vitro. In one patient, the induction of CEA-specific T cells was associated with a decrease of serum CEA levels and a partial response. Thus, graft-versus-host reactions associated with allogeneic HCT can trigger the generation of T cells specific for CEA, and this may be associated with a clinical response.

  18. Hyaluronate - Peanut Agglutinin Conjugates for Target-Specific Bioimaging of Colon Cancer.

    PubMed

    Beack, Songeun; Cho, Minsoo; Kim, Young-Eun; Ahn, G-One; Hahn, Sei Kwang

    2017-03-27

    Colon cancer is one of the most common death-related cancers in the world. For treating the colon cancer, it is crucial to detect and remove malignant lesions in the early time. Here, we developed hyaluronate (HA) - peanut agglutinin (PNA) conjugates for bioimaging of colon cancer. The HA-PNA conjugates were successfully synthesized by the coupling reaction between aldehyde modified HA and the N-terminal amine group of PNA. For diagnostic imaging, rhodamine B (RhoB) was chemically conjugated onto PNA in HA-PNA conjugates. After intraluminal injection of HA-PNA-RhoB conjugates into tumor-bearing mice, small-sized colon cancers could be effectively visualized by ex vivo IVIS imaging and two-photon microscopy. Taken together, we could confirm the feasibility of HA-PNA-RhoB conjugates as a bioimaging agent for detecting colon cancers. [Keywords] Hyaluronate; Peanut agglutinin; Colon cancer; Two-photon imaging; Diagnostics.

  19. Shed syndecan-2 enhances tumorigenic activities of colon cancer cells

    PubMed Central

    Choi, Sojoong; Choi, Youngsil; Jun, Eunsung; Kim, In-San; Kim, Seong-Eun; Jung, Sung-Ae; Oh, Eok-Soo

    2015-01-01

    Because earlier studies showed the cell surface heparan sulfate proteoglycan, syndecan-2, sheds from colon cancer cells in culture, the functional roles of shed syndecan-2 were assessed. A non-cleavable mutant of syndecan-2 in which the Asn148-Leu149 residues were replaced with Asn148-Ile149, had decreased shedding, less cancer-associated activities of syndecan-2 in vitro, and less syndecan-2-mediated metastasis of mouse melanoma cells in vivo, suggesting the importance of shedding on syndecan-2-mediated pro-tumorigenic functions. Indeed, shed syndecan-2 from cancer-conditioned media and recombinant shed syndecan-2 enhanced cancer-associated activities, and depletion of shed syndecan-2 abolished these effects. Similarly, shed syndecan-2 was detected from sera of patients from advanced carcinoma (625.9 ng/ml) and promoted cancer-associated activities. Furthermore, a series of syndecan-2 deletion mutants showed that the tumorigenic activity of shed syndecan-2 resided in the C-terminus of the extracellular domain and a shed syndecan-2 synthetic peptide (16 residues) was sufficient to establish subcutaneous primary growth of HT29 colon cancer cells, pulmonary metastases (B16F10 cells), and primary intrasplenic tumor growth and liver metastases (4T1 cells). Taken together, these results demonstrate that shed syndecan-2 directly enhances colon cancer progression and may be a promising therapeutic target for controlling colon cancer development. PMID:25686828

  20. Identifying colon cancer risk modules with better classification performance based on human signaling network.

    PubMed

    Qu, Xiaoli; Xie, Ruiqiang; Chen, Lina; Feng, Chenchen; Zhou, Yanyan; Li, Wan; Huang, Hao; Jia, Xu; Lv, Junjie; He, Yuehan; Du, Youwen; Li, Weiguo; Shi, Yuchen; He, Weiming

    2014-10-01

    Identifying differences between normal and tumor samples from a modular perspective may help to improve our understanding of the mechanisms responsible for colon cancer. Many cancer studies have shown that signaling transduction and biological pathways are disturbed in disease states, and expression profiles can distinguish variations in diseases. In this study, we integrated a weighted human signaling network and gene expression profiles to select risk modules associated with tumor conditions. Risk modules as classification features by our method had a better classification performance than other methods, and one risk module for colon cancer had a good classification performance for distinguishing between normal/tumor samples and between tumor stages. All genes in the module were annotated to the biological process of positive regulation of cell proliferation, and were highly associated with colon cancer. These results suggested that these genes might be the potential risk genes for colon cancer. Copyright © 2013. Published by Elsevier Inc.

  1. A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene.

    PubMed Central

    Markowitz, S D; Myeroff, L; Cooper, M J; Traicoff, J; Kochera, M; Lutterbaugh, J; Swiriduk, M; Willson, J K

    1994-01-01

    We describe the spontaneous progression of a colon adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of colon cancer suppressor genes and oncogenes. VACO-235, a human colon adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonic cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation. Images PMID:8132740

  2. Elevated mean platelet volume is associated with presence of colon cancer.

    PubMed

    Li, Jia-Ying; Li, Ying; Jiang, Zheng; Wang, Rui-Tao; Wang, Xi-Shan

    2014-01-01

    Colon cancer is the second most common cancer in developed countries. Activated platelets play a key role in inflammation and atherothrombosis, with mean platelet volume (MPV) is an early marker of platelet activation. The aim of the study was to clarify the relevance of MPV in patients with colon cancer. We measured MPV levels in 128 patients with colon cancer before and after surgery, and 128 controls matched for age, gender, body mass index (BMI) and smoking status. The odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer were calculated using multivariate logistic regression analyses across MPV quartiles. Patients with colon cancer had higher MPV compared with controls. Surgical tumor resection resulted in a significant decrease in MPV levels (11.4 fL vs 10.7 fL; p<0.001). A positive correlation between MPV and tumor-nodule-metastases (TNM) stage was found. Furthermore, after adjusting for other risk factors, the ORs (95%CIs) for colon cancer according to MPV quartiles were 1.000, 2.238 (1.014-4.943), 3.410 (1.528-7.613), and 5.379 (2.372-12.198), respectively. The findings show that patients with colon cancer have higher MPV levels compared with controls, and these are reduced after surgery. In addition, MPV was found to be independently associated with the presence of colon cancer. Further studies are warranted to assess the utility of MPV as a novel diagnostic screening tool for colon cancer.

  3. Oncotype DX(®) colon cancer assay for prediction of recurrence risk in patients with stage II and III colon cancer: A review of the evidence.

    PubMed

    You, Y Nancy; Rustin, Rudolph B; Sullivan, James D

    2015-06-01

    Advances in molecular biology have enabled identification of tumor biomarkers that allow for individualized risk assessment for patients with cancer. Molecular predictors of clinical outcome can help inform discussion regarding the role of adjuvant chemotherapy in patients with resected colon cancer, such as those with stage II colon cancer in which the benefit of adjuvant therapy is controversial or those with stage III colon cancer who may have a lower risk of recurrence and less absolute benefit from oxaliplatin therapy. This article summarizes the data surrounding the development, validation, and clinical and economic utility of the Oncotype DX(®) colon cancer assay, a multigene expression assay validated to independently predict recurrence risk in patients with stage II and III colon cancer beyond traditional factors.

  4. Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models.

    PubMed

    Panebianco, Concetta; Adamberg, Kaarel; Adamberg, Signe; Saracino, Chiara; Jaagura, Madis; Kolk, Kaia; Di Chio, Anna Grazia; Graziano, Paolo; Vilu, Raivo; Pazienza, Valerio

    2017-03-27

    Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a

  5. Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models

    PubMed Central

    Panebianco, Concetta; Adamberg, Kaarel; Adamberg, Signe; Saracino, Chiara; Jaagura, Madis; Kolk, Kaia; Di Chio, Anna Grazia; Graziano, Paolo; Vilu, Raivo; Pazienza, Valerio

    2017-01-01

    Background/aims: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Results: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. Conclusion: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that

  6. Protein Kinase Cβ Is an Effective Target for Chemoprevention of Colon Cancer

    PubMed Central

    Fields, Alan P.; Calcagno, Shelly R.; Krishna, Murli; Rak, Sofija; Leitges, Michael; Murray, Nicole R.

    2009-01-01

    Colon cancer develops over a period of 10 to 15 years, providing a window of opportunity for chemoprevention and early intervention. However, few molecular targets for effective colon cancer chemoprevention have been characterized and validated. Protein kinase CβII (PKCβII) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased β-catenin accumulation. In this study, we test the hypothesis that PKCβII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCβ-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCβII-mediated tumor cell proliferation and β-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCβII- and β-catenin/T-cell factor–regulated genes PKCβII, cyclooxygenase II, and vascular endothelial growth factor, three genes implicated in colon carcinogenesis. Our results show that enzastaurin is an effective chemopreventive agent in a mouse model of sporadic colon cancer that significantly reduces both tumor initiation and progression by inhibiting expression of proproliferative genes. Thus, PKCβII is an important target for colon cancer chemoprevention and the PKCβ-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer. PMID:19221092

  7. Methylselenol, a selenium metabolite, inhibits colon cancer cell growth and cancer xenografts in C57BL/6 mice

    USDA-ARS?s Scientific Manuscript database

    Data indicate that methylselenol is a critical selenium (Se) metabolite for anticancer activity in vivo but its role in colon cancer prevention remains to be characterized. This study tested the hypothesis that methylselenol inhibits the growth of colon cancer cells and tumors. We found that submicr...

  8. CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype

    PubMed Central

    Paschall, Amy V.; Yang, Dafeng; Lu, Chunwan; Redd, Priscilla S.; Choi, Jeong-Hyeon; Heaton, Christopher M.; Lee, Jeffrey R.; Nayak-Kapoor, Asha; Liu, Kebin

    2016-01-01

    The chemotherapeutic agent 5-Fluorouracil (5-FU) is the most commonly used drug for patients with advanced colon cancer. However, development of resistance to 5-FU is inevitable in almost all patients. The mechanism by which colon cancer develops 5-FU resistance is still unclear. One recently proposed theory is that cancer stem-like cells underlie colon cancer 5-FU resistance, but the phenotypes of 5-FU-resistant colon cancer stem cells are still controversial. We report here that 5-FU treatment selectively enriches a subset of CD133+ colon cancer cells in vitro. 5-FU chemotherapy also increases CD133+ tumor cells in human colon cancer patients. However, sorted CD133+ colon cancer cells exhibit no increased resistance to 5-FU, and CD133 levels exhibit no correlation with colon cancer patient survival or cancer recurrence. Genome-wide analysis of gene expression between sorted CD133+ colon cancer cells and 5-FU-selected colon cancer cells identifies 207 differentially expressed genes. CD24 is one of the genes whose expression level is lower in the CD133+ and 5-FU-resistant colon cancer cells as compared to CD133+ and 5-FU-sensitive colon cancer cells. Consequently, CD133+CD24lo cells exhibit decreased sensitivity to 5-FU. Therefore, we determine that CD133+CD24lo phenotype defines 5-FU-resistant human colon cancer stem cell-like cells. PMID:27659530

  9. Clinical investigation of TROP-2 as an independent biomarker and potential therapeutic target in colon cancer.

    PubMed

    Zhao, Peng; Yu, Hai-Zheng; Cai, Jian-Hui

    2015-09-01

    Colon cancer is associated with a severe demographic and economic burden worldwide. The pathogenesis of colon cancer is highly complex and involves sequential genetic and epigenetic mechanisms. Despite extensive investigation, the pathogenesis of colon cancer remains to be elucidated. As the third most common type of cancer worldwide, the treatment options for colon cancer are currently limited. Human trophoblast cell‑surface marker (TROP‑2), is a cell‑surface transmembrane glycoprotein overexpressed by several types of epithelial carcinoma. In addition, TROP‑2 has been demonstrated to be associated with tumorigenesis and invasiveness in solid types of tumor. The aim of the present study was to investigate the protein expression of TROP‑2 in colon cancer tissues, and further explore the association between the expression of TROP‑2 and clinicopathological features of patients with colon cancer. The expression and localization of the TROP‑2 protein was examined using western blot analysis and immunofluorescence staining. Finally, the expression of TROP‑2 expression was correlated to conventional clinicopathological features of colon cancer using a χ2 test. The results revealed that TROP‑2 protein was expressed at high levels in the colon cancer tissues, which was associated with the development and pathological process of colon cancer. Therefore, TROP‑2 may be used as a biomarker to determine the clinical prognosis, and as a potential therapeutic target in colon cancer.

  10. Sporadic colon cancer murine models demonstrate the value of autoantibody detection for preclinical cancer diagnosis

    PubMed Central

    Barderas, Rodrigo; Villar-Vázquez, Roi; Fernández-Aceñero, María Jesús; Babel, Ingrid; Peláez-García, Alberto; Torres, Sofía; Casal, J. Ignacio

    2013-01-01

    Although autoantibody detection has been proposed for diagnosis of colorectal cancer, little is known about their initial production and development correlation with cancer progression. Azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice developed colon adenocarcinoma in the distal colon similar to human sporadic colon cancer. We assessed this model together with AOM and DSS-only models for their applicability to early detection of cancer. All AOM/DSS-treated mice produced autoantibodies to tumor-associated antigens analogous to those observed in human colon cancer patients. Autoantibody response was related to tumor antigen overexpression. Cancer autoantibodies were detected 21 days after starting treatment, when no malignant histopathological features were detectable, and they increased according to tumor progression. When carcinogenesis was induced separately by AOM or DSS, only those mice that developed malignant lesions produced significant levels of autoantibodies. These findings demonstrate that autoantibody development is an early event in tumorigenesis and validates its use for preclinical colon cancer diagnosis. PMID:24126910

  11. S100A8/A9 activate key genes and pathways in colon tumor progression.

    PubMed

    Ichikawa, Mie; Williams, Roy; Wang, Ling; Vogl, Thomas; Srikrishna, Geetha

    2011-02-01

    The tumor microenvironment plays an important role in modulating tumor progression. Earlier, we showed that S100A8/A9 proteins secreted by myeloid-derived suppressor cells (MDSC) present within tumors and metastatic sites promote an autocrine pathway for accumulation of MDSC. In a mouse model of colitis-associated colon cancer, we also showed that S100A8/A9-positive cells accumulate in all regions of dysplasia and adenoma. Here we present evidence that S100A8/A9 interact with RAGE and carboxylated glycans on colon tumor cells and promote activation of MAPK and NF-κB signaling pathways. Comparison of gene expression profiles of S100A8/A9-activated colon tumor cells versus unactivated cells led us to identify a small cohort of genes upregulated in activated cells, including Cxcl1, Ccl5 and Ccl7, Slc39a10, Lcn2, Zc3h12a, Enpp2, and other genes, whose products promote leukocyte recruitment, angiogenesis, tumor migration, wound healing, and formation of premetastatic niches in distal metastatic organs. Consistent with this observation, in murine colon tumor models we found that chemokines were upregulated in tumors, and elevated in sera of tumor-bearing wild-type mice. Mice lacking S100A9 showed significantly reduced tumor incidence, growth and metastasis, reduced chemokine levels, and reduced infiltration of CD11b(+)Gr1(+) cells within tumors and premetastatic organs. Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis.

  12. Redefining Adjuvant Therapy for Colon Cancer

    Cancer.gov

    In this trial, patients with resected stage III colon cancer are being randomly assigned to receive FOLFOX chemotherapy for either 3 or 6 months and to take either a pill called celecoxib or a matching placebo pill for 3 years.

  13. Bufalin Inhibits HCT116 Colon Cancer Cells and Its Orthotopic Xenograft Tumor in Mice Model through Genes Related to Apoptotic and PTEN/AKT Pathways

    PubMed Central

    Wang, Jie; Chen, Chao; Wang, Shiying; Zhang, Yong; Yin, Peihao; Gao, Zhongxiang; Xu, Jie; Feng, Dianxu; Zuo, Qinsong; Zhao, Ronghua; Chen, Teng

    2015-01-01

    Aims. To investigate the anticolorectal cancer (CRC) effects of Bufalin, a bioactive polyhydroxysteroid from Venenum Bufonis, using HCT116 human CRC cell and an established orthotopic xenograft model in mice, and to explore the mechanisms of action. Material and Methods. Cultured HCT116 cells or BALB/c mice with orthotopic tumor were treated by Bufalin (positive control: 5-FU). Cell proliferation, apoptosis, and cycling were determined by MTT, Annexin V/PI staining, and flow cytometry, respectively. In mice, tumor inhibition rate and animal survival were calculated. The expressions of PTEN/phosphate-PTEN, AKT/phosphate-AKT, Bad, Bcl-xl, Bax, or Caspase-3 in cells and/or tumors were determined by Western blot or immunohistochemical staining. Results. Bufalin significantly inhibited cell proliferation and induced cell apoptosis and cycle arrest in a dose/time-dependent manner. In the animal model, Bufalin treatment resulted in significant inhibition of tumor growth and prolonged survival. In the Bufalin-treated cultured cells and/or xenograft tumors, the expressions of PTEN, Bad, Bax, and Caspase-3 were significantly increased, while p-AKT and Bcl-xL significantly decreased. Conclusions. Our results indicate that Bufalin inhibit cell proliferation and orthotopic tumor growth by inducing cell apoptosis through the intrinsic apoptotic pathway, which is of pivotal significance in the identification of an anticancer drug that may synergize with Bufalin. PMID:26770191

  14. Diet-induced obesity promotes colon tumor development in azoxymethane-treated mice.

    PubMed

    Tuominen, Iina; Al-Rabadi, Leina; Stavrakis, Dimitris; Karagiannides, Iordanis; Pothoulakis, Charalabos; Bugni, James M

    2013-01-01

    Obesity is an important risk factor for colon cancer in humans, and numerous studies have shown that a high fat diet enhances colon cancer development. As both increased adiposity and high fat diet can promote tumorigenesis, we examined the effect of diet-induced obesity, without ongoing high fat diet, on colon tumor development. C57BL/6J male mice were fed regular chow or high fat diet for 8 weeks. Diets were either maintained or switched resulting in four experimental groups: regular chow (R), high fat diet (H), regular chow switched to high fat diet (RH), and high fat diet switched to regular chow (HR). Mice were then administered azoxymethane to induce colon tumors. Tumor incidence and multiplicity were dramatically smaller in the R group relative to all groups that received high fat diet at any point. The effect of obesity on colon tumors could not be explained by differences in aberrant crypt foci number. Moreover, diet did not alter colonic expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, interleukin-1β, and interferon-γ, which were measured immediately after azoxymethane treatment. Crypt apoptosis and proliferation, which were measured at the same time, were increased in the HR relative to all other groups. Our results suggest that factors associated with obesity - independently of ongoing high fat diet and obesity - promote tumor development because HR group animals had significantly more tumors than R group, and these mice were fed the same regular chow throughout the entire carcinogenic period. Moreover, there was no difference in the number of aberrant crypt foci between these groups, and thus the effect of obesity appears to be on subsequent stages of tumor development when early preneoplastic lesions transition into adenomas.

  15. Diet-Induced Obesity Promotes Colon Tumor Development in Azoxymethane-Treated Mice

    PubMed Central

    Tuominen, Iina; Al-Rabadi, Leina; Stavrakis, Dimitris; Karagiannides, Iordanis; Pothoulakis, Charalabos; Bugni, James M.

    2013-01-01

    Obesity is an important risk factor for colon cancer in humans, and numerous studies have shown that a high fat diet enhances colon cancer development. As both increased adiposity and high fat diet can promote tumorigenesis, we examined the effect of diet-induced obesity, without ongoing high fat diet, on colon tumor development. C57BL/6J male mice were fed regular chow or high fat diet for 8 weeks. Diets were either maintained or switched resulting in four experimental groups: regular chow (R), high fat diet (H), regular chow switched to high fat diet (RH), and high fat diet switched to regular chow (HR). Mice were then administered azoxymethane to induce colon tumors. Tumor incidence and multiplicity were dramatically smaller in the R group relative to all groups that received high fat diet at any point. The effect of obesity on colon tumors could not be explained by differences in aberrant crypt foci number. Moreover, diet did not alter colonic expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, interleukin-1β, and interferon-γ, which were measured immediately after azoxymethane treatment. Crypt apoptosis and proliferation, which were measured at the same time, were increased in the HR relative to all other groups. Our results suggest that factors associated with obesity – independently of ongoing high fat diet and obesity – promote tumor development because HR group animals had significantly more tumors than R group, and these mice were fed the same regular chow throughout the entire carcinogenic period. Moreover, there was no difference in the number of aberrant crypt foci between these groups, and thus the effect of obesity appears to be on subsequent stages of tumor development when early preneoplastic lesions transition into adenomas. PMID:23560112

  16. Affinity-based strategies to fast track development of colon cancer biomarkers — EDRN Public Portal

    Cancer.gov

    Our goal is to discover plasma and tissue-based tumor biomarkers that work well enough together to identity colon cancer at early stages, lead to accurate diagnosis and could ultimately allow for individualized treatment.

