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Sample records for cancer tumor colonization

  1. Colon cancer

    MedlinePlus

    Colorectal cancer; Cancer - colon; Rectal cancer; Cancer - rectum; Adenocarcinoma - colon; Colon - adenocarcinoma ... In the United States, colorectal cancer is one of the leading causes of deaths due to cancer. Early diagnosis can often lead to a complete cure. Almost ...

  2. Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

    PubMed Central

    Kaiser, Sergio; Park, Young-Kyu; Franklin, Jeffrey L; Halberg, Richard B; Yu, Ming; Jessen, Walter J; Freudenberg, Johannes; Chen, Xiaodi; Haigis, Kevin; Jegga, Anil G; Kong, Sue; Sakthivel, Bhuvaneswari; Xu, Huan; Reichling, Timothy; Azhar, Mohammad; Boivin, Gregory P; Roberts, Reade B; Bissahoyo, Anika C; Gonzales, Fausto; Bloom, Greg C; Eschrich, Steven; Carter, Scott L; Aronow, Jeremy E; Kleimeyer, John; Kleimeyer, Michael; Ramaswamy, Vivek; Settle, Stephen H; Boone, Braden; Levy, Shawn; Graff, Jonathan M; Doetschman, Thomas; Groden, Joanna; Dove, William F; Threadgill, David W; Yeatman, Timothy J; Coffey, Robert J; Aronow, Bruce J

    2007-01-01

    Background The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5. Results We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear β-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF). Conclusion Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and

  3. 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

  4. KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and is Upregulated in a Subset of Human Colon Cancers

    PubMed Central

    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.

    2015-01-01

    Background & Aims Receptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. We investigated the role of the RTK KIT in development of human colon cancer. Methods 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 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 PCR, 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 following injection of cancer cells; tumor growth was measured based on bioluminescence. We assessed tumorigenicity using limiting dilution analysis. Results 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 cell lines. However, KITLG-knockdown DLD1 cells formed smaller xenograft tumors than control cells. Gene expression analysis of single CD44+ cells indicated that KIT may 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

  5. Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages.

    PubMed

    Nandi, Bisweswar; Shapiro, Mia; Samur, Mehmet K; Pai, Christine; Frank, Natasha Y; Yoon, Charles; Prabhala, Rao H; Munshi, Nikhil C; Gold, Jason S

    2016-08-01

    Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been implicated in promoting colon cancer; however, the mechanisms behind this effect are poorly understood. We have previously demonstrated that deficiency of CCR6 is associated with decreased tumor macrophage accumulation in a model of sporadic intestinal tumorigenesis. In this study, we aimed to determine the role of stromal CCR6 expression in a murine syngeneic transplantable colon cancer model. We show that deficiency of host CCR6 is associated with decreased growth of syngeneic CCR6-expressing colon cancers. Colon cancers adoptively transplanted into CCR6-deficient mice have decreased tumor-associated macrophages without alterations in the number of monocytes in blood or bone marrow. CCL20, the unique ligand for CCR6, promotes migration of monocytes in vitro and promotes accumulation of macrophages in vivo. Depletion of tumor-associated macrophages decreases the growth of tumors in the transplantable tumor model. Macrophages infiltrating the colon cancers in this model secrete the inflammatory mediators CCL2, IL-1α, IL-6 and TNFα. Ccl2, Il1α and Il6 are consequently downregulated in tumors from CCR6-deficient mice. CCL2, IL-1α and IL-6 also promote proliferation of colon cancer cells, linking the decreased macrophage migration into tumors mediated by CCL20-CCR6 interactions to the delay in tumor growth in CCR6-deficient hosts. The relevance of these findings in human colon cancer is demonstrated through correlation of CCR6 expression with that of the macrophage marker CD163 as well as that of CCL2, IL1α and TNFα. Our findings support the exploration of targeting the CCL20-CCR6 pathway for the treatment of colon cancer. PMID:27622061

  6. Smaller tumor size is associated with poor survival in T4b colon cancer

    PubMed Central

    Huang, Ben; Feng, Yang; Mo, Shao-Bo; Cai, San-Jun; Huang, Li-Yong

    2016-01-01

    AIM: To hypothesize that in patients with colon cancer showing heavy intestinal wall invasion without distant metastasis (T4bN0-2M0), small tumor size would correlate with more aggressive tumor behaviors and therefore poorer cancer-specific survival (CSS). METHODS: We analyzed T4bN0-2M0 colon cancer patients in the Surveillance, Epidemiology and End Results (SEER) database. A preliminary analysis of T4bN0-2M0 colon cancer patients at the Fudan University Shanghai Cancer Center is also presented. RESULTS: A total of 1734 T4bN0-2M0 colon cancer patients from the SEER database were included. Kaplan-Meier analysis revealed decreasing CSS with decreasing tumor size (P < 0.001). Subgroup analysis showed a significant association between poorer CSS with smaller tumor size in T4bN0 patients (P = 0.024), and a trend of association in T4bN1 (P = 0.182) and T4bN2 patients (P = 0.191). Multivariate analysis identified tumor size as an independent prognostic factor for CSS in T4bN0-2M0 patients (P = 0.024). Preliminary analysis of Fudan University Shanghai Cancer Center samples suggested the 5-year CSS was 50.0%, 72.9% and 77.1% in patients with tumors ≤ 4.0 cm, 4.0-7.0 cm and ≥ 7.0 cm. CONCLUSION: Smaller tumor size is associated with poorer CSS in the T4bN0-2M0 subset of colon cancer, particularly in the T4bN0M0 subgroup. PMID:27547015

  7. Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling

    PubMed Central

    Seth, Chandan; Ruiz i Altaba, Ariel

    2016-01-01

    Human colon cancers commonly harbor loss of function mutations in APC, a repressor of the canonical WNT pathway, thus leading to hyperactive WNT-TCF signaling. Re-establishment of Apc function in mice, engineered to conditionally repress Apc through RNAi, resolve the intestinal tumors formed due to hyperactivated Wnt-Tcf signaling. These and other results have prompted the search for specific WNT pathway antagonists as therapeutics for clinically problematic human colon cancers and associated metastases, which remain largely incurable. This widely accepted view seems at odds with a number of findings using patient-derived material: Canonical TCF targets are repressed, instead of being hyperactivated, in advanced colon cancers, and repression of TCF function does not generally result in tumor regression in xenografts. The results of a number of genetic mouse studies have also suggested that canonical WNT-TCF signaling drives metastases, but direct in vivo tests are lacking, and, surprisingly, TCF repression can enhance directly seeded metastatic growth. Here we have addressed the abilities of enhanced and blocked WNT-TCF signaling to alter tumor growth and distant metastases using xenografts of advanced human colon cancers in mice. We find that endogenous WNT-TCF signaling is mostly anti-metastatic since downregulation of TCF function with dnTCF generally enhances metastatic spread. Consistently, elevating the level of WNT signaling, by increasing the levels of WNT ligands, is not generally pro-metastatic. Our present and previous data reveal a heterogeneous response to modulating WNT-TCF signaling in human cancer cells. Nevertheless, the findings that a fraction of colon cancers tested require WNT-TCF signaling for tumor growth but all respond to repressed signaling by increasing metastases beg for a reevaluation of the goal of blocking WNT-TCF signaling to universally treat colon cancers. Our data suggest that WNT-TCF blockade may be effective in inhibiting tumor

  8. 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

    2015-01-01

    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.

  9. 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. PMID:26637872

  10. 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.

  11. 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.

  12. 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

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

    PubMed

    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

  14. 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 ...

  15. [Tumor lysis syndrome after FOLFIRI+cetuximab for ascending colon cancer].

    PubMed

    Matsuyama, Satoru; Kuramoto, Takako; Tanaka, Ryosuke; Hashiguchi, Kazutoshi

    2015-04-01

    We report a case of an 83-year-old woman who developed tumor lysis syndrome (TLS) 5 days after FOLFIRI+cetuximab (Cmab) therapy. A huge ascending colon cancer measuring 10 cm in diameter and with peritoneal dissemination was diagnosed. Following successful therapy with FOLFIRI alone, FOLFIRI+Cmab was administered. On day 5, TLS was diagnosed with hyperuricemia, hyperkalemia, hyperphosphatemia, and an increase in serum creatinine. Intravenous furosemide, volume loading, and glucose-insulin therapy resulted in improvement of laboratory data in 2 days. However, she died on the 34th day due to multiple organ failure caused by aspiration pneumonia following small intestine functional ileus. Although TLS is a rare complication in colon cancer, its onset must be taken into consideration. Also, risk assessment and preventive therapy for TLS should be performed before cancer treatment. PMID:25843460

  16. Identification of Novel Tumor Markers in Prostate, Colon and Breast Cancer by Unbiased Methylation Profiling

    PubMed Central

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

    2008-01-01

    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. PMID:18446232

  17. Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer

    PubMed Central

    2014-01-01

    Background A colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient’s gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response. Methods A set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software). Results Here we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue. Conclusions The systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients. PMID:24597571

  18. Inter- and intra-tumor profiling of multi-regional colon cancer and metastasis.

    PubMed

    Kogita, Akihiro; Yoshioka, Yasumasa; Sakai, Kazuko; Togashi, Yosuke; Sogabe, Shunsuke; Nakai, Takuya; Okuno, Kiyotaka; Nishio, Kazuto

    2015-02-27

    Intra- and inter-tumor heterogeneity may hinder personalized molecular-target treatment that depends on the somatic mutation profiles. We performed mutation profiling of formalin-fixed paraffin embedded tumors of multi-regional colon cancer and characterized the consequences of intra- and inter-tumor heterogeneity and metastasis using targeted re-sequencing. We performed targeted re-sequencing on multiple spatially separated samples obtained from multi-regional primary colon carcinoma and associated metastatic sites in two patients using next-generation sequencing. In Patient 1 with four primary tumors (P1-1, P1-2, P1-3, and P1-4) and one liver metastasis (H1), mutually exclusive pattern of mutations was observed in four primary tumors. Mutations in primary tumors were identified in three regions; KARS (G13D) and APC (R876*) in P1-2, TP53 (A161S) in P1-3, and KRAS (G12D), PIK3CA (Q546R), and ERBB4 (T272A) in P1-4. Similar combinatorial mutations were observed between P1-4 and H1. The ERBB4 (T272A) mutation observed in P1-4, however, disappeared in H1. In Patient 2 with two primary tumors (P2-1 and P2-2) and one liver metastasis (H2), mutually exclusive pattern of mutations were observed in two primary tumors. We identified mutations; KRAS (G12V), SMAD4 (N129K, R445*, and G508D), TP53 (R175H), and FGFR3 (R805W) in P2-1, and NRAS (Q61K) and FBXW7 (R425C) in P2-2. Similar combinatorial mutations were observed between P2-1 and H2. The SMAD4 (N129K and G508D) mutations observed in P2-1, however, were nor detected in H2. These results suggested that different clones existed in primary tumors and metastatic tumor in Patient 1 and 2 likely originated from P1-4 and P2-1, respectively. In conclusion, we detected the muti-clonalities between intra- and inter-tumors based on mutational profiling in multi-regional colon cancer using next-generation sequencing. Primary region from which metastasis originated could be speculated by mutation profile. Characterization of inter- and

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

    PubMed Central

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

    2012-01-01

    Background 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. Methods 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. Results 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.,12x) 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. Conclusion 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. PMID:22965195

  20. miR-526b-3p functions as a tumor suppressor in colon cancer by regulating HIF-1α

    PubMed Central

    Zhang, Rui; Zhao, Jian; Xu, Jian; Wang, Jian; Jia, Jianhui

    2016-01-01

    HIF-1α is an important transcriptional factor, which plays roles in cancer development and progression. But its regulation by miRNAs is not clear. Here, to investigate the regulation of HIF-1α by miRNAs, miRNAs were predicted and miR-526b-3p was verified as a regulator of HIF-1α in colon cancer cells. Using TaqMan RT-PCR analysis, we analyzed the expression of miR-526b-3p in tumor tissues and cell lines and found that miR-526b-3p was consistently under-expressed in cancer tissues and cell lines compared with their normal controls. When miR-526b-3p was induced into the colon cancer cells, cell proliferation, metastasis and glycolysis of colon cancer cells were suppressed. We also found that miR-526b-3p was down-regulated in metastatic colon cancer tissues and negatively with HIF-1α mRNA in colon cancer tissues. In a summary, miR-526b-3p plays as a tumor suppressor by down-regulation of HIF-1α expression in colon cancer and may be a new diagnosis or therapeutic target. PMID:27398161

  1. 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

  2. Infliximab enhances the therapeutic effects of 5-fluorouracil resulting in tumor regression in colon cancer

    PubMed Central

    Liu, Fen; Ai, Feiyan; Tian, Li; Liu, Shaojun; Zhao, Lian; Wang, Xiaoyan

    2016-01-01

    Colon cancer (CC) is among the most common malignant diseases with a dismal survival. Tumor necrosis factor-alpha (TNF-α) has been identified as a therapeutic target in various cancers, and anti-TNF-α treatment has shown promising effects in different cancer models. However, if TNF-α can be targeted in CC, the therapeutic values of anti-TNF-α treatment in CC remain unknown. Our study indicated that TNF-α is highly expressed in CC cell lines and patient tumor samples. High expression of TNF-α is an independent adverse prognosticator of CC. Targeting the TNF-α by its antibody infliximab induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity and enhanced apoptosis leading to cell death. The combination of infliximab with 5-fluorouracil showed better responses in vitro and in vivo than 5-fluorouracil alone. In conclusion, this study identified TNF-α as a target of CC and anti-TNF-α treatment synergized with chemotherapy leading to a better outcome in preclinical models. PMID:27757041

  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. PMID:21220492

  4. Overexpression of laminin alpha1 chain in colonic cancer cells induces an increase in tumor growth.

    PubMed

    De Arcangelis, A; Lefebvre, O; Méchine-Neuville, A; Arnold, C; Klein, A; Rémy, L; Kedinger, M; Simon-Assmann, P

    2001-10-01

    Laminins represent a growing family of glycoproteins constituting the basement membrane. They are known to direct many biological processes. With respect to carcinogenesis, laminins play an important role in cell adhesion, mitogenesis, differentiation and even metastasis. To further study the biological significance of laminin-1 (composed of alpha1, beta1 and gamma1 chains) in intestinal cell differentiation or tumorigenesis, an alpha1-laminin expression vector was introduced into the HT29 colonic cancer cells, in which laminin alpha1 chain is not expressed. Upon transfection of the alpha1 chain, the alpha1beta1gamma1 trimer was found secreted in the media along with free alpha1 chain as assessed by immunoprecipitation. The presence of the laminin alpha1 chain did not significantly modify the levels of the other laminin chains nor the integrins expressed by the HT29 cells. In spite of similar growth properties with the control cells in vitro (plastic dish, soft agar), the laminin alpha1 transfectants showed a significantly increased tumor growth when injected in nude mice. Histologic and immunohistochemic examination of the laminin alpha1-expressing tumors points to an increased recruitment of the host stromal and vascular cells, without modification in the differentiation profile and invasion potential. In parallel, a clear accumulation of laminin-10 (alpha5beta1gamma1) at the carcinoma/stromal interface and a segregation of the integrin beta4 subunit at the basal pole of the cancer cells occurred, compared to control tumors. Overall, our observations emphasize the importance of laminin-1 as a chemoattractant of both stromal and vascular cells and in epithelial/stromal cell interactions for the organization of the basement membrane and segregation of integrins leading to an epithelial cell growth signal. Such a sequence of events is reminiscent of what occurs during development.

  5. The anti-tumor effect of Euchema serra agglutinin on colon cancer cells in vitro and in vivo.

    PubMed

    Fukuda, Yuki; Sugahara, Takuya; Ueno, Masashi; Fukuta, Yusuke; Ochi, Yukari; Akiyama, Koichi; Miyazaki, Tatsuhiko; Masuda, Seizo; Kawakubo, Akihiro; Kato, Keiichi

    2006-09-01

    Eucheuma serra agglutinin (ESA) is a lectin derived from a marine red alga E. serra and binds specifically to mannose-rich sugar chains. Previous reports have indicated that ESA associates with several cancer cells via sugar chains on cell surfaces and induces apoptotic cell death. In this study, we investigated the effect of ESA on Colon26 mouse colon adenocarcinoma cells both in vitro and in vivo. ESA induced cell death against Colon26 cells in vitro, and the expression of caspase-3 and the translocation of phosphatidylserine in ESA-treated Colon26 cells suggested that this cell death was induced through apoptosis. An intravenous injection of ESA significantly inhibited the growth of Colon26 tumors in BALB/c mice; moreover, DNA fragmentation was detected in tumor cells following ESA treatment. These results indicated that ESA is effective as an anti-cancer drug not only in vitro but also in vivo. The side-effects of ESA were not considered to be serious because the decrease in body weight of the mice injected with it was negligible. These observations suggest that ESA has the potential to be an effective anti-tumor drug. PMID:16940804

  6. 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

  7. 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 ...

  8. Assessing tumor mutations to gain insight into base excision repair sequence polymorphisms and smoking in colon cancer

    PubMed Central

    Curtin, Karen; Samowitz, Wade S.; Wolff, Roger K.; Ulrich, Cornelia M.; Caan, Bette J.; Potter, John D.; Slattery, Martha L.

    2009-01-01

    DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a two-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (OR= 2.2, 95%CI 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG Island Methylator Phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (OR=1.4, 95%CI 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer. PMID:19959686

  9. TSU-68 (SU6668) inhibits local tumor growth and liver metastasis of human colon cancer xenografts via anti-angiogenesis.

    PubMed

    Yorozuya, Kyoko; Kubota, Tetsuro; Watanabe, Masahiko; Hasegawa, Hirotoshi; Ozawa, Soji; Kitajima, Masaki; Chikahisa, Lumi Muramatsu; Yamada, Yuji

    2005-09-01

    A number of receptor tyrosine kinases (RTKs) are involved in angiogenesis. TSU-68 (SU-6668) was developed as an inhibitor of RTKs involved in VEGF, bFGF and PDGF signaling, which then inhibits endothelial cell proliferation. We investigated the antitumor effects of TSU-68 against human colon cancer xenografts in male SCID mice and its anti-angiogenic activity using a dorsal air-sac (DAS) assay. TSU-68 was administered orally at a dose of 200 mg/kg twice daily. Mice bearing human colon carcinoma, HT-29, or WiDr xenografts were treated for 16 days. To determine the effect on hepatic metastasis, cell suspensions of HT-29 or WAV-I were injected into the spleen of mice on day 0, and mice treated for 28 days starting from day 1. For the DAS assay, HT-29, WiDr or WAV-I cells suspended in PBS at 2 x 10(7) cells/Millipore chamber were implanted subcutaneously into SCID mice, which were then treated from day 0 to 5, On day 6, the anti-angiogenic effects were assessed. Results indicated that TSU-68 significantly inhibited the growth of subcutaneous tumors. In the hepatic metastasis model, liver weights of the TSU-68-treated group were significantly reduced, compared to those of control mice. In the DAS assay, the angiogenic indices of the treated groups were significantly decreased for HT-29, WiDr and WAV-I tumors, with T/C ratios of 13.4, 50 and 35.3%, respectively. As TSU-68 significantly inhibited tumor growth and liver metastasis formation of human colon cancer xenografts, probably through anti-angiogenic activity, this agent may be useful for the treatment of colon cancer.

  10. Chemokine (C-C Motif) Ligand 5 is Involved in Tumor-Associated Dendritic Cell-Mediated Colon Cancer Progression Through Non-Coding RNA MALAT-1.