  17. Molecular alterations associated with sulindac-resistant colon tumors in ApcMin/+ mice.

    PubMed

    Greenspan, Emily J; Nichols, Frank C; Rosenberg, Daniel W

    2010-09-01

    Although nonsteroidal anti-inflammatory drugs (NSAID), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer, results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study, we evaluated the effect of sulindac on colon tumorigenesis in the Apc(Min/+) mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to Apc(Min/+) mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 versus 1.6 tumors per mouse, respectively; P < 0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 versus 42.0 tumors per mouse, respectively; P < 0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many noncyclooxygenase targets, including p21, beta-catenin, E-cadherin, mitochondrial apoptotic proteins, and peroxisome proliferator-activated receptor-gamma. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear beta-catenin accumulation. Importantly, p21(WAF1/cip1) and peroxisome proliferator-activated receptor-gamma expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies using combinations of agents that target multiple molecular pathways to overcome sulindac resistance.

  18. Molecular alterations associated with sulindac resistant colon tumors in ApcMin/+ mice

    PubMed Central

    Greenspan, Emily J.; Nichols, Frank C.; Rosenberg, Daniel W.

    2010-01-01

    Although non-steroidal anti-inflammatory drugs (NSAIDs), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer (CRC), results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study we evaluated the effect of sulindac on colon tumorigenesis in the ApcMin/+ mouse model. Sulindac (180 p.p.m.) given in drinking water for 9 weeks to ApcMin/+ mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 vs. 1.6 tumors/mouse, respectively; P<0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 vs. 42.0 tumors/mouse, respectively; P<0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many non-COX targets, including p21, β-catenin, E-cadherin, mitochondrial apoptotic proteins and PPARγ. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear β-catenin accumulation. Importantly, p21WAF1/cip1 and PPARγ expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies utilizing combinations of agents that target multiple molecular pathways to overcome sulindac resistance. PMID:20716632

  19. Potentiation of Colon Cancer Susceptibility in Mice by Colonic Epithelial PPAR-δ/β Overexpression

    PubMed Central

    2014-01-01

    Background The nuclear receptor peroxisome proliferator-activated receptor-δ/β (PPAR-d) is upregulated in human colorectal cancers, but its role in colonic tumorigenesis remains controversial. Methods We generated a novel mouse model of intestinally targeted PPAR-d overexpression to simulate PPAR-d upregulation in human colon carcinogenesis. Colon-specific PPAR-d overexpression was confirmed by real-time reverse transcription polymerase chain reaction, immunoblotting, and activity assays. Mice with and without targeted PPAR-d overexpression were tested for azoxymethane (AOM)–induced colonic tumorigenesis. Mouse whole-genome transcriptome microarray analyses were performed to identify PPAR-d target genes to promote tumorigenesis. We used linear models to test for PPAR-d overexpression trend effects on tumor multiplicity. All statistical tests were two-sided. Results Targeted PPAR-d overexpression markedly increased colonic tumor incidence (from 0 of 10 wild-type [WT] littermate mice to 9 of 10 mice [P < .001] in 2 FVB/N background mouse lines [villin-PPAR-d-1 and villin-PPAR-d-2] at a 5-mg/kg AOM dose) and multiplicity (number of tumors per mouse per mg/kg dose of AOM increased from 0.47 [95% confidence interval [CI] = 0.22 to 0.72] for the WT littermates to 2.15 [95% CI = 1.90 to 2.40] [P < .001] for the villin-PPAR-d-1 mice and from 0.44 [95% CI = 0.09 to 0.79] for the WT littermates to 1.91 [95% CI = 1.57 to 2.25] [P < .001] for the villin-PPAR-d-2 mice). PPAR-d overexpression reversed resistance to AOM-induced colonic tumorigenesis in C57BL/6 mice. PPAR-d overexpression modulated expression of several novel PPAR-d target genes in normal-appearing colonic epithelial cells of mice with PPAR-d overexpression in a pattern that matched the changes in colonic tumors. Conclusions Our finding that PPAR-d upregulation profoundly enhances susceptibility to colonic tumorigenesis should impact the development of strategies of molecularly targeting PPAR-d in cancer and

  20. Colon Cancer Worry in Appalachia.

    PubMed

    Attarabeen, Omar F; Sambamoorthi, Usha; Larkin, Kevin T; Kelly, Kimberly M

    2017-07-06

    Appalachia has a higher incidence of and mortality from colon cancer (CC) than other regions of the United States; thus, it is important to know the potential impact of elevated risk on cancer worry. Guided by the Self-regulation model, we investigated the association of demographic, cultural (e.g., fatalism, religious commitment), and psychological factors (e.g., perceived risk, general mood) with CC worry among a sample of Appalachian women. A mixed method design was utilized. Appalachian women completed surveys in the quantitative section (n = 134) and semi-structured interviews in the qualitative section (n = 24). Logistic regression was employed to calculate odds ratios (OR) for quantitative data, and immersion/crystallization was utilized to analyze qualitative data. In the quantitative section, 45% of the participants expressed some degree of CC worry. CC worry was associated with higher than high school education (OR 3.63), absolute perceived risk for CC (OR 5.82), high anxiety (OR 4.68), and awareness of easy access (OR 3.98) or difficult access (OR 3.18) to health care specialists as compared to not being aware of the access. there was no association between CC worry and adherence to CC screening guidelines. The qualitative section revealed fear, disengagement, depression, shock, and worry. Additionally, embarrassment, discomfort, and worry were reported with regard to CC screening. Fears included having to wear a colostomy bag and being a burden on family. CC worry was common in Appalachians and associated with higher perceptions of risk for CC and general anxiety, but not with adherence to screening guidelines. The mixed method design allowed for enhanced understanding of CC-related feelings, especially CC worry, including social/contextual fears.

  1. The appearance of Tregs in cancer nest is a promising independent risk factor in colon cancer.

    PubMed

    Xu, Wei; Liu, Hao; Song, Jun; Fu, Hai-Xiao; Qiu, Lei; Zhang, Bao-Fu; Li, Hui-Zhong; Bai, Jin; Zheng, Jun-Nian

    2013-11-01

    To investigate the prognostic value of tumor-infiltrating regulatory T cells (Tregs) in the distribution of cancer nest, cancer stroma and normal mucosa and FOXP3-positive cancer cells in colon cancer patients after resection. Paraffin blocks of operation resection of primary adenocarcinoma of colon were obtained from ninety patients. The distribution of tumor-infiltrating Tregs was detected by tissue microarray and immunohistochemistry staining technique to evaluate the prognostic effects by Kaplan-Meier and Cox regression analysis using median values as cutoff. The intratumoral Tregs counts were significantly higher than that in corresponding normal mucosa tissues (P < 0.001); the Tregs counts in cancer nest were significantly lower than that in corresponding cancer stroma tissues (P < 0.001); the increased intratumoral Tregs counts were associated with favorable prognosis (P < 0.05); the presence of Tregs in cancer nest was associated with unfavorable prognosis and was an independent prognostic factor for overall survival (P < 0.05). The appearance of FOXP3-positive cancer cells was associated with worse prognosis (P < 0.05). In addition, the frequency of the presence of FOXP3-positive cancer cells was higher in patients with lymphatic invasion (P < 0.001) and lower in patients with early TNM stage (P < 0.01). The higher tumor-infiltrating Tregs counts are closely associated with the improved prognostic effects of colon carcinoma. Tregs play different roles in cancer nest and cancer stroma. And the appearance of Tregs in cancer nest is a promising independent risk factor for overall survival in colon carcinoma. FOXP3-positive cancer cells may also be a risk factor for overall survival in colon carcinoma.

  2. Interleukin-37 mediates the antitumor activity in colon cancer through β-catenin suppression.

    PubMed

    Yan, Xiaofei; Zhao, Jian; Zhang, Rui

    2017-07-25

    The occurrence and development of colon cancer is closely related to inflammation. Thus, we conducted the present retrospective study to investigate the effects of IL-37 (Interleukin 37), a newly identified anti-inflammatory factor, on colon cancer development. We first evaluated the IL-37 expression in 186 pairs of colon cancer samples and their adjacent normal mucosa by real-time PCR, ELISA (Enzyme-linked immunoassay) and tissue microarrays. Then the role of IL-37 on patient survival rates, colon cancer progression and their sensitivity to chemotherapy drugs were assessed. IL-37 was barely expressed in the colon cancer tissue but highly expressed in the adjacent normal tissue. The down-regulation of IL-37 was significantly correlated with the results of American Joint Committee on Cancer stage, nodal involvement, invasion depth, distant metastasis, differentiation and it was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with colon cancer. Overexpression of IL-37 in colon cancer cell suppressed cell migration, invasion, proliferation, colony formation and cancer stem cells through suppressing β-catenin. IL-37 inhibited colon tumor formation in the mice model and sensitize the cancer cell to chemotherapy drugs. Our results showed that IL-37 plays an inhibitory role in colon cancer development and function as a novel prognostic indicator and a potential therapeutic target.

  3. Interleukin-37 mediates the antitumor activity in colon cancer through β-catenin suppression

    PubMed Central

    Yan, Xiaofei; Zhao, Jian; Zhang, Rui

    2017-01-01

    The occurrence and development of colon cancer is closely related to inflammation. Thus, we conducted the present retrospective study to investigate the effects of IL-37 (Interleukin 37), a newly identified anti-inflammatory factor, on colon cancer development. We first evaluated the IL-37 expression in 186 pairs of colon cancer samples and their adjacent normal mucosa by real-time PCR, ELISA (Enzyme-linked immunoassay) and tissue microarrays. Then the role of IL-37 on patient survival rates, colon cancer progression and their sensitivity to chemotherapy drugs were assessed. IL-37 was barely expressed in the colon cancer tissue but highly expressed in the adjacent normal tissue. The down-regulation of IL-37 was significantly correlated with the results of American Joint Committee on Cancer stage, nodal involvement, invasion depth, distant metastasis, differentiation and it was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with colon cancer. Overexpression of IL-37 in colon cancer cell suppressed cell migration, invasion, proliferation, colony formation and cancer stem cells through suppressing β-catenin. IL-37 inhibited colon tumor formation in the mice model and sensitize the cancer cell to chemotherapy drugs. Our results showed that IL-37 plays an inhibitory role in colon cancer development and function as a novel prognostic indicator and a potential therapeutic target. PMID:28467774

  4. Valproic acid enhances bosutinib cytotoxicity in colon cancer cells.

    PubMed

    Mologni, Luca; Cleris, Loredana; Magistroni, Vera; Piazza, Rocco; Boschelli, Frank; Formelli, Franca; Gambacorti-Passerini, Carlo

    2009-04-15

    Unbalanced histone deacetylase (HDAC) hyperactivity is a common feature of tumor cells. Inhibition of HDAC activity is often associated with cancer cell growth impairment and death. Valproic acid (VPA) is a HDAC inhibitor used for the treatment of epilepsy. It has recently been recognized as a promising anticancer drug. We investigated the effects of VPA on growth and survival of colon cancer cells. VPA caused growth inhibition and programmed cell death that correlated with histone hyperacetylation. VPA modulated the expression of various factors involved in cell cycle control and apoptosis and induced caspase activation. Interestingly, VPA induced downregulation of c-Src and potentiated the cytotoxic effects of the c-Src inhibitor bosutinib, both in vitro and in vivo. The combination of sublethal doses of VPA and bosutinib led to massive apoptosis of colon cancer cells, irrespective of their genetic background. These results suggest that VPA may be employed as a positive modulator of bosutinib antitumor activity in colorectal cancer.

  5. Black Raspberry-Derived Anthocyanins Demethylate Tumor Suppressor Genes Through the Inhibition of DNMT1 and DNMT3B in Colon Cancer Cells

    PubMed Central

    Wang, Li-Shu; Kuo, Chieh-Ti; Cho, Seung-Ju; Seguin, Claire; Siddiqui, Jibran; Stoner, Kristen; Weng, Yu-I; Huang, Tim H.-M.; Tichelaar, Jay; Yearsley, Martha; Stoner, Gary D.; Huang, Yi-Wen

    2013-01-01

    We previously reported that oral administration of black raspberry powder decreased promoter methylation of tumor suppressor genes in tumors from patients with colorectal cancer. The anthocyanins (ACs) in black raspberries are responsible, at least in part, for their cancer-inhibitory effects. In the present study, we asked if ACs are responsible for the demethylation effects observed in colorectal cancers. Three days of treatment of ACs at 0.5, 5, and 25 μg/ml suppressed activity and protein expression of DNMT1 and DNMT3B in HCT116, Caco2 and SW480 cells. Promoters of CDKN2A, and SFRP2, SFRP5, and WIF1, upstream of Wnt pathway, were demethylated by ACs. mRNA expression of some of these genes was increased. mRNA expression of β-catenin and c-Myc, downstream of Wnt pathway, and cell proliferation were decreased; apoptosis was increased. ACs were taken up into HCT116 cells and were differentially localized with DNMT1 and DNMT3B in the same cells visualized using confocal laser scanning microscopy. Although it was reported that DNMT3B is regulated by c-Myc in mouse lymphoma, DNMT3B did not bind with c-Myc in HCT116 cells. In conclusion, our results suggest that ACs are responsible, at least in part, for the demethylation effects of whole black raspberries in colorectal cancers. PMID:23368921

  6. Carbohydrate-containing molecules as potential biomarkers in colon cancer.

    PubMed

    Joo, Eun Ji; Weyers, Amanda; Li, Guoyun; Gasimli, Leyla; Li, Lingyun; Choi, Won Jun; Lee, Kyung Bok; Linhardt, Robert J

    2014-04-01

    Glycans play a critical role in physiological and pathological processes through interaction with a variety of ligands. Altered expression and dysregulation of these molecules can cause aberrant cellular function such as malignancy. Glycomics provide information of the structure and function of glycans, glycolipids, and glycoproteins such as proteoglycans, and may help to predict cancer development and progression as biomarkers. In this report, we compared the expression of proteoglycans, the content and structure of glycosaminoglycans and glycolipids between patient-matched normal and cancer tissues obtained from colon cancer patients. Tumor-related proteoglycans, glypican-3, and syndecan-1 showed downregulation in cancer tissues compared to normal tissues. In cancer tissue, the total amount of chondroitin sulfate (CS)/dermatan sulfate and heparan sulfate were lower and, interestingly, the level of disaccharide units of both 4S6S (CS-E) and 6S (CS-C) were higher compared to normal tissue. Also, overall lipids including glycolipids, a major glycomics target, were analyzed by hydrophilic interaction liquid chromatography mass spectrometry. Increase of lyso-phosphatidylcholine (phospholipid), sphingomyelin (sphigolipid), and four types of glycolipids (glucosylceramide, lactosylceramide, monosialic acid ganglioside, and globoside 4) in cancer tissue showed the possibility as potential biomarkers in colon cancer. While requiring the need for careful interpretation, this type of broad investigation gives us a better understanding of pathophysiological roles on glycosaminoglycans and glycolipids and might be a powerful tool for colon cancer diagnosis.

  7. Carbohydrate-Containing Molecules as Potential Biomarkers in Colon Cancer

    PubMed Central

    Joo, Eun Ji; Weyers, Amanda; Li, Guoyun; Gasimli, Leyla; Li, Lingyun; Choi, Won Jun

    2014-01-01

    Abstract Glycans play a critical role in physiological and pathological processes through interaction with a variety of ligands. Altered expression and dysregulation of these molecules can cause aberrant cellular function such as malignancy. Glycomics provide information of the structure and function of glycans, glycolipids, and glycoproteins such as proteoglycans, and may help to predict cancer development and progression as biomarkers. In this report, we compared the expression of proteoglycans, the content and structure of glycosaminoglycans and glycolipids between patient-matched normal and cancer tissues obtained from colon cancer patients. Tumor-related proteoglycans, glypican-3, and syndecan-1 showed downregulation in cancer tissues compared to normal tissues. In cancer tissue, the total amount of chondroitin sulfate (CS)/dermatan sulfate and heparan sulfate were lower and, interestingly, the level of disaccharide units of both 4S6S (CS-E) and 6S (CS-C) were higher compared to normal tissue. Also, overall lipids including glycolipids, a major glycomics target, were analyzed by hydrophilic interaction liquid chromatography mass spectrometry. Increase of lyso-phosphatidylcholine (phospholipid), sphingomyelin (sphigolipid), and four types of glycolipids (glucosylceramide, lactosylceramide, monosialic acid ganglioside, and globoside 4) in cancer tissue showed the possibility as potential biomarkers in colon cancer. While requiring the need for careful interpretation, this type of broad investigation gives us a better understanding of pathophysiological roles on glycosaminoglycans and glycolipids and might be a powerful tool for colon cancer diagnosis. PMID:24502776

  8. Lack of functioning intratumoral lymphatics in colon and pancreas cancer tissue.

    PubMed

    Olszewski, Waldemar L; Stanczyk, Marek; Gewartowska, Magdalena; Domaszewska-Szostek, Anna; Durlik, Marek

    2012-09-01

    There are controversial views as to whether intratumoral or peritumoral lymphatics play a dominant role in the metastatic process. Most clinical observations originate from studies of colon cancer. Colon contains mucosa and submucosa rich in lymphatics and with high lymph formation rate. This seems to be a prerequisite for easy metastasis of cancer cells to regional lymph nodes. However, there are other tissues as pancreas with a rudimentary lymphatic network where cancer metastasis formation is as intensive as in colon cancer. This contradicts the common notion that intratumor lymphatics play major role in metastases. We visualized interstitial space and lymphatics in the central and peripheral regions of colon and pancreas tumors using the color stereoscopic lymphography and simultaneously immunohistochemical performed stainings specific for lymphatic and blood endothelial cells. The density of open and compressed lymphatic and blood vessels was measured in the tumor core and edge. There were very few lymphatics in the colon and pancreas tumor core but numerous minor fluid "lakes" with no visible connection to the peritumoral lymphatics. Lining of "lakes" did not express molecular markers specific for lymphatic endothelial cells. Dense connective tissue surrounding tumor foci did not contain lymphatics. Peritumoral lymphatics were irregularly distributed in both types of tumor and only sporadically contained cells that might be tumor cells. Similar lymphoscintigraphic and histological pictures were seen in colon and pancreas cancer despite of different structure of both tissues. This suggests a uniform reaction of tissues to the growing cancer irrespective of the affected organ.

  9. Collection of Biospecimen & Clinical Information in Patients w/ Gastrointestinal Cancers

    ClinicalTrials.gov

    2012-05-24

    Gastrointestinal Neoplasms; Gynecologic Cancers; Gynecologic Cancers Cervical Cancer; Gastric (Stomach) Cancer; Gastro-Esophageal(GE) Junction Cancer; Gastrointenstinal Stromal Tumor (GIST); Colon/Rectal Cancer; Colon/Rectal Cancer Colon Cancer; Colon/Rectal Cancer Rectal Cancer; Colon/Rectal Cancer Anal Cancer; Anal Cancer; Hepatobiliary Cancers; Hepatobiliary Cancers Liver; Pancreatic Cancer

  10. Treatment Option Overview (Colon Cancer)

    MedlinePlus

    ... colon. The colon is part of the body’s digestive system . The digestive system removes and processes nutrients ( vitamins , minerals , carbohydrates , fats, ... pass waste material out of the body. The digestive system is made up of the esophagus , stomach , and ...

  11. Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis.

    PubMed

    Reddivari, Lavanya; Charepalli, Venkata; Radhakrishnan, Sridhar; Vadde, Ramakrishna; Elias, Ryan J; Lambert, Joshua D; Vanamala, Jairam K P

    2016-08-09

    We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo. RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear β-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocation of β-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/β-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE. The suppression of Wnt/β-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy.

  12. Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation.

    PubMed

    Le Rolle, Anne-France; Chiu, Thang K; Zeng, Zhaoshi; Shia, Jinru; Weiser, Martin R; Paty, Philip B; Chiu, Vi K

    2016-01-19

    Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer.