    PubMed

    Kan, Jung-Yu; Wu, Deng-Chyang; Yu, Fang-Jung; Wu, Cheng-Ying; Ho, Ya-Wen; Chiu, Yen-Jung; Jian, Shu-Fang; Hung, Jen-Yu; Wang, Jaw-Yuan; Kuo, Po-Lin

    2015-08-01

    Tumor micro-environment is a critical factor in the development of cancer. The aim of this study was to investigate the inflammatory cytokines secreted by tumor-associated dendritic cells (TADCs) that contribute to enhanced migration, invasion, and epithelial-to-mesenchymal transition (EMT) in colon cancer. The administration of recombinant human chemokine (C-C motif) ligand 5 (CCL5), which is largely expressed by colon cancer surrounding TADCs, mimicked the stimulation of TADC-conditioned medium on migration, invasion, and EMT in colon cancer cells. Blocking CCL5 by neutralizing antibodies or siRNA transfection diminished the promotion of cancer progression by TADCs. Tumor-infiltrating CD11c(+) DCs in human colon cancer specimens were shown to produce CCL5. The stimulation of colon cancer progression by TADC-derived CCL5 was associated with the up-regulation of non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), which subsequently increased the expression of Snail. Blocking MALAT-1 significantly decreased the TADC-conditioned medium and CCL5-mediated migration and invasion by decreasing the enhancement of Snail, suggesting that the MALAT-1/Snail pathway plays a critical role in TADC-mediated cancer progression. In conclusion, the inhibition of CCL5 or CCL5-related signaling may be an attractive therapeutic target in colon cancer patients.

  11. 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

  12. Dependence receptor TrkC is a putative colon cancer tumor suppressor.

    PubMed

    Genevois, Anne-Laure; Ichim, Gabriel; Coissieux, Marie-May; Lambert, Marie-Pierre; Lavial, Fabrice; Goldschneider, David; Jarrosson-Wuilleme, Loraine; Lepinasse, Florian; Gouysse, Géraldine; Herceg, Zdenko; Scoazec, Jean-Yves; Tauszig-Delamasure, Servane; Mehlen, Patrick

    2013-02-19

    The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore generally considered to be a proto-oncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-of-proapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor. PMID:23341610

  13. Dependence receptor TrkC is a putative colon cancer tumor suppressor.

    PubMed

    Genevois, Anne-Laure; Ichim, Gabriel; Coissieux, Marie-May; Lambert, Marie-Pierre; Lavial, Fabrice; Goldschneider, David; Jarrosson-Wuilleme, Loraine; Lepinasse, Florian; Gouysse, Géraldine; Herceg, Zdenko; Scoazec, Jean-Yves; Tauszig-Delamasure, Servane; Mehlen, Patrick

    2013-02-19

    The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore generally considered to be a proto-oncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-of-proapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor.

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

    PubMed

    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

    2016-07-01

    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.

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

    PubMed

    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

    2016-07-01

    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

  16. Retrieval of Disseminated Tumor Cells Colonizing the Bone in Murine Breast Cancer Metastasis Models

    PubMed Central

    Welte, Thomas; Yu, Cuijuan

    2016-01-01

    In breast cancer, the most frequent site of metastasis is bone. Disseminated tumor cells (DTCs) can be detected in the bone marrow of patients by their expression of epithelial or oncogenic markers [1], and the presence and frequency of these DTCs are associated with poor prognosis. However, many of the details behind this process remain elusive, including the biological properties and fates of these apparently indolent cancer cells. To provide pre-clinical models of DTCs, we have developed a procedure that allows for controlled and enhanced delivery of tumor cells to the bone in animal experiments via injection into the iliac artery of the hind limb [2]. To our surprise, we found that most cancer cells became integrated into the solid bone matrix shortly after arriving in the bone, and only a minority can be flushed out with the bone marrow. Here we describe a method that helps to retrieve DTCs homing to the bone in which we achieve an improved recovery of those tumor cells closely associated with the bone microenvironment. In our view it is especially important to analyze these tumor cell subpopulations, as they may take full advantage of growth-, survival- and immune-protective signals provided by neighbor cells. We also show a pilot study on how this approach may be applied to the analysis of cancer dormancy. Our study suggests that the detection and retrieval of DTCs in clinical studies are incomplete because they are conducted exclusively with bone marrow aspirates. PMID:26490041

  17. 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

  18. GTI-2040, Oxaliplatin, and Capecitabine in Treating Patients With Locally Advanced or Metastatic Colorectal Cancer or Other Solid Tumors

    ClinicalTrials.gov

    2013-03-26

    Recurrent Colon Cancer; Recurrent 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; Unspecified Adult Solid Tumor, Protocol Specific

  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. Chloroquine inhibits colon cancer cell growth in vitro and tumor growth in vivo via induction of apoptosis.

    PubMed

    Zheng, Yuzhu; Zhao, Ying-Lan; Deng, Xiaoqiang; Yang, Shengyong; Mao, Yongqiu; Li, Zhengguang; Jiang, Peidu; Zhao, Xia; Wei, Yuquan

    2009-03-01

    The present study was to investigate the anticancer effect of chloroquine on proliferation of mouse colon cancer cell line CT26 in vivo and in vitro and the possible mechanism. We found that chloroquine inhibited CT26 proliferation by concentration- and time-dependent manner. This effect was associated with apoptosis induction and decreased level of phosphorylated p42/44 mitogen-activated protein kinase and phosphorylated Akt. The in vivo study showed chloroquine-reduced tumor volume and prolonged survival time in CT26-bearing mice. These observations indicated chloroquine could inhibit CT26 proliferation by inducing apoptosis both in vitro and in vivo, providing its chemotherapeutic potential of human cancers. PMID:19194831

  1. Understanding your colon cancer risk

    MedlinePlus

    Colon cancer risk factors are things that increase the chance that you could get cancer. Some risk factors ... risk factors never get cancer. Other people get colon cancer but do not have any known risk factors. ...

  2. 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

  3. Tumor-colonizing bacteria: a potential tumor targeting therapy.

    PubMed

    Zu, Chao; Wang, Jiansheng

    2014-08-01

    In 1813, Vautier published his observation of tumor regression in patients who had suffered from gas gangrene. Since then, many publications have described the use of bacteria as antitumor therapy. For example, Bifidobacterium and Clostridium have been shown to selectively colonize tumors and to reduce tumor size. In addition, recent studies have focused on the use of genetic engineering to induce the expression of pro-drug converting enzymes, cytokines, specific antibodies, or suicide genes in tumor-colonizing bacteria. Moreover, some animal experiments have reported the treatment of tumors with engineered bacteria, and few side effects were observed. Therefore, based on these advances in tumor targeting therapy, bacteria may represent the next generation of cancer therapy.

  4. Primary tumor- and metastasis-derived colon cancer cells differently modulate connexin expression and function in human capillary endothelial cells

    PubMed Central

    Thuringer, Dominique; Berthenet, Kevin; Cronier, Laurent; Solary, Eric; Garrido, Carmen

    2015-01-01

    A gradual loss of functional gap junction between tumor cells has been reported with colorectal cancer (CRC) progression. Here, we explored if colon cancer cells could also affect gap junctions in blood capillary cells. Human microvascular endothelial cells (HMEC) were cultured with two CRC cell lines established from a unique patient. SW480 cells, derived from the primary tumor, migrate much faster across HMEC monolayer than SW620 cells derived from a metastatic site. The motile SW480 cells highly express and release HSP27 that increases gap junction formation with HMEC. Soluble HSP27 phosphorylates the connexin Cx43 on serine residues and induces its interaction with the oncoprotein 14-3-3, which promotes Cx43 delivery at the plasma membrane. The factors secreted by less motile SW620 cells do not affect Cx43 expression but up-regulate the expression of the connexin Cx32 through an activation of the chemokine receptor CXCR2. In turn, SW620 secreted factors induce tubulogenesis and ATP release. Altogether, cell lines derived from CRC primary tumor and metastasis differentially adapt endothelial cell functions by modulating connexin expression through released mediators. PMID:26320187

  5. Biologic Determinants of Tumor Recurrence in Stage II Colon Cancer: Validation Study of the 12-Gene Recurrence Score in Cancer and Leukemia Group B (CALGB) 9581

    PubMed Central

    Venook, Alan P.; Niedzwiecki, Donna; Lopatin, Margarita; Ye, Xing; Lee, Mark; Friedman, Paula N.; Frankel, Wendy; Clark-Langone, Kim; Millward, Carl; Shak, Steven; Goldberg, Richard M.; Mahmoud, Najjia N.; Warren, Robert S.; Schilsky, Richard L.; Bertagnolli, Monica M.

    2013-01-01

    Purpose A greater understanding of the biology of tumor recurrence should improve adjuvant treatment decision making. We conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. Patients and Methods CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. Results Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. Conclusion The 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients. PMID:23530100

  6. 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

  7. Antidepressant fluoxetine and its potential against colon tumors

    PubMed Central

    Stopper, Helga; Garcia, Sergio Britto; Waaga-Gasser, Ana Maria; Kannen, Vinicius

    2014-01-01

    Colon cancer is one of the most common tumors worldwide, with increasing incidence in developing countries. Patients treated with fluoxetine (FLX) have a reduced incidence of colon cancer, although there still remains great controversy about the nature of its effects. Here we explore the latest achievements related to FLX treatment and colon cancer. Moreover, we discuss new ideas about the mechanisms of the effects of FLX treatment in colon cancer. This leads to the hypothesis of FLX arresting colon tumor cells at the at G1 cell-cycle phase through a control of the tumor-related energy generation machinery. We believe that the potential of FLX to act against tumor metabolism warrants further investigation. PMID:24578784

  8. 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. PMID:27455418

  9. The TF-antigen binding lectin from Sclerotium rolfsii inhibits growth of human colon cancer cells by inducing apoptosis in vitro and suppresses tumor growth in vivo.

    PubMed

    Inamdar, Shashikala R; Savanur, Mohammed Azharuddin; Eligar, Sachin M; Chachadi, Vishwanath B; Nagre, Nagaraja N; Chen, Chen; Barclays, Monica; Ingle, Aravind; Mahajan, Praveen; Borges, Anita; Shastry, Padma; Kalraiya, Rajiv D; Swamy, Bale M; Rhodes, Jonathan M; Yu, Lu-Gang

    2012-09-01

    Glycan array analysis of Sclerotium rolfsii lectin (SRL) revealed its exquisite binding specificity to the oncofetal Thomsen-Friedenreich (Galβ1-3GalNAcα-O-Ser/Thr, T or TF) antigen and its derivatives. This study shows that SRL strongly inhibits the growth of human colon cancer HT29 and DLD-1 cells by binding to cell surface glycans and induction of apoptosis through both the caspase-8 and -9 mediated signaling. SRL showed no or very weak binding to normal human colon tissues but strong binding to cancerous and metastatic tissues. Intratumor injection of SRL at subtoxic concentrations in NOD-SCID mice bearing HT29 xenografts resulted in total tumor regression in 9 days and no subsequent tumor recurrence. As the increased expression of TF-associated glycans is commonly seen in human cancers, SRL has the potential to be developed as a therapeutic agent for cancer. PMID:22653662

  10. Visualization of the Biological Behavior of Tumor-Associated Macrophages in Living Mice with Colon Cancer Using Multimodal Optical Reporter Gene Imaging

    PubMed Central

    Choi, Yun Ju; Oh, Seul-Gi; Singh, Thoudam Debraj; Ha, Jeoung-Hee; Kim, Dong Wook; Lee, Sang Woo; Jeong, Shin Young; Ahn, Byeong-Cheol; Lee, Jaetae; Jeon, Young Hyun

    2016-01-01

    We sought to visualize the migration of tumor-associated macrophages (TAMs) to tumor lesions and to evaluate the effects of anti-inflammatory drugs on TAM-modulated tumor progression in mice with colon cancer using a multimodal optical reporter gene system. Murine macrophage Raw264.7 cells expressing an enhanced firefly luciferase (Raw/effluc) and murine colon cancer CT26 cells coexpressing Rluc and mCherry (CT26/Rluc-mCherry, CT26/RM) were established. CT26/RM tumor-bearing mice received Raw/effluc via their tail veins, and combination of bioluminescence imaging (BLI) and fluorescence imaging (FLI) was conducted for in vivo imaging of TAMs migration and tumor progression. Dexamethasone (DEX), a potent anti-inflammatory drug, was administered intraperitoneally to tumor-bearing mice following the intravenous transfer of Raw/effluc cells. The migration of TAMs and tumor growth was monitored by serial FLI and BLI. The migration of Raw/effluc cells to tumor lesions was observed at day 1, and BLI signals were still distinct at tumor lesions on day 4. Localization of BLI signals from migrated Raw/effluc cells corresponded to that of FLI signals from CT26/RM tumors. In vivo FLI of tumors demonstrated enhanced tumor growth associated with macrophage migration to tumor lesions. Treatment with DEX inhibited the influx of Raw/effluc cells to tumor lesions and abolished the enhanced tumor growth associated with macrophage migration. These findings suggest that molecular imaging approach for TAM tracking is a valuable tool for evaluating the role of TAMs in the tumor microenvironment as well as for the development of new drugs to control TAM involvement in the modulation of tumor progression. PMID:26992914

  11. Visualization of the Biological Behavior of Tumor-Associated Macrophages in Living Mice with Colon Cancer Using Multimodal Optical Reporter Gene Imaging.

    PubMed

    Choi, Yun Ju; Oh, Seul-Gi; Singh, Thoudam Debraj; Ha, Jeoung-Hee; Kim, Dong Wook; Lee, Sang Woo; Jeong, Shin Young; Ahn, Byeong-Cheol; Lee, Jaetae; Jeon, Young Hyun

    2016-03-01

    We sought to visualize the migration of tumor-associated macrophages (TAMs) to tumor lesions and to evaluate the effects of anti-inflammatory drugs on TAM-modulated tumor progression in mice with colon cancer using a multimodal optical reporter gene system. Murine macrophage Raw264.7 cells expressing an enhanced firefly luciferase (Raw/effluc) and murine colon cancer CT26 cells coexpressing Rluc and mCherry (CT26/Rluc-mCherry, CT26/RM) were established. CT26/RM tumor-bearing mice received Raw/effluc via their tail veins, and combination of bioluminescence imaging (BLI) and fluorescence imaging (FLI) was conducted for in vivo imaging of TAMs migration and tumor progression. Dexamethasone (DEX), a potent anti-inflammatory drug, was administered intraperitoneally to tumor-bearing mice following the intravenous transfer of Raw/effluc cells. The migration of TAMs and tumor growth was monitored by serial FLI and BLI. The migration of Raw/effluc cells to tumor lesions was observed at day 1, and BLI signals were still distinct at tumor lesions on day 4. Localization of BLI signals from migrated Raw/effluc cells corresponded to that of FLI signals from CT26/RM tumors. In vivo FLI of tumors demonstrated enhanced tumor growth associated with macrophage migration to tumor lesions. Treatment with DEX inhibited the influx of Raw/effluc cells to tumor lesions and abolished the enhanced tumor growth associated with macrophage migration. These findings suggest that molecular imaging approach for TAM tracking is a valuable tool for evaluating the role of TAMs in the tumor microenvironment as well as for the development of new drugs to control TAM involvement in the modulation of tumor progression. PMID:26992914

  12. 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

  13. 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.

  14. 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.

  15. Colon Cancer Metastatic to the Biliary Tree

    PubMed Central

    Clayton, Steven B.; Markow, Michael; Mamel, Jay

    2016-01-01

    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. PMID:27144209

  16. Long-term survival case of a recurrent colon cancer owing to successful resection of a tumor at hepaticojejunostomy: report of a case.

    PubMed

    Natsume, Seiji; Shimizu, Yasuhiro; Sano, Tsuyoshi; Senda, Yoshiki; Ito, Seiji; Komori, Koji; Abe, Tetsuya; Yanagisawa, Akio; Yamao, Kenji

    2015-12-01

    With advances in surgical procedures and perioperative management, hepato-biliary-pancreatic surgery, including hepatectomy and pancreaticoduodenectomy, has been employed for recurrent colon cancer. However, no report has described a case of major hepatectomy with the combined resection of hepaticojejunostomy following pancreaticoduodenectomy for locoregionally recurrent colon cancer. Here, such a case is reported. The patient, a 37-year-old woman, had undergone pancreaticoduodenectomy for lymph node recurrence along the extrahepatic bile duct from cecal cancer. Thirteen months later, a biliary stricture was found at the hepaticojejunostomy site and right hepatectomy was performed. The resected specimen showed a papillary tumor at the hepaticojejunostomy. Based on its histological features, the pathogenesis of this tumor was considered to be intramural recurrence via lymphatic vessels. Although she underwent resection of a lymph node recurrence at her mesentery 12 months later, she has remained well thereafter, without any sign of further recurrence during 5 years of follow-up after hepatectomy.

  17. The ADAMTS12 metalloprotease gene is epigenetically silenced in tumor cells and transcriptionally activated in the stroma during progression of colon cancer.

    PubMed

    Moncada-Pazos, Angela; Obaya, Alvaro J; Fraga, Mario F; Viloria, Cristina G; Capellá, Gabriel; Gausachs, Mireia; Esteller, Manel; López-Otín, Carlos; Cal, Santiago

    2009-08-15

    Proteases have long been associated with tumor progression, given their ability to degrade extracellular matrix components and facilitate invasion and metastasis. However, recent findings indicate that different proteases can also act as tumor-suppressor enzymes. We have recently reported that lung carcinoma cells expressing the ADAMTS-12 metalloprotease show a remarkable impairment of growth in immunodeficient mice as compared with parental cells. Here, we show that ADAMTS12 promoter is hypermethylated in cancer cell lines and tumor tissues. Interestingly, ADAMTS12 expression in the stromal cells surrounding epithelial malignant cells is higher than in the paired normal tissues. Moreover, the expression of this metalloprotease in colon fibroblasts co-cultured with colon cancer cell lines is higher than in those cultured alone. Furthermore, the expression of ADAMTS-12 by these fibroblasts is linked with an anti-proliferative effect on tumor cells. Based on these findings, we hypothesize that ADAMTS-12 is a novel anti-tumor protease that can reduce the proliferative properties of tumor cells. This function is lost by epigenetic silencing in tumor cells, but concurrently induced in stromal cells, probably as part of a response of the normal tissue aimed at controlling the progression of cancer.

  18. Combined therapeutic effects of vinblastine and Astragalus saponins in human colon cancer cells and tumor xenograft via inhibition of tumor growth and proangiogenic factors.

    PubMed

    Auyeung, Kathy K W; Law, P C; Ko, Joshua K S

    2014-01-01

    Our previous study had demonstrated that Astragalus saponins (AST) could reduce the side effects of orthodox chemotherapeutic drugs, while concurrently promote antitumor activity. In the present study, we attempted to investigate the potential synergistic anticarcinogenic effects of AST and a vinca alkaloid vinblastine (VBL). Reduced expression of key proangiogenic and metastatic factors including VEGF, bFGF, metalloproteinase (MMP)-2, and MMP-9 was detected in VBL-treated colon cancer cells, with further downregulation by combined VBL/AST treatment. Subsequently, VBL or AST decreased LoVo cell invasiveness, with further reduction when the drugs were cotreated. Significant growth inhibition and cell cycle arrest at G2/M phase were achieved by either drug treatment with apparent synergistic effects. VBL-induced apoptosis was confirmed but found to be unrelated to induction of the novel apoptotic protein NSAID-activated gene 1. In vivo study in tumor xenograft indicates that combined VBL/AST treatment resulted in sustained regression of tumor growth, with attenuation of the neutropenic and anemic effects of VBL. In addition, downregulation of proangiogenic and proliferative factors was also visualized, with boosting effect by combined drug treatment. These findings have provided evidence that AST combined with adjuvant chemotherapeutics like VBL could alleviate cancer development through diversified modes of action, including the regulation of angiogenesis.