  13. Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon

    PubMed Central

    Rocha, Cecilia; Papon, Laura; Cacheux, Wulfran; Marques Sousa, Patricia; Lascano, Valeria; Tort, Olivia; Giordano, Tiziana; Vacher, Sophie; Lemmers, Benedicte; Mariani, Pascale; Meseure, Didier; Medema, Jan Paul; Bièche, Ivan; Hahne, Michael; Janke, Carsten

    2014-01-01

    TTLL3 and TTLL8 are tubulin glycine ligases catalyzing posttranslational glycylation of microtubules. We show here for the first time that these enzymes are required for robust formation of primary cilia. We further discover the existence of primary cilia in colon and demonstrate that TTLL3 is the only glycylase in this organ. As a consequence, colon epithelium shows a reduced number of primary cilia accompanied by an increased rate of cell division in TTLL3-knockout mice. Strikingly, higher proliferation is compensated by faster tissue turnover in normal colon. In a mouse model for tumorigenesis, lack of TTLL3 strongly promotes tumor development. We further demonstrate that decreased levels of TTLL3 expression are linked to the development of human colorectal carcinomas. Thus, we have uncovered a novel role for tubulin glycylation in primary cilia maintenance, which controls cell proliferation of colon epithelial cells and plays an essential role in colon cancer development. PMID:25180231

  14. Stabilization of MDA-7/IL-24 for colon cancer therapy.

    PubMed

    Xu, Shili; Oshima, Takashi; Imada, Toshio; Masuda, Munetaka; Debnath, Bikash; Grande, Fedora; Garofalo, Antonio; Neamati, Nouri

    2013-07-28

    Colon cancer is one of the most commonly diagnosed cancers in the United States. Recombinant MDA-7/IL-24 has showed its selective cytotoxicity against cancer cells, and Ad-mda7 (INGN-241) is currently under clinical investigation for solid tumors. Here, we investigated the expression of MDA-7/IL-24 in colorectal cancer (CRC) tissues from 202 patients. Compared with the adjacent mucosa, CRC tissues displayed significantly lower MDA-7/IL-24 levels. The MDA-7/IL-24 levels in CRC were significantly associated with patients' survival rate in a 6-year period. These results indicate MDA-7/IL-24 level is both a diagnostic and prognostic biomarker for CRC, and support the role of MDA-7/IL-24 in the treatment of CRC. To elevate MDA-7/IL-24 level for colon cancer treatment, we successfully developed a small-molecule compound SC144 with the ability to up-regulate MDA-7/IL-24 expression via direct binding and stabilizing MDA-7/IL-24 in human colon cancer cells. Among the analogs tested, SC144 exhibited the highest cytotoxicity in a panel of colon cancer cell lines in a p53-independent manner, accompanied by cell cycle arrest in G0/G1 with downregulation of Cyclin D1 levels, and apoptosis induction with upregulation of cell surface-bound Fas/CD95. These results combined with our previous studies support the anticancer role of MDA-7/IL-24 as well as the clinical development of SC144 for colon cancer treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells

    PubMed Central

    Charepalli, Venkata; Reddivari, Lavanya; Vadde, Ramakrishna; Walia, Suresh; Radhakrishnan, Sridhar; Vanamala, Jairam K. P

    2016-01-01

    The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. PMID:26927179

  16. EF5 and Motexafin Lutetium in Detecting Tumor Cells in Patients With Abdominal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-15

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Fallopian Tube Cancer; Gastrointestinal Stromal Tumor; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Gastrointestinal Carcinoid Tumor; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Primary Peritoneal Cavity Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Adult Soft Tissue Sarcoma; Recurrent Colon Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Small Intestine Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage 0 Non-small Cell Lung Cancer; Stage I Adult Soft Tissue Sarcoma; Stage I Colon Cancer; Stage I Gastric Cancer; Stage I Non-small Cell Lung Cancer; Stage I Ovarian Epithelial Cancer; Stage I Ovarian Germ Cell Tumor; Stage I Pancreatic Cancer; Stage I Rectal Cancer; Stage I Uterine Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage II Colon Cancer; Stage II Gastric Cancer; Stage II Non-small Cell Lung Cancer; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; Stage II Pancreatic Cancer; Stage II Rectal Cancer; Stage II Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Colon Cancer; Stage III Gastric Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Uterine Sarcoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Colon Cancer; Stage

  17. Lap colectomy and robotics for colon cancer.

    PubMed

    Parra-Davila, Eduardo; Ramamoorthy, Sonia

    2013-01-01

    Robotic approaches have seen significant growth in the last 5 years. Taking advantage of three-dimensional visualization, improved articulation, and multiple operating arms provides theoretical and real advantages in colorectal cancer surgery. This article reviews the potential advantages and disadvantages, current outcomes, and future directions for robotic approaches to colon cancer surgery. Copyright © 2013. Published by Elsevier Inc.

  18. Differences in gene expression profiles and carcinogenesis pathways between colon and rectal cancer.

    PubMed

    Li, Jing Nan; Zhao, Li; Wu, Jun; Wu, Bin; Yang, Hong; Zhang, Heng Hui; Qian, Jia Ming

    2012-01-01

    Colon cancer is more common in the USA and Europe than that in China, for reasons that are unclear. The aim of this study was to investigate the differences in gene expression profiles and carcinogenesis pathways between colon and rectal cancer. Expression profiling of primary tumor tissues from 12 colon and 12 rectal cancers was performed using oligonucleotide microarray analysis. All samples were strictly matched by clinical features. Bioinformatic analyses such as the Kyoto Encyclopedia of Genes and Genomes were used to identify genes and pathways specifically associated with colon or rectal cancers. A total of 824 genes were differentially expressed in colon and rectal cancers. All differential gene interactions in the Signal-Net were analyzed. More genes were differentially expressed and included in the Signal-Net for rectal than colon cancer. Of the genes differentially expressed between colon and rectal cancer, S100P, the Reg family, ACTN1, CAMK2G and ACAT1 were the most significantly altered. Genes involved in the cell cycle pathway were present in rectal and colon cancers, but were more important in rectal cancer. The p53 and metabolic signaling pathways were significantly different in colon and rectal cancers. Gene expression profiles differed between colon and rectal cancer, with metabolic pathways being more important in rectal cancer. The oncogenesis of rectal cancer may be more complex than that of colon cancer. Some genes could be new biomarkers for distinguishing between these two cancers. © 2011 The Authors. Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

  19. How to improve colon cancer screening rates

    PubMed Central

    Alberti, Luiz Ronaldo; Garcia, Diego Paim Carvalho; Coelho, Debora Lucciola; De Lima, David Correa Alves; Petroianu, Andy

    2015-01-01

    Colorectal carcinoma is a common cause of death throughout the world and may be prevented by routine control, which can detect precancerous neoplasms and early cancers before they undergo malignant transformation or metastasis. Three strategies may improve colon cancer screening rates: convince the population about the importance of undergoing a screening test; achieve higher efficacy in standard screening tests and make them more available to the community and develop new more sensitive and efficacious screening methods and make them available as routine tests. In this light, the present study seeks to review these three means through which to increase colon cancer screening rates. PMID:26688708

  20. How to improve colon cancer screening rates.

    PubMed

    Alberti, Luiz Ronaldo; Garcia, Diego Paim Carvalho; Coelho, Debora Lucciola; De Lima, David Correa Alves; Petroianu, Andy

    2015-12-15

    Colorectal carcinoma is a common cause of death throughout the world and may be prevented by routine control, which can detect precancerous neoplasms and early cancers before they undergo malignant transformation or metastasis. Three strategies may improve colon cancer screening rates: convince the population about the importance of undergoing a screening test; achieve higher efficacy in standard screening tests and make them more available to the community and develop new more sensitive and efficacious screening methods and make them available as routine tests. In this light, the present study seeks to review these three means through which to increase colon cancer screening rates.

  1. Colon cancer proliferating desulfosinigrin in wasabi (Wasabia japonica).

    PubMed

    Weil, Marvin J; Zhang, Yanjun; Nair, Muraleedharan G

    2004-01-01

    A reduced incidence of different types of cancer has been linked to consumption of Brassica vegetables, and there is evidence that glucosinolates (GSLs) and their hydrolysis products play a role in reducing cancer risk. Wasabi (Wasabia japonica) and horseradish (Armoracia rusticana), both Brassica vegetables, are widely used condiments both in Japanese cuisine and in the United States. Desulfosinigrin (DSS) (1) was isolated from a commercially available wasabi powder and from fresh wasabi roots. Sinigrin (2) was isolated from horseradish roots. DSS and sinigrin were evaluated for their inhibitory effects on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, on lipid peroxidation, and on the proliferation of human colon (HCT-116), breast (MCF-7), lung (NCIH460), and central nervous system (CNS, SF-268) cancer cell lines. DSS did not inhibit COX enzymes or lipid peroxidation at 250 microg/ml. Sinigrin inhibited lipid peroxidation by 71% at 250 microg/ml. However, DSS promoted the growth of HCT-116 (colon) and NCI H460 (lung) human cancer cells as determined by the MTT assay in a concentration-dependent manner. At 3.72 microg/ml, a 27% increase in the number of viable human HCT-116 colon cancer cells was observed; the corresponding increases at 7.50 and 15 microg/ml were 42 and 69%, respectively. At 60 microg/ml, DSS doubled the number of HCT-16 colon cancer cells. For NCI H460 human lung cancer cells, DSS at 60 microg/ml increased the cell number by 20%. Sinigrin showed no proliferating effect on the tumor cells tested. This is the first report of the tumor cell-proliferating activity by a desulfoglucosinolate, the biosynthetic precursor of GSLs found in Brassica spp.

  2. Colon cancer: diagnosis and prognosis in the elderly.

    PubMed

    Block, G E

    1989-05-01

    Cancer of the colon and rectum appear to be epidemic in the US, with 150,000 cases expected during 1988. Two thirds of these patients are over age 60, and two thirds also have either full penetration of the bowel wall or metastases to regional lymph nodes. Mass screening via tests for occult blood in the stool is invaluable for detecting early carcinomas of the colon and rectum. Digital examination, endoscopy, and barium contrast radiographs help to confirm the diagnosis. Tumors of the colon and rectum are best treated operatively with appropriate lymphadenectomy and adequate margins, both proximally and distally, to guard against local recurrence. Certain factors, such as mucinous tumors, microinvasion, and non-exophytic tumors of the rectum have been shown to have a propensity for local recurrence. Local treatment by fulguration or electrocoagulation is advocated only for tiny tumors confined to a polyp, or for the extremely elderly or poor-risk patient. Radiation therapy appears to be an appropriate adjuvant to the treatment of rectal cancer either preoperatively or postoperatively.

  3. Anthocyanin-containing purple-fleshed potatoes suppress colon tumorigenesis via elimination of colon cancer stem cells.

    PubMed

    Charepalli, Venkata; Reddivari, Lavanya; Radhakrishnan, Sridhar; Vadde, Ramakrishna; Agarwal, Rajesh; Vanamala, Jairam K P

    2015-12-01

    Cancer stem cells (CSCs) are shown to be responsible for initiation and progression of tumors in a variety of cancers. We previously showed that anthocyanin-containing baked purple-fleshed potato (PP) extracts (PA) suppressed early and advanced human colon cancer cell proliferation and induced apoptosis, but their effect on colon CSCs is not known. Considering the evidence of bioactive compounds, such as anthocyanins, against cancers, there is a critical need to study anticancer activity of PP, a global food crop, against colon CSCs. Thus, isolated colon CSCs (positive for CD44, CD133 and ALDH1b1 markers) with functioning p53 and shRNA-attenuated p53 were treated with PA at 5.0 μg/ml. Effects of baked PP (20% wt/wt) against colon CSCs were also tested in vivo in mice with azoxymethane-induced colon tumorigenesis. Effects of PA/PP were compared to positive control sulindac. In vitro, PA suppressed proliferation and elevated apoptosis in a p53-independent manner in colon CSCs. PA, but not sulindac, suppressed levels of Wnt pathway effector β-catenin (a critical regulator of CSC proliferation) and its downstream proteins (c-Myc and cyclin D1) and elevated Bax and cytochrome c, proteins-mediating mitochondrial apoptosis. In vivo, PP reduced the number of crypts containing cells with nuclear β-catenin (an indicator of colon CSCs) via induction of apoptosis and suppressed tumor incidence similar to that of sulindac. Combined, our data suggest that PP may contribute to reduced colon CSCs number and tumor incidence in vivo via suppression of Wnt/β-catenin signaling and elevation of mitochondria-mediated apoptosis.

  4. Activated macrophages containing tumor marker in colon carcinoma: immunohistochemical proof of a concept.

    PubMed

    Faber, T J E; Japink, D; Leers, M P G; Sosef, M N; von Meyenfeldt, M F; Nap, M

    2012-04-01

    The presence of carcinoembryonic antigen (CEA)-containing activated macrophages has been demonstrated in peripheral blood from patients with colorectal carcinoma. Macrophages migrate from the circulation into the tissue, phagocytose debris, and return to the bloodstream. Hence it seems likely that activated macrophages containing tumor debris, i.e., tumor marker, are present in the stroma of colorectal carcinoma. After phagocytosis, they could follow a hematogenic or lymphogenic route to the peripheral blood. The aim of this study is to assess the presence of tumor marker-containing activated macrophages in the stroma of colon carcinoma and in regional lymph nodes. From 10 cases of colon carcinoma, samples of tumor tissue and metastasis-free lymph nodes were cut in serial sections and stained for CD68 to identify macrophages and for CEA, cytokeratin, or M30 presence. Slides were digitalised and visually inspected using two monitors, comparing the CD68 stain to the tumor marker stain to evaluate the presence of tumor marker-positive macrophages. Macrophages containing tumor marker could be identified in tumor stroma and in metastasis-free regional lymph nodes. The distribution varied for the different markers, CEA-positive macrophages being most abundant. The presence of macrophages containing tumor marker in the tumor stroma and lymph nodes from patients with colon carcinoma could be confirmed in this series using serial immunohistochemistry. This finding supports the concept of activated macrophages, after phagocytosing cell debris, being transported or migrating through the lymphatic system. These results support the potential of tumor marker-containing macrophages to serve as a marker for diagnosis and follow-up of colon cancer patients.

  5. Targeting the metabolic pathway of human colon cancer overcomes resistance to TRAIL-induced apoptosis.

    PubMed

    Carr, Ryan M; Qiao, Guilin; Qin, Jianzhong; Jayaraman, Sundararajan; Prabhakar, Bellur S; Maker, Ajay V

    2016-01-01

    Colon cancer is a leading cause of cancer-related mortality for which targeted therapy is needed; however, trials using apoptosis-inducing ligand monotherapy to overcome resistance to apoptosis have not shown clinical responses. Since colon cancer cells selectively uptake and rapidly metabolize glucose, a property utilized for clinical staging, we investigated mechanisms to alter glucose metabolism in order to selectively target the cancer cells and to overcome evasion of apoptosis. We demonstrate TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) resistance in the majority of human colon cancers tested and utilize the glucose analog 2-deoxy-d-glucose to sensitize TRAIL-resistant gastrointestinal adenocarcinoma cells, and not normal gastrointestinal epithelial cells, to TRAIL-induced apoptosis through enhanced death receptor 5 expression, downstream modulation of MAPK signaling and subsequent miRNA expression modulation by increasing the expression of miR-494 via MEK activation. Further, established human colon cancer xenografts treated with this strategy experience anti-tumor responses. These findings in colon adenocarcinoma support further investigation of manipulation of cellular energetics to selectively overcome resistance to apoptosis and to impart tumor regressions in established colon cancer tumors.

  6. Targeting the metabolic pathway of human colon cancer overcomes resistance to TRAIL-induced apoptosis

    PubMed Central

    Carr, Ryan M; Qiao, Guilin; Qin, Jianzhong; Jayaraman, Sundararajan; Prabhakar, Bellur S; Maker, Ajay V

    2016-01-01

    Colon cancer is a leading cause of cancer-related mortality for which targeted therapy is needed; however, trials using apoptosis-inducing ligand monotherapy to overcome resistance to apoptosis have not shown clinical responses. Since colon cancer cells selectively uptake and rapidly metabolize glucose, a property utilized for clinical staging, we investigated mechanisms to alter glucose metabolism in order to selectively target the cancer cells and to overcome evasion of apoptosis. We demonstrate TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) resistance in the majority of human colon cancers tested and utilize the glucose analog 2-deoxy-d-glucose to sensitize TRAIL-resistant gastrointestinal adenocarcinoma cells, and not normal gastrointestinal epithelial cells, to TRAIL-induced apoptosis through enhanced death receptor 5 expression, downstream modulation of MAPK signaling and subsequent miRNA expression modulation by increasing the expression of miR-494 via MEK activation. Further, established human colon cancer xenografts treated with this strategy experience anti-tumor responses. These findings in colon adenocarcinoma support further investigation of manipulation of cellular energetics to selectively overcome resistance to apoptosis and to impart tumor regressions in established colon cancer tumors. PMID:27648301

  7. Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer.

    PubMed

    Zhou, Encheng; Huang, Qing; Wang, Ji; Fang, Chengfeng; Yang, Leilei; Zhu, Min; Chen, Jianhui; Chen, Lihua; Dong, Milian

    2015-01-01

    Tim-3 (T cell immunoglobulin and mucin domain 3), belonging to the member of the novel Tim family, has been confirmed that it plays a critical negative role in regulating the immune responses against viral infection and carcinoma. Recently, it has also been reported that the over-expression of Tim-3 is associated with poor prognosis in solid tumors. However, the role of Tim-3 in colorectal cancer remains largely unknown. In the current study, we aim to investigate the expression of Tim-3 in colorectal carcinoma and discuss the relationship between Tim-3 expression and colon cancer prognosis, thus speculating the possible role of Tim-3 in colon cancer progression. Colon cancer tissues and paired normal tissue were obtained from 201 patients with colon cancer for preparation of tissue microarray. Tim-3 expression was evaluated by immunohistochemical staining. The Tim-3 expression level was evaluated by q-RT-PCR, western blot and immunocytochemistry in four colon cancer cell lines (HT-29, HCT116, LoVo, SW620). Tim-3 was expressed in 92.5% tumor tissue samples and 86.5% corresponding normal tissue samples. Expression of Tim-3 was significantly higher in tumor tissues than in normal tissues (P < 0.0001). Tim-3 expression in colon cancer tissues is in correlation with colon cancer lymphatic metastasis and TNM (P < 0.0001). Multivariate analysis demonstrated that Tim-3 expression could be a potential independent prognostic factor for colon cancer patients (P < 0.0001). Kaplan-Meier survival analysis result showed that patients with higher Tim-3 expression had a significantly shorter survival time than those with lower Tim-3 expression patients. Our results indicated that Tim-3 might participate in the tumorgenesis of colon cancer and Tim-3 expression might be a potential independent prognostic factor for patients with colorectal cancer.

  8. γδ T cells as a potential tool in colon cancer immunotherapy.

    PubMed

    Ramutton, Thiranut; Buccheri, Simona; Dieli, Francesco; Todaro, Matilde; Stassi, Giorgio; Meraviglia, Serena

    2014-01-01

    γδ T cells are capable of recognizing tumor cells and exert potent cellular cytotoxicity against a large range of tumors, including colon cancer. However, tumors utilize numerous strategies to escape recognition or killing by patrolling γδ T cells, such a downregulation of NKG2D ligands, MICA/B and ULBPs. Therefore, the combined upregulation of T-cell receptorand NKG2D ligands on tumor cells and induction of NKG2D expression on γδ T cells may greatly enhance tumor killing and unlock the functions of γδ T cells. Here, we briefly review current data on the mechanisms of γδ T-cell recognition and killing of colon cancer cells and propose that γδ T cells may represent a promising target for the design of novel and highly innovative immunotherapy in patients with colon cancer.