  19. Suppressor of Ty homolog-5, a novel tumor-specific human telomerase reverse transcriptase promoter-binding protein and activator in colon cancer cells

    PubMed Central

    Dong, Yong; He, Chao; Hu, Xiaotong

    2015-01-01

    The human telomerase reverse transcriptase (hTERT) promoter promotes differential hTERT gene expression in tumor cells and normal cells. However, information on the mechanisms underlying the differential hTERT transcription and induction of telomerase activity in tumor cells is limited. In the present study, suppressor of Ty homolog-5 (SPT5), a protein encoded by the SUPT5H gene, was identified as a novel tumor-specific hTERT promoter-binding protein and activator in colon cancer cells. We verified the tumor-specific binding activity of SPT5 to the hTERT promoter in vitro and in vivo and detected high expression levels of SUPT5H in colorectal cancer cell lines and primary human colorectal cancer tissues. SUPT5H was more highly expressed in colorectal cancer cases with distant metastasis than in cases without distant metastasis. Inhibition of endogenous SUPT5H expression by SUPT5H gene-specific short hairpin RNAs effectively attenuated hTERT promoter-driven green fluorescent protein (GFP) expression, whereas no detectable effects on CMV promoter-driven GFP expression in the same cells were observed. In addition, inhibition of SUPT5H expression not only effectively repressed telomerase activity, accelerated telomere shortening, and promoted cell senescence in colon cancer cells, but also suppressed cancer cell growth and migration. Our results demonstrated that SPT5 contributes to the up-regulation of hTERT expression and tumor development, and SUPT5H may potentially be used as a novel tumor biomarker and/or cancer therapeutic target. PMID:26418880

  20. Influence of myeloperoxidase on colon tumor occurrence in inflamed versus non-inflamed colons of ApcMin/+ mice☆

    PubMed Central

    Al-Salihi, Mazin; Reichert, Ethan; Fitzpatrick, F.A.

    2015-01-01

    Control of colorectal cancer needs to be tailored to its etiology. Tumor promotion mechanisms in colitis-associated colon cancer differ somewhat from the mechanisms involved in hereditary and sporadic colorectal cancer. Unlike sporadic or inherited tumors, some experimental models show that colitis-associated colon tumors do not require cyclooxygenase (COX) expression for progression, and non-steroidal anti-inflammatory drugs (NSAIDs) which prevent sporadic or inherited colon cancer do not prevent colitis-associated colon cancer. We report that myeloperoxidase (MPO), an ancestor of the COX isoenzymes, is a determinant of colitis-associated colon tumors in ApcMin/+ mice. During experimentally induced colitis, inhibition of MPO by resorcinol dampened colon tumor development. Conversely, in the bowels of ApcMin/+ mice without colitis, resorcinol administration or ‘knockout’ of MPO gene coincided with a slight, but discernible increase in colon tumor incidence. Acrolein, a by-product of MPO catalysis, formed a covalent adduct with the phosphatase tensin homolog (PTEN) tumor suppressor and enhanced the activity of the Akt kinase proto-oncogene in vitro and in vivo. Thus, MPO may be an important determinant of diet and inflammation on colon cancer risk via its effect on endogenous exposure to oxidants and acrolein. We propose a hypothetical model to explain an apparent dichotomy between colon tumor occurrence and MPO inhibition in inflamed versus non-inflamed colons. PMID:26262998

  1. Oncolytic reovirus against ovarian and colon cancer.

    PubMed

    Hirasawa, Kensuke; Nishikawa, Sandra G; Norman, Kara L; Alain, Tommy; Kossakowska, Anna; Lee, Patrick W K

    2002-03-15

    Reovirus selectively replicates in and destroys cancer cells with an activated Ras signaling pathway. In this study, we evaluated the feasibility of using reovirus (serotype 3, strain Dearing) as an antihuman colon and ovarian cancer agent. In in vitro studies, reovirus infection in human colon and ovarian cell lines was assessed by cytopathic effect as detected by light microscopy, [(35)S]Methionine labeling of infected cells for viral protein synthesis and progeny virus production by plaque assay. We observed that reovirus efficiently infected all five human colon cancer cell lines (Caco-2, DLD-1, HCT-116, HT-29, and SW48) and four human ovarian cancer cell lines (MDAH2774, PA-1, SKOV3, and SW626) which were tested, but not a normal colon cell line (CCD-18Co) or a normal ovarian cell line (NOV-31). We also observed that the Ras activity in the human colon and ovarian cancer cell lines was elevated compared with that in normal colon and ovarian cell lines. In animal models, intraneoplastic as well as i.v. inoculation of reovirus resulted in significant regression of established s.c. human colon and ovarian tumors implanted at the hind flank. Histological studies revealed that reovirus infection in vivo was restricted to tumor cells, whereas the surrounding normal tissue remained uninfected. Additionally, in an i.p. human ovarian cancer xenograft model, inhibition of ascites tumor formation and the survival of animals treated with live reovirus was significantly greater than of control mice treated with UV-inactivated reovirus. Reovirus infection in ex vivo primary human ovarian tumor surgical samples was also confirmed, further demonstrating the potential of reovirus therapy. These results suggest that reovirus holds promise as a novel agent for human colon and ovarian cancer therapy. PMID:11912142

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

    ClinicalTrials.gov

    2016-02-16

    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

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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

    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

  8. Exposure to ACEI/ARB and β-Blockers Is Associated with Improved Survival and Decreased Tumor Progression and Hospitalizations in Patients with Advanced Colon Cancer1

    PubMed Central

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

    2013-01-01

    BACKGROUND: 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. METHODS: Retrospective chart review included patients with advanced colorectal cancer. Survival, stage, hospitalization, cancer progression, cancer treatment, and body weight history were collected. RESULTS: 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. CONCLUSIONS: 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. PMID:24151534

  9. Hydroxyethyl starch 200/0.5 decreases circulating tumor cells of colorectal cancer patients and reduces metastatic potential of colon cancer cell line through inhibiting platelets activation.

    PubMed

    Liang, Hua; Yang, Chengxiang; Zhang, Bin; Wang, Hanbing; Liu, Hongzhen; Zhao, Zhenlong; Zhang, Zhiming; Wen, Xianjie; Lai, Xiaohong

    2015-05-01

    Platelets play an important role in metastasis of circulating tumor cells (CTCs). It has been demonstrated that hydroxyethyl starch (HES) inhibits platelets function. However, the effect of HES on CTCs in patients with colorectal cancer remains unclear. We compared the effects of HES 200/0.5 and HES 130/0.4 on CTCs and platelets activation of colorectal patients in this study. Additionally, the effects of HES 200/0.5 or HES 130/0.4 on metastasis ability of colon cancer cell line that stimulated by activated platelets have been explored. In vivo, 90 patients undergoing colorectal cancer radical surgery received randomly 15 mL/kg of HES 200/0.5 (n = 45) or HES 130/0.4 (n = 45) infusion before surgery. Platelet glycoprotein IIb/IIIa (GPIIb/IIIa), CD62P and platelets aggregation rate (PAR) were evaluated pre-, intra- and postoperatively. Cytokeratin-20 (CK-20) mRNA was detected by reverse transcriptase polymerase chain reaction before and after surgery. In vitro, colon cancer SW480 cells were incubated with activated platelets in the presence or absence HES 200/0.5 or HES 130/0.4. The metastasis ability of SW480 cells was assessed by Transwell assay. The results showed that CK-20 mRNA positive rate in HES 200/0.5 group after surgery was decreased significantly as compared to group HES 130/0.4 (χ (2) = 6.164, P = 0.013). Simultaneously, a more pronounced inhibition of platelets activation was observed in group HES 200/0.5. A positive correlation between platelets activation marker and CK-20 mRNA positive rate was found. In vitro, HES 200/0.5, but not HES 130/0.4, decreased the invasion and migration ability of SW480 cells that induced by activated platelets. Besides, the expression of GPIIb/IIIa, CD62P and PAR was inhibited more strongly in group HES 200/0.5 than those in group HES 130/0.4. In summary, we found that HES 200/0.5 significantly decreased CTCs of patients undergoing colorectal cancer radical surgery as compared to HES 130/0.4, which might be associated

  10. Inhibition of Single Minded 2 gene expression mediates tumor-selective apoptosis and differentiation in human colon cancer cells.

    PubMed

    Aleman, Mireille J; DeYoung, Maurice Phil; Tress, Matthew; Keating, Patricia; Perry, Gary W; Narayanan, Ramaswamy

    2005-09-01

    A Down's syndrome associated gene, Single Minded 2 gene short form (SIM2-s), is specifically expressed in colon tumors but not in the normal colon. Antisense inhibition of SIM2-s in a RKO-derived colon carcinoma cell line causes growth inhibition, apoptosis, and inhibition of tumor growth in a nude mouse tumoriginicity model. The mechanism of cell death in tumor cells is unclear. In the present study, we investigated the pathways underlying apoptosis. Apoptosis was seen in a tumor cell-specific manner in RKO cells but not in normal renal epithelial cells, despite inhibition of SIM2-s expression in both of these cells by the antisense. Apoptosis was depended on WT p53 status and was caspase-dependent; it was inhibited by a pharmacological inhibitor of mitogen-activated protein kinase activity. Expression of a key stress response gene, growth arrest and DNA damage gene (GADD)45alpha, was up-regulated in antisense-treated tumor cells but not in normal cells. In an isogenic RKO cell line expressing stable antisense RNA to GADD45alpha, a significant protection of the antisense-induced apoptosis was seen. Whereas antisense-treated RKO cells did not undergo cell cycle arrest, several markers of differentiation were deregulated, including alkaline phosphatase activity, a marker of terminal differentiation. Protection of apoptosis and block of differentiation showed a correlation in the RKO model. Our results support the tumor cell-selective nature of SIM2-s gene function, provide a direct link between SIM2-s and differentiation, and may provide a model to identify SIM2-s targets.

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

    PubMed Central

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

    2014-01-01

    Objective 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 increased risk of developing several cancer types including colorectal cancer. We evaluated whether SNPs in obesity-related genes may predict tumor recurrence in colon cancer patients. Methods 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 3-year recurrence rate. Positive associations were also tested in an independent Japanese cohort of 350 stage III CRC patients. Results In univariate analysis, for PPAR rs1801282, patients with a CC genotype had significantly lower recurrence probability (29± 4% standard error, SE) compared to patients with a CG genotype (48% ± 8% SE), HR: 1.77; 95%CI, 1.01-3.10; p=0.040. For DSCR1 rs6517239, 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. Conclusion 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 further evaluated. PMID:25379721

  12. 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.

  13. A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.

    PubMed

    Thompson, Bryony A; Goldgar, David E; Paterson, Carol; Clendenning, Mark; Walters, Rhiannon; Arnold, Sven; Parsons, Michael T; Michael D, Walsh; Gallinger, Steven; Haile, Robert W; Hopper, John L; Jenkins, Mark A; Lemarchand, Loic; Lindor, Noralane M; Newcomb, Polly A; Thibodeau, Stephen N; Young, Joanne P; Buchanan, Daniel D; Tavtigian, Sean V; Spurdle, Amanda B

    2013-01-01

    Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ~12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing.

  14. 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

  15. 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.

  16. 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.

  17. An Immune-Modulating Diet in Combination with Chemotherapy Prevents Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice.

    PubMed

    Nakamura, Kentaro; Sasayama, Akina; Takahashi, Takeshi; Yamaji, Taketo

    2015-01-01

    Cancer cachexia is characterized by muscle wasting caused partly by systemic inflammation. We previously demonstrated an immune-modulating diet (IMD), an enteral diet enriched with immunonutrition and whey-hydrolyzed peptides, to have antiinflammatory effects in some experimental models. Here, we investigated whether the IMD in combination with chemotherapy could prevent cancer cachexia in colon 26 tumor-bearing mice. Forty tumor-bearing mice were randomized into 5 groups: tumor-bearing control (TB), low dose 5-fluorouracil (5-FU) and standard diet (LF/ST), low dose 5-FU and IMD (LF/IMD), high dose 5-FU and standard diet (HF/ST) and high dose 5-FU and IMD (HF/IMD). The ST and IMD mice received a standard diet or the IMD ad libitum for 21 days. Muscle mass in the IMD mice was significantly higher than that in the ST mice. The LF/IMD in addition to the HF/ST and HF/IMD mice preserved their body and carcass weights. Plasma prostaglandin E2 levels were significantly lower in the IMD mice than in the ST mice. A combined effect was also observed in plasma interleukin-6, glucose, and vascular endothelial growth factor levels. Tumor weight was not affected by different diets. In conclusion, the IMD in combination with chemotherapy prevented cancer cachexia without suppressing chemotherapeutic efficacy.

  18. 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

  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. 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.

  1. Clinical significance of HOTAIR expression in colon cancer

    PubMed Central

    Luo, Zhi-Fen; Zhao, Dan; Li, Xi-Qing; Cui, Yong-Xia; Ma, Ning; Lu, Chuang-Xin; Liu, Ming-Yue; Zhou, Yun

    2016-01-01

    AIM: To detect the expression of the long noncoding RNA HOTAIR in colon cancer and analyze its relationship with clinicopathological parameters of colon cancer. METHODS: Total RNA was extracted from 80 colon cancer tissues and matched tumor-adjacent normal colon tissues and reverse transcribed. Quantitative polymerase chain reaction was used to detect the expression of HOTAIR. The relationship between the expression of HOTAIR and clinicopathological parameters of colon cancer was analyzed. RESULTS: The expression of HOTAIR was significantly higher in colon cancer tissues than in matched tumor-adjacent normal colon tissues (P < 0.05). HOTAIR expression was significantly higher in cases with lymph node metastasis than in those without metastasis; in lowly differentiated and undifferentiated cases than in highly and moderately differentiated cases; and in stages III + IV cases than in stages I + II cases (P < 0.05). CONCLUSION: HOTAIR expression is upregulated in colon cancer, suggesting that HOTAIR plays an important role in the tumorigenesis, development and metastasis of colon cancer. HOTAIR may act as an oncogene and represents a new molecular target for the treatment of colon cancer. PMID:27298568

  2. Oncostatic effects of fluoxetine in experimental colon cancer models.

    PubMed

    Kannen, Vinicius; Garcia, Sergio Britto; Silva, Wilson A; Gasser, Martin; Mönch, Romana; Alho, Eduardo Joaquim Lopes; Heinsen, Helmut; Scholz, Claus-Jürgen; Friedrich, Mike; Heinze, Katrin Gertrud; Waaga-Gasser, Ana Maria; Stopper, Helga

    2015-09-01

    Colon cancer is one of the most common tumors in the human population. Recent studies have shown a reduced risk for colon cancer in patients given the antidepressant fluoxetine (FLX). The exact mechanism by which FLX might protect from colon cancer remains however controversial. Here, FLX reduced the development of different colon tumor xenografts, as well as proliferation in hypoxic tumor areas within them. FLX treatment also decreased microvessel numbers in tumors. Although FLX did not increase serum and tumor glucose levels as much as the colon chemotherapy gold standard Fluorouracil did, lactate levels were significantly augmented within tumors by FLX treatment. The gene expression of the MCT4 lactate transporter was significantly downregulated. Total protein amounts from the third and fifth mitochondrial complexes were significantly decreased by FLX in tumors. Cell culture experiments revealed that FLX reduced the mitochondrial membrane potential significantly and disabled the reactive oxygen species production of the third mitochondrial complex. Furthermore, FLX arrested hypoxic colon tumor cells in the G0/G1 phase of the cell-cycle. The expression of key cell-cycle-related checkpoint proteins was enhanced in cell culture and in vivo experiments. Therefore, we suggest FLX impairs energy generation, cell cycle progression and proliferation in tumor cells, especially under condition of hypoxia. This then leads to reduced microvessel formation and tumor shrinkage in xenograft models. PMID:26004136

  3. 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.

  4. Drugs Approved for Colon and Rectal Cancer

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Colon and Rectal Cancer This page ... and rectal cancer that are not listed here. Drugs Approved for Colon Cancer Avastin (Bevacizumab) Bevacizumab Camptosar ( ...

  5. Colonic macrophage polarization in homeostasis, inflammation, and cancer.

    PubMed

    Isidro, Raymond A; Appleyard, Caroline B

    2016-07-01

    Our review focuses on the colonic macrophage, a monocyte-derived, tissue-resident macrophage, and the role it plays in health and disease, specifically in inflammatory conditions such as inflammatory bowel disease and cancer of the colon and rectum. We give special emphasis to macrophage polarization, or phenotype, in these different states. We focus on macrophages because they are one of the most numerous leukocytes in the colon, and because they normally contribute to homeostasis through an anti-inflammatory phenotype. However, in conditions such as inflammatory bowel disease, proinflammatory macrophages are increased in the colon and have been linked to disease severity and progression. In colorectal cancer, tumor cells may employ anti-inflammatory macrophages to promote tumor growth and dissemination, whereas proinflammatory macrophages may antagonize tumor growth. Given the key roles that this cell type plays in homeostasis, inflammation, and cancer, the colonic macrophage is an intriguing therapeutic target. As such, potential macrophage-targeting strategies are discussed.

  6. Anti-G-CSF treatment induces protective tumor immunity in mouse colon cancer by promoting NK cell, macrophage and T cell responses

    PubMed Central

    Morris, Katherine T.; Castillo, Eliseo F.; Ray, Anita L.; Weston, Lea L.; Nofchissey, Robert A.; Hanson, Joshua A.; Samedi, Von G.; Pinchuk, Irina V.; Hudson, Laurie G.; Beswick, Ellen J.

    2015-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a cytokine that is highly expressed in human and mouse colorectal cancers (CRC). We previously reported that G-CSF stimulated human CRC cell growth and migration, therefore in this study we sought to examine the therapeutic potential of anti-G-CSF treatment for CRC. G-CSF is known to mobilize neutrophils, however its impact on other immune cells has not been well examined. Here, we investigated the effects of therapeutic anti-G-CSF treatment on CRC growth and anti-tumor immune responses. C57BL/6 mice treated with azoxymethane/dextran sodium sulfate (AOM/DSS) to induce neoplasms were administered anti-G-CSF or isotype control antibodies three times a week for three weeks. Animals treated with anti-G-CSF antibodies had a marked decrease in neoplasm number and size compared to the isotype control group. Colon neutrophil and macrophage frequency were unchanged, but the number of macrophages producing IL-10 were decreased while IL-12 producing macrophages were increased. NK cells were substantially increased in colons of anti-G-CSF treated mice, along with IFNγ producing CD4+ and CD8+ T cells. These studies are the first to indicate a crucial role for G-CSF inhibition in promoting protective anti-tumor immunity, and suggest that anti-G-CSF treatment is a potential therapeutic approach for CRC. PMID:26061815

  7. 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

  8. 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

  9. Lysyl oxidase-like 2 expression is increased in colon and esophageal tumors and associated with less differentiated colon tumors.

    PubMed

    Fong, Sheri F T; Dietzsch, Erin; Fong, Keith S K; Hollosi, Peter; Asuncion, Lloyd; He, Qingping; Parker, M Iqbal; Csiszar, Katalin

    2007-07-01

    Lysyl oxidase-like 2 (LOXL2) belongs to an amine oxidase family whose members have been implicated in crosslink formation in stromal collagens and elastin, cell motility, and tumor development and progression. We previously demonstrated the association between increased LOXL2 expression and invasive/metastatic behavior in human breast cancer cells and mouse squamous and spindle cell carcinomas, interaction between LOXL2 and SNAIL in epithelial-mesenchymal transition, and localization of the LOXL2 gene to 8p21.2-21.3, within a minimally deleted region in several cancers, including colon and esophagus. In the present study, we analyzed LOXL2 expression in colon and esophageal tumors, and explored methylation as a regulator of LOXL2 expression. Immunohistochemistry using normal tissues demonstrated intracellular localization of LOXL2 in colonic enteroendocrine cells and esophageal squamous cells at the luminal surface, but not in mitotically active cells. Tissue array analysis of 52 colon adenocarcinomas and 50 esophageal squamous cell carcinomas revealed presence of LOXL2 expression in 83 and 92% of the samples, respectively, and a significant association between increased number of LOXL2-expressing cells and less-differentiated colon carcinomas. We determined that the methylation status of the 1150 bp 5' CpG island may contribute to the regulation of the gene. Loss of heterozygosity studies, using a microsatellite within intron 4 of the LOXL2 gene, revealed that loss of LOXL2 was unlikely to play a major role in either colon or esophageal tumors. These results suggest that increased LOXL2 expression in colon and esophageal cancer may contribute to tumor progression.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. Sentinel Lymph Node Biopsy in Colon Cancer

    PubMed Central

    Bembenek, Andreas E.; Rosenberg, Robert; Wagler, Elke; Gretschel, Stephan; Sendler, Andreas; Siewert, Joerg-Ruediger; Nährig, Jörg; Witzigmann, Helmut; Hauss, Johann; Knorr, Christian; Dimmler, Arno; Gröne, Jörn; Buhr, Heinz-Johannes; Haier, Jörg; Herbst, Hermann; Tepel, Juergen; Siphos, Bence; Kleespies, Axel; Koenigsrainer, Alfred; Stoecklein, Nikolas H.; Horstmann, Olaf; Grützmann, Robert; Imdahl, Andreas; Svoboda, Daniel; Wittekind, Christian; Schneider, Wolfgang; Wernecke, Klaus-Dieter; Schlag, Peter M.

    2007-01-01

    Introduction: The clinical impact of sentinel lymph node biopsy (SLNB) in colon cancer is still controversial. The purpose of this prospective multicenter trial was to evaluate its clinical value to predict the nodal status and identify factors that influence these results. Methods: Colon cancer patients without prior colorectal surgery or irradiation were eligible. The sentinel lymph node (SLN) was identified intraoperatively by subserosal blue dye injection around the tumor. The SLN underwent step sections and immunohistochemistry (IHC), if classified free of metastases after routine hematoxylin and eosin examination. Results: At least one SLN (median, n = 2) was identified in 268 of 315 enrolled patients (detection rate, 85%). Center experience, lymphovascular invasion, body mass index (BMI), and learning curve were positively associated with the detection rate. The false-negative rate to identify pN+ patients by SLNB was 46% (38 of 82). BMI showed a significant association to the false-negative rate (P < 0.0001), the number of tumor-involved lymph nodes was inversely associated. If only slim patients (BMI ≤24) were investigated in experienced centers (>22 patients enrolled), the sensitivity increased to 88% (14 of 16). Moreover, 21% (30 of 141) of the patients, classified as pN0 by routine histopathology, revealed micrometastases or isolated tumor cells (MM/ITC) in the SLN. Conclusions: The contribution of SLNB to conventional nodal staging of colon cancer patients is still unspecified. Technical problems have to be resolved before a definite conclusion can be drawn in this regard. However, SLNB identifies about one fourth of stage II patients to reveal MM/ITC in lymph nodes. Further studies must clarify the clinical impact of these findings in terms of prognosis and the indication of adjuvant therapy. PMID:17522509

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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. PMID:26437221

  2. 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.

  3. [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.

  4. 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.

  5. Liver acid sphingomyelinase inhibits growth of metastatic colon cancer.

    PubMed

    Osawa, Yosuke; Suetsugu, Atsushi; Matsushima-Nishiwaki, Rie; Yasuda, Ichiro; Saibara, Toshiji; Moriwaki, Hisataka; Seishima, Mitsuru; Kozawa, Osamu

    2013-02-01

    Acid sphingomyelinase (ASM) regulates the homeostasis of sphingolipids, including ceramides and sphingosine-1-phosphate (S1P). These sphingolipids regulate carcinogenesis and proliferation, survival, and apoptosis of cancer cells. However, the role of ASM in host defense against liver metastasis remains unclear. In this study, the involvement of ASM in liver metastasis of colon cancer was examined using Asm-/- and Asm+/+ mice that were inoculated with SL4 colon cancer cells to produce metastatic liver tumors. Asm-/- mice demonstrated enhanced tumor growth and reduced macrophage accumulation in the tumor, accompanied by decreased numbers of hepatic myofibroblasts (hMFs), which express tissue inhibitor of metalloproteinase 1 (TIMP1), around the tumor margin. Tumor growth was increased by macrophage depletion or by Timp1 deficiency, but was decreased by hepatocyte-specific ASM overexpression, which was associated with increased S1P production. S1P stimulated macrophage migration and TIMP1 expression in hMFs in vitro. These findings indicate that ASM in the liver inhibits tumor growth through cytotoxic macrophage accumulation and TIMP1 production by hMFs in response to S1P. Targeting ASM may represent a new therapeutic strategy for treating liver metastasis of colon cancer.

  6. miR-126: A novel regulator in colon cancer

    PubMed Central

    HUANG, WEINA; LIN, JIE; ZHANG, HONGXUAN

    2016-01-01

    Colon cancer is one of the most common, lethal diseases worldwide. Tumor metastasis and chemotherapy resistance are the main reasons for its poor prognosis and high fatality rate. Tumor development is thought of as one of the most complex cellular events as it is a multi-step cascading process involving infinite proliferation, invasion and immigration. Recently, increasing studies have demonstrated that microRNA-126 (miR-126) has an important role in colon cancer. The expression of miR-126 decreased significantly in colon cancer, particularly in highly metastatic cell lines. miR-126 controls tumor cell growth, metastasis and survival via inactivation of the oncogene signaling pathway, indicating that miR-126 may serve as a therapeutic target for anticancer therapy. Potentially, miR-126 was also reported to be an ideal molecular target as a novel biomarker for liver metastasis from colorectal cancer due to its changeable expression level. In the present review, the current knowledge regarding regulatory function of miR-126 is summarized along with its underlying mechanisms in colon cancer. PMID:26893826

  7. [Multidisciplinary tailoring of therapy of metastatic colon cancer].

    PubMed

    Österlund, Pia; Isoniemi, Helena; Scheinin, Tom; Ristimäki, Ari; Lantto, Eila

    2016-01-01

    Treatment of colon cancer requires multidisciplinary team work. The multitude of therapies in metastatic colon cancer have led to longer overall survival with fewer symptoms. Median survival has increased from 5 months with the best supportive care to 30-40 months in randomized studies, even with curative treatment in some patients. Tailoring of the treatment is best done by a multidisciplinary team considering radiotherapy and operation of the primary tumor, resection of liver, lung and peritoneal metastases, medical treatment alternatives, palliative care, ablative methods etc. Without skillful surgeons, oncologists, pathologists, geneticists, radiologists etc. the best treatment opportunities may be missed. PMID:27483635

  8. Accessory spleen hypertrophy mimicking colon cancer metastasis.

    PubMed

    Ates, I; Yazici, O; Yazilitas, D; Ozdemir, N; Zengin, N

    2016-09-01

    Accessory spleen is a congenital form of an ectopic splenic tissue. In this report, we present a case of a patient who was followed with the diagnosis of rectal and sigmoid colon cancer and an accessory spleen hypertrophy, which was thought to be colon cancer metastasis in the left hypochondriac region. After colectomy and splenectomy, accessory spleen that mimics cancer metastasis was diffrentially diagnosed using scintigraphy. PMID:27685531

  9. Colon cancer: genomics and apoptotic events.

    PubMed

    Rupnarain, Charleen; Dlamini, Zodwa; Naicker, Sarala; Bhoola, Kanti

    2004-06-01

    Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly. PMID:15255176

  10. 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

  11. 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).

  12. Effect of caloric intake on Western-style diet-induced intestinal tumors in a mouse model for hereditary colon cancer.

    PubMed

    Itano, Osamu; Fan, Kunhua; Yang, Kan; Suzuki, Keiich; Quimby, Fred; Dong, Zhiqian; Jin, Bo; Edelmann, Winfried; Lipkin, Martin

    2012-04-01

    Increased caloric intake has been associated with increased risk for cancer of the large intestine. We studied caloric intake effect on tumor formation in Apc1638( N/+ ) mice, a preclinical model for human familial adenomatous polyposis. Mice were fed a controlled AIN-76A diet or a new Western-style diet (NWD). Intestinal tumor development was evaluated after 6 mo of feeding 1) AIN-76A diet (fed ad libitum) vs. AIN-76A (caloric intake reduced 30%); 2) NWD (fed ad libitum) vs. NWD (caloric intake reduced 30%); and 3) AIN-76A (fed ad libitum) vs. NWD (paired-fed with NWD providing equal caloric intakes to AIN-76A). Intestinal tumor incidences were 78-100% with intergroup variation P > 0.05; however, tumor multiplicity responded differently to dietary treatment: 1) Tumor multiplicity was unchanged after AIN-76A (caloric intake reduced 30% vs. mice fed AIN-76A ad libitum); 2) tumor multiplicity was unchanged after NWD (caloric intake reduced 30% vs. NWD ad libitum); and 3) tumor multiplicity increased 130% after NWD was paired-fed with the same caloric intake as mice fed AIN-76A ad libitum (P < 0.05). Body weights showed no association with tumor development. Findings indicated modified nutrients in NWD were mainly responsible for increased tumors in mice fed NWD vs. AIN-76A in this preclinical mouse model for human FAP.

  13. 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

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

    PubMed Central

    ZHANG, ZEWEI; CHEN, HAITAO; XU, CHAO; SONG, LU; HUANG, LULU; LAI, YUEBIAO; WANG, YUQI; CHEN, HANLU; GU, DANLIN; REN, LILI; YAO, QINGHUA

    2016-01-01

    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. PMID:26985708

  15. COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status

    PubMed Central

    2011-01-01

    Background Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. Method Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. Results Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1β, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-κB, TCF4) showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3) were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. Conclusions Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue. PMID:21668942

  16. Genomic profiling of patient-derived colon cancer xenograft models.

    PubMed

    Lee, Won-Suk; Kim, Hye-Youn; Seok, Jae Yeon; Jang, Ho Hee; Park, Yeon Ho; Kim, So-Young; Shin, Dong Bok; Hong, Suntaek

    2014-12-01

    Recent evidence suggests that patient derived xenograft (PDX) models can maintain certain pathological and molecular features of the original disease. However, these characterizations are limited to immunohistochemistry or by tissue microarray analysis. We conducted a high-throughput sequencing of primary colon tumor and PDX has not been reported yet. Fresh primary colon cancer tissues that originate from surgery were implanted into the subcutaneous space of 6- to 8-week-old female BALB/c nu/nu or NOD/SCID mice and serially passaged in vivo. Ion AmpliSeq Cancer Hotspot Panel v2 (Ion Torrent) was used to detect frequent somatic mutations and similarity of molecular characteristics between the 10 patient tumors and matched PDX. Histologic and immunohistochemical analyses revealed a high degree of pathologic similarity including histologic architecture and expression of CEA, CK7, and CD20 between the patient and xenograft tumors. In 80% cases, all of the somatic mutations detected in primary tumor were concordantly detected in PDX models. However, 2 PDX models showed gained mutations such as PIK3CA or FBWX7 mutation. Ten patient-derived advanced colon cancer xenograft models were established. These models maintained the key characteristic features of the original tumors, suggesting useful tool for preclinical personalized medicine platform.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  18. 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.

  19. 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

  20. Cancer of the Colon and Rectum

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 134,490 % of All New Cancer Cases 8.0% Estimated Deaths in 2016 49,190 % of All Cancer ... of This Cancer : In 2013, there were an estimated 1,177,556 people living with colon and ...

  1. 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.

  2. Enhanced anti-tumor effects of combined MDR1 RNA interference and human sodium/iodide symporter (NIS) radioiodine gene therapy using an adenoviral system in a colon cancer model

    PubMed Central

    Ahn, S J; Jeon, Y H; Lee, Y J; Lee, Y L; Lee, S-W; Ahn, B-C; Ha, J-H; Lee, J

    2010-01-01

    Using an adenoviral system as a delivery mediator of therapeutic gene, we investigated the therapeutic effects of the use of combined MDR1 shRNA and human NIS (hNIS) radioiodine gene therapy in a mouse colon xenograft model. In vitro uptake of Tc-99m sestamibi was increased approximately two-fold in cells infected with an adenovirus vector that expressed MDR1 shRNA (Ad-shMDR1) and I-125 uptake was 25-fold higher in cells infected with an adenovirus vector that expressed human NIS (Ad-hNIS) as compared with control cells. As compared with doxorubicin or I-131 treatment alone, the combination of doxorubicin and I-131 resulted in enhanced cytotoxicity for both Ad-shMDR1- and Ad-hNIS-infected cells, but not for control cells. In vivo uptake of Tc-99m sestamibi and Tc-99m pertechnetate was twofold and 10-fold higher for Ad-shMDR1 and Ad-hNIS-infected tumors as compared with tumors infected with a control adenovirus construct that expressed β-galactrosidase (Ad-LacZ), respectively. In mice treated with either doxorubicin or I-131 alone, there was a slight delay in tumor growth as compared to mice treated with Ad-LacZ. However, combination therapy with doxorubicin and I-131 induced further significant inhibition of tumor growth as compared with mice treated with Ad-LacZ. We have shown successful therapeutic efficacy of combined MDR shRNA and hNIS radioiodine gene therapy using an adenoviral vector system in a mouse colon cancer model. Adenovirus-mediated cancer gene therapy using MDR1 shRNA and hNIS would be a useful tool for the treatment of cancer cells expressing multi-drug resistant genes. PMID:20186172

  3. TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells.

    PubMed

    Lozupone, F; Borghi, M; Marzoli, F; Azzarito, T; Matarrese, P; Iessi, E; Venturi, G; Meschini, S; Canitano, A; Bona, R; Cara, A; Fais, S

    2015-10-01

    An inverted pH gradient across the cell membranes is a typical feature of malignant cancer cells that are characterized by extracellular acidosis and cytosol alkalization. These dysregulations are able to create a unique milieu that favors tumor progression, metastasis and chemo/immune-resistance traits of solid tumors. A key event mediating tumor cell pH alterations is an aberrant activation of ion channels and proton pumps such as (H+)-vacuolar-ATPase (V-ATPase). TM9SF4 is a poorly characterized transmembrane protein that we have recently shown to be related to cannibal behavior of metastatic melanoma cells. Here, we demonstrate that TM9SF4 represents a novel V-ATPase-associated protein involved in V-ATPase activation. We have observed in HCT116 and SW480 colon cancer cell lines that TM9SF4 interacts with the ATP6V1H subunit of the V-ATPase V1 sector. Suppression of TM9SF4 with small interfering RNAs strongly reduces assembly of V-ATPase V0/V1 sectors, thus reversing tumor pH gradient with a decrease of cytosolic pH, alkalization of intracellular vesicles and a reduction of extracellular acidity. Such effects are associated with a significant inhibition of the invasive behavior of colon cancer cells and with an increased sensitivity to the cytotoxic effects of 5-fluorouracil. Our study shows for the first time the important role of TM9SF4 in the aberrant constitutive activation of the V-ATPase, and the development of a malignant phenotype, supporting the potential use of TM9SF4 as a target for future anticancer therapies.

  4. Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression

    PubMed Central

    Zhai, Hui-yuan; Sui, Ming-hua; Yu, Xiao; Qu, Zhen; Hu, Jin-chen; Sun, Hai-qing; Zheng, Hai-tao; Zhou, Kai; Jiang, Li-xin

    2016-01-01

    Background Colon cancer is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore therapeutic targets of colon cancer. Dysregulation of long noncoding RNAs (lncRNAs) has been shown to be correlated with diverse biological processes, including tumorigenesis. This study aimed to characterize the biological mechanism of taurine-upregulated gene 1 (TUG1) in colon cancer. Material/Methods qRT-PCR was used to analyze the expression level of TUG1 and p63 in 75 colon cancer tissues and the matched adjacent non-tumor tissue. In vitro, cultured colon cancer cell lines HCT-116 and LoVo were used as cell models. TUG1 and p63 were silenced via transferring siRNA into HCT-116 or LoVo. The effects of TUG1 were investigated by examining cell proliferation, apoptosis, and migration. Results Among the 75 colon cancer cases, the expression of TUG1 was significantly higher in colon cancer tissues compared with the matched adjacent non-tumor tissue, while p63 expression was lower in the tumor tissue. In HCT-116 and LoVo, the expression of TUG1 was significantly increased by p63 siRNA transfection. Furthermore, down-regulation of TUG1 by siRNA significantly inhibited the cell proliferation and promoted colon cancer cell apoptosis. In addition, inhibition of TUG1 expression significantly blocked the cell migration ability of colon cancer cells. Conclusions LncRNA TUG1 may serve as a potential oncogene for colon cancer. Overexpressed TUG1 may contribute to promoting cell proliferation and migration in colon cancer cells. PMID:27634385

  5. Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression.

    PubMed

    Zhai, Hui-Yuan; Sui, Ming-Hua; Yu, Xiao; Qu, Zhen; Hu, Jin-Chen; Sun, Hai-Qing; Zheng, Hai-Tao; Zhou, Kai; Jiang, Li-Xin

    2016-01-01

    BACKGROUND Colon cancer is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore therapeutic targets of colon cancer. Dysregulation of long noncoding RNAs (lncRNAs) has been shown to be correlated with diverse biological processes, including tumorigenesis. This study aimed to characterize the biological mechanism of taurine-upregulated gene 1 (TUG1) in colon cancer. MATERIAL AND METHODS qRT-PCR was used to analyze the expression level of TUG1 and p63 in 75 colon cancer tissues and the matched adjacent non-tumor tissue. In vitro, cultured colon cancer cell lines HCT-116 and LoVo were used as cell models. TUG1 and p63 were silenced via transferring siRNA into HCT-116 or LoVo. The effects of TUG1 were investigated by examining cell proliferation, apoptosis, and migration. RESULTS Among the 75 colon cancer cases, the expression of TUG1 was significantly higher in colon cancer tissues compared with the matched adjacent non-tumor tissue, while p63 expression was lower in the tumor tissue. In HCT-116 and LoVo, the expression of TUG1 was significantly increased by p63 siRNA transfection. Furthermore, down-regulation of TUG1 by siRNA significantly inhibited the cell proliferation and promoted colon cancer cell apoptosis. In addition, inhibition of TUG1 expression significantly blocked the cell migration ability of colon cancer cells. CONCLUSIONS LncRNA TUG1 may serve as a potential oncogene for colon cancer. Overexpressed TUG1 may contribute to promoting cell proliferation and migration in colon cancer cells. PMID:27634385

  6. 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.