  9. The roles of miR-200c in colon cancer and associated molecular mechanisms.

    PubMed

    Chen, Jianmei; Wang, Weining; Zhang, Yangde; Hu, Tiehui; Chen, Yuxiang

    2014-07-01

    The expression of miR-200c has been widely reported to be elevated in tumor tissues and sera of patients with colorectal cancer (CRC) and has been found to correlate with poor prognosis. However, how miR-200c regulates the apoptosis, survival, invasion, metastasis, and tumor growth in colon cancer cells remains to be fully elucidated. This study seeks to further investigate the role of miR-200c in colon cancer development. The expression of miR-200c in tumor and peritumoral tissues of 101 colon cancer patients was measured by real-time PCR. miR-200c expression in HCT-116 and HT-29 colon cancer cells was silenced by adenovirus-carried expression of antisense mRNA against miR-200c. The protein levels of PTEN, p53 Ser(15), PP1, and activated caspase-3 in HCT-116 and HT-29 cells were measured by Western blot. This study demonstrated that the expression of miR-200c was significantly higher in tumor tissues than in peritumoral tissues of colon cancer patients. The elevated miR-200c expression significantly correlated with the TNM stage, lymph node metastasis, and invasion of colon cancer. Silencing miR-200c expression significantly induced cell apoptosis, inhibited long-term survival, invasion, and metastasis, and delayed xenograft tumor growth. Importantly, silencing miR-200c expression sensitized the therapeutic effect of Ara-C (Cytarabine). The effects of silencing miR-200c expression were associated with upregulation of PTEN protein and p53 Ser(15) phosphorylation levels in HCT-116 cells and PTEN protein expression in HT-29 cells. In conclusion, miR-200c functions as an oncogene in colon cancer cells through regulating tumor cell apoptosis, survival, invasion, and metastasis as well as xenograft tumor growth through inhibition of PTEN expression and p53 phosphorylation.

  10. Tumor necrosis factor-alpha induces apoptosis associated with poly(ADP-ribose) polymerase cleavage in HT-29 colon cancer cells.

    PubMed

    Vaculová, Alena; Hofmanova, Jirina; Soucek, Karel; Kovariková, Martina; Kozubík, Alois

    2002-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is known for its selective cytotoxic activity on tumour cells. We analysed the response of HT-29 human colon carcinoma cells to this cytokine. After TNF-alpha treatment, cell proliferation, cell cycle, reactive oxygen species (ROS) production (flow cytometry), the amount of apoptotic cells (flow cytometry, fluorescence microscopy), cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-3 activity (Western blotting) were detected. TNF-alpha induced a decrease of cell growth and viability, an accumulation of cells in the S-phase of the cell cycle, an increase of subdiploid cell population and nuclear chromatin condensation and fragmentation, but not sooner than 96-120 hours. However, earlier events characteristic of apoptosis occurred, such as caspase-3 activation, PARP cleavage to 89 kDa fragment and changes in ROS production. We demonstrated that, in addition to being an early marker of apoptosis, activation of caspase-3 and degradation of PARP may play a causative role in HT-29 cell death induced by TNF-alpha.

  11. Metastasis of colon cancer to medullary thyroid carcinoma: a case report.

    PubMed

    Yeo, So-Jung; Kim, Kyu-Jin; Kim, Bo-Yeon; Jung, Chan-Hee; Lee, Seung-Won; Kwak, Jeong-Ja; Kim, Chul-Hee; Kang, Sung-Koo; Mok, Ji-Oh

    2014-10-01

    Metastasis to the primary thyroid carcinoma is extremely rare. We report here a case of colonic adenocarcinoma metastasis to medullary thyroid carcinoma in a 53-yr old man with a history of colon cancer. He showed a nodular lesion, suggesting malignancy in the thyroid gland, in a follow-up examination after colon cancer surgery. Fine needle aspiration biopsy (FNAB) of the thyroid gland showed tumor cell clusters, which was suspected to be medullary thyroid carcinoma (MTC). The patient underwent a total thyroidectomy. Using several specific immunohistochemical stains, the patient was diagnosed with colonic adenocarcinoma metastasis to MTC. To the best of our knowledge, the present patient is the first case of colonic adenocarcinoma metastasizing to MTC. Although tumor-tumor metastasis to primary thyroid carcinoma is very rare, we still should consider metastasis to the thyroid gland, when a patient with a history of other malignancy presents with a new thyroid finding.

  12. External Beam Radiotherapy for Colon Cancer: Patterns of Care

    SciTech Connect

    Dunn, Emily F.; Kozak, Kevin R.; Moody, John S.

    2010-04-15

    Purpose: Despite its common and well characterized use in other gastrointestinal malignancies, little is known about radiotherapy (RT) use in nonmetastatic colon cancer in the United States. To address the paucity of data regarding RT use in colon cancer management, we examined the RT patterns of care in this patient population. Methods and Materials: Patients with nonmetastatic colon cancer, diagnosed between 1988 and 2005, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate methods were used to identify factors associated with RT use. Results: On univariate analysis, tumor location, age, sex, race, T stage, N stage, and geographic location were each associated with differences in RT use (all p < 0.01). In general, younger patients, male patients, and patients with more advanced disease were more likely to receive RT. On multivariate analysis, tumor location, age, gender, T and N stage, time of diagnosis and geographic location were significantly associated with RT use (all p < 0.001). Race, however, was not associated with RT use. On multivariate analysis, patients diagnosed in 1988 were 2.5 times more likely to receive RT than those diagnosed in 2005 (p = 0.001). Temporal changes in RT use reflect a responsiveness to evolving evidence related to the therapeutic benefits of adjuvant RT. Conclusions: External beam RT is infrequently used for colon cancer, and its use varies according to patient and tumor characteristics. RT use has declined markedly since the late 1980s; however, it continues to be used for nonmetastatic disease in a highly individualized manner.

  13. Application of serex-analysis for identification of human colon cancer antigens.

    PubMed

    Garifulin, O M; Kykot, V O; Gridina, N Y; Kiyamova, R G; Gout, I T; Filonenko, V V

    2015-09-01

    Colorectal, lung and breast tumors are the most devastating and frequent malignances in clinical oncology. SEREX-analysis of colon cancer leads to identification of more than hundred antigens which are potential tumor markers. With idea that immunoscreening with pool of allogeneic sera is more productive for antigen isolation, SEREX-analysis was applied to four cases of stages II-IV primary colon tumor and 22 new antigens were isolated. To characterize 22 primary colon cancer antigens isolated by SEREX-technique. Allogenic screening, real-time PCR analysis. After allogeneic immunoscreening, for 5 of 22 (22%) isolated antigens were confirmed colon cancer restricted serological profile solely positive for 14% of tested colon cancer sera. Through these five antigens, KY-CC-17/β-actin has cytoskeleton function; KY-CC-14/ACTR1A and KY-CC-19/TSGA2 participate in chromosome segregation; KY-CC-12/FKBP4 regulates steroid receptor function and KY-CC-15/PLRG1 is a component of spliceosome complex. For the last four antigens tested were found aberrant mRNA expression in some cases of colon tumor. The exploration of identified antigens may define suitable targets for immunotherapy or diagnostic of colon cancer.

  14. Genistein regulates tumor microenvironment and exhibits anticancer effect in dimethyl hydrazine-induced experimental colon carcinogenesis.

    PubMed

    Sekar, Vasudevan; Anandasadagopan, Suresh Kumar; Ganapasam, Sudhandiran

    2016-11-12

    Colon cancer is one of the leading causes of cancer mortality, worldwide. Cancer stem cells are attractive targets for therapeutic interventions since their abnormal growth may trigger tumor initiation, progression, and recurrence. Colon cancer in rats were induced with 1, 2-dimethyl hydrazine (DMH) and treated with genistein, an isoflavone rich in the soy food products, which also possesses various biological activities. Genistein treatment regulates enzymatic and non-enzymatic anti-oxidants in the DMH-induced colonic tissue microenvironment. Alcian blue staining in colonic tissue reveals that mucin secretion was found to be depleted in DMH-induced group of animals. The alterations were normalized in the genistein-treated groups. Also, the mast cell population and collagen deposition were reduced as compared to induced group. Genistein treatment reduces the prognostic marker Argyrophilic nuclear organizer region (AgNOR) and proliferating cell nucleolar antigen (PCNA) in DMH-induced group of rats. DMH administration induces oxidative stress, whereas genistein activates nuclear factor-erythroid 2 related factor 2 (Nrf-2) and its downstream target hemoxygenase-1 (HO-1). Colonic stem cell marker protein CD133, CD44, and β-catenin expressions were found to be increased in DMH-induced group of animals as compared to control group of rats. Genistein treatment suppressed the expression of these stem cell markers suggesting rapid dysfunctional activation and proliferation of colonic stem cell-induced by DMH. The results of this study indicate that genistein administration in rats restored the colonic niche that was damaged by DMH and inhibits colon cancer progression. © 2016 BioFactors, 42(6):623-637, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

  15. Engineering Approach to Identifying Patients with Colon Tumors on the Basis of Electrophotonic Imaging Technique Data

    PubMed Central

    Yakovleva, E.G.; Korotkov, K.G.; Fedorov, E.D.; Ivanova, E.V.; Plahov, R.V.; Belonosov, S.S.

    2016-01-01

    Background: Colonic neoplasms are quite a serious problem today. Screening methods play an important role in diagnosing the disease. Colorectal cancer screening is a complex undertaking, having various options, which require a lot of efforts both from the doctor and from the patient, including the use of sedatives and the necessity of the presence of an assistant for some procedures such as colonoscopy. This is why it is very important to find a method by which one can make a diagnosis quickly, easily, and painlessly. Methods: The ability to identify patients with tumors of the colon using the Electrophotonic Imaging (EPI) technique, as well as using it for differential diagnosis of tumors of the colon by their morphology, size and quantity was investigated. Selection of the most significant parameters of the EPI-graphy for the separation of the control group and the group of patients with tumors of the colon was developed. 137 people were studied with the EPI camera, with ages ranging from 16 to 86 years, including 49 males and 88 females. Based on the results of the colonoscopy and histological findings all subjects were divided into 2 groups: control group of 55 people, 9 males, 46 females; and patients with tumors (benign or malignant) of the colon - 82 people; 40 males and 42 females. Then all subjects were divided into smaller groups based on morphology, size, number of tumors and localization. Results: Based on the identified indicators decision rules to determine the patients with tumors of the colon were constructed. The specificity of the resulting function was 80.0% and sensitivity 75.6%. Decision rule was built as well with logistic regression. The specificity of the resulting function was 78.2% and sensitivity 90.0%. The accuracy of this approach was higher than using discriminant analysis. Conclusions: The results of this study have proven the ability to identify patients with tumors of the colon using EPI technology, as well as use it for

  16. Association between TLR-9 polymorphisms and colon cancer susceptibility in Saudi Arabian female patients

    PubMed Central

    Semlali, Abdelhabib; Parine, Narasimha Reddy; Al Amri, Abdullah; Azzi, Arezki; Arafah, Maha; Kohailan, Muhammad; Shaik, Jilani P; Almadi, Majid Abdulrahman; Aljebreen, Abdulrahman M; Alharbi, Othman; Ali Azzam, Nahla; Rouabhia, Mahmoud; Alanazi, Mohammad Saud

    2017-01-01

    Objective The authors aimed to explore the relationship between the expression/polymorphisms of TLR-9 and susceptibility to colon cancer development in the Saudi Arabian population. Methods In total, blood samples from 115 patients with colon cancer and 102 participants without colon cancer were analyzed in this study. Three single-nucleotide polymorphisms (SNPs) were selected from the TLR-9 gene, including two sites within the TLR-9 gene’s promoter region (rs352144 and rs187084) and one site in a TLR-9 intron region (rs5743839). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models after adjusting for age, gender, and tumor localization. To investigate the differential expression of TLR-9 in colon cancer, TLR-9 expression was evaluated using quantitative real-time reverse transcription polymerase chain reaction on 40 matched normal and colon tissues. Results The authors found that TLR-9 expression was decreased in colon cancer tissues as compared with that in normal tissues. Moreover, significant associations between the TLR-9 rs187084 SNP and colon cancer risk were observed in female patients only. In rs187084, the T allele had a significantly lower frequency (2.8 times) in female cancer patients than in controls (0.27 vs 0.41). The TLR-9 rs352139 and rs352144 SNPs were significantly associated with colon cancer development when the tumor was located in the rectal area. Conclusion The findings support the hypothesis that TLR-9 has an anticancer role in colon cancer development. Furthermore, genetic variation may influence colon cancer development, and SNPs in TLR-9 could serve as biomarkers for decision making in the treatment of females with rectal cancer. PMID:28031717

  17. Walnut Phenolic Extract and Its Bioactive Compounds Suppress Colon Cancer Cell Growth by Regulating Colon Cancer Stemness.

    PubMed

    Lee, Jisoo; Kim, Yoo-Sun; Lee, JaeHwan; Heo, Seung Chul; Lee, Kook Lae; Choi, Sang-Woon; Kim, Yuri

    2016-07-21

    Walnut has been known for its health benefits, including anti-cardiovascular disease and anti-oxidative properties. However, there is limited evidence elucidating its effects on cancer stem cells (CSCs) which represent a small subset of cancer cells that provide resistance against chemotherapy. This study aimed to evaluate the anti-CSCs potential of walnut phenolic extract (WPE) and its bioactive compounds, including (+)-catechin, chlorogenic acid, ellagic acid, and gallic acid. In the present study, CD133⁺CD44⁺ cells were isolated from HCT116 cells using fluorescence-activated cell sorting (FACS) and then treated with WPE. As a result, survival of the CD133⁺CD44⁺ HCT116 cells was inhibited and cell differentiation was induced by WPE. In addition, WPE down-regulated the CSC markers, CD133, CD44, DLK1, and Notch1, as well as the β-catenin/p-GSK3β signaling pathway. WPE suppressed the self-renewal capacity of CSCs. Furthermore, the WPE exhibited stronger anti-CSC effects than its individual bioactive compounds. Finally, the WPE inhibited specific CSC markers in primary colon cancer cells isolated from primary colon tumor. These results suggest that WPE can suppress colon cancer by regulating the characteristics of colon CSCs.

  18. Walnut Phenolic Extract and Its Bioactive Compounds Suppress Colon Cancer Cell Growth by Regulating Colon Cancer Stemness

    PubMed Central

    Lee, Jisoo; Kim, Yoo-Sun; Lee, JaeHwan; Heo, Seung Chul; Lee, Kook Lae; Choi, Sang-Woon; Kim, Yuri

    2016-01-01

    Walnut has been known for its health benefits, including anti-cardiovascular disease and anti-oxidative properties. However, there is limited evidence elucidating its effects on cancer stem cells (CSCs) which represent a small subset of cancer cells that provide resistance against chemotherapy. This study aimed to evaluate the anti-CSCs potential of walnut phenolic extract (WPE) and its bioactive compounds, including (+)-catechin, chlorogenic acid, ellagic acid, and gallic acid. In the present study, CD133+CD44+ cells were isolated from HCT116 cells using fluorescence-activated cell sorting (FACS) and then treated with WPE. As a result, survival of the CD133+CD44+ HCT116 cells was inhibited and cell differentiation was induced by WPE. In addition, WPE down-regulated the CSC markers, CD133, CD44, DLK1, and Notch1, as well as the β-catenin/p-GSK3β signaling pathway. WPE suppressed the self-renewal capacity of CSCs. Furthermore, the WPE exhibited stronger anti-CSC effects than its individual bioactive compounds. Finally, the WPE inhibited specific CSC markers in primary colon cancer cells isolated from primary colon tumor. These results suggest that WPE can suppress colon cancer by regulating the characteristics of colon CSCs. PMID:27455311

  19. Pectin matrix as oral drug delivery vehicle for colon cancer treatment.

    PubMed

    Wong, Tin Wui; Colombo, Gaia; Sonvico, Fabio

    2011-03-01

    Colon cancer is the fourth most common cancer globally with 639,000 deaths reported annually. Typical chemotherapy is provided by injection route to reduce tumor growth and metastasis. Recent research investigates the oral delivery profiles of chemotherapeutic agents. In comparison to injection, oral administration of drugs in the form of a colon-specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin is suitable for use as colon-specific drug delivery vehicle as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. The present review examines the physicochemical attributes of formulation needed to retard drug release of pectin matrix prior to its arrival at colon, and evaluate the therapeutic value of pectin matrix in association with colon cancer. The review suggests that multi-particulate calcium pectinate matrix is an ideal carrier to orally deliver drugs for site-specific treatment of colon cancer as (1) crosslinking of pectin by calcium ions in a matrix negates drug release in upper gastrointestinal tract, (2) multi-particulate carrier has a slower transit and a higher contact time for drug action in colon than single-unit dosage form, and (3) both pectin and calcium have an indication to reduce the severity of colon cancer from the implication of diet and molecular biology studies. Pectin matrix demonstrates dual advantages as drug carrier and therapeutic for use in treatment of colon cancer.

  20. High-fat diet induced leptin and Wnt expression: RNA-sequencing and pathway analysis of mouse colonic tissue and tumors.

    PubMed

    Penrose, Harrison M; Heller, Sandra; Cable, Chloe; Nakhoul, Hani; Baddoo, Melody; Flemington, Erik; Crawford, Susan E; Savkovic, Suzana D

    2017-03-01

    Obesity, an immense epidemic affecting approximately half a billion adults, has doubled in prevalence in the last several decades. Epidemiological data support that obesity, due to intake of a high-fat, western diet, increases the risk of colon cancer; however, the mechanisms underlying this risk remain unclear. Here, utilizing next generation RNA sequencing, we aimed to determine the high-fat diet (HFD) mediated expression profile in mouse colon and the azoxymethane/dextran sulfate sodium model of colon cancer. Mice on HFD had significantly higher colonic inflammation, tumor burden, and a number of differentially expressed transcripts compared to mice on regular diet (RD). We identified 721 transcripts differentially expressed in mouse HFD colon that were in a shared pattern with colonic tumors (RD and HFD). Importantly, in mouse colon, HFD stimulated an expression signature strikingly similar to human colon cancer, especially those with inflammatory microsatellite instability. Furthermore, pathway analysis of these transcripts demonstrated their association with active inflammation and colon cancer signaling, with leptin and Wnt as the top two transcripts elevated in mouse HFD colon shared with tumors. Moreover, in mouse colon, HFD-stimulated tumorigenic Wnt pathway activation was further validated by upregulation of β-catenin transcriptional targets. Finally, in human colon cancer, upregulation of leptin pathway members was shown with a large network of dysregulated transcripts being linked with worse overall survival. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Chemoembolization Using Irinotecan in Treating Patients With Liver Metastases From Metastatic Colon or Rectal Cancer

    ClinicalTrials.gov

    2015-09-10

    Liver Metastases; Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Recurrent Colon Cancer; Recurrent Rectal Cancer; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Stage IV Colon Cancer; Stage IV Rectal Cancer

  2. Asian and Hispanic Americans' cancer fatalism and colon cancer screening.

    PubMed

    Jun, Jungmi; Oh, Kyeung Mi

    2013-03-01

    To explore fatalistic attributions of colon cancer development among Asian and Hispanic Americans in comparison with non-Hispanic whites; also to examine the impacts of fatalism on adherence to the colon cancer screening guideline. For the analysis, the 2005 Health Information National Trends Survey data were employed. Both Asian and Hispanic Americans were more likely to make fatalistic attribution and were less likely to follow the guideline than whites. Particularly for Asians, fatalism was a significant predictor for not adhering to the guideline. These findings emphasize the need for cultural interventions to disrupt fatalistic attitudes towards colon cancer preventions.

  3. miR-193a-3p is a Key Tumor Suppressor in Ulcerative Colitis-Associated Colon Cancer and Promotes Carcinogenesis through Upregulation of IL17RD.