  7. Childhood colon cancer in a patient with ataxia telangiectasia

    PubMed Central

    Jo, Kyeong Min; Park, Jong Ha; Kim, Tae Oh; Jeong, Heui Jeong; Heo, Chang Min; Jang, Ji Hoon; Hur, So Chong; Jeong, Na Ri; Jeong, Su Jin; Seol, Sang Hoon; Nam, Kyung Han

    2016-01-01

    Background Ataxia-telangiectasia (AT) is a rare autosomal recessive disease characterized by progressive neurologic impairment and cerebellar ataxia. In addition, patients with this disease are known to have an inherent increased susceptibility to the development of cancer, predominantly hematologic malignancies. Methods We report the case of a young boy with AT from Russia, who had abdominal pain. Laboratory tests and radiologic examinations were performed to him. Results After abdominal computed tomography (CT), colonoscopy and surgical interventions, the young boy was diagnosed with colon cancer that had signet ring cell features. Conclusions It is known that the patient with AT appeared to be predisposed to various tumors, including leukemia or lymphoma, which are more common in childhood. Even if the patient with AT could have solid tumor such as stomach cancer or breast cancer, it is less likely to have colon cancer, especially signet ring cell type. Actually, no case of colon cancer has ever been reported, especially in young patient and hence, we have focused on this point and are hereby reporting this unique case. PMID:26855947

  8. EphrinA5 suppresses colon cancer development by negatively regulating epidermal growth factor receptor stability.

    PubMed

    Wang, Tong-Hong; Chang, Junn-Liang; Ho, Jar-Yi; Wu, Hsiao-Chun; Chen, Tse-Ching

    2012-01-01

    Colon cancer is one of the most common human cancers worldwide. Owing to its aggressiveness and lethality, it is necessary to determine the mechanisms regulating the carcinogenesis of colon cancer. EphrinA5 has been reported to act as a putative tumor suppressor in glioma; however, little is known concerning the role of this protein in the context of colon cancer. To elucidate the biological significance of ephrinA5 in colon cancer, we examined ephrinA5 and epidermal growth factor receptor (EGFR) expression profiles in both colon cancer and normal tissues, using immunohistochemistry on a 96-spot tissue microarray. Gain-of-function and loss-of-function experiments were performed on the human colon cancer cell lines SW480 and WiDr to determine the biological effects of ephrinA5 in relation to cell proliferation, survival, and migration. It was found that ephrinA5 mRNA and protein levels were significantly reduced in colon cancer as compared with normal colon tissue specimens. EphrinA5 expression was also negatively associated with tumor differentiation and clinical stage. In colon cancer cell line models, ephrinA5 exerted an inhibitory effect on EGFR by promoting c-Cbl-mediated EGFR ubiquitination and degradation. EphrinA5 did not affect the transcriptional regulation of EGFR mRNA expression in colon cancer cells. Expression of ephrinA5 suppressed colon cancer cell proliferation, migration, and chemotherapeutic resistance. In conclusion, ephrinA5 inhibited colon cancer progression by promoting c-Cbl-mediated EGFR degradation. Our findings identify a novel mechanism that could be utilized to improve the therapeutic efficiency of EGFR-targeting strategies.

  9. 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

  10. 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

  11. Field Cancerization in Sporadic Colon Cancer

    PubMed Central

    Park, Soo-Kyung; Song, Chang Seok; Yang, Hyo-Joon; Jung, Yoon Suk; Choi, Kyu Yong; Koo, Dong Hoe; Kim, Kyung Eun; Jeong, Kyung Uk; Kim, Hyung Ook; Kim, Hungdai; Chun, Ho-Kyung; Park, Dong Il

    2016-01-01

    Background/Aims Aberrant DNA methylation has a specific role in field cancerization. Certain molecular markers, including secreted frizzled-related protein 2 (SFRP2), tissue factor pathway inhibitor 2 (TFPI2), N-Myc downstream-regulated gene 4 (NDRG4) and bone morphogenic protein 3 (BMP3), have previously been shown to be hypermethylated in colorectal cancer (CRC). We aim to examine field cancerization in CRC based on the presence of aberrant DNA methylation in normal-appearing tissue from CRC patients. Methods We investigated promoter methylation in 34 CRC patients and five individuals with normal colonoscopy results. CRC patients were divided into three tissue groups: tumor tissue, adjacent and nonadjacent normal-appearing tissue. The methylation status (positive: methylation level >20%) of SFRP2, TFPI2, NDRG4, and BMP3 promoters was investigated using methylation-specific PCR. Results The methylation frequencies of the SFRP2, TFPI2, NDRG4 and BMP3 promoters in tumor/adjacent/nonadjacent normal-appearing tissue were 79.4%/63.0%/70.4%, 82.4%/53.6%/60.7%, 76.5%/61.5%/69.2%, 41.2%/35.7%/50.0%, respectively. The methylation levels of the SFRP,TFPI2, NDRG4 and BMP3 promoters in tumor tissues were significantly higher than those in normal-appearing tissue (SFRP2, p=0.013; TFPI2, p<0.001; NDRG4, p=0.003; BMP3, p=0.001). No significant correlation was observed between the methylation levels of the promoters and the clinicopathological variables. Conclusions The field effect is present in CRC and affects both the adjacent and nonadjacent normal-appearing mucosa. PMID:27114416

  12. miRNA Expression in Colon Polyps Provides Evidence for a Multihit Model of Colon Cancer

    PubMed Central

    Oberg, Ann L.; French, Amy J.; Sarver, Aaron L.; Subramanian, Subbaya; Morlan, Bruce W.; Riska, Shaun M.; Borralho, Pedro M.; Cunningham, Julie M.; Boardman, Lisa A.; Wang, Liang; Smyrk, Thomas C.; Asmann, Yan; Steer, Clifford J.; Thibodeau, Stephen N.

    2011-01-01

    Changes in miRNA expression are a common feature in colon cancer. Those changes occurring in the transition from normal to adenoma and from adenoma to carcinoma, however, have not been well defined. Additionally, miRNA changes among tumor subgroups of colon cancer have also not been adequately evaluated. In this study, we examined the global miRNA expression in 315 samples that included 52 normal colonic mucosa, 41 tubulovillous adenomas, 158 adenocarcinomas with proficient DNA mismatch repair (pMMR) selected for stage and age of onset, and 64 adenocarcinomas with defective DNA mismatch repair (dMMR) selected for sporadic (n = 53) and inherited colon cancer (n = 11). Sporadic dMMR tumors all had MLH1 inactivation due to promoter hypermethylation. Unsupervised PCA and cluster analysis demonstrated that normal colon tissue, adenomas, pMMR carcinomas and dMMR carcinomas were all clearly discernable. The majority of miRNAs that were differentially expressed between normal and polyp were also differentially expressed with a similar magnitude in the comparison of normal to both the pMMR and dMMR tumor groups, suggesting a stepwise progression for transformation from normal colon to carcinoma. Among the miRNAs demonstrating the largest fold up- or down-regulated changes (≥4), four novel (miR-31, miR-1, miR-9 and miR-99a) and two previously reported (miR-137 and miR-135b) miRNAs were identified in the normal/adenoma comparison. All but one of these (miR-99a) demonstrated similar expression differences in the two normal/carcinoma comparisons, suggesting that these early tumor changes are important in both the pMMR- and dMMR-derived cancers. The comparison between pMMR and dMMR tumors identified four miRNAs (miR-31, miR-552, miR-592 and miR-224) with statistically significant expression differences (≥2-fold change). PMID:21694772

  13. Thrombin drives tumorigenesis in colitis-associated colon cancer

    PubMed Central

    Rosenfeldt, Leah; Kombrinck, Keith; Flick, Matthew J.; Steinbrecher, Kris A.; Harmel-Laws, Eleana; Mullins, Eric S.; Shaw, Maureen; Witte, David P.; Revenko, Alexey; Monia, Brett; Palumbo, Joseph S.

    2014-01-01

    The established association between inflammatory bowel disease and colorectal cancer underscores the importance of inflammation in colon cancer development. Based on evidence that hemostatic proteases are powerful modifiers of both inflammatory pathologies and tumor biology, gene-targeted mice carrying low levels of prothrombin were used to directly test the hypothesis that prothrombin contributes to tumor development in colitis-associated colon cancer (CAC). Remarkably, imposing a modest 50% reduction in circulating prothrombin in fII+/− mice, a level that carries no significant bleeding risk, dramatically decreased adenoma formation following an azoxymethane/dextran sodium sulfate challenge. Similar results were obtained with pharmacological inhibition of prothrombin expression or inhibition of thrombin proteolytic activity. Detailed longitudinal analyses showed that the role of thrombin in tumor development in CAC was temporally associated with the antecedent inflammatory colitis. However, direct studies of the antecedent colitis showed that mice carrying half-normal prothrombin levels were comparable to control mice in mucosal damage, inflammatory cell infiltration and associated local cytokine levels. These results suggest that thrombin supports early events coupled to inflammation-mediated tumorigenesis in CAC that are distinct from overall inflammation-induced tissue damage and inflammatory cell trafficking. That prothrombin is linked to early events in CAC was strongly inferred by the observation that prothrombin deficiency dramatically reduced the formation of very early, pre-cancerous aberrant crypt foci. Given the importance of inflammation in the development of colon cancer, these studies suggest that therapeutic interventions at the level of hemostatic factors may be an effective means to prevent and/or impede colitis-associated colon cancer progression. PMID:24710407

  14. 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

  15. 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.

  16. 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

  17. 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

    Charepalli, Venkata; Reddivari, Lavanya; Vadde, Ramakrishna; Walia, Suresh; Radhakrishnan, Sridhar; Vanamala, Jairam K P

    2016-02-26

    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.

  18. 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. PMID:26688708

  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. 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. PMID:26383537

  1. 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

  2. Metastatic Male Ductal Breast Cancer Mimicking Obstructing Primary Colon Cancer

    PubMed Central

    Koleilat, Issam; Syal, Anil; Hena, Muhammad

    2010-01-01

    Male breast cancer comprises only about 1% of all breast cancers. Commonly, sites of metastases include the central nervous system, lungs, bones, and even liver. In females, extrahepatic gastrointestinal metastases are unusual but have been reported with various clinical presentations. We are reporting the first case of a male patient with a history of ductal breast carcinoma that developed colonic metastasis and presented with mechanical large bowel obstruction masquerading as primary colon cancer. PMID:23675178

  3. 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

  4. 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

  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. PMID:27648301

  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.

  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. 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.

  9. 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.

  10. 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

    2016-01-01

    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

  11. 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

  12. The Colon Cancer Stem Cell Microenvironment Holds Keys to Future Cancer Therapy

    PubMed Central

    Huang, Emina H.

    2014-01-01

    Background Colorectal cancer remains the most common gastrointestinal cancer. While screening combined with effective surgical treatment has reduced its mortality, we still do not have effective means to prevent recurrence nor to treat metastatic disease. What we know about cancer biology has gone through revolutionary changes in recent decades. The advent of the cancer stem cell theory has accelerated our understanding of the cancer cell. However, there is increasing evidence that cancer cells are influenced by their surrounding microenvironment. Purpose This review divides the tumor microenvironment into four functional components—the stem cell niche, cancer stroma, immune cells, and vascular endothelia—and examines their individual and collective influence on the growth and metastasis of the colon cancer stem cell. The discussion will highlight the need to fully exploit the tumor microenvironment when designing future prognostic tools and therapies. PMID:24643495

  13. 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

  14. Chemotherapy for Stage II Colon Cancer.

    PubMed

    Varghese, Anna

    2015-12-01

    The adjuvant treatment of patients with stage II colon cancer is an area of controversy in medical oncology. Adjuvant chemotherapy aims to eradicate micrometastatic disease present at the time of surgery, preventing the development of distant metastatic disease and thereby curing those patients of their cancer. National and international guidelines for the adjuvant treatment of stage II colon cancer recommend a range of treatment options from observation to chemotherapy with single-agent or combination regimens, depending on the presence or absence of high-risk features (poorly differentiated histology, presence of lymphovascular invasion, presence of perineural invasion, report of < 12 lymph nodes, bowel obstruction, localized perforation, or positive margins). In the one prospective study designed to address the role of adjuvant chemotherapy in stage II colon cancer, a small but statistically significant benefit in overall survival was seen for those patients who received adjuvant chemotherapy; however, multiple meta-analyses and retrospective subgroup analyses have called these findings into question. Though there may be a role for adjuvant chemotherapy in the treatment of patients with stage II colon cancer, its incremental benefit is small, at best, and comes with the risks of real and rarely fatal complications of chemotherapy. PMID:26648796

  15. Vitamin D resistance and colon cancer prevention

    PubMed Central

    Giardina, Charles; Madigan, James P.; Godman Tierney, Cassandra A.; M. Brenner, Bruce; Rosenberg, Daniel W.

    2012-01-01

    Observational studies have been largely consistent in showing an inverse association between vitamin D and an individual’s risk of developing colorectal cancer. Vitamin D protection is further supported by a range of preclinical colon cancer models, including carcinogen, genetic and dietary models. A large number of mechanistic studies in both humans and rodents point to vitamin D preventing cancer by regulating cell proliferation. Counterbalancing this mostly positive data are the results of human intervention studies in which supplemental vitamin D was found to be ineffective for reducing colon cancer risk. One explanation for these discrepancies is the timing of vitamin D intervention. It is possible that colon lesions may progress to a stage where they become unresponsive to vitamin D. Such a somatic loss in vitamin D responsiveness bears the hallmarks of an epigenetic change. Here, we review data supporting the chemopreventive effectiveness of vitamin D and discuss how gene silencing and other molecular changes somatically acquired during colon cancer development may limit the protection that may otherwise be afforded by vitamin D via dietary intervention. Finally, we discuss how understanding the mechanisms by which vitamin D protection is lost might be used to devise strategies to enhance its chemopreventive actions. PMID:22180570

  16. Researchers Get Closer to Test Predicting Colon Cancer's Return

    MedlinePlus

    ... Get Closer to Test Predicting Colon Cancer's Return DNA-based screen would aid treatment decisions for people ... News) -- A blood test that detects bits of DNA shed from colon cancers may someday help doctors ...

  17. To Help Prevent Colon Cancer, 'Listen to Your Gut'

    MedlinePlus

    ... gov/news/fullstory_161185.html To Help Prevent Colon Cancer, 'Listen to Your Gut' Belly pain and black ... between life and death, especially for people with colon cancer, researchers report. People who pay attention to their ...

  18. 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.

  19. Tumor-associated antigens in gynecologic cancer.

    PubMed

    DiSaia, P J

    1975-12-01

    If the study of tumor immunology is to have a profound impact on clinical medicine, certain hypotheses must be proven to be valid. First and foremost, it must be demonstrated that malignant tissue possesses antigenic substances (probably protein moieties) that are unique to that particular malignant process. In addition, these antigenic substances must be very similar in histologically similar tumors. Second, the host defense mechanisms must be capable of reacting to these tumor-associated antigens. The reaction is, of course, necessary in order to develop both diagnostic and therapeutic routes of application. The reaction of the immunologic system to these tumor-associated antigens could be monitored as an early serodiagnostic tool for subclinical cancer, and the cytotoxic reaction holds great promise as an immunotherapeutic tool. The essence of tumor immunologic research can thus be stated in the form of the following questions: 1. Do histologically similar cancers from identical primary sites share common tumor-associated antigens? 2. Does the immunologic system react to these antigens? 3. Can this reaction be assayed on one hand for serodiagnosis and augmented on the other for immunotherapy? Specific antigens have been found in animal tumors and have been divided into two classes: the viral induced tumors, which share common antigens when caused by the same viral agent, and carcinogen-induced tumors, which appear to have unique antigenic determinants for each tumor. In recent years a great many human tumors have been found to have tumor-associated antigens; these include colonic carcinoma, neuroblastoma, melanoma, soft tissue and osteogenic sarcoma, bladder carcinoma and Burkitt's lymphoma. This report includes evidence for the existence of such antigens in adenocarcinoma of the ovary and squamous cell carcinoma of the cervix. The laboratory evidence that has been presented would suggest that there are both a cell-mediated response and humoral response to the

  20. 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

  1. Wnt signaling in cancer stem cells and colon cancer metastasis

    PubMed Central

    Ben-Ze'ev, Avri

    2016-01-01

    Overactivation of Wnt signaling is a hallmark of colorectal cancer (CRC). The Wnt pathway is a key regulator of both the early and the later, more invasive, stages of CRC development. In the normal intestine and colon, Wnt signaling controls the homeostasis of intestinal stem cells (ISCs) that fuel, via proliferation, upward movement of progeny cells from the crypt bottom toward the villus and differentiation into all cell types that constitute the intestine. Studies in recent years suggested that cancer stem cells (CSCs), similar to ISCs of the crypts, consist of a small subpopulation of the tumor and are responsible for the initiation and progression of the disease. Although various ISC signature genes were also identified as CRC markers and some of these genes were even demonstrated to have a direct functional role in CRC development, the origin of CSCs and their contribution to cancer progression is still debated. Here, we describe studies supporting a relationship between Wnt-regulated CSCs and the progression of CRC. PMID:27134739

  2. Theranostic nanoparticles based on PEGylated hyaluronic acid for the diagnosis, therapy and monitoring of colon cancer.

    PubMed

    Choi, Ki Young; Jeon, Eun Jung; Yoon, Hong Yeol; Lee, Beom Suk; Na, Jin Hee; Min, Kyung Hyun; Kim, Sang Yoon; Myung, Seung-Jae; Lee, Seulki; Chen, Xiaoyuan; Kwon, Ick Chan; Choi, Kuiwon; Jeong, Seo Young; Kim, Kwangmeyung; Park, Jae Hyung

    2012-09-01

    Colon cancer is the second leading cause of cancer-related death in the United States. The considerable mortality from colon cancer is due to metastasis to other organs, mainly the liver. In the management of colon cancer, early detection and targeted therapy are crucial. In this study, we aimed to establish a versatile theranostic system for early tumor detection and targeted tumor therapy by using poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) which can selectively accumulate in tumor tissue. For the diagnostic application, a near-infrared fluorescence (NIRF) imaging dye (Cy 5.5) was chemically conjugated onto the HA backbone of P-HA-NPs. After intravenous injection of Cy5.5-P-HA-NPs into the tumor-bearing mice, small-sized colon tumors as well as liver-implanted colon tumors were effectively visualized using the NIRF imaging technique. For targeted therapy, we physically encapsulated the anticancer drug, irinotecan (IRT), into the hydrophobic cores of P-HA-NPs. Owing to their notable tumor targeting capability, IRT-P-HA-NPs exhibited an excellent antitumor activity while showing a reduction in undesirable systemic toxicity. Importantly, we demonstrated the theranostic application using Cy5.5-P-HA-NPs and IRT-P-HA-NPs in orthotopic colon cancer models. Following the systemic administration of Cy5.5-P-HA-NPs, neoplasia was clearly visualized, and the tumor growth was effectively suppressed by intravenous injection of IRT-P-HA-NPs. It should be emphasized that the therapeutic responses could be simultaneously monitored by Cy5.5-P-HA-NPs. Our results suggest that P-HA-NPs can be used as a versatile theranostic system for the early detection, targeted therapy, and therapeutic monitoring of colon cancer.