    PubMed

    Pekow, Joel; Meckel, Katherine; Dougherty, Urszula; Huang, Yong; Chen, Xindi; Almoghrabi, Anas; Mustafi, Reba; Ayaloglu-Butun, Fatma; Deng, Zifeng; Haider, Haider I; Hart, John; Rubin, David T; Kwon, John H; Bissonnette, Marc

    2017-09-01

    Purpose: Patients with ulcerative colitis are at increased risk for colorectal cancer, although mechanisms underlying neoplastic transformation are poorly understood. We sought to evaluate the role of microRNAs in neoplasia development in this high-risk population.Experimental Design: Tissue from 12 controls, 9 ulcerative colitis patients without neoplasia, and 11 ulcerative colitis patients with neoplasia was analyzed. miRNA array analysis was performed and select miRNAs assayed by real-time PCR on the discovery cohort and a validation cohort. DNA methylation of miR-193a was assessed. Following transfection of miR-193a-3p, proliferation, IL17RD expression, and luciferase activity of the 3'UTR of IL17RD were measured. Tumor growth in xenografts as well as EGFR signaling were assessed in HCT116 cells expressing IL17RD with either a mutant 3' untranslated region (UTR) or wild-type (WT) 3'UTR.Results: miR-31, miR-34a, miR-106b, and miR-193a-3p were significantly dysregulated in ulcerative colitis-neoplasia and adjacent tissue. Significant down-regulation of miR-193a-3p was also seen in an independent cohort of ulcerative colitis cancers. Changes in methylation of miR-193a or expression of pri-miR-193a were not observed in ulcerative colitis cancer. Transfection of miR-193a-3p resulted in decreased proliferation, and identified IL17RD as a direct target of miR-193a-3p. IL17RD expression was increased in ulcerative colitis cancers, and miR-193a-3p treatment decreased growth and EGFR signaling of HCT116 cells in xenografts expressing both IL17RD with WT 3'UTR compared with cells expressing IL17RD with mutant 3'UTR.Conclusions: miR-193a-3p is downregulated in ulcerative colitis neoplasia, and its loss promotes carcinogenesis through upregulation of IL17RD. These findings provide novel insight into inflammation-driven colorectal cancer and could suggest new therapeutic targets in this high-risk population. Clin Cancer Res; 23(17); 5281-91. ©2017 AACR. ©2017 American

  4. Proteogenomic characterization of human colon and rectal cancer

    SciTech Connect

    Zhang, Bing; Wang, Jing; Wang, Xiaojing; Zhu, Jing; Liu, Qi; Shi, Zhiao; Chambers, Matthew C.; Zimmerman, Lisa J.; Shaddox, Kent F.; Kim, Sangtae; Davies, Sherri; Wang, Sean; Wang, Pei; Kinsinger, Christopher; Rivers, Robert; Rodriguez, Henry; Townsend, Reid; Ellis, Matthew; Carr, Steven A.; Tabb, David L.; Coffey, Robert J.; Slebos, Robbert; Liebler, Daniel

    2014-09-18

    We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Protein sequence variants encoded by somatic genomic variations displayed reduced expression compared to protein variants encoded by germline variations. mRNA transcript abundance did not reliably predict protein expression differences between tumors. Proteomics identified five protein expression subtypes, two of which were associated with the TCGA "MSI/CIMP" transcriptional subtype, but had distinct mutation and methylation patterns and associated with different clinical outcomes. Although CNAs showed strong cis- and trans-effects on mRNA expression, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. Our analyses identified HNF4A, a novel candidate driver gene in tumors with chromosome 20q amplifications. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords novel insights into cancer biology.

  5. GDP-mannose-4,6-dehydratase (GMDS) deficiency renders colon cancer cells resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor- and CD95-mediated apoptosis by inhibiting complex II formation.

    PubMed

    Moriwaki, Kenta; Shinzaki, Shinichiro; Miyoshi, Eiji

    2011-12-16

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis through binding to TRAIL receptors, death receptor 4 (DR4), and DR5. TRAIL has potential therapeutic value against cancer because of its selective cytotoxic effects on several transformed cell types. Fucosylation of proteins and lipids on the cell surface is a very important posttranslational modification that is involved in many cellular events. Recently, we found that a deficiency in GDP-mannose-4,6-dehydratase (GMDS) rendered colon cancer cells resistant to TRAIL-induced apoptosis, resulting in tumor development and metastasis by escape from tumor immune surveillance. GMDS is an indispensable regulator of cellular fucosylation. In this study, we investigated the molecular mechanism of inhibition of TRAIL signaling by GMDS deficiency. DR4, but not DR5, was found to be fucosylated; however, GMDS deficiency inhibited both DR4- and DR5-mediated apoptosis despite the absence of fucosylation on DR5. In addition, GMDS deficiency also inhibited CD95-mediated apoptosis but not the intrinsic apoptosis pathway induced by anti-cancer drugs. Binding of TRAIL and CD95 ligand to their cognate receptors primarily leads to formation of a complex comprising the receptor, FADD, and caspase-8, referred to as the death-inducing signaling complex (DISC). GMDS deficiency did not affect formation of the primary DISC or recruitment to and activation of caspase-8 on the DISC. However, formation of secondary FADD-dependent complex II, comprising caspase-8 and cFLIP, was significantly inhibited by GMDS deficiency. These results indicate that GMDS regulates the formation of secondary complex II from the primary DISC independent of direct fucosylation of death receptors.

  6. Family History of Colon Cancer Calls for Earlier Screening

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_164202.html Family History of Colon Cancer Calls for Earlier Screening ... 2017 (HealthDay News) -- If you've got a family history of colon or rectal cancers, you probably ...

  7. Mast Cell Targeted Chimeric Toxin Can Be Developed as an Adjunctive Therapy in Colon Cancer Treatment

    PubMed Central

    Wang, Shan; Li, Linmei; Shi, Renren; Liu, Xueting; Zhang, Junyan; Zou, Zehong; Hao, Zhuofang; Tao, Ailin

    2016-01-01

    The association of colitis with colorectal cancer has become increasingly clear with mast cells being identified as important inflammatory cells in the process. In view of the relationship between mast cells and cancer, we studied the effect and mechanisms of mast cells in the development of colon cancer. Functional and mechanistic insights were gained from ex vivo and in vivo studies of cell interactions between mast cells and CT26 cells. Further evidence was reversely obtained in studies of mast cell targeted Fcε-PE40 chimeric toxin. Experiments revealed mast cells could induce colon tumor cell proliferation and invasion. Cancer progression was found to be related to the density of mast cells in colonic submucosa. The activation of MAPK, Rho-GTPase, and STAT pathways in colon cancer cells was triggered by mast cells during cell-to-cell interaction. Lastly, using an Fcε-PE40 chimeric toxin we constructed, we confirmed the promoting effect of mast cells in development of colon cancer. Mast cells are a promoting factor of colon cancer and thus also a potential therapeutic target. The Fcε-PE40 chimeric toxin targeting mast cells could effectively prevent colon cancer in vitro and in vivo. Consequently, these data may demonstrate a novel immunotherapeutic approach for the treatment of tumors. PMID:26978404

  8. MicroRNA-455-3p Inhibits Tumor Cell Proliferation and Induces Apoptosis in HCT116 Human Colon Cancer Cells

    PubMed Central

    Zheng, Jiantao; Lin, Zhenlv; Zhang, Lin; Chen, Hui

    2016-01-01

    Background MicroRNAs have been reported to play significant roles in pathogenesis of colorectal cancer (CRC). In the present study, we aimed to investigate the functional role of microRNA-455-3p (miR-455-3p) in CRC, as well as its underlying mechanisms. Material/Methods Human colon cancer cell line HCT116 cells were transfected with miR-455-3p mimics, inhibitors, or controls. After transfection, the effects of miR-455-3p mimics or inhibitors on cell proliferation were analyzed by 3-(4, 5-dimethyl-2- thiazolyl)-2, 5-diphenyl -2-H-tetrazolium bromide (MTT) assay and BrdU assay, and the effects of miR-455-3p mimics or inhibitors on cell apoptosis were determined. In addition, the underlying mechanisms of cell proliferation and apoptosis were explored by assessing the protein levels of cell cycle regulators and apoptosis-related protein. Results The results showed that overexpression of miR-455-3p significantly inhibited the cell proliferation (P<0.05 or <0.01) in HCT116 cells compared with the control group, but significantly increased the apoptosis (P<0.01). On the contrary, suppression of miR-455-3p significantly increased the cell proliferation but decreased the apoptosis. Moreover, we found that overexpression of miR-455-3p significantly elevated the protein levels of p27 kinase inhibition protein (KIP) 1, Bax, pro-caspase-3, and active caspase-3, and markedly downregulated the levels of B-cell lymphoma-2 (Bcl-2). Contrary results were found by suppression of miR-455-3p. However, there were no significant differences in p21 expression. Conclusions MiRNA-455-3p functions as an anti-oncogene in HCT116 cells by inhibiting cell proliferation and inducing of apoptosis. PMID:27861461

  9. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression.

    PubMed

    Neufert, Clemens; Becker, Christoph; Neurath, Markus F

    2007-01-01

    Colorectal cancer is a life-threatening disease that can develop spontaneously or as a complication of inflammatory bowel diseases. Mouse models are essential tools for the preclinical testing of novel therapeutic options in vivo. Here, we provide a highly reliable protocol for an experimental mouse model to study the development of colon cancers. It is based on the mutagenic agent azoxymethane (AOM), which exerts colonotropic carcinogenicity. Repeated intraperitoneal administration of AOM results in the development of spontaneous tumors within 30 weeks. As an alternative option, inflammation-dependent tumor growth can be investigated by combining the administration of AOM with the inflammatory agent dextran sodium sulfate in drinking water, which causes rapid growth of multiple colon tumors per mouse within 10 weeks. Different scoring systems including number of tumors and tumor size identify factors promoting or inhibiting tumor initiation and/or tumor progression, respectively.

  10. Enterobacter Strains Might Promote Colon Cancer.

    PubMed

    Yurdakul, Dilşad; Yazgan-Karataş, Ayten; Şahin, Fikrettin

    2015-09-01

    Many studies have been performed to determine the interaction between bacterial species and cancer. However, there has been no attempts to demonstrate a possible relationship between Enterobacter spp. and colon cancer so far. Therefore, in the present study, it is aimed to investigate the effects of Enterobacter strains on colon cancer. Bacterial proteins were isolated from 11 Enterobacter spp., one Morganella morganii, and one Escherichia coli strains, and applied onto NCM460 (Incell) and CRL1790 (ATCC) cell lines. Cell viability and proliferation were determined in MTS assay. Flow Cytometry was used to detect CD24 level and apoptosis. Real-Time PCR studies were performed to determine NFKB and Bcl2 expression. Graphpad Software was used for statistical analysis. The results showed that proteins, isolated from the Enterobacter spp., have significantly increased cell viability and proliferation, while decreasing the apoptosis of the cell lines tested. The data in the present study indicated that Enterobacter strains might promote colon cancer. Moreover, Enterobacter spp. could be a clinically important factor for colon cancer initiation and progression. Studies can be extended on animal models in order to develop new strategies for treatment.

  11. Effect of grape seed proanthocyanidins on colon aberrant crypts and breast tumors in a rat dual-organ tumor model.

    PubMed

    Singletary, K W; Meline, B

    2001-01-01

    Cancers of the colon and breast are two of the most prevalent cancers in developed countries. The present experiments were conducted to determine the influence of several dietary doses of grape seed proanthocyanidins on 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis and azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a dual-organ tumor model. In addition, the effects of the grape seed proanthocyanidins on liver cytochrome P-450 1A and 2E1 and glutathione S-transferase activities and on colonic ornithine decarboxylase activity were examined to determine possible mechanisms of action. Feeding female rats diets containing 0.1-1.0% grape seed proanthocyanidins was associated with a significant 72-88% inhibition of AOM-induced aberrant crypt foci formation and a 20-56% inhibition of ornithine decarboxylase activity in the distal third of the colon. Feeding the grape proanthocyanidins resulted in no significant effect on the activity of liver cytochrome P-450 2E1. There was no effect of feeding these doses of proanthocyanidins on 7,12-dimethylbenz[a]anthracene-induced rat mammary tumorigenesis. This lack of action on mammary tumorigenesis in part may be due to lack of effect of dietary proanthocyanidins on the liver carcinogen-metabolizing enzymes cytochrome P-450 1A and glutathione S-transferase. These results indicate that grape polyphenolics warrant further evaluation as potential colon cancer chemopreventive agents.

  12. General Information about Colon Cancer

    MedlinePlus

    ... D Resources Conducting Clinical Trials Statistical Tools and Data Terminology Resources NCI Data Catalog Cryo-EM NCI's Role in Cancer Research ... major research initiatives R&D Resources Tools and data sets for researchers Research by Cancer Type Find ...

  13. Novel roles of DC-SIGNR in colon cancer cell adhesion, migration, invasion, and liver metastasis.

    PubMed

    Na, Heya; Liu, Xiaoli; Li, Xiaomeng; Zhang, Xinsheng; Wang, Yu; Wang, Zhaohui; Yuan, Menglang; Zhang, Yu; Ren, Shuangyi; Zuo, Yunfei

    2017-01-21

    Tumor metastasis is an essential cause of the poor prognosis of colon cancer. DC-SIGNR is a C-type lectin that is frequently found on human liver sinusoidal endothelial cells. LSECtin, which is a homologue of DC-SIGNR, has been demonstrated to participate in colon cancer liver metastasis. Due to the similarities in the expression pattern and structure of the two proteins, we speculated that DC-SIGNR could also be involved in this process. Colon cancer cells were treated with the DC-SIGNR protein or control IgG, after which cell migration, invasion, and morphology were assayed. Xenograft mouse models were used to determine the role of DC-SIGNR in colon cancer liver metastasis in vivo. In addition, a human gene expression array was used to detect differential gene expression in colon cancer cells stimulated with the DC-SIGNR protein. The serum level of DC-SIGNR was examined in colon cancer patients by ELISA, and the significance of DC-SIGNR was determined. In our research, we investigated whether DC-SIGNR promotes colon cancer cell adhesion, migration, and invasion. Knocking down mouse DC-SIGNR decreased the liver metastatic potency of colon cancer cells and increased survival time. Expressing human DC-SIGNR enhanced colon cancer liver metastasis. Furthermore, DC-SIGNR conferred metastatic capability on cancer cells by upregulating various metallothionein isoforms. To validate the above results, we also found that the serum DC-SIGNR level was statistically higher in colon cancer patients with liver metastasis compared with those without metastasis. These results imply that DC-SIGNR may promote colon carcinoma hepatic metastasis and could serve as a promising therapeutic target for anticancer treatment.

  14. Up-regulation of tumor suppressor carcinoembryonic antigen-related cell adhesion molecule 1 in human colon cancer Caco-2 cells following repetitive exposure to dietary levels of a polyphenol-rich chokeberry juice.

    PubMed

    Bermúdez-Soto, María J; Larrosa, Mar; Garcia-Cantalejo, Jesús M; Espín, Juan C; Tomás-Barberan, Francisco A; García-Conesa, María T

    2007-04-01

    Consumption of berries and red fruits rich in polyphenols may contribute to the reduction of colon cancer through mechanisms not yet understood. In this study, we investigated the response of subconfluent Caco-2 cells (a human colon carcinoma model) to repetitive exposure (2 h a day for a 4-day period) of a subtoxic dose of a chokeberry (Aronia melanocarpa) juice containing mixed polyphenols. To mimic physiological conditions, we subjected the chokeberry juice to in vitro gastric and pancreatic digestion. The effects on viability, proliferation and cell cycle were determined, and changes in the expression of genes in response to the chokeberry treatment were screened using Affymetrix oligonucleotide microarrays. Exposure to the chokeberry juice inhibited Caco-2 cell proliferation by causing G(2)/M cell cycle arrest. We detected changes in the expression of a group of genes involved in cell growth and proliferation and cell cycle regulation, as well as those associated to colorectal cancer. A selection of these genes was further confirmed by quantitative RT-PCR. Among these, the tumor suppressor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), whose expression is known to be reduced in the majority of early adenomas and carcinomas, was up-regulated by the treatment both at the mRNA and protein levels (as shown by flow cytometry analysis). CEACAM1, with a significant regulatory role on cell proliferation of particular interest at early stages of cancer development, may be a potential target for chemoprevention by food components such as those present in polyphenol-rich fruits.

  15. FXR silencing in human colon cancer by DNA methylation and KRAS signaling.

    PubMed

    Bailey, Ann M; Zhan, Le; Maru, Dipen; Shureiqi, Imad; Pickering, Curtis R; Kiriakova, Galina; Izzo, Julie; He, Nan; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Liang, Han; Kopetz, Scott; Powis, Garth; Guo, Grace L

    2014-01-01

    Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

  16. AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival

    PubMed Central

    Fisher, Kurt W.; Das, Binita; Kim, Hyun Seok; Clymer, Beth K.; Gehring, Drew; Smith, Deandra R.; Costanzo-Garvey, Diane L.; Fernandez, Mario R.; Brattain, Michael G.; Kelly, David L.; MacMillan, John

    2015-01-01

    A major goal of cancer research is the identification of tumor-specific vulnerabilities that can be exploited for the development of therapies that are selectively toxic to the tumor. We show here that the transcriptional coactivators peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β) and estrogen-related receptor α (ERRα) are aberrantly expressed in human colon cell lines and tumors. With kinase suppressor of Ras 1 (KSR1) depletion as a reference standard, we used functional signature ontology (FUSION) analysis to identify the γ1 subunit of AMP-activated protein kinase (AMPK) as an essential contributor to PGC1β expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (α2β2γ1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1β. In contrast, PGC1β and ERRα are not detectable in nontransformed human colon epithelial cells, and depletion of the AMPKγ1 subunit has no effect on their viability. These data indicate that Ras oncogenesis relies on the aberrant activation of a PGC1β-dependent transcriptional pathway via a specific AMPK isoform. PMID:26351140

  17. Oral 5-fluorouracil colon-specific delivery through in vivo pellet coating for colon cancer and aberrant crypt foci treatment.

    PubMed

    Bose, A; Elyagoby, A; Wong, T W

    2014-07-01

    In situ coating of 5-fluorouracil pellets by ethylcellulose and pectin powder mixture (8:3 weight ratio) in capsule at simulated gastrointestinal media provides colon-specific drug release in vitro. This study probes into pharmacodynamic and pharmacokinetic profiles of intra-capsular pellets coated in vivo in rats with reference to their site-specific drug release outcomes. The pellets were prepared by extrusion-spheronization technique. In vitro drug content, drug release, in vivo pharmacokinetics, local colonic drug content, tumor, aberrant crypt foci, systemic hematology and clinical chemistry profiles of coated and uncoated pellets were examined against unprocessed drug. In vivo pellet coating led to reduced drug bioavailability and enhanced drug accumulation at colon (179.13 μg 5-FU/g rat colon content vs 4.66 μg/g of conventional in vitro film-coated pellets at 15 mg/kg dose). The in vivo coated pellets reduced tumor number and size, through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike uncoated pellets and unprocessed drug, the coated pellets eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. In vivo pellet coating to orally target 5-fluorouracil delivery at cancerous colon is a feasible therapeutic treatment approach.

  18. How MicroRNAs Influence both Hereditary and Inflammatory-mediated Colon Cancer

    PubMed Central

    Hutchison, Jennifer; Cohen, Zoe; Onyeaguchi, Benjamin C.; Funk, Janet; Nelson, Mark A.

    2013-01-01

    MicroRNAs have emerged as important post-translational regulators of gene expression and are involved in several physiological and pathological states including the pathogenesis of human colon cancers. In regards to tumor development, microRNAs can act as oncogenes or tumor suppressors. Both hereditary predispositions (i.e. Lynch Syndrome and Familial Adenomatous Polyposis) contribute to the development of colon cancer. In addition, individuals who suffer from inflammatory bowel diseases such as Crohn’s disease or ulcerative colitis have a higher risk of developing colon cancer. Here, we discuss the occurrence of the deregulated expression of miRNAs in colon cancer that arise due to hereditary predisposition and inflammatory bowel disease. PMID:24042167

  19. A case of very well-differentiated adenocarcinoma with carcinoid tumor in the ascending colon.

    PubMed

    Yamauchi, Hayato; Sakurai, Shinji; Tsukagoshi, Ritsuko; Suzuki, Masaki; Tabe, Yuichi; Fukasawa, Takaharu; Kiriyama, Shinsuke; Fukuchi, Minoru; Naitoh, Hiroshi; Kuwano, Hiroyuki

    2014-01-01

    Malignant tumors with mixed glandular and neuroendocrine characteristics with at least 30% of each component are classified as mixed adenoneuroendocrine carcinoma (MANEC) by the World Health Organization 2010 classification. We report here a case of very well-differentiated adenocarcinoma accompanied by carcinoid tumor, categorized as MANEC. A 41-year-old Japanese man was clinically diagnosed with ascending colon cancer and underwent right hemicolectomy. Using an immunohistologic technique, the pathologic diagnosis was very well-differentiated adenocarcinoma accompanied by carcinoid tumor and marked eosinophil infiltration, which was categorized as MANEC. By immunohistochemical analysis, tumor cells of the carcinoid component exhibited very low proliferation activity. Our case was thought to be MANEC without high malignant potential. MANEC as per the World Health Organization 2010 classification seems to include tumors with diverse grades of malignancy, and it might need to have subclassifications according to the malignancy potential of the tumor cells.