  3. Theranostic nanoparticles based on PEGylated hyaluronic acid for the diagnosis, therapy and monitoring of colon cancer

    PubMed Central

    Choi, Ki Young; Jeon, Eun Jung; Yoon, Hong Yeol; Lee, Beom Suk; Na, Jin Hee; Min, Kyung Hyun; Kim, Sang Yoon; Myung, Seung-Jae; Lee, Seulki; Chen, Xiaoyuan; Kwon, Ick Chan; Choi, Kuiwon; Jeong, Seo Young; Kim, Kwangmeyung; Park, Jae Hyung

    2013-01-01

    Colon cancer is the second leading cause of cancer-related death in the United States. The considerable mortality from colon cancer is due to metastasis to other organs, mainly the liver. In the management of colon cancer, early detection and targeted therapy are crucial. In this study, we aimed to establish a versatile theranostic system for early tumor detection and targeted tumor therapy by using poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) which can selectively accumulate in tumor tissue. For the diagnostic application, a near-infrared fluorescence (NIRF) imaging dye (Cy 5.5) was chemically conjugated onto the HA backbone of P-HA-NPs. After intravenous injection of Cy5.5-P-HA-NPs into the tumor-bearing mice, small-sized colon tumors as well as liver-implanted colon tumors were effectively visualized using the NIRF imaging technique. For targeted therapy, we physically encapsulated the anticancer drug, irinotecan (IRT), into the hydrophobic cores of P-HA-NPs. Owing to their notable tumor targeting capability, IRT-P-HA-NPs exhibited an excellent antitumor activity while showing a reduction in undesirable systemic toxicity. Importantly, we demonstrated the theranostic application using Cy5.5-P-HA-NPs and IRT-P-HA-NPs in orthotopic colon cancer models. Following the systemic administration of Cy5.5-P-HA-NPs, neoplasia was clearly visualized, and the tumor growth was effectively suppressed by intravenous injection of IRT-P-HA-NPs. It should be emphasized that the therapeutic responses could be simultaneously monitored by Cy5.5-P-HA-NPs. Our results suggest that P-HA-NPs can be used as a versatile theranostic system for the early detection, targeted therapy, and therapeutic monitoring of colon cancer. PMID:22687759

  4. Prognostic impact of Metadherin-SND1 interaction in colon cancer.

    PubMed

    Wang, Nan; Du, Xilin; Zang, Li; Song, Nuan; Yang, Tao; Dong, Rui; Wu, Tao; He, Xianli; Lu, Jianguo

    2012-12-01

    The interaction between Metadherin (MTDH) and Staphylococcal nuclease homology domain containing 1 (SND1) is involved in tumorigenesis and tumor progression of several human malignancies. However, its roles in colon cancer are still unclear. To investigate the clinical value of MTDH and SND1 expression in colon cancer. Immunohistochemical staining was performed to detect the expression of MTDH and SND1 using human colon cancer and their corresponding non-cancerous colon tissues from 196 patients' biopsies. Positive expression of MTDH and SND1 were both increased in colon cancer tissues compared to paired non-cancerous colon tissues. There was a positive correlation between MTDH and SND1 expression in colon cancer tissues (r = 0.86, p < 0.001). In addition, their positive expression were both significantly associated with nodal status (both p = 0.02), pathological stage (p = 0.006 and 0.008, respectively) and differentiation (both p = 0.03). Moreover, the overall survival in colon cancer patients with positive expression of MTDH and SND1 were significantly shorter than those without their expression (both p = 0.01). Furthermore, multivariate Cox regression analysis suggested that positive expression of MTDH and SND1 was an independent poor prognostic predictor in colon cancer. Our data suggest that the increased expression of MTDH and/or SND1 is closely related to carcinogenesis, progression, and prognosis of colon cancer. The co-expression of MTDH/SND1 may be a novel distinctive marker to benefit us in prediction of the prognosis in colon cancer.

  5. 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.

  6. 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.

  7. 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

  8. Over-expression of EphB3 enhances cell-cell contacts and suppresses tumor growth in HT-29 human colon cancer cells.

    PubMed

    Chiu, Sou-Tyau; Chang, King-Jen; Ting, Chen-Hung; Shen, Hsi-Che; Li, Hung; Hsieh, Fon-Jou

    2009-09-01

    Receptor tyrosine kinase EphB3 is expressed in cells in the bottom of intestinal crypts near stem cell niches. Loss of Ephb3 has recently been reported to produce invasive colorectal carcinoma in Apc(Min/+) mice and EphB-mediated compartmentalization was demonstrated to be a mechanism suppressing colorectal cancer progression; however, it is unknown whether other factors contribute to EphB-mediated tumor suppression. EphA4-ephrin-A and EphB4-ephrin-B2 signaling have been reported to promote mesenchymal-to-epithelial transition (MET). Here, we examine whether EphB3-ephrin-B interaction has a similar effect and investigate its role in tumor suppression. We found in a clinical cohort that EphB3 expression was significantly reduced in advanced Dukes' stage tumor specimens, so we over-expressed EphB3 in HT-29 cells by stable transfection. EphB3 over-expression inhibited HT-29 growth in monolayer cultures, anchorage-independent growth in soft agar and xenograft growth in nude mice and initiated morphological, behavioral and molecular changes consistent with MET. Specifically, EphB3 over-expression re-organized cytoskeleton (converting spreading cells to a cobble-like epithelial morphology, patterning cortical actin cytoskeleton and polarizing E-cadherin and ZO-1), induced functional changes favoring MET (decreased transwell migration, increased apoptosis and Ca(2+)-dependent cell-cell adhesion), decreased mesenchymal markers (fibronectin and nuclear beta-catenin), increased epithelial markers (ZO-1, E-cadherin and plakoglobin) and inactivated CrkL-Rac1, a known epithelial-to-mesenchymal transition signaling pathway. Additionally, cross talk from Wnt signaling potentiated the restoration of epithelial cell polarity. Noteworthily, the same factors contributing to MET, owing to EphB3 signaling, also facilitated tumor suppression. We conclude that EphB3-ephrin-B interaction promotes MET by re-establishing epithelial cell-cell junctions and such an MET-promoting effect

  9. [Malignant tumors of the colon and rectum].

    PubMed

    Komljenović, Zoran; Prodanović, Lazar; Lukić, Vladan; Randelović, Tomo; Drljević, Milorad; Rakić, Mile

    2003-01-01

    The authors present their five year long experience in surgical treatment of colorectal cancer at Zvornik Health Center. 77 patients diagnosed with colorectal cancer underwent surgery during the five year period (1998-2002). This number represented about 2% of the total number of surgeries performed during the same time period. 80% of surgical interventions were elective, (82 patients), and 20% urgent (35 patients). Standard surgical procedures were applied in determining of the anatomical location of the pathological substrate. Aggravating factors in successful application of surgical intervention in treatment of colorectal cancer are: late diagnosis of colorectal cancer, low level of health education of the population, inadequate training of the physicians in primary health care, nonexistent national program for early detection of noninfectious diseases. In cases where colorectal cancer was diagnosed in an advanced stage, two-stage treatment and multi modal approach in combination with chemotherapy were treatments of choice. Incidence of colorectal cancer is still on the rise. PMID:14569684

  10. 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

    2015-04-01

    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.

  11. Splenic flexure colon cancers: minimally invasive treatment.

    PubMed

    Fiscon, Valentino; Portale, Giuseppe; Migliorini, Giovanni; Frigo, Flavio

    2015-03-01

    Optimal treatment of splenic flexure (SF) colon cancer-less than 10% of all colorectal cancers is a matter of debate, in particular with regard to the optimal extent of radical surgery, according to the oncological principles of curative resection. Aims of this study were to assess the clinicopathological characteristics and report operative data and survival of patients with SF colon cancers. Short- and mid-term outcome of patients undergoing laparoscopic curative resection for SF colon cancer between June 2005 and September 2011 was assessed. The analysis considered 16 patients: 10 underwent segmental resection, 4 left hemicolectomy and 2 subtotal colectomy. There were no intraoperative deaths or major morbidity. The median operative time was 185 min. The median number of lymph nodes harvested was 17. Disease-free survival rate at 30-month follow-up was 75%. Laparoscopic resection of SF cancer is feasible and safe. Oncological principles of disease-free margins and minimum node harvest can be respected even with segmental resection.

  12. 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

    2015-04-01

    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. PMID:25712450

  13. 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.

  14. Definition of Prostaglandin E2-EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth.

    PubMed

    Ma, Xiaojun; Aoki, Tomohiro; Tsuruyama, Tatsuaki; Narumiya, Shuh

    2015-07-15

    Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFα and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFα, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFα, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer.

  15. [Surgical therapy of right colon cancer].

    PubMed

    Turoldo, A; Balani, A; Tonello, C; Scaramucci, M; Roseano, M

    1999-01-01

    The debate about the management of frequent advanced right colon cancer is still opened: the opportunity of extended resections when the surrounding organs or tissues are infiltrated, the lymphadenectomy extension and its role, the possibility of identifying prognostic factors that could be useful to decide adjuvant therapy, the definition of the role of laparoscopy. Considering these problems, we have reviewed a series of 159 operations performed by the Institute of Clinical Surgery of the University of Trieste from 1980. 112 of these operations had a curative goal. The reconstruction of intestinal continuity was carried out manually in 28 cases and with mechanical stapler in 78. As far as the curative resection are concerned, in 89 of them an extended lymphadenectomy was performed (D3), while in 18 cases the lymphadenectomy was limited to the lymph nodes of first and second level due to the general bed conditions of the patient. 27 of the curative exeresis were performed in patients with T4 tumor infiltrating the nearby tissues. Referring to Dukes' classification, 8 were included in stage A, 59 in stage B and 40 in stage C, while as far as the depth of wall infiltration is concerned 2 were categorized as T1, 9 as T2, 69 as T3 and 27 as T4. The overall operative mortality was of 5 patients, the overall morbidity of 14%, that specific of 4.6%. The final incidence of local recurrences was 13.8% for Dukes A cancers, 10.9% for Dukes B and 120.5% for Dukes C (p = 0.0614). Half of the recurrences (50%) occurred in patients with a cancer infiltrating the nearby tissues. The 5 year survival rate for patients with Dukes A lesions was 100%, for patients with Dukes B lesions 73.4% and for Dukes C 52.3% (p = 0.00510). With Cox' multivariate analysis only the stage disease, T and grading showed a significative correlation with the survival rate. Our experience, therefore, suggests the execution of an exeresis with lymphadenectomy D3 in each cases where the local site of the

  16. 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.

  17. Detection of colon cancer by terahertz techniques

    NASA Astrophysics Data System (ADS)

    Wahaia, Faustino; Valusis, Gintaras; Bernardo, Luis M.; Almeida, Abílio; Moreira, J. Agostinho; Lopes, Patricia C.; Macutkevic, Jan; Kasalynas, Irmantas; Seliuta, Dalius; Adomavicius, Ramunas; Henrique, Rui; Lopes, Machado

    2011-05-01

    Normal and cancer affected samples of colon tissue have been measured using transmission time-domain terahertz spectroscopy and continuous wave terahertz imaging. We show that it is possible to distinguish between normal and cancerous regions in the samples when they are fixed in formalin or embedded in paraffin. Plots of the refractive index of normal and cancer affected tissues as well as 2-D transmission THz images are shown. Experimental results will be presented and the conditions for discrimination between normal and affected tissue will be discussed.

  18. Eradication of large colon tumor xenografts by targeted delivery of maytansinoids.

    PubMed Central

    Liu, C; Tadayoni, B M; Bourret, L A; Mattocks, K M; Derr, S M; Widdison, W C; Kedersha, N L; Ariniello, P D; Goldmacher, V S; Lambert, J M; Blättler, W A; Chari, R V

    1996-01-01

    The maytansinoid drug DM1 is 100- to 1000-fold more cytotoxic than anticancer drugs that are currently in clinical use. The immunoconjugate C242-DM1 was prepared by conjugating DM1 to the monoclonal antibody C242, which recognizes a mucin-type glycoprotein expressed to various extents by human colorectal cancers. C242-DM1 was found to be highly cytotoxic toward cultured colon cancer cells in an antigen-specific manner and showed remarkable antitumor efficacy in vivo. C242-DM1 cured mice bearing subcutaneous COLO 205 human colon tumor xenografts (tumor size at time of treatment 65-130 mm3), at doses that showed very little toxicity and were well below the maximum tolerated dose. C242-DM1 could even effect complete regressions or cures in animals with large (260- to 500-mm3) COLO 205 tumor xenografts. Further, C242-DM1 induced complete regressions of subcutaneous LoVo and HT-29 colon tumor xenografts that express the target antigen in a heterogeneous manner. C242-DM1 represents a new generation of immunoconjugates that may yet fulfill the promise of effective cancer therapy through antibody targeting of cytotoxic agents. Images Fig. 3 PMID:8710920

  19. Variation in the CYP19A1 gene and risk of colon and rectal cancer

    PubMed Central

    Slattery, Martha L.; Lundgreen, Abbie; Herrick, Jennifer S.; Kadlubar, Susan; Caan, Bette J.; Potter, John D.; Wolff, Roger K.

    2011-01-01

    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. PMID:21479914

  20. 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.

  1. 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

  2. Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis.

    PubMed

    Wu, Zhen-Zhen; Chen, Li-Shan; Zhou, Rui; Bin, Jian-Ping; Liao, Yu-Lin; Liao, Wang-Jun

    2016-08-01

    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

  3. 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

  4. Colon Adenocarcinoma Associated with Synchronous Extramural Gastrointestinal Stromal Tumor (GIST) of the Ileum

    PubMed Central

    Gavriilidis, Paschalis; Nikolaidou, Anastasia

    2015-01-01

    Patient: Female, 68 Final Diagnosis: Gastrointestinal stromal tumour and colon adenocarcinoma Symptoms: Fatigue Medication: — Clinical Procedure: Right Hemicolectomy and enterectomy Specialty: Surgery Objective: Rare disease Background: GISTs are mesenchymal tumors representing approximately 1% of all gastrointestinal neoplasia. Their concurrence with colorectal cancers is rare. Case Report: We present a case of coexistence of colon adenocarcinoma and GIST of the ileum in a 68-year-old white woman. Conclusions: The coexistence of mesenchymal and epithelial neoplasia is very challenging; further research is needed to clarify the role of oncogenic mutations and signalling pathways in carcinogenesis of neoplasia of various histiogenic origins. PMID:26608682

  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. Recent advances in the treatment of colon cancer.

    PubMed

    Xu, R; Zhou, B; Fung, P C W; Li, X

    2006-08-01

    Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Although surgical resection is still the only treatment capable of curing colon cancer, adjuvant therapy continues to play an important role in preventing recurrence and metastasis. In recent years remarkable progress has been made in the treatment of colon cancer. This review discusses recent advances in adjuvant therapy for colon cancer, including chemotherapy, immunotherapy, antiangiogenic therapy and apoptosis induction. In the meantime, molecular therapy is also elucidated in the above methods. All these new advances will provide new promises for patients of colon cancer. PMID:16691539

  7. [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.

  8. Circulating tumor cells in lung cancer.

    PubMed

    Young, Rachel; Pailler, Emma; Billiot, Fanny; Drusch, Françoise; Barthelemy, Amélie; Oulhen, Marianne; Besse, Benjamin; Soria, Jean-Charles; Farace, Françoise; Vielh, Philippe

    2012-01-01

    Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a 'liquid biopsy' is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment. PMID:23207444

  9. 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

  10. Epicatechin gallate impairs colon cancer cell metabolic productivity.

    PubMed

    Sánchez-Tena, Susana; Alcarraz-Vizán, Gema; Marín, Silvia; Torres, Josep Lluís; Cascante, Marta

    2013-05-01

    Green tea and grape phenolics inhibit cancer growth and modulate cellular metabolism. Targeting the tumor metabolic profile is a novel therapeutic approach to inhibit cancer cell proliferation. Therefore, we treated human colon adenocarcinoma HT29 cells with the phenolic compound epicatechin gallate (ECG), one of the main catechins in green tea and the most important catechin in grape extracts, and evaluated its antiproliferation effects. ECG reduced tumor viability and induced apoptosis, necrosis, and S phase arrest in HT29 cells. Later, biochemical determinations combined with mass isotopomer distribution analysis using [1,2-(13)C2]-D-glucose as a tracer were used to characterize the metabolic network of HT29 cells in response to different concentrations of ECG. Glucose consumption was importantly decreased after ECG treatment. Moreover, metabolization of [1,2-(13)C2]-D-glucose indicated that the de novo synthesis of fatty acids and the pentose phosphate pathway were reduced in ECG-treated cells. Interestingly, ECG inhibited the activity of transketolase and glucose-6-phosphate dehydrogenase, the key enzymes of the pentose phosphate pathway. Our data point to ECG as a promising chemotherapeutic agent for the treatment of colon cancer.

  11. [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.

  12. 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 1000-fold with an IC50 of 2 to 7 x 10-8 nM. This conjugate was also shown to be highly selective. Taken together, all of these studies indicate that in vitro experiments have shown that we have a highly potent IT that selectively kills colon cancer cells. The next step was to show that the EpCam IT had the ability to inhibit the growth of flank tumors in vivo in nude mice. The same human colon tumor cells, HT29 used in the in vitro studies were injected into the flank of nude mice. Tumor cells were injected into groups of mice and when tumors reached the size of 0.5 cm3, we injected our best-performing EpCam IT called EpCamKDEL intratumorally. There was a significant drop in tumor size indicating that this agent was very effective against human colon cancer. Since the EpCamKDEL was injected intratumorally, it did not have to travel through the systemic circulation to find its target. Our next step will be to inject EpCamKDEL intravenously into mice with flank tumors to determine if EpCamKDEL has the ability to migrate to the tumor systemically. The next step was to radiolabel EpCamKDEL to see whether it could serve as an RIT. We radiolabeled EpCam with 111In as a surrogate for 90Y and then incubated it with HT29. The labeling efficiency was over 90% indicating that a high percentage of the protein molecules could be readily radiolabeled. However, the immunoreactivity was only

  13. Signaling in colon cancer stem cells.

    PubMed

    Roy, Sanchita; Majumdar, Adhip Pn

    2012-01-01

    : Colorectal cancer is the fourth most common form of cancer worldwide and ranks third among the cancer-related deaths in the US and other Western countries. It occurs with equal frequency in men and women, constituting 10% of new cancer cases in men and 11% in women. Despite recent advancement in therapeutics, the survival rates from metastatic are less than 5%. Growing evidence supports the contention that epithelial cancers including colorectal cancer, the incidence of which increases with aging, are diseases driven by the pluripotent, self-renewing cancer stem cells (CSCs). Dysregulation of Wnt, Notch, Hedgehog and/or TGF-β signaling pathways that are involved in proliferation and maintenance of CSCs leads to the development of CRC. This review focuses on the signaling pathways relevant for CRC to understand the mechanisms leading to tumor progression and therapy resistance, which may help in the development of therapeutic strategies for CRC. PMID:22866952

  14. Nutraceuticals as potential therapeutic agents for colon cancer: a review

    PubMed Central

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M.; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-01-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis. PMID:26579381

  15. Inhibition of Human Colon Cancer Growth by Antibody-Directed Human LAK Cells in SCID Mice

    NASA Astrophysics Data System (ADS)

    Takahashi, Hiroshi; Nakada, Tetsuya; Puisieux, Isabelle

    1993-03-01

    Advanced human colon cancer does not respond to lymphokine-activated killer (LAK) cells. In order to direct cytotoxic cells to the tumor, human LAK cells linked with antibodies to a tumor cell surface antigen were tested with established hepatic metastases in severe combined immunodeficient (SCID) mice. These cells had increased uptake into the tumor and suppression of tumor growth as compared with LAK cells alone, thereby improving the survival of tumor-bearing mice. Thus, tumor growth can be inhibited by targeted LAK cells, and SCID mice can be used to test the antitumor properties of human effector cells.

  16. Fra-1 is a key driver of colon cancer metastasis and a Fra-1 classifier predicts disease-free survival

    PubMed Central

    Iskit, Sedef; Schlicker, Andreas; Wessels, Lodewyk; Peeper, Daniel S.