  20. Laparoscopic resection of colon Cancer: consensus of the European Association of Endoscopic Surgery (EAES).

    PubMed

    Veldkamp, R; Gholghesaei, M; Bonjer, H J; Meijer, D W; Buunen, M; Jeekel, J; Anderberg, B; Cuesta, M A; Cuschierl, A; Fingerhut, A; Fleshman, J W; Guillou, P J; Haglind, E; Himpens, J; Jacobi, C A; Jakimowicz, J J; Koeckerling, F; Lacy, A M; Lezoche, E; Monson, J R; Morino, M; Neugebauer, E; Wexner, S D; Whelan, R L

    2004-08-01

    The European Association of Endoscopic Surgery (EAES) initiated a consensus development conference on the laparoscopic resection of colon cancer during the annual congress in Lisbon, Portugal, in June 2002. A systematic review of the current literature was combined with the opinions, of experts in the field of colon cancer surgery to formulate evidence-based statements and recommendations on the laparoscopic resection of colon cancer. Advanced age, obesity, and previous abdominal operations are not considered absolute contraindications for laparoscopic colon cancer surgery. The most common cause for conversion is the presence of bulky or invasive tumors. Laparoscopic operation takes longer to perform than the open counterpart, but the outcome is similar in terms of specimen size and pathological examination. Immediate postoperative morbidity and mortality are comparable for laparoscopic and open colonic cancer surgery. The laparoscopically operated patients had less postoperative pain, better-preserved pulmonary function, earlier restoration of gastrointestinal function, and an earlier discharge from the hospital. The postoperative stress response is lower after laparoscopic colectomy. The incidence of port site metastases is <1%. Survival after laparoscopic resection of colon cancer appears to be at least equal to survival after open resection. The costs of laparoscopic surgery for colon cancer are higher than those for open surgery. Laparoscopic resection of colon cancer is a safe and feasible procedure that improves short-term outcome. Results regarding the long-term survival of patients enrolled in large multicenter trials will determine its role in general surgery.

  1. Colon cancer: it's CIN or CIMP.

    PubMed

    Issa, Jean-Pierre

    2008-10-01

    Combined genetic and epigenetic analysis of sporadic colon cancer suggest that it can no longer be viewed as a single disease. There are at least three different subsets with distinct clinico-pathologic features, with important implications for preventions, screening, and therapy.

  2. Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer

    PubMed Central

    Richter, Cornelia; Herrero San Juan, Martina; Weigmann, Benno; Bergis, Dominik; Dauber, Katrin; Muders, Michael H.; Baretton, Gustavo B.; Pfeilschifter, Josef Martin; Bonig, Halvard; Brenner, Sebastian; Radeke, Heinfried H.

    2017-01-01

    In the colon, a sophisticated balance between immune reaction and tolerance is absolutely required. Dysfunction may lead to pathologic phenotypes ranging from chronic inflammatory processes to cancer development. Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively. In this study, we investigated the impact of the NADPH oxidase protein p47phox, which negatively regulates IL-12 in dendritic cells, on colon cancer development in a colitis-associated colon cancer model. Initially, we found that IL-12−/− mice developed less severe colitis but are highly susceptible to colon cancer. By contrast, p47phox−/− mice showed lower tumor scores and fewer high grade tumors than wild-type (WT) littermates. Treatment with toll-like receptor 9 ligand CpG2216 significantly enhanced colitis in p47phox−/− mice, whereas tumor growth was simultaneously reduced. In tumor tissue of p47phox−/− mice, the IL-23/IL-17 axis was crucially hampered. IL-23p19 protein expression in tumor tissue correlated with tumor stage. Reconstitution of WT mice with IL-23p19−/− bone marrow protected these mice from colon cancer, whereas transplantation of WT hematopoiesis into IL-23p19−/− mice increased the susceptibility to tumor growth. Our study strengthens the divergent role of IL-12 and IL-23 in colon cancer development. With the characterization of p47phox as a novel modulator of both cytokines our investigation introduces a promising new target for antitumor strategies. PMID:28191009

  3. Optimization of chitosan nanoparticles for colon tumors using experimental design methodology.

    PubMed

    Jain, Anekant; Jain, Sanjay K

    2016-12-01

    Purpose Colon-specific drug delivery systems (CDDS) can improve the bio-availability of drugs through the oral route. A novel formulation for oral administration using ligand coupled chitosan nanoparticles bearing 5-Flurouracil (5FU) encapsulated in enteric coated pellets has been investigated for CDDS. Method The effect of polymer concentration, drug concentration, stirring time and stirring speed on the encapsulation efficiency, and size of nanoparticles were evaluated. The best (or optimum) formulation was obtained by response surface methodology. Using the experimental data, analysis of variance has been carried out to evolve linear empirical models. Using a new methodology, polynomial models have been evolved and the parametric analysis has been carried out. In order to target nanoparticles to the hyaluronic acid (HA) receptors present on colon tumors, HA coupled nanoparticles were tested for their efficacy in vivo. The HA coupled nanoparticles were encapsulated in pellets and were enteric coated to release the drug in the colon. Results Drug release studies under conditions of mimicking stomach to colon transit have shown that the drug was protected from being released in the physiological environment of the stomach and small intestine. The relatively high local drug concentration with prolonged exposure time provides a potential to enhance anti-tumor efficacy with low systemic toxicity for the treatment of colon cancer. Conclusions Conclusively, HA coupled nanoparticles can be considered as the potential candidate for targeted drug delivery and are anticipated to be promising in the treatment of colorectal cancer.

  4. Identification of colonic fibroblast secretomes reveals secretory factors regulating colon cancer cell proliferation.

    PubMed

    Chen, Sun-Xia; Xu, Xiao-En; Wang, Xiao-Qing; Cui, Shu-Jian; Xu, Lei-Lei; Jiang, Ying-Hua; Zhang, Yang; Yan, Hai-Bo; Zhang, Qian; Qiao, Jie; Yang, Peng-Yuan; Liu, Feng

    2014-10-14

    Stromal microenvironment influences tumor cell proliferation and migration. Fibroblasts represent the most abundant stromal constituents. Here, we established two pairs of normal fibroblast (NF) and cancer-associated fibroblast (CAF) cultures from colorectal adenocarcinoma tissues and the normal counterparts. The NFs and CAFs were stained positive for typical fibroblast markers and inhibited colon cancer (CC) cell proliferation in in vitro cocultures and in xenograft mouse models. The fibroblast conditioned media were analyzed using LC-MS and 227 proteins were identified at a false discovery rate of 1.3%, including 131 putative secretory and 20 plasma membrane proteins. These proteins were enriched for functional categories of extracellular matrix, adhesion, cell motion, inflammatory response, redox homeostasis and peptidase inhibitor. Secreted protein acidic and rich in cysteine, transgelin, follistatin-related protein 1 (FSTL1) and decorin was abundant in the fibroblast secretome as confirmed by Western blot. Silencing of FSTL1 and transgelin in colonic fibroblast cell line CCD-18Co induced an accelerated proliferation of CC cells in cocultures. Exogenous FSTL1 attenuates CC cell proliferation in a negative fashion. FSTL1 was upregulated in CC patient plasma and cancerous tissues but had no implication in prognosis. Our results provided novel insights into the molecular signatures and modulatory role of CC associated fibroblasts. In this study, a label-free LC-MS was performed to analyze the secretomes of two paired primary fibroblasts, which were isolated from fresh surgical specimen of colorectal adenocarcinoma and adjacent normal colonic tissues and exhibited negative modulatory activity for colon cancer cell growth in in vitro cocultures and in vivo xenograph mouse models. Follistatin-related protein 1 was further revealed to be one of the stroma-derived factors of potential suppression role for colon cancer cell proliferation. Our results provide novel

  5. Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis

    PubMed Central

    Ro, Seung-Hyun; Xue, Xiang; Ramakrishnan, Sadeesh K; Cho, Chun-Seok; Namkoong, Sim; Jang, Insook; Semple, Ian A; Ho, Allison; Park, Hwan-Woo; Shah, Yatrik M; Lee, Jun Hee

    2016-01-01

    The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53’s control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis. DOI: http://dx.doi.org/10.7554/eLife.12204.001 PMID:26913956

  6. Patient Beliefs About Colon Cancer Screening.

    PubMed

    Ely, John W; Levy, Barcey T; Daly, Jeanette; Xu, Yinghui

    2016-03-01

    Only about half of eligible individuals undergo colon cancer screening. We have limited knowledge about the patient beliefs that adversely affect screening decisions and about which beliefs might be amenable to change through education. As part of a clinical trial, 641 rural Iowans, aged 52 to 79 years, reported their beliefs about colon cancer screening in response to a mailed questionnaire. Consenting subjects were randomized into four groups, which were distinguished by four levels of increasingly intensive efforts to promote screening. Two of the groups received mailed educational materials and completed a follow-up questionnaire, which allowed us to determine whether their beliefs about screening changed following the education. We also completed a factor analysis to identify underlying (latent) factors that might explain the responses to 33 questions about readiness, attitudes, and perceived barriers related to colon cancer screening. The strongest predictors of a patient's stated readiness to be screened were a physician's recommendation to be screened (1 point difference on 10-point Likert scale, 95 % confidence interval [CI], 0.5 to 1.6 point difference), a family history of colon cancer (0.85-point Likert scale difference, 95 % CI, 0.1 to 1.6), and a belief that health-care decisions should be mostly left to physicians rather than patients (Spearman correlation coefficient 0.21, P < .001). Of the 33 questionnaire items about screening beliefs, 11 (33 %) changed favorably following the educational intervention. In the factor analysis, the 33 items were reduced to 8 underlying factors, such as being too busy to undergo screening and worries about screening procedures. We found a limited number of underlying factors that may help explain patient resistance to colon cancer screening.

  7. Clinical significance and prognostic value of Nek2 protein expression in colon cancer.

    PubMed

    Lu, Lei; Zhai, Xiaofeng; Yuan, Ronghua

    2015-01-01

    To determine the expression of NIMA-related kinase NEK2 and evaluate its clinical value in colon cancer. Sixty specimens of colon cancer, 30 specimens of paracancerous colon tissues and 10 specimens of normal colon tissues conventionally resected in surgery at the Second Affiliated Hospital of Nantong University from February 2006 to February 2014 were collected. These tissues were detected for the expression of Nek2 using Western Blot and immunohistochemical staining. The relationship between Nek2 protein expression and the clinicopathology and prognosis of colon tissues was discussed. The expression level and positive expression rate of Nek2 protein in the colon cancer were obviously higher than that in the paracancerous tissues and normal colon tissues. They were also significantly higher in the paracancerous tissues than in the normal tissues (P<0.05). Statistical analysis revealed that Nek2 protein expression was not obviously correlated with gender, age and tumor size, but obviously correlated with degree of differentiation (P=0.008), TNM staging (P=0.000), lymph node metastasis (P=0.022) and tumor invasion (P=0.011). With the plotting of Kaplan-Meier survival curve, it could be seen that Nek2 protein expression was not significantly correlated with survival (P=0.0048). High Nek2 protein expression may be an independent risk factor for colon cancer (HR=0.227, 95% CI 0.101-0.510). High Nek2 protein expression reflects the malignant behavior of colon cancer. Playing important roles in the occurrence of colon cancer, Nek2 protein expression has diagnostic and prognostic value in colon cancer.

  8. Clinical significance and prognostic value of Nek2 protein expression in colon cancer

    PubMed Central

    Lu, Lei; Zhai, Xiaofeng; Yuan, Ronghua

    2015-01-01

    Objective: To determine the expression of NIMA-related kinase NEK2 and evaluate its clinical value in colon cancer. Method: Sixty specimens of colon cancer, 30 specimens of paracancerous colon tissues and 10 specimens of normal colon tissues conventionally resected in surgery at the Second Affiliated Hospital of Nantong University from February 2006 to February 2014 were collected. These tissues were detected for the expression of Nek2 using Western Blot and immunohistochemical staining. The relationship between Nek2 protein expression and the clinicopathology and prognosis of colon tissues was discussed. Results: The expression level and positive expression rate of Nek2 protein in the colon cancer were obviously higher than that in the paracancerous tissues and normal colon tissues. They were also significantly higher in the paracancerous tissues than in the normal tissues (P<0.05). Statistical analysis revealed that Nek2 protein expression was not obviously correlated with gender, age and tumor size, but obviously correlated with degree of differentiation (P=0.008), TNM staging (P=0.000), lymph node metastasis (P=0.022) and tumor invasion (P=0.011). With the plotting of Kaplan-Meier survival curve, it could be seen that Nek2 protein expression was not significantly correlated with survival (P=0.0048). High Nek2 protein expression may be an independent risk factor for colon cancer (HR=0.227, 95% CI 0.101-0.510). Conclusion: High Nek2 protein expression reflects the malignant behavior of colon cancer. Playing important roles in the occurrence of colon cancer, Nek2 protein expression has diagnostic and prognostic value in colon cancer. PMID:26823916

  9. Butyrate-rich Colonic Microenvironment Is a Relevant Selection Factor for Metabolically Adapted Tumor Cells*

    PubMed Central

    Serpa, Jacinta; Caiado, Francisco; Carvalho, Tânia; Torre, Cheila; Gonçalves, Luís G.; Casalou, Cristina; Lamosa, Pedro; Rodrigues, Margarida; Zhu, Zhenping; Lam, Eric W. F.; Dias, Sérgio

    2010-01-01

    The short chain fatty acid (SCFA) buyrate is a product of colonic fermentation of dietary fibers. It is the main source of energy for normal colonocytes, but cannot be metabolized by most tumor cells. Butyrate also functions as a histone deacetylase (HDAC) inhibitor to control cell proliferation and apoptosis. In consequence, butyrate and its derived drugs are used in cancer therapy. Here we show that aggressive tumor cells that retain the capacity of metabolizing butyrate are positively selected in their microenvironment. In the mouse xenograft model, butyrate-preselected human colon cancer cells gave rise to subcutaneous tumors that grew faster and were more angiogenic than those derived from untreated cells. Similarly, butyrate-preselected cells demonstrated a significant increase in rates of homing to the lung after intravenous injection. Our data showed that butyrate regulates the expression of VEGF and its receptor KDR at the transcriptional level potentially through FoxM1, resulting in the generation of a functional VEGF:KDR autocrine growth loop. Cells selected by chronic exposure to butyrate express higher levels of MMP2, MMP9, α2 and α3 integrins, and lower levels of E-cadherin, a marker for epithelial to mesenchymal transition. The orthotopic model of colon cancer showed that cells preselected by butyrate are able to colonize the animals locally and at distant organs, whereas control cells can only generate a local tumor in the cecum. Together our data shows that a butyrate-rich microenvironment may select for tumor cells that are able to metabolize butyrate, which are also phenotypically more aggressive. PMID:20926374

  10. Cell surface fucosylation does not affect development of colon tumors in mice with germline Smad3 mutation

    PubMed Central

    Domino, Steven E.; Karnak, David M.; Hurd, Elizabeth A.

    2006-01-01

    Background/Aims: Neoplasia-related alterations in cell surface α(1,2)fucosylated glycans have been reported in multiple tumors including colon, pancreas, endometrium, cervix, bladder, lung, and choriocarcinoma. Spontaneous colorectal tumors from mice with a germline null mutation of transforming growth factor-β signaling gene Smad3 (Madh3) were tested for α(1,2)fucosylated glycan expression. Methods: Ulex Europaeus Agglutinin-I lectin staining, fucosyltransferase gene northern blot analysis, and a cross of mutant mice with Fut2 and Smad3 germline mutations were performed. Results: Spontaneous colorectal tumors from Smad3 (-/-) homozygous null mice were found to express α(1,2)fucosylated glycans in an abnormal pattern compared to adjacent nonneoplastic colon. Northern blot analysis of α(1,2)fucosyltransferase genes Fut1 and Fut2 revealed that Fut2, but not Fut1, steady-state mRNA levels were significantly increased in tumors relative to adjacent normal colonic mucosa. Mutant mice with a Fut2-inactivating germline mutation were crossed with Smad3 targeted mice. In Smad3 (-/-)/Fut2 (-/-) double knock-out mice, UEA-I lectin staining was eliminated from colon and colon tumors, however, the number and size of tumors present by 24 weeks of age did not vary regardless of the Fut2 genotype. Conclusions: In this model of colorectal cancer, cell surface α(1,2)fucosylation does not affect development of colon tumors. PMID:17264540

  11. Isolation and phenotypic characterization of cancer stem-like side population cells in colon cancer.

    PubMed

    Feng, Long; Wu, Jian-Bing; Yi, Feng-Ming

    2015-09-01

    Previous studies in cancer biology suggest that chemotherapeutic drug resistance and tumor relapse are driven by cells within a tumor termed 'cancer stem cells'. In the present study, a Hoechst 33342 dye exclusion technique was used to identify cancer stem‑like side population (SP) cells in colon carcinoma, which accounted for 3.4% of the total cell population. Following treatment with verapamil, the population of SP cells was reduced to 0.6%. In addition, the sorted SP cells exhibited marked multidrug resistance and enhanced cell survival rates compared with non‑SP cells. The SP cells were able to generate more tumor spheres and were CD133 positive. Subsequent biochemical analysis revealed that the levels of the adenosine triphosphate‑binding cassette sub‑family G member 2 transporter protein, B‑cell lymphoma anti‑apoptotic factor and autocrine production of interleukin‑4 were significantly enhanced in the colon cancer SP cells, which contributed to drug resistance, protection of the cells from apoptosis and tumor recurrence. Therefore, the findings suggested that treatment failure and colon tumorigenesis is dictated by a small population of SP cells, which indicate a potential target in future therapies.

  12. Role of colonic stents in the management of colorectal cancers

    PubMed Central

    Sagar, Jayesh

    2016-01-01

    Colorectal cancer is one of the commonly encountered cancers across the Western World. In United Kingdom, this constitutes third most common ranked cancer and second most common ranked cause of cancer related deaths. Its acute presentation as a malignant colonic obstruction imposes challenges in its management. Colonic stent has been used for many years to alleviate acute obstruction in such cases allowing optimisation of patient’s physiological status and adequate staging of cancer. In this review, current literature evidence regarding use of colonic stent in acute malignant colonic obstruction is critically appraised and recommendations on the use of colonic stent are advocated. PMID:26962401

  13. Modulation of colon cancer by nutmeg.

    PubMed

    Li, Fei; Yang, Xiu-Wei; Krausz, Kristopher W; Nichols, Robert G; Xu, Wei; Patterson, Andrew D; Gonzalez, Frank J

    2015-04-03

    Colon cancer is the most common cancer and the third leading cause of cancer mortality in humans. Using mass spectrometry-based metabolomics, the current study revealed the accumulation of four uremic toxins (cresol sulfate, cresol glucuronide, indoxyl sulfate, and phenyl sulfate) in the serum of mice harboring adenomatous polyposis coli (APC) gene mutation-induced colon cancer. These uremic toxins, likely generated from the gut microbiota, were associated with an increase in the expression of the proinflammatory cytokine IL-6 and a disorder of lipid metabolism. Nutmeg, which exhibits antimicrobial activity, attenuated the levels of uremic toxins and decreased intestinal tumorigenesis in Apc(min/+) mice. Nutmeg-treated Apc(min/+) mice had decreased IL-6 levels and normalized dysregulated lipid metabolism, suggesting that uremic toxins are responsible, in part, for the metabolic disorders that occur during tumorigenesis. These studies demonstrate a potential biochemical link among gut microbial metabolism, inflammation, and metabolic disorders and suggest that modulation of gut microbiota and lipid metabolism using dietary intervention or drugs may be effective in colon cancer chemoprevention strategies.