    2015-01-01

    Fra-1 (Fos-related antigen-1) is a member of the AP-1 (activator protein-1) family of transcription factors. We previously showed that Fra-1 is necessary for breast cancer cells to metastasize in vivo, and that a classifier comprising genes that are expressed in a Fra-1-dependent fashion can predict breast cancer outcome. Here, we show that Fra-1 plays an important role also in colon cancer progression. Whereas Fra-1 depletion does not affect 2D proliferation of human colon cancer cells, it impairs growth in soft agar and in suspension. Consistently, subcutaneous tumors formed by Fra-1-depleted colon cancer cells are three times smaller than those produced by control cells. Most remarkably, when injected intravenously, Fra-1 depletion causes a 200-fold reduction in tumor burden. Moreover, a Fra-1 classifier generated by comparing RNA profiles of parental and Fra-1-depleted colon cancer cells can predict the prognosis of colon cancer patients. Functional pathway analysis revealed Wnt as one of the central pathways in the classifier, suggesting a possible mechanism of Fra-1 function in colon cancer metastasis. Our results demonstrate that Fra-1 is an important determinant of the metastatic potential of human colon cancer cells, and that the Fra-1 classifier can be used as a prognostic predictor in colon cancer patients. PMID:26646695

  17. Circadian Clock in a Mouse Colon Tumor Regulates Intracellular Iron Levels to Promote Tumor Progression.

    PubMed

    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

    2016-03-25

    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 thatIrp2mRNA 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 (CLOCK(Δ19)) 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 CLOCK(Δ19)expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor.

  18. Decorin in Human Colon Cancer: Localization In Vivo and Effect on Cancer Cell Behavior In Vitro.

    PubMed

    Nyman, Marie C; Sainio, Annele O; Pennanen, Mirka M; Lund, Riikka J; Vuorikoski, Sanna; Sundström, Jari T T; Järveläinen, Hannu T

    2015-09-01

    Decorin is generally recognized as a tumor suppressing molecule. Nevertheless, although decorin has been shown to be differentially expressed in malignant tissues, it has often remained unclear whether, in addition to non-malignant stromal cells, cancer cells also express it. Here, we first used two publicly available databases to analyze the current information about decorin expression and immunoreactivity in normal and malignant human colorectal tissue samples. The analyses demonstrated that decorin expression and immunoreactivity may vary in cancer cells of human colorectal tissues. Therefore, we next examined decorin expression in normal, premalignant and malignant human colorectal tissues in more detail using both in situ hybridization and immunohistochemistry for decorin. Our results invariably demonstrate that malignant cells within human colorectal cancer tissues are devoid of both decorin mRNA and immunoreactivity. Identical results were obtained for cells of neuroendocrine tumors of human colon. Using RT-qPCR, we showed that human colon cancer cell lines are also decorin negative, in accordance with the above in vivo results. Finally, we demonstrate that decorin transduction of human colon cancer cell lines causes a significant reduction in their colony forming capability. Thus, strategies to develop decorin-based adjuvant therapies for human colorectal malignancies are highly rational.

  19. [Possibilities of CT and US in the diagnosis of colonic cancer].

    PubMed

    Gorshkov, A N

    2001-01-01

    The data of examination of 59 patients with colonic cancer were used to consider the potentialities of transabdominal, transrectal ultrasonography and X-ray computed tomography and to assess their value in diagnosing colonic cancer, including its "minor" forms. The paper describes the ultrasound and computed tomographic semiotics of colonic cancer and determines a place of the above techniques in the algorithm of radiation and instrumental studies. Inclusion of these techniques into the diagnostic algorithm may solve a range of differentially diagnostic problems and allows a preliminary analysis to be made in a tumor lesion according to the International TNM classification. Ultrasonography and X-ray computed tomography should be included into a range of basic methods for diagnosis of colonic cancer.

  20. PPARδ deficiency disrupts hypoxia-mediated tumorigenic potential of colon cancer cells.

    PubMed

    Jeong, Eunshil; Koo, Jung Eun; Yeon, Sang Hyeon; Kwak, Mi-Kyoung; Hwang, Daniel H; Lee, Joo Young

    2014-11-01

    Peroxisome proliferator-activated receptor (PPAR) δ is highly expressed in colon epithelial cells and closely linked to colon carcinogenesis. However, the role of PPARδ in colon cancer cells in a hypoxic tumor microenvironment is not fully understood. We found that expression of the tumor-promoting cytokines, IL-8 and VEGF, induced by hypoxia (<1% O2) and deferoxamine (a hypoxia mimetic) was significantly attenuated in PPARδ-deficient HCT116 colon cancer cells. Consequently, PPARδ-knockout colon cancer cells exposed to hypoxia and deferoxamine failed to stimulate endothelial cell vascularization and macrophage migration/proliferation, whereas wild-type cells were able to induce angiogenesis and macrophage activation in response to hypoxic stress. Hypoxic stress induced transcriptional activation of PPARδ, but not its protein expression, in HCT116 cells. Exogenous expression of p300 potentiated deferoxamine-induced PPARδ transactivation, while siRNA knockdown of p300 abolished hypoxia- and deferoxamine-induced PPARδ transactivation. PPARδ associated with p300 upon hypoxic stress as demonstrated by coimmunoprecipitation studies. PI3K inhibitors or siRNA knockdown of Akt suppressed the PPARδ transactivation induced by hypoxia and deferoxamine in HCT116 cells, leading to decreased expression of IL-8 and VEGF. Collectively, these results reveal that PPARδ is required for hypoxic stress-mediated cytokine expression in colon cancer cells, resulting in promotion of angiogenesis, macrophage recruitment, and macrophage proliferation in the tumor microenvironment. p300 and the PI3K/Akt pathway play a role in the regulation of PPARδ transactivation induced by hypoxic stress. Our results demonstrate the positive crosstalk between PPARδ in tumor cells and the hypoxic tumor microenvironment and provide potential therapeutic targets for colon cancer.

  1. A recellularized human colon model identifies cancer driver genes.

    PubMed

    Chen, Huanhuan Joyce; Wei, Zhubo; Sun, Jian; Bhattacharya, Asmita; Savage, David J; Serda, Rita; Mackeyev, Yuri; Curley, Steven A; Bu, Pengcheng; Wang, Lihua; Chen, Shuibing; Cohen-Gould, Leona; Huang, Emina; Shen, Xiling; Lipkin, Steven M; Copeland, Neal G; Jenkins, Nancy A; Shuler, Michael L

    2016-08-01

    Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology. PMID:27398792

  2. Methylation status at HYAL2 predicts overall and progression-free survival of colon cancer patients under 5-FU chemotherapy.

    PubMed

    Pfütze, Katrin; Benner, Axel; Hoffmeister, Michael; Jansen, Lina; Yang, Rongxi; Bläker, Hendrik; Herpel, Esther; Ulrich, Alexis; Ulrich, Cornelia M; Chang-Claude, Jenny; Brenner, Hermann; Burwinkel, Barbara

    2015-12-01

    DNA methylation variations in gene promoter regions are well documented tumor-specific alterations in human malignancies including colon cancer, which may influence tumor behavior and clinical outcome. As a subset of colon cancer patients does not benefit from adjuvant chemotherapy, predictive biomarkers are desirable. Here, we describe that DNA methylation levels at CpG loci of hyaluronoglucosaminidase 2 (HYLA2) could be used to identify stage II and III colon cancer patients who are most likely to benefit from 5-flourouracil (5-FU) chemotherapy with respect to overall survival and progression-free survival. PMID:26453961

  3. IFN-γ Mediates the Antitumor Effects of Radiation Therapy in a Murine Colon Tumor

    PubMed Central

    Gerber, Scott A.; Sedlacek, Abigail L.; Cron, Kyle R.; Murphy, Shawn P.; Frelinger, John G.; Lord, Edith M.

    2014-01-01

    Cancer treatments using ionizing radiation (IR) therapy are thought to act primarily through the induction of tumor cell damage at a molecular level. However, a new concept has recently emerged, suggesting that the immune system is required for effective IR therapy. Our work here has identified interferon gamma (IFN-γ) as an essential cytokine for the efficacy of IR therapy. Local IR (15 Gy) to mice bearing Colon38, a colon adenocarcinoma, decreases tumor burden in wild-type animals. Interestingly, IR therapy had no effect on tumor burden in IFNγKO mice. We further determined that intratumoral levels of IFN-γ increased 2 days following IR, which directly correlated with a decrease in tumor burden that was not a result of direct cytotoxic effects of IFN-γ on tumor cells. T cells from IR-treated tumors exhibited a far greater capacity to lyse tumor cells in a 51Cr release assay, a process that was dependent on IFN-γ. CD8+ T cells were the predominant producers of IFN-γ, as demonstrated by IFN-γ intracellular staining and studies in IFN-γ reporter mice. Elimination of CD8+ T cells by antibody treatment reduced the intratumoral levels of IFN-γ by over 90%. More importantly, elimination of CD8+ T cells completely abrogated the effects of radiation therapy. Our data suggest that IFN-γ plays a pivotal role in mediating the antitumor effects of IR therapy. PMID:23583648

  4. Soluble OX40L favors tumor rejection in CT26 colon carcinoma model.

    PubMed

    Serebrovskaya, Ekaterina O; Yuzhakova, Diana V; Ryumina, Alina P; Druzhkova, Irina N; Sharonov, George V; Kotlobay, Alexey A; Zagaynova, Elena V; Lukyanov, Sergey A; Shirmanova, Marina V

    2016-08-01

    OX40 receptor-expressing regulatory T cells (Tregs) populate tumors and suppress a variety of immune cells, posing a major obstacle for cancer immunotherapy. Different ways to functionally inactivate Tregs by triggering OX40 receptor have been suggested, including anti-OX40 antibodies and Fc:OX40L fusion proteins. To investigate whether the soluble extracellular domain of OX40L (OX40Lexo) is sufficient to enhance antitumor immune response, we generated an OX40Lexo-expressing CT26 colon carcinoma cell line and studied its tumorigenicity in immunocompetent BALB/c and T cell deficient nu/nu mice. We found that soluble OX40L expressed in CT26 colon carcinoma favors the induction of an antitumor response which is not limited just to cells co-expressing EGFP as an antigenic determinant, but also eliminates CT26 cells expressing another fluorescent protein, KillerRed. Tumor rejection required the presence of T lymphocytes, as indicated by the unhampered tumor growth in nu/nu mice. Subsequent re-challenge of tumor-free BALB/c mice with CT26 EGFP cells resulted in no tumor growth, which is indicative of the formation of immunological memory. Adoptive transfer of splenocytes from mice that successfully rejected CT26 OX40Lexo EGFP tumors to naïve mice conferred 100% resistance to subsequent challenge with the CT26 EGFP tumor. PMID:27203665

  5. [The development process of colon cancer centres].

    PubMed

    Sahm, M; Wesselmann, S; Kube, R; Schöffel, N; Pross, M; Lippert, H; Kahl, S

    2013-02-01

    Colon carcinomas are the most common malignant tumours in the Western world. Important findings about the overall quality of medical care have been reported in multi-centre observational studies. A quality enhancement of therapeutic care can be achieved by an additional increase in diagnostic and therapeutic measures in the interdisciplinary setting. The development of colon cancer centres improves the chance to objectively observe the results of medical care induced by the development of an interdisciplinary and cross-sectoral unit that includes a comprehensive medical care for patients. The implementation of the current medical findings based on evidence in clinical routine, the inspection of the usage of guidelines by external specialists as part of an audit and the continuous correction of analysed deficits in the course of treatment guarantee a continuous improvement of service.

  6. Differential localization of LGR5 and Nanog in clusters of colon cancer stem cells.

    PubMed

    Amsterdam, Abraham; Raanan, Calanit; Schreiber, Letizia; Freyhan, Ora; Fabrikant, Yakov; Melzer, Ehud; Givol, David

    2013-05-01

    One paradigm of cancer development claims that cancer emerges at the niche of tissue stem cells and these cells continue to proliferate in the tumor as cancer stem cells. LGR5, a membrane receptor, was recently found to be a marker of normal colon stem cells in colon polyps and is also expressed in colon cancer stem cells. Nanog, an embryonic stem cell nuclear factor, is expressed in several embryonic tissues, but Nanog expression is not well documented in cancerous stem cells. Our aim was to examine whether both LGR5 and Nanog are expressed in the same clusters of colon stem cells or cancer stem cells, using immunocytochemistry with specific antibodies to each antigen. We analyzed this aspect using paraffin embedded tumor tissue sections obtained from 18 polyps and 36 colon cancer specimens at stages I-IV. Antibodies to LGR5 revealed membrane and cytoplasm immunostaining of scattered labeled cells in normal crypts, with no labeling of Nanog. However, in close proximity to the tumors, staining to LGR5 was much more intensive in the crypts, including that of the epithelial cells. In cancer tissue, positive LGR5 clusters of stem cells were observed mainly in poorly differentiated tumors and in only a few scattered cells in the highly differentiated tumors. In contrast, antibodies to Nanog mainly stained the growing edges of carcinoma cells, leaving the poorly differentiated tumor cells unlabeled, including the clustered stem cells that could be detected even by direct morphological examination. In polyp tissues, scattered labeled cells were immunostained with antibodies to Nanog and to a much lesser extent with antibodies to LGR5. We conclude that expression of LGR5 is probably specific to stem cells of poorly differentiated tumors, whereas Nanog is mainly expressed at the edges of highly differentiated tumors. However, some of the cell layers adjacent to the carcinoma cell layers that still remained undifferentiated, expressed mainly Nanog with only a few cells

  7. Detection of colon cancer by terahertz techniques

    NASA Astrophysics Data System (ADS)

    Wahaia, Faustino; Valusis, Gintaras; Bernardo, Luis M.; Almeida, Abílio; Moreira, Joaquim A.; Lopes, Patricia C.; Macutkevic, Jan; Kasalynas, Irmantas; Seliuta, Dalius; Adomavicius, Ramunas; Henrique, Rui; Lopes, Machado

    2011-12-01

    Human normal and cancer affected samples of colon tissue have been measured using transmission time-domain terahertz spectroscopy and continuous wave terahertz imaging. We show that it is possible to distinguish between normal and cancerous regions in the samples when they are fixed in formalin or embedded in paraffin. The still noticeable contrast in the dried paraffin-embedded tissues could indicate that there are additional contrast-contributing factors other than water, which is the main goal of the present work. Plots of the refractive index of normal and cancer affected tissues as well as 2-D transmission THz images are shown. Experimental results are presented and the conditions for discrimination between normal and affected formalin-fixed and paraffin-embedded tissue are discussed.

  8. Risk of colonic cancer is not higher in the obese Lep(ob) mouse model compared to lean littermates.

    PubMed

    Sikalidis, Angelos K; Fitch, Mark D; Fleming, Sharon E

    2013-10-01

    Epidemiological data suggest that obesity increases the risk of colorectal cancer in humans. Given that diet-induced obesity mouse models verified the epidemiological data, the present study aimed to determine whether obese C57BL/6J-Lep(ob) male mice (a different obesity in vivo model) were at greater risk of colonic cancer than their lean male littermates. Risk of colonic tumorigenesis was assessed by numbers of aberrant crypts, aberrant crypt foci and colonic tumors. Proliferation of the colonic epithelia was assessed histochemically following administration of BrdU. Availability of the procarcinogen, azoxymethane (AOM) to target tissues was assessed by quantifying via HPLC plasma AOM concentrations during the 60 min period following AOM injection. When obese and lean mice were injected with azoxymethane (AOM) at doses calculated to provide equivalent AOM levels per kg lean body mass, obese animals had significantly fewer aberrant crypts/colon and fewer aberrant crypt foci/colon than the lean animals. Tumors were identified in the colonic mucosa of lean (4 tumors in 14 mice) but not obese (0 tumors in 15 mice) mice. Colonic cell proliferation was not significantly different for obese and lean mice. Because these results were unexpected, plasma AOM concentrations were measured and were found to be lower in the obese than lean mice. When plasma AOM levels were comparable for the lean and obese mice, the Lep(ob) mice continued to have significantly fewer aberrant crypt foci/colon than the lean mice, but differences were not statistically different for aberrant crypts/colon. Interestingly, obese Lep(ob) mice did not exhibit increased risk of colonic cancer as expected. Instead, Lep(ob) mice exhibited equivalent or lower risk of colon cancer when compared to the lean group. These results taken together with in vivo results from diet-induced obesity studies, imply that leptin may be responsible for the increased risk of colon cancer associated with obesity.

  9. Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer

    SciTech Connect

    Wu, Zehua; Cui, Feifei; Yu, Fudong; Peng, Xiao; Jiang, Tao; Chen, Dawei; Lu, Su; Tang, Huamei; Peng, Zhihai

    2014-06-27

    Highlights: • We identified that CHAF1A was up-regulated in colon tumor mucosa in TMA. • The expression pattern of CHAF1A was validated with qPCR and western-blot. • CHAF1A overexpression is an independent indicator for poor colon cancer survival. • CHAF1A facilitates cell proliferation of colon cancer both in vitro and in vivo. - Abstract: Deregulation of chromatin assembly factor 1, p150 subunit A (CHAF1A) has recently been reported to be involved in the development of some cancer types. In this study, we identified that the frequency of positive CHAF1A staining in primary tumor mucosa (45.8%, 93 of 203 samples) was significantly elevated compared to that in paired normal mucosa (18.7%, 38 of 203 samples). The increased expression was strongly associated with cancer stage, tumor invasion, and histological grade. The five-year survival rate of patients with CHAF1A-positive tumors was remarkably lower than that of patients with CHAF1A-negative tumors. Colon cancer cells with CHAF1A knockdown exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate as well as impaired colon tumorigenicity in nude mice. Hence, CHAF1A upregulation functions as a poor prognostic indicator of colon cancer, potentially contributing to its progression by mediating cancer cell proliferation.

  10. The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment

    PubMed Central

    Dalmasso, Guillaume; Cougnoux, Antony; Delmas, Julien; Darfeuille-Michaud, Arlette; Bonnet, Richard

    2014-01-01

    The gut microbiota is suspected to promote colorectal cancer (CRC). Escherichia coli are more frequently found in CCR biopsies than in healthy mucosa; furthermore, the majority of mucosa-associated E. coli isolated from CCR harbors the pks genomic island (pks+ E. coli) that is responsible for the synthesis of colibactin, a genotoxic compound. We have recently reported that transient contact of a few malignant cells with colibactin-producing E. coli increases tumor growth in a xenograft mouse model. Growth is sustained by cellular senescence that is accompanied by the production of growth factors. We demonstrated that cellular senescence is a consequence of the pks+ E. coli-induced alteration of p53 SUMOylation, an essential post-translational modification in eukaryotic cells. The underlying mechanisms for this process involve the induction of miR-20a-5p expression, which targets SENP1, a key protein in the regulation of the SUMOylation process. These results are consistent with the expression of SENP1, miR-20a-5p and growth factors that are observed in a CRC mouse model and in human CCR biopsies colonized by pks+ E. coli. Overall, the data reveal a new paradigm for carcinogenesis in which pks+ E. coli infection induces cellular senescence characterized by the production of growth factors that promote the proliferation of uninfected cells and, subsequently, tumor growth. PMID:25483338

  11. Prognostic value of hedgehog signaling pathway in patients with colon cancer.

    PubMed

    Xu, Meihua; Li, Xinhua; Liu, Ting; Leng, Aimin; Zhang, Guiying

    2012-06-01

    Hedgehog signaling pathway plays an important role in normal mammalian gastrointestinal development and is implicated in the oncogenesis of various tumors. However, its correlation with progression and prognosis of colon cancer has not been well documented. This study was designed to investigate expression patterns of related proteins in hedgehog signaling pathway in colon cancer to elucidate its prognostic value in this tumor. Using human colon cancer and their corresponding non-diseased colon from 228 patients' biopsies, the expression of sonic hedgehog, its receptor Patched, and downstream transcription factor Gli1 was investigated by immunohistochemical staining to assess their association with the clinicopathological characteristics of colon cancer. Disease-free survival and overall survival were examined by Kaplan-Meier estimates and the log-rank test. Prognostic factors were determined by multivariate Cox analysis. One hundred and thirty-eight patients (59.6%) had sonic hedgehog-positive tumors and that the disease-free survival (43.5 vs. 73.3%, P < 0.001), and overall survival rates (50.7 vs. 88.9%, P < 0.001) of patients with sonic hedgehog-positive tumors were much lower than those of patients with sonic hedgehog-negative tumors. In addition, 163 patients (71.5%) had Patched-positive tumors, and the disease-free survival (41.7 vs. 76.9%, P < 0.001) and overall survival rates (55.2 vs. 80.0%, P = 0.002) of patients with Patched-positive tumors were also lower than those of patients with Patched-negative tumors. Moreover, positive Gli1 expression had a bad effect on the disease-free survival (41.9 vs. 73.2%, P < 0.001) and overall survival rate of patients with colon cancer (50.0 vs. 89.3%, P < 0.001). In a multivariate analysis, sonic hedgehog, Patched, and Gli1 status were indicators for poor disease-free survival and overall survival. These results have shown that the increasing expression of sonic hedgehog, Patched, and Gli1 are indicators for a poor

  12. Diagnosis of colon cancer using frequency domain fluorescence imaging technique

    NASA Astrophysics Data System (ADS)

    Dinish, U. S.; Gulati, P.; Murukeshan, V. M.; Seah, L. K.

    2007-03-01

    Early detection and treatment of colon cancer has been associated with better disease prognosis. Conventional and reported optical techniques have limitations in detecting early stages of colon cancer growth. In this paper, a homodyne signal processing assisted frequency domain (FD) fluorescence imaging methodology is proposed for the early diagnosis of colon cancer. Simulated phantom tissues representing the biopsy samples at different stages of colon cancer growth are prepared and used for the imaging study. Selective imaging of healthy and diseased sites simulated in the samples was achieved even for fluorescence emissions having close lifetimes and wavelength values. Possible extension of the methodology for in vivo investigations is also discussed.

  13. Development and characterization of a colon PDX model that reproduces drug responsiveness and the mutation profiles of its original tumor.

    PubMed

    Seol, Hyang Sook; Kang, Hyo Jeong; Kang, Hyojeong; Lee, Seul-I; Kim, Na Eun; Kim, Tae Im; Chun, Sung Min; Kim, Tae Won; Yu, Chang Sik; Suh, Young-Ah; Singh, Shree Ram; Chang, Suhwan; Jang, Se Jin

    2014-04-01

    Cultures of primary tumors are very useful as a personalized screening system for effective therapeutic options. We here describe an effective method of reproducing human primary colon tumors through primary culture and a mouse xenograft model. A total of 199 primary colon tumor cultures were successfully established under optimized conditions to enrich for tumor cells and to expand it for long-term storage in liquid nitrogen. To examine whether these stored cultures retained original tumor properties, fifty primary cultures were xenografted into NOD-SCID mouse. Histological and tumor marker analysis of four representative tumor xenografts revealed that all of the xenograft retained its primary tumor characteristics. Oncomap analysis further showed no change in the major mutations in the xenografts, confirming that our method faithfully reproduced human colon tumors. A drug sensitivity assay revealed that two of the primary cultures were hypersensitive to oxaliplatin rather than 5-FU, which was used in the patients, suggesting it as an effective therapeutic option. We thus present an effective, reproducible preclinical model for testing various personalized therapeutic options in colon cancer patients.

  14. Different effects of ERβ and TROP2 expression in Chinese patients with early-stage colon cancer.

    PubMed

    Fang, Yu-Jing; Wang, Guo-Qiang; Lu, Zhen-Hai; Zhang, Lin; Li, Ji-Bin; Wu, Xiao-Jun; Ding, Pei-Rong; Ou, Qing-Jian; Zhang, Mei-Fang; Jiang, Wu; Pan, Zhi-Zhong; Wan, De-Sen

    2012-12-01

    Estrogen receptor beta (ERβ) and TROP2 expressed in colon carcinoma and might play an important role there. We explored the relationship of ERβ and TROP2 expression with the prognosis of early-stage colon cancer. ERβ and TROP2 levels were assessed by immunohistochemistry in normal mucosa and tumoral tissues from 220 Chinese patients with T(3)N(0)M(0) (stage IIa) and T(4)N(0)M(0) (stage IIb) colon cancer in the Cancer Center, Sun Yat-sen University, who underwent curative surgical resection between 1995 and 2003. The Cox proportional hazards regression model was applied to analyze the overall survival (OS) data, and the ROC curve, Kaplan-Meier estimate, log rank test, and Jackknife method were used to show the effect of ERβ and TROP2 expression at different stages of cancer. The 5-year survival rates were not significantly different between the patients with stage IIa and stage IIb colon cancer (83 vs. 80 %, respectively). The high expression of ERβ was related to decreasing OS in stage IIa and stage IIb colon cancer, while the high expression of TROP2 was related to decreasing OS in stage IIb colon cancer. The expression of ERβ and TROP2 has tumor-suppressive and tumor-promoting effect in stage IIa and stage IIb colon cancer, respectively.

  15. Akt Inhibitor MK2206 in Treating Patients With Previously Treated Colon or Rectal Cancer That is Metastatic or Locally Advanced and Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-06-10

    Colon Mucinous Adenocarcinoma; Colon Signet Ring Cell Adenocarcinoma; Rectal Mucinous Adenocarcinoma; Rectal Signet Ring Cell Adenocarcinoma; Recurrent Colon Carcinoma; Recurrent Rectal Carcinoma; 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

  16. Sweets for a bitter end: lung cancer cell surface protein glycosylation mediates metastatic colonization

    PubMed Central

    Arnal-Estapé, Anna; Nguyen, Don X.

    2015-01-01

    Summary Glycosylation is one of the most predominant forms of cell surface protein modifications and yet its de-regulation in cancer and contribution to tumor microenvironment interactions remains poorly understood. In this issue of Cancer Discovery, Reticker-Flynn and Bhatia characterize an enzymatic switch in lung cancer cells that triggers aberrant surface protein glycosylation patterns, adhesion to lectins on the surface of inflammatory cells, and subsequent metastatic colonization of the liver. PMID:25656895

  17. Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver

    PubMed Central

    2014-01-01

    Background Colorectal cancer is the third most frequently diagnosed cancer and the third cause of cancer deaths in the United States. Despite the fact that tumor cell-intrinsic mechanisms controlling colorectal carcinogenesis have been identified, novel prognostic and diagnostic tools as well as novel therapeutic strategies are still needed to monitor and target colon cancer progression. We and others have previously shown, using mouse models, that the extracellular matrix (ECM), a major component of the tumor microenvironment, is an important contributor to tumor progression. In order to identify candidate biomarkers, we sought to define ECM signatures of metastatic colorectal cancers and their metastases to the liver. Methods We have used enrichment of extracellular matrix (ECM) from human patient samples and proteomics to define the ECM composition of primary colon carcinomas and their metastases to liver in comparison with normal colon and liver samples. Results We show that robust signatures of ECM proteins characteristic of each tissue, normal and malignant, can be defined using relatively small samples from small numbers of patients. Comparisons with gene expression data from larger cohorts of patients confirm the association of subsets of the proteins identified by proteomic analysis with tumor progression and metastasis. Conclusions The ECM protein signatures of metastatic primary colon carcinomas and metastases to liver defined in this study, offer promise for development of diagnostic and prognostic signatures of metastatic potential of colon tumors. The ECM proteins defined here represent candidate serological or tissue biomarkers and potential targets for imaging of occult metastases and residual or recurrent tumors and conceivably for therapies. Furthermore, the methods described here can be applied to other tumor types and can be used to investigate other questions such as the role of ECM in resistance to therapy. PMID:25037231

  18. Specific Colon Cancer Cell Cytotoxicity Induced by Bacteriophage E Gene Expression under Transcriptional Control of Carcinoembryonic Antigen Promoter.

    PubMed

    Rama, Ana R; Hernandez, Rosa; Perazzoli, Gloria; Burgos, Miguel; Melguizo, Consolación; Vélez, Celia; Prados, Jose

    2015-06-04

    Colorectal cancer is one of the most prevalent cancers in the world. Patients in advanced stages often develop metastases that require chemotherapy and usually show a poor response, have a low survival rate and develop considerable toxicity with adverse symptoms. Gene therapy may act as an adjuvant therapy in attempts to destroy the tumor without affecting normal host tissue. The bacteriophage E gene has demonstrated significant antitumor activity in several cancers, but without any tumor-specific activity. The use of tumor-specific promoters may help to direct the expression of therapeutic genes so they act against specific cancer cells. We used the carcinoembryonic antigen promoter (CEA) to direct E gene expression (pCEA-E) towards colon cancer cells. pCEA-E induced a high cell growth inhibition of human HTC-116 colon adenocarcinoma and mouse MC-38 colon cancer cells in comparison to normal human CCD18co colon cells, which have practically undetectable levels of CEA. In addition, in vivo analyses of mice bearing tumors induced using MC-38 cells showed a significant decrease in tumor volume after pCEA-E treatment and a low level of Ki-67 in relation to untreated tumors. These results suggest that the CEA promoter is an excellent candidate for directing E gene expression specifically toward colon cancer cells.

  19. Diet, genes, and microbes: complexities of colon cancer prevention.

    PubMed

    Birt, Diane F; Phillips, Gregory J

    2014-01-01

    Colorectal cancer is one of the leading causes of cancer-related deaths in the United States, and generally, as countries climb the economic ladder, their rates of colon cancer increase. Colon cancer was an early disease where key genetic mutations were identified as important in disease progression, and there is considerable interest in determining whether specific mutations sensitize the colon to cancer prevention strategies. Epidemiological studies have revealed that fiber- and vegetable-rich diets and physical activity are associated with reduced rates of colon cancer, while consumption of red and processed meat, or alcoholic beverages, and overconsumption as reflected in obesity are associated with increased rates. Animal studies have probed these effects and suggested directions for further refinement of diet in colon cancer prevention. Recently a central role for the microorganisms in the gastrointestinal tract in colon cancer development is being probed, and it is hypothesized that the microbes may integrate diet and host genetics in the etiology of the disease. This review provides background on dietary, genetic, and microbial impacts on colon cancer and describes an ongoing project using rodent models to assess the ability of digestion-resistant starch in the integration of these factors with the goal of furthering colon cancer prevention.

  20. Vancomycin-sensitive bacteria trigger development of colitis-associated colon cancer by attracting neutrophils

    PubMed Central

    Tanaka, Yuriko; Ito, Sachiko; Isobe, Ken-ichi

    2016-01-01

    Inflammatory bowel disease confers an increased risk of developing colitis-associated colon cancer (CAC). During the active colitis or developing tumor stage, commensal bacteria show dynamic translocation. However, whether alteration of the bacterial composition in the gut causes CAC is still unclear. To clarify the effect of commensal bacteria on CAC development, we employed an azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine CAC model treated with or without antibiotics. In addition, we analyzed the effects of antibiotics on infiltration of myeloid cells, colonic inflammatory responses, and colorectal cancer formation. We found that vancomycin treatment dramatically suppressed tumor development. In addition, AOM/DSS treatment greatly induced the infiltration of Gr-1high/CD11bhigh neutrophils to the colon, which led to the production of tumor necrosis factor α and inducible nitric oxide synthase. Vancomycin treatment suppressed the infiltration of neutrophils induced by AOM/DSS. Moreover, vancomycin treatment greatly reduced the colon injury and DNA damage caused by AOM/DSS-induced NO radicals. Our results indicate that vancomycin-sensitive bacteria induced colon inflammation and DNA damage by attracting neutrophils into damaged colon tissue, thus promoting tumor formation. PMID:27050089

  1. Vancomycin-sensitive bacteria trigger development of colitis-associated colon cancer by attracting neutrophils.

    PubMed

    Tanaka, Yuriko; Ito, Sachiko; Isobe, Ken-ichi

    2016-01-01

    Inflammatory bowel disease confers an increased risk of developing colitis-associated colon cancer (CAC). During the active colitis or developing tumor stage, commensal bacteria show dynamic translocation. However, whether alteration of the bacterial composition in the gut causes CAC is still unclear. To clarify the effect of commensal bacteria on CAC development, we employed an azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine CAC model treated with or without antibiotics. In addition, we analyzed the effects of antibiotics on infiltration of myeloid cells, colonic inflammatory responses, and colorectal cancer formation. We found that vancomycin treatment dramatically suppressed tumor development. In addition, AOM/DSS treatment greatly induced the infiltration of Gr-1(high)/CD11b(high) neutrophils to the colon, which led to the production of tumor necrosis factor α and inducible nitric oxide synthase. Vancomycin treatment suppressed the infiltration of neutrophils induced by AOM/DSS. Moreover, vancomycin treatment greatly reduced the colon injury and DNA damage caused by AOM/DSS-induced NO radicals. Our results indicate that vancomycin-sensitive bacteria induced colon inflammation and DNA damage by attracting neutrophils into damaged colon tissue, thus promoting tumor formation. PMID:27050089

  2. X-ray fluorescence microscopy demonstrates preferential accumulation of a vanadium-based magnetic resonance imaging contrast agent in murine colonic tumors.

    PubMed

    Mustafi, Devkumar; Ward, Jesse; Dougherty, Urszula; Bissonnette, Marc; Hart, John; Vogt, Stefan; Karczmar, Gregory S

    2015-01-01

    Contrast agents that specifically enhance cancers on magnetic resonance imaging (MRI) will allow earlier detection. Vanadium-based chelates (VCs) selectively enhance rodent cancers on MRI, suggesting selective uptake of VCs by cancers. Here we report x-ray fluorescence microscopy (XFM) of VC uptake by murine colon cancer. Colonic tumors in mice treated with azoxymethane/dextran sulfate sodium were identified by MRI. Then a gadolinium-based contrast agent and a VC were injected intravenously; mice were sacrificed and colons sectioned. VC distribution was sampled at 120 minutes after injection to evaluate the long-term accumulation. Gadolinium distribution was sampled at 10 minutes after injection due to its rapid washout. XFM was performed on 72 regions of normal and cancerous colon from five normal mice and four cancer-bearing mice. XFM showed that all gadolinium was extracellular, with similar concentrations in colon cancers and normal colon. In contrast, the average VC concentration was twofold higher in cancers versus normal tissue (p < .002). Cancers also contained numerous "hot spots" with intracellular VC concentrations sixfold higher than the concentration in normal colon (p < .0001). No hot spots were detected in normal colon. This is the first direct demonstration that VCs selectively accumulate in cancer cells and thus may improve cancer detection.

  3. Gene Signature in Sessile Serrated Polyps Identifies Colon Cancer Subtype.

    PubMed

    Kanth, Priyanka; Bronner, Mary P; Boucher, Kenneth M; Burt, Randall W; Neklason, Deborah W; Hagedorn, Curt H; Delker, Don A

    2016-06-01

    Sessile serrated colon adenoma/polyps (SSA/P) are found during routine screening colonoscopy and may account for 20% to 30% of colon cancers. However, differentiating SSA/Ps from hyperplastic polyps (HP) with little risk of cancer is challenging and complementary molecular markers are needed. In addition, the molecular mechanisms of colon cancer development from SSA/Ps are poorly understood. RNA sequencing (RNA-Seq) was performed on 21 SSA/Ps, 10 HPs, 10 adenomas, 21 uninvolved colon, and 20 control colon specimens. Differential expression and leave-one-out cross-validation methods were used to define a unique gene signature of SSA/Ps. Our SSA/P gene signature was evaluated in colon cancer RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify a subtype of colon cancers that may develop from SSA/Ps. A total of 1,422 differentially expressed genes were found in SSA/Ps relative to controls. Serrated polyposis syndrome (n = 12) and sporadic SSA/Ps (n = 9) exhibited almost complete (96%) gene overlap. A 51-gene panel in SSA/P showed similar expression in a subset of TCGA colon cancers with high microsatellite instability. A smaller 7-gene panel showed high sensitivity and specificity in identifying BRAF-mutant, CpG island methylator phenotype high, and MLH1-silenced colon cancers. We describe a unique gene signature in SSA/Ps that identifies a subset of colon cancers likely to develop through the serrated pathway. These gene panels may be utilized for improved differentiation of SSA/Ps from HPs and provide insights into novel molecular pathways altered in colon cancer arising from the serrated pathway. Cancer Prev Res; 9(6); 456-65. ©2016 AACR.

  4. Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K

    PubMed Central

    Yueh, Alexander E.; Payne, Susan N.; Leystra, Alyssa A.; Van De Hey, Dana R.; Foley, Tyler M.; Pasch, Cheri A.; Clipson, Linda; Matkowskyj, Kristina A.; Deming, Dustin A.

    2016-01-01

    The phosphoinositide 3-kinase (PI3K) signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin), indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling. PMID:26863299

  5. PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis

    PubMed Central

    Nguyen, Alexander; Loo, Jia Min; Mital, Rohit; Weinberg, Ethan M.; Man, Fung Ying; Zeng, Zhaoshi; Paty, Philip B.; Saltz, Leonard; Janjigian, Yelena Y.; de Stanchina, Elisa; Tavazoie, Sohail F.

    2016-01-01

    Colorectal cancer metastasis to the liver is a major cause of cancer-related death; however, the genes and pathways that govern this metastatic colonization event remain poorly characterized. Here, using a large-scale in vivo RNAi screen, we identified liver and red blood cell pyruvate kinase (PKLR) as a driver of metastatic liver colonization. PKLR expression was increased in liver metastases as well as in primary colorectal tumors of patients with metastatic disease. Evaluation of a murine liver colonization model revealed that PKLR promotes cell survival in the tumor core during conditions of high cell density and oxygen deprivation by increasing glutathione, the primary endogenous antioxidant. PKLR negatively regulated the glycolytic activity of PKM2, the major pyruvate kinase isoenzyme known to regulate cellular glutathione levels. Glutathione is critical for metastasis, and we determined that the rate-limiting enzyme of glutathione synthesis, GCLC, becomes overexpressed in patient liver metastases, promotes cell survival under hypoxic and cell-dense conditions, and mediates metastatic liver colonization. RNAi-mediated inhibition of glutathione synthesis impaired survival of multiple colon cancer cell lines, and pharmacological targeting of this metabolic pathway reduced colonization in a primary patient-derived xenograft model. Our findings highlight the impact of metabolic reprogramming within the niche as metastases progress and suggest clinical potential for targeting this pathway in colorectal cancer. PMID:26784545

  6. MicroRNA-26b Represses Colon Cancer Cell Proliferation by Inhibiting Lymphoid Enhancer Factor 1 (LEF-1) Expression

    PubMed Central

    Zhang, Zichao; Kim, KyoungHyun; Li, Xiao; Moreno, Myriam; Sharp, Thad; Goodheart, Micheal J.; Safe, Stephen; Dupuy, Adam J.; Amendt, Brad A.

    2014-01-01

    microRNAs (miR) can act as oncogenes and tumor suppressors and several miRs are associated with cancer development and progression through the modulation of multiple cellular processes. miR-26b is down regulated in several cancers and tumors and miR-26b directly targets the Lef-1 3'UTR and inhibits endogenous Lef-1 expression. We report that miR-26b expression is associated with human colon cancer through the regulation of LEF-1 expression in colon cancer cells. Analyses of multiple colon cancer cell lines revealed an inverse correlation between miR-26b and LEF-1 expression. Normal human colon cells express low levels of LEF-1 and high levels of miR-26b, however human colon cancer cells have decreased miR-26b expression and increased LEF-1 expression. We demonstrate that miR-26b expression is a potent