  14. Linear Discriminant Functions in Connection with the micro-RNA Diagnosis of Colon Cancer.

    PubMed

    Nikas, Jason B; Low, Walter C

    2012-01-01

    Early detection (localized stage) of colon cancer is associated with a five-year survival rate of 91%. Only 39% of colon cancers, however, are diagnosed at that early stage. Early and accurate diagnosis, therefore, constitutes a critical need and a decisive factor in the clinical treatment of colon cancer and its success. In this study, using supervised linear discriminant analysis, we have developed three diagnostic biomarker models that-based on global micro-RNA expression analysis of colonic tissue collected during surgery-can discriminate with a perfect accuracy between subjects with colon cancer (stages II-IV) and normal healthy subjects. We developed our three diagnostic biomarker models with 57 subjects [40 with colon cancer (stages II-IV) and 17 normal], and we validated them with 39 unknown (new and different) subjects [28 with colon cancer (stages II-IV) and 11 normal]. For all three diagnostic models, both the overall sensitivity and specificity were 100%. The nine most significant micro-RNAs identified, which comprise the input variables to the three linear discriminant functions, are associated with genes that regulate oncogenesis, and they play a paramount role in the development of colon cancer, as evidenced in the tumor tissue itself. This could have a significant impact in the fight against this disease, in that it may lead to the development of an early serum or blood diagnostic test based on the detection of those nine key micro-RNAs.

  15. Coffee, colon function and colorectal cancer.

    PubMed

    Vitaglione, Paola; Fogliano, Vincenzo; Pellegrini, Nicoletta

    2012-09-01

    For several years the physiological effects of coffee have been focused on its caffeine content, disregarding the hundreds of bioactive coffee components, such as polyphenols, melanoidins, carbohydrates, diterpenes, etc. These compounds may exert their protection against colorectal cancer (CRC), the third most common cancer worldwide. However, the amount and type of compounds ingested with the beverage may be highly different depending on the variety of coffee used, the roasting degree, the type of brewing method as well as the serving size. In this frame, this paper reviews the mechanisms by which coffee may influence the risk of CRC development focusing on espresso and filtered coffee, as well as on the components that totally or partially reach the colon i.e. polyphenols and dietary fiber, including melanoidins. In particular the effects of coffee on some colon conditions whose deregulation may lead to cancer, namely microbiota composition and lumen reducing environment, were considered. Taken together the discussed studies indicated that, due to their in vivo metabolism and composition, both coffee chlorogenic acids and dietary fiber, including melanoidins, may reduce CRC risk, increasing colon motility and antioxidant status. Further studies should finally assess whether the coffee benefits for colon are driven through a prebiotic effect.

  16. Variation in the CYP19A1 gene and risk of colon and rectal cancer.

    PubMed

    Slattery, Martha L; Lundgreen, Abbie; Herrick, Jennifer S; Kadlubar, Susan; Caan, Bette J; Potter, John D; Wolff, Roger K

    2011-07-01

    CYP19A1, or aromatase, influences estrogen-metabolizing enzymes and may influence cancer risk. We examine variation in the CYP19A1 gene and risk of colorectal cancer using data from population-based case-control studies (colon n = 1,574 cases, 1,970 controls; rectal n = 791 cases, 999 controls). Four SNPs were statistically significantly associated with colon cancer and four were associated with rectal cancer. After adjustment for multiple comparisons, the AA genotype of rs12591359 was associated with an increased risk of colon cancer (OR 1.44 95% CI 1.16-1.80) and the AA genotype of rs2470144 was associated with a reduced risk of rectal cancer (OR 0.65 95% CI 0.50-0.84). Variants of CYP19A1 were associated with CIMP+ and CIMP+/KRAS2-mutated tumors. CT/TT genotypes of rs1961177 were significantly associated with an increased likelihood of a MSI+ colon tumor (OR 1.77 95% CI 1.26-2.37). We observed statistically significant interactions between genetic variation in NFκB1 and CYP19A1 for both colon and rectal cancer. Our data suggest the importance of CYP19A1 in the development of colon and rectal cancer and that estrogen may influence risk through an inflammation-related mechanism.

  17. Rectal prolapse as initial clinical manifestation of colon cancer.

    PubMed

    Chen, C-W; Hsiao, C-W; Wu, C-C; Jao, S-W

    2008-04-01

    Rectal prolapse as the initial clinical manifestation of colorectal cancer is uncommon. We describe the case of a 75-year-old woman who was diagnosed as having adenocarcinoma of the sigmoid colon after presenting with complete rectal prolapse. The tumor caused rectosigmoid intussusception and then it prolapsed out through the anus. She underwent rectosigmoidectomy and rectopexy. The postoperative course was uneventful. The relationship between colorectal cancer and rectal prolapse has not been clearly established. This case report describes an unusual presentation of colorectal cancer. It suggests that rectal prolapse can present as the initial symptom of colorectal cancer and may also be a presenting feature of the occult intra-abdominal pathology. The importance of adequate investigation such as colonoscopy should be emphasized in patients who develop a new onset of rectal prolapse.

  18. Prognostic significance of preoperative fibrinogen in patients with colon cancer

    PubMed Central

    Sun, Zhen-Qiang; Han, Xiao-Na; Wang, Hai-Jiang; Tang, Yong; Zhao, Ze-Liang; Qu, Yan-Li; Xu, Rui-Wei; Liu, Yan-Yan; Yu, Xian-Bo

    2014-01-01

    AIM: To investigate the prognostic significance of preoperative fibrinogen levels in colon cancer patients. METHODS: A total of 255 colon cancer patients treated at the Affiliated Tumor Hospital of Xinjiang Medical University from June 1st 2005 to June 1st 2008 were enrolled in the study. All patients received radical surgery as their primary treatment method. Preoperative fibrinogen was detected by the Clauss method, and all patients were followed up after surgery. Preoperative fibrinogen measurements were correlated with a number of clinicopathological parameters using the Student t test and analysis of variance. Survival analyses were performed by the Kaplan-Meier method and Cox regression modeling to measure 5-year disease-free survival (DFS) and overall survival (OS). RESULTS: The mean preoperative fibrinogen concentration of all colon cancer patients was 3.17 ± 0.88 g/L. Statistically significant differences were found between preoperative fibrinogen levels and the clinicopathological parameters of age, smoking status, tumor size, tumor location, tumor-node-metastasis (TNM) stage, modified Glasgow prognostic scores (mGPS), white blood cell (WBC) count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA) levels. Univariate survival analysis showed that TNM stage, tumor cell differentiation grade, vascular invasion, mGPS score, preoperative fibrinogen, WBC, NLR, PLR and CEA all correlated with both OS and DFS. Alpha-fetoprotein (AFP) and body mass index correlated only with OS. Kaplan-Meier analysis revealed that both OS and DFS of the total cohort, as well as of the stage II and III patients, were higher in the hypofibrinogen group compared to the hyperfibrinogen group (all P < 0.05). In contrast, there was no significant difference between OS and DFS in stage I patients with low or high fibrinogen levels. Cox regression analysis indicated preoperative fibrinogen levels, TNM stage, mGPS score, CEA, and

  19. Prognostic significance of preoperative fibrinogen in patients with colon cancer.

    PubMed

    Sun, Zhen-Qiang; Han, Xiao-Na; Wang, Hai-Jiang; Tang, Yong; Zhao, Ze-Liang; Qu, Yan-Li; Xu, Rui-Wei; Liu, Yan-Yan; Yu, Xian-Bo

    2014-07-14

    To investigate the prognostic significance of preoperative fibrinogen levels in colon cancer patients. A total of 255 colon cancer patients treated at the Affiliated Tumor Hospital of Xinjiang Medical University from June 1(st) 2005 to June 1(st) 2008 were enrolled in the study. All patients received radical surgery as their primary treatment method. Preoperative fibrinogen was detected by the Clauss method, and all patients were followed up after surgery. Preoperative fibrinogen measurements were correlated with a number of clinicopathological parameters using the Student t test and analysis of variance. Survival analyses were performed by the Kaplan-Meier method and Cox regression modeling to measure 5-year disease-free survival (DFS) and overall survival (OS). The mean preoperative fibrinogen concentration of all colon cancer patients was 3.17 ± 0.88 g/L. Statistically significant differences were found between preoperative fibrinogen levels and the clinicopathological parameters of age, smoking status, tumor size, tumor location, tumor-node-metastasis (TNM) stage, modified Glasgow prognostic scores (mGPS), white blood cell (WBC) count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA) levels. Univariate survival analysis showed that TNM stage, tumor cell differentiation grade, vascular invasion, mGPS score, preoperative fibrinogen, WBC, NLR, PLR and CEA all correlated with both OS and DFS. Alpha-fetoprotein (AFP) and body mass index correlated only with OS. Kaplan-Meier analysis revealed that both OS and DFS of the total cohort, as well as of the stage II and III patients, were higher in the hypofibrinogen group compared to the hyperfibrinogen group (all P < 0.05). In contrast, there was no significant difference between OS and DFS in stage I patients with low or high fibrinogen levels. Cox regression analysis indicated preoperative fibrinogen levels, TNM stage, mGPS score, CEA, and AFP levels correlated

  20. The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals.

    PubMed

    Koblansky, A Alicia; Truax, Agnieszka D; Liu, Rongrong; Montgomery, Stephanie A; Ding, Shengli; Wilson, Justin E; Brickey, W June; Mühlbauer, Marcus; McFadden, Rita-Marie T; Hu, Peizhen; Li, Zengshan; Jobin, Christian; Lund, Pauline Kay; Ting, Jenny P-Y

    2016-03-22

    NOD-like receptor (NLR) proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1(-/-) mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and interleukin 6 (IL-6). The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apc(min/+) genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apc(min/+) colon tumorigenesis, cellular proliferation, NF-κB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R) antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1(-/-)Apc(min/+) mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1.

  1. Radioimmunoguided surgery in primary colon cancer

    SciTech Connect

    Nieroda, C.A.; Mojzisik, C.; Sardi, A.; Ferrara, P.J.; Hinkle, G.; Thurston, M.O.; Martin, E.W. Jr. )

    1990-01-01

    Radioimmunoguided surgery (RIGS), the intraoperative use of a hand-held gamma detecting probe (GDP) to identify tissue containing radiolabeled monoclonal antibody (MAb), was performed upon 30 patients with primary colon carcinoma. Each patient received an intravenous injection of MAb B72.3 (1.0 to 0.25 mg) radiolabeled with {sup 125}I (5.0 to 1.0 mCi) 8 to 34 days before exploration. The GDP was used to measure radioactivity in colon tissue, tumor bed, nodal drainage areas, and areas of suspected metastases. Antibody localized to histologically documented tumor in 23 of 30 patients (77%). Tumor margins were more clearly defined in 20 of 30 patients (67%). GDP counts led to major alterations in surgical resection in five patients (17%) and changes in adjuvant therapy in four (14%). GDP counts identified occult liver metastases in two patients (7%) and correctly indicated the benign nature of liver masses in three (10%). In four patients (13%), occult nodal metastases were identified. RIGS can precisely delineate tumor margins, define the extent of nodal involvement, and localize occult tumor, providing a method of immediate intraoperative staging that may lessen recurrences and produce higher survival rates.

  2. Circadian Clock in a Mouse Colon Tumor Regulates Intracellular Iron Levels to Promote Tumor Progression*

    PubMed Central

    Okazaki, Fumiyasu; Matsunaga, Naoya; Okazaki, Hiroyuki; Azuma, Hiroki; Hamamura, Kengo; Tsuruta, Akito; Tsurudome, Yuya; Ogino, Takashi; Hara, Yukinori; Suzuki, Takuya; Hyodo, Kenji; Ishihara, Hiroshi; Kikuchi, Hiroshi; To, Hideto; Aramaki, Hironori; Koyanagi, Satoru; Ohdo, Shigehiro

    2016-01-01

    Iron is an important biological catalyst and is critical for DNA synthesis during cell proliferation. Cellular iron uptake is enhanced in tumor cells to support increased DNA synthesis. Circadian variations in DNA synthesis and proliferation have been identified in tumor cells, but their relationship with intracellular iron levels is unclear. In this study, we identified a 24-h rhythm in iron regulatory protein 2 (IRP2) levels in colon-26 tumors implanted in mice. Our findings suggest that IRP2 regulates the 24-h rhythm of transferrin receptor 1 (Tfr1) mRNA expression post-transcriptionally, by binding to RNA stem-loop structures known as iron-response elements. We also found that Irp2 mRNA transcription is promoted by circadian clock genes, including brain and muscle Arnt-like 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK) heterodimer. Moreover, growth in colon-26(Δ19) tumors expressing the clock-mutant protein (CLOCKΔ19) was low compared with that in wild-type colon-26 tumor. The time-dependent variation of cellular iron levels, and the proliferation rate in wild-type colon-26 tumor was decreased by CLOCKΔ19 expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor. PMID:26797126

  3. Predicting survival after curative colectomy for cancer: individualizing colon cancer staging.

    PubMed

    Weiser, Martin R; Gönen, Mithat; Chou, Joanne F; Kattan, Michael W; Schrag, Deborah

    2011-12-20

    Cancer staging determines extent of disease, facilitating prognostication and treatment decision making. The American Joint Committee on Cancer (AJCC) TNM classification system is the most commonly used staging algorithm for colon cancer, categorizing patients on the basis of only these three variables (tumor, node, and metastasis). The purpose of this study was to extend the seventh edition of the AJCC staging system for colon cancer to incorporate additional information available from tumor registries, thereby improving prognostic accuracy. Records from 128,853 patients with primary colon cancer reported to the Surveillance, Epidemiology and End Results Program from 1994 to 2005 were used to construct and validate three survival models for patients with primary curative-intent surgery. Independent training/test data sets were used to develop and test alternative models. The seventh edition TNM staging system was compared with models supplementing TNM staging with additional demographic and tumor variables available from the registry by calculating a concordance index, performing calibration, and identifying the area under receiver operating characteristic (ROC) curves. Inclusion of additional registry covariates improved prognostic estimates. The concordance index rose from 0.60 (95% CI, 0.59 to 0.61) for the AJCC model, with T- and N-stage variables, to 0.68 (95% CI, 0.67 to 0.68) for the model including tumor grade, number of collected metastatic lymph nodes, age, and sex. ROC curves for the extended model had higher sensitivity, at all values of specificity, than the TNM system; calibration curves indicated no deviation from the reference line. Prognostic models incorporating readily available data elements outperform the current AJCC system. These models can assist in personalizing treatment and follow-up for patients with colon cancer.

  4. Tumor-associated macrophages favor C26 murine colon carcinoma cell proliferation in an oxidative stress-dependent manner.

    PubMed

    Luput, Lavinia; Licarete, Emilia; Sesarman, Alina; Laura, Patras; Alupei, Marius Costel; Banciu, Manuela

    2017-02-17

    The role of tumor-associated macrophages (TAMs) in the development of colon carcinoma is still controversial. Therefore, the present study aimed to investigate the TAM‑driven processes that may affect colon cancer cell proliferation. To achieve this purpose, murine macrophages were co-cultured with C26 murine colon carcinoma cells at a cell density ratio that approximates physiological conditions for colon carcinoma development in vivo. In this respect, the effects of TAM-mediated angiogenesis, inflammation and oxidative stress on the proliferative capacity of C26 murine colon carcinoma cells were studied. To gain insight into the TAM-driven oxidative stress, NADPH oxidase, the main pro-oxidant enzyme in macrophages, was inhibited. Our data revealed that the stimulatory effects of TAMs on C26 cell proliferation may be related mainly to their pro-oxidant actions exerted by NADPH oxidase activity, which maintains the redox status and the angiogenic capacity of the tumor microenvironment. Additionally, the anti-inflammatory and pro-angiogenic effects of TAMs on tumor cells were found to create a favorable microenvironment for C26 colon carcinoma development and progression. In conclusion, our data confirmed the protumor role of TAMs in the development of colon carcinoma in an oxidative stress-dependent manner that potentiates the angiogenic capacity of the tumor microenvironment. These data may offer valuable information for future tumor-targeted therapies based on TAM 're-education' strategies.

  5. Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis

    PubMed Central

    Wu, Zhen-Zhen; Chen, Li-Shan; Zhou, Rui; Bin, Jian-Ping; Liao, Yu-Lin; Liao, Wang-Jun

    2016-01-01

    Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer (GC), MACC1 has been shown to be involved in oncogenesis and tumor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelial-to-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry (VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment. PMID:27547006

  6. Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer.

    PubMed

    Iwasaki, Kenichi; Zheng, Yun-Wen; Murata, Soichiro; Ito, Hiromu; Nakayama, Ken; Kurokawa, Tomohiro; Sano, Naoki; Nowatari, Takeshi; Villareal, Myra O; Nagano, Yumiko N; Isoda, Hiroko; Matsui, Hirofumi; Ohkohchi, Nobuhiro

    2016-11-28

    To investigate the anticancer mechanisms of the monoterpenoid alcohol linalool in human colon cancer cells. The cytotoxic effect of linalool on the human colon cancer cell lines and a human fibroblast cell line was examined using the WST-8 assay. The apoptosis-inducing effect of linalool was measured using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and flow cytometry with Annexin V. Oxidative stress was investigated by staining for diphenyl-1-pyrenylphosphine, which is a cellular lipid peroxidation marker, and electron spin resonance spectroscopy. Sixteen SCID mice xenografted with human cancer cells were randomized into 3 groups for in vivo analysis: control and low-dose and high-dose linalool groups. The control group was administered tap water orally every 3 d. The linalool treatment groups were administered 100 or 200 μg/kg linalool solution orally for the same period. All mice were sacrificed under anesthesia 21 d after tumor inoculation, and tumors and organs were collected for immunohistochemistry using an anti-4-hydroxynonenal antibody. Tumor weights were measured and compared between groups. Linalool induced apoptosis of cancer cells in vitro, following the cancer-specific induction of oxidative stress, which was measured based on spontaneous hydroxyl radical production and delayed lipid peroxidation. Mice in the high-dose linalool group exhibited a 55% reduction in mean xenograft tumor weight compared with mice in the control group (P < 0.05). In addition, tumor-specific lipid peroxidation was observed in the in vivo model. Linalool exhibited an anticancer effect via cancer-specific oxidative stress, and this agent has potential for application in colon cancer therapy.

  7. Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer

    PubMed Central

    Iwasaki, Kenichi; Zheng, Yun-Wen; Murata, Soichiro; Ito, Hiromu; Nakayama, Ken; Kurokawa, Tomohiro; Sano, Naoki; Nowatari, Takeshi; Villareal, Myra O; Nagano, Yumiko N; Isoda, Hiroko; Matsui, Hirofumi; Ohkohchi, Nobuhiro

    2016-01-01

    AIM To investigate the anticancer mechanisms of the monoterpenoid alcohol linalool in human colon cancer cells. METHODS The cytotoxic effect of linalool on the human colon cancer cell lines and a human fibroblast cell line was examined using the WST-8 assay. The apoptosis-inducing effect of linalool was measured using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and flow cytometry with Annexin V. Oxidative stress was investigated by staining for diphenyl-1-pyrenylphosphine, which is a cellular lipid peroxidation marker, and electron spin resonance spectroscopy. Sixteen SCID mice xenografted with human cancer cells were randomized into 3 groups for in vivo analysis: control and low-dose and high-dose linalool groups. The control group was administered tap water orally every 3 d. The linalool treatment groups were administered 100 or 200 μg/kg linalool solution orally for the same period. All mice were sacrificed under anesthesia 21 d after tumor inoculation, and tumors and organs were collected for immunohistochemistry using an anti-4-hydroxynonenal antibody. Tumor weights were measured and compared between groups. RESULTS Linalool induced apoptosis of cancer cells in vitro, following the cancer-specific induction of oxidative stress, which was measured based on spontaneous hydroxyl radical production and delayed lipid peroxidation. Mice in the high-dose linalool group exhibited a 55% reduction in mean xenograft tumor weight compared with mice in the control group (P < 0.05). In addition, tumor-specific lipid peroxidation was observed in the in vivo model. CONCLUSION Linalool exhibited an anticancer effect via cancer-specific oxidative stress, and this agent has potential for application in colon cancer therapy. PMID:27956800

  8. Colon cancer: cancer stem cells markers, drug resistance and treatment.

    PubMed

    Kozovska, Zuzana; Gabrisova, Veronika; Kucerova, Lucia

    2014-10-01

    Malignant tumours consist of heterogeneous populations of tumour cells. Cancer stem cells (CSC) represent a population of cells within a tumour with highly tumorigenic and chemoresistant properties. These cells may be identified by the expression of CSC markers. There are several key stem cells markers specified for colon cancer: CD133, CD44, ALDH1, ALCAM. These days, a major obstacle to effective cancer management is development of a multidrug resistance (MDR). The principal mechanism responsible for development of MDR phenotype is the over-expression of ABC transporters. Tumours and relapsing tumours after therapy are drived by subpopulations of tumour cells with aggressive phenotype resistant to chemotherapeutics. These cells are called CSC or tumour-initiating cells (TIC). Here we outline recent information about MDR of colon cancer and CSC markers. We have focused on novel therapeutic strategies which have been developed to prevent or overcome MDR. One such strategy is a combination of chemotherapy and modulators of MDR pumps or chemotherapy and monoclonal antibodies against vascular endothelial growth factor VEGF. Colon cancer is characterized by the presence of colon CSC expressing specific stem cell markers. The divergent presence of these markers can help to adjust personalized therapy. The review provides a detailed overview of resistance of colon cancer cells and discusses how the presence of CSC markers can influence therapy and prognosis of patients.

  9. Targeting Lymph Node Retrieval and Assessment in Stage II Colon Cancer: A Quality Outcome Community-Based Cancer Center Study

    PubMed Central

    Grote, Thomas; Hughes, Amy H.; Rimmer, Cathy C.; Less, Dale A.; Abernethy, Amy P.

    2008-01-01

    Purpose Adequate lymph node evaluation is required for the proper staging of colon cancer. The current recommended number of lymph nodes that should be retrieved and assessed is 12. Methods The multidisciplinary Gastrointestinal Tumor Board at the Derrick L. Davis Forsyth Regional Cancer Center reviewed and recommended that a minimum of 12 lymph nodes be examined in all cases of colon cancer to ensure proper staging. This recommendation occurred at the end of the first quarter of 2005. To ensure this new standard was being followed, an outcomes study looking at the number of lymph nodes evaluated in stage II colon cancer was initiated. All patients with stage II colon cancer diagnosed between 2004 and 2006 were reviewed. Results There was a statistically significant improvement in the number of stage II colon cancer patients with 12 or more lymph nodes evaluated. Before the Gastrointestinal Tumor Board's recommendation, 49% (40 out of 82 patients) had 12 or more lymph nodes sampled. The median number of lymph nodes evaluated was 11. After the Gastrointestinal Tumor Board's recommendation, 79% (70 out of 88 patients) had 12 or more lymph nodes sampled. The median number of lymph nodes was 16. Conclusion Multidisciplinary tumor boards can impact the quality of care of patients as demonstrated in this study. Although we do not yet have survival data on these patients, based on the previous literature referenced in this article, we would expect to see an improvement in survival rates in patients with 12 or more nodes retrieved and assessed. PMID:20856779

  10. Colon cancer treatment: Are there racial disparities in an equal-access healthcare system?

    PubMed Central

    Gill, Abegail A.; Enewold, Lindsey; Zahm, Shelia H.; Shriver, Craig D.; Stojadinovic, Alexander; McGlynn, Katherine A.; Zhu, Kangmin

    2014-01-01

    Background In the general US population, blacks and whites have been shown to undergo colon cancer treatment at disproportionate rates. Accessibility to medical care may be the most important factor influencing differences in colon cancer treatment among whites and blacks. Objective This study assessed whether racial disparities in colon cancer surgery and chemotherapy existed in an equal-access healthcare system. Additionally, we sought to examine whether racial differences varied by demographic and tumor characteristics. Design and Setting Database research using the United States Department of Defense’s (DoD) Military Health System. Patients Patients included 2,560 Non-Hispanic Whites (NHW) and Non-Hispanic Blacks (NHB) with colon cancer diagnosed from 1998 to 2007. Main Outcome Measures Logistic regression was used to assess the associations between race and the receipt of colon cancer surgery or chemotherapy, while controlling for available potential confounders, both overall and stratified by age at diagnosis, sex, and tumor stage. Results After multivariate adjustment, the odds of receiving colon cancer surgery or chemotherapy NHBs versus NHWs were similar (OR: 0.75, 95% CI: 0.37–1.53; OR: 0.79, 95% CI: 0.59–1.04; respectively). Additionally, no effect modification by age at diagnosis, sex, and tumor stage were observed. Limitations Treatment data might not be complete for beneficiaries who also had non-DoD health insurance. Conclusions When access to medical care is equal, racial disparities in the provision of colon cancer surgery and chemotherapy were not apparent. Thus, it is possible that the inequalities in access to care play a major role in the racial disparities seen in colon cancer treatment in the general population. PMID:25101601

  11. [Pancreatic-duodenectomy for invasive colon cancer in a patient with Lynch syndrome. Case report.].

    PubMed

    Vergara-Fernández, O; Zamora-Valdés, D; Rodríguez-Zentner, H A; Tapia, H; Sánchez-Fernández, N; Gamboa-Domínguez, A; Medina-Franco, H; Chan-Núñez, C

    2009-01-01

    Despite the screening efforts in the general population and particularly in families with hereditary colon cancer, locally advanced colon cancer remains a common clinical problem. In block resection is considered mainstay therapy in these patients. The aim of this report is to present a case of right-sided colon cancer with a medullar phenotype invading the duodenum treated through in block resection. A case of a 54-year-old male with a family history of colon and pancreatic cancer with lower gastrointestinal tract bleeding is presented. Colonoscopy and computed tomography scan showed a tumor in the colonic hepatic flexure invading the duodenum. The patient underwent an in block resection of the right colon, duodenum, pancreas and antrum. The histopathological study showed a T4N0M0 adenocarcinoma invading the duodenum, pancreas and antrum with negative margins. His postoperative evolution was complicated with a pancreatic fistula, which resolved with conservative measures. In conclusion, in block resection is the treatment of choice for locally advanced colon cancer with invasion to duodenum and pancreas and should be performed in high-volume centers familiar with this type of procedures. Key words: pancreaticoduodenectomy, colon cancer, Lynch syndrome, pancreas, surgery, Mexico.

  12. STMN1 in colon cancer: expression and prognosis in Chinese patients.

    PubMed

    Zhang, H-Q; Guo, X; Guo, S-Q; Wang, Q; Chen, X-Q; Li, X-N; Guo, L-S

    2016-05-01

    To study the stathmin (STMN1) expression in colorectal cancer and tumor-adjacent normal tissue and discuss its prognostic significance in colon cancer. STMN1 was tested with qRT-PCR in 30 samples of fresh colon cancer tissue and tumor-adjacent issue, and with immunohistochemical SP method in 105 samples of fresh colon cancer tissue and tumor-adjacent issue to analyze the association between its expression and clinical pathological parameters. Clinical data was combined to study the relationship between STMN1 expression and 5-year survival rate. Univariate analysis and Cox multivariate regression were performed to study the correlation between STMN1 expression and prognosis. The mRNA and protein level of STMN1 were significantly higher in colon cancer samples than tumor-adjacent normal tissues (p<0.05). STMN1 expression was independent of patient age, gender or location, but significantly related to lymph node metastasis and TNM staging (p<0.05). Survival analysis by Kaplan-Meier method showed that STMN1 expression was significantly related with the survival of colon cancer patients. The median survival time of STMN1-positive patients (37.5 months) was significantly shorter than STMN1-negative patients (57.1 months, p<0.05). Cox multivariate regression indicated that STMN1 is independent prognostic factors predicting the development, invasion and metastasis of colon cancer (p<0.05). STMN1 overexpression in colon cancer is independently associated with improved survival and significantly related to the development of the disease. Our findings suggest that presence of a STMN1-prognosis interaction that potentially determines clinical outcome.

  13. [Case of Colon Metastasis from Early Gastric Cancer 4 Years after Laparoscopic Assisted Distal Gastrectomy].

    PubMed

    Ikeda, Kosuke; Sato, Tsutomu; Maezawa, Yukio; Kano, Kazuki; Satoyoshi, Tetsuta; Segami, Kenki; Nakajima, Tetsushi; Ogata, Takashi; Cho, Haruhiko; Yoshikawa, Takaki

    2016-11-01

    A 69-year-old woman who underwent laparoscopic assisted distal gastrectomy for early gastric cancer(pathological T1bN1M0)in June 2011was admitted to the hospital because of abdominal pain in May 2015.A n abdominal CT scan showed ileus caused by a transverse colon tumor and ascending colon perforation.We performed emergency right hemicolectomy and diverting ileostomy.The postoperative pathological findings revealed poorly differentiated adenocarcinoma and signetring cell carcinoma similar to the gastric cancer resected 4 years ago.Immunohistochemical findings showed that the colon tumor was positive for CK7, but negative for CK20 and expressed a gastric mucin phenotype.From these findings, the colon tumor was diagnosed as a metastasis from early gastric cancer.Colon metastasis from early gastric cancer is rare and the diagnosis is difficult in some cases.We herein report this case and discuss the clinical and pathologic features of colon metastasis from gastric cancer.

  14. The Sirtuin 3 Expression Profile Is Associated with Pathological and Clinical Outcomes in Colon Cancer Patients

    PubMed Central

    Liu, Chunyuan; Huang, Zonghai; Jiang, Hong; Shi, Fujun

    2014-01-01

    Aim. To investigate the correlation between Sirtuin 3 (SIRT3) expression and the clinical outcome of patients with colon cancer. Methods. The tumor specimens from 127 patients with colon cancer were obtained for SIRT3 immunohistochemical staining. Patients were followed up. In in vitro study, SIRT3 gene was inhibited to observe the effects of SIRT3 on the biological behavior of cultured colon cells. Results. The SIRT3 expression level was found to be significantly associated with the lymph node metastasis (P < 0.001) and tumor stages (P < 0.001). The colon cancer-specific survival was 64.6% among patients with high SIRT3 expressions and 88.6% among patients with low SIRT3 expressions (log-rank P = 0.016). The overall survival was 80.2% among patients with low SIRT3 expressions and 55.9% among patients with high SIRT3 expressions (log-rank P = 0.002). In vitro study showed that silencing of SIRT3 gene inhibited the proliferation, invasion, and cells migration but increased the apoptosis in the cultured colon cell lines. Conclusion. This study provides evidence supporting that SIRT3 is closely associated with the clinical outcomes of colon cancer. SIRT3 may be considered as a marker for colon cancer. PMID:25105144

  15. [A Case of Intussusception Caused by Descending Colon Cancer].

    PubMed

    Hotta, Shinnosuke; Kameyama, Hitoshi; Sato, Kenji; Oyamatsu, Manabu; Hashimoto, Yoshifumi; Sato, Yu; Iwaki, Takawa; Shimada, Yoshifumi; Sakata, Jun; Kobayashi, Takashi; Wakai, Toshifumi

    2016-11-01

    A46 -year-old male presented with bloody stool and a descending colon tumor, as identified using colon fiberscopy. The patient did not complain of any remarkable abdominal symptoms. Computed tomography revealed descending colon tumor intussusception. We performed partial resection of the descending colon and D2 lymphadenectomy without intraoperative reduction. The descending colon was barely attached to the retroperitoneum and was mobile. The underlying tumor was type 1 and measured 8.3×5.8 cm. The pathology report indicated a mucinous adenocarcinoma with extension through the submucosa into the subserosa, and metastasis in 6 nearby lymph nodes(n2). Intussusception is relatively rare in adults, particularly in portions of the colon fixed to the retroperitoneum, such as the descending colon. In contrast to previous reports of descending colon intussusception caused by age-related tissue dysfunction, we report our experience with a young patient and present the results obtained.

  16. Active Chinese mistletoe lectin-55 enhances colon cancer surveillance through regulating innate and adaptive immune responses.

    PubMed

    Ma, Yan-Hui; Cheng, Wei-Zhi; Gong, Fang; Ma, An-Lun; Yu, Qi-Wen; Zhang, Ji-Ying; Hu, Chao-Ying; Chen, Xue-Hua; Zhang, Dong-Qing

    2008-09-14

    To investigate the potential role of active Chinese mistletoe lectin-55 (ACML-55) in tumor immune surveillance. In this study, an experimental model was established by hypodermic inoculating the colon cancer cell line CT26 (5 x 10(5) cells) into BALB/c mice. The experimental treatment was orally administered with ACML-55 or PBS, followed by the inoculation of colon cancer cell line CT26. Intracellular cytokine staining was used to detect IFN-gamma production by tumor antigen specific CD8+ T cells. FACS analysis was employed to profile composition and activation of CD4+, CD8+, gammadelta T and NK cells. Our results showed, compared to PBS treated mice, ACML-55 treatment significantly delayed colon cancer development in colon cancer-bearing Balb/c mice in vivo. Treatment with ACML-55 enhanced both Ag specific activation and proliferation of CD4+ and CD8+ T cells, and increased the number of tumor Ag specific CD8+ T cells. It was more important to increase the frequency of tumor Ag specific IFN-gamma producing-CD8+ T cells. Interestingly, ACML-55 treatment also showed increased cell number of NK, and gammadeltaT cells, indicating the role of ACML-55 in activation of innate lymphocytes. Our results demonstrate that ACML-55 therapy can enhance function in immune surveillance in colon cancer-bearing mice through regulating both innate and adaptive immune responses.

  17. [A Case of Pseudo-Meigs Syndrome Associated with Metachronous Ovarian Metastasis from Ascending Colon Cancer].

    PubMed

    Yachi, Takafumi; Nishikawa, Shinsuke; Tokura, Tomohisa; Iwama, Masahiro; Akaishi, Takanobu; Umehara, Minoru; Umehara, Yutaka; Murata, Akihiko; Takahashi, Kenichi; Morita, Takayuki

    2015-10-01

    We experienced a case of pseudo-Meigs syndrome associated with metachronous metastasis to the ovary from ascending colon cancer. A 65-year-old woman underwent curative surgery for ascending colon cancer at another hospital. A follow-up CT carried out 3 months after the surgery revealed a right ovarian tumor and a large amount of ascites. The patient was diagnosed with ovarian metastasis from ascending colon cancer with carcinomatous peritonitis. Palliative care was recommended, and she presented at our department for a second opinion. In spite of a large amount of ascites and pleural effusion, no disseminating tumor was detected on contrast-enhanced CT at our hospital, and we recommended that she undergo a diagnostic laparotomy. The laparotomy was negative for carcinomatous peritonitis and a right oophorectomy was performed. The histopathological findings indicated that the ovarian tumor was consistent with metastasis from ascending colon cancer. After the surgery, we initiated chemotherapy with mFOLFOX6+bevacizumab and the symptoms were well controlled. A follow-up CT carried out 11 months after the surgery revealed a left ovarian tumor and increased ascites, and the patient underwent a left oophorectomy. Then, chemotherapy with the same regimen was administered for 12 months, and she did not develop any signs of recurrence for 27 months after the surgery. Ovarian metastasis from colon cancer may occasionally cause pseudo-Meigs syndrome, and it is important to be aware of the usefulness of oophorectomy for the control of ascites and pleural effusion.

  18. Active chinese mistletoe lectin-55 enhances colon cancer surveillance through regulating innate and adaptive immune responses

    PubMed Central

    Ma, Yan-Hui; Cheng, Wei-Zhi; Gong, Fang; Ma, An-Lun; Yu, Qi-Wen; Zhang, Ji-Ying; Hu, Chao-Ying; Chen, Xue-Hua; Zhang, Dong-Qing

    2008-01-01

    AIM: To investigate the potential role of Active Chinese mistletoe lectin-55 (ACML-55) in tumor immune surveillance. METHODS: In this study, an experimental model was established by hypodermic inoculating the colon cancer cell line CT26 (5 × 105 cells) into BALB/c mice. The experimental treatment was orally administered with ACML-55 or PBS, followed by the inoculation of colon cancer cell line CT26. Intracellular cytokine staining was used to detect IFN-γ production by tumor antigen specific CD8+ T cells. FACS analysis was employed to profile composition and activation of CD4+, CD8+, γδ T and NK cells. RESULTS: Our results showed, compared to PBS treated mice, ACML-55 treatment significantly delayed colon cancer development in colon cancer -bearing Balb/c mice in vivo. Treatment with ACML-55 enhanced both Ag specific activation and proliferation of CD4+ and CD8+ T cells, and increased the number of tumor Ag specific CD8+ T cells. It was more important to increase the frequency of tumor Ag specific IFN-γ producing-CD8+ T cells. Interestingly, ACML-55 treatment also showed increased cell number of NK, and γδT cells, indicating the role of ACML-55 in activation of innate lymphocytes. CONCLUSION: Our results demonstrate that ACML-55 therapy can enhance function in immune surveillance in colon cancer-bearing mice through regulating both innate and adaptive immune responses. PMID:18785279

  19. Adjuvant treatment strategies for early colon cancer.

    PubMed

    Waterston, Ashita M; Cassidy, Jim

    2005-01-01

    Colon cancer remains a major cause of death; however, in the last 3 years a number of trials have been published that have led to changes in the treatment of patients with this disease. Initially, the adjuvant treatment of patients following curative resection was based on their Dukes staging; this is now being refined by consideration of other pathological factors, as well as the investigation of newer prognostic markers such as p53, Ki67 and a number of genes on chromosome 18. Tumours generally develop from the progressive accumulation of genetic events, although some develop through mutation or inactivation of DNA mismatch repair proteins leading to microsatellite instability; this is particularly important in Lynch's syndrome. The loss of gene expression can occur by deletion or mutation of genes or by aberrant methylation of CpG islands. In patients with Dukes C colon cancer the standard of care for adjuvant chemotherapy was previously based on bolus fluorouracil (5-fluorouracil) and folinic acid (leucovorin) administered 5 days per month or weekly for 6 months. Recent studies with a combination of infusional fluorouracil, folinic acid and oxaliplatin have been found to be superior. A further study replacing fluorouracil with oral capecitabine has also demonstrated equivalent disease-free survival. Although some debate remains regarding the benefit of adjuvant treatment for patients with Dukes B colon cancer, the emerging consensus is that, for those patients who are younger and have high-risk features, chemotherapy should be discussed. A number of large vaccine trials have also been conducted in the adjuvant setting and, overall, these have been disappointing. This is a rapidly advancing area of therapy and the results of new trials are awaited to determine whether additional benefits can be achieved with biological therapies such as anti-vascular endothelial growth factor and anti-epithelial growth factor receptor monoclonal antibodies, which have already

  20. Could JC virus provoke metastasis in colon cancer?

    PubMed Central

    Sinagra, Emanuele; Raimondo, Dario; Gallo, Elena; Stella, Mario; Cottone, Mario; Orlando, Ambrogio; Rossi, Francesca; Orlando, Emanuele; Messina, Marco; Tomasello, Giovanni; Lo Monte, Attilio Ignazio; La Rocca, Ennio; Rizzo, Aroldo Gabriele

    2014-01-01

    AIM: To evaluate the prevalence of John Cunningham virus (JC virus) in a small cohort of patients with colon cancer and to assess its presence in hepatic metastasis. METHODS: Nineteen consecutive patients with histologically diagnosed colon cancer were included in our study, together with ten subjects affected by histologically and serologically diagnosed hepatitis C virus infection. In the patients included in the colon cancer group, JC virus was searched for in the surgical specimen; in the control group, JC virus was searched for in the hepatic biopsy. The difference in the prevalence of JC virus in the hepatic biopsy between the two groups was assessed through the χ2 test. RESULTS: Four out of 19 patients with colon cancer had a positive polymerase chain reaction (PCR) test for JC virus, and four had liver metastasis. Among the patients with liver metastasis, three out of four had a positive PCR test for JC virus in the surgical specimen and in the liver biopsy; the only patient with liver metastasis with a negative test for JC virus also presented a negative test for JC virus in the surgical specimen. In the control group of patients with hepatitis C infection, none of the ten patients presented JC virus infection in the hepatic biopsy. The difference between the two groups regarding JC virus infection was statistically significant (χ2 = 9.55, P = 0.002). CONCLUSION: JC virus may play a broader role than previously thought, and may be mechanistically involved in the late stages of these tumors. PMID:25400458

  1. Radioimmunotoxin Therapy of Experimental Colon and Ovarian Cancer

    SciTech Connect

    Buchsbaum, Donald J.; Vallera, Daniel A.

    2006-02-09

    mixed with the EpCam sFv that was synthesized without any toxin attached. The proliferation studies showed that EpCam sFv was able to block the killing of the EpCam expressing cells by DTEpCam. An irrelevant control protein, 1D10Fc was unable to block. Together, these studies indicated that EpCam was exquisitely selective. In order to produce an IT of even greater potency, we used a toxin containing the Golgi retention sequence KDEL. The same EpCam sFv was spliced to truncated PE containing the terminal KDEL sequence. The addition of KDEL enhanced the potency of the EpCam sFv IT at least 6 logs or 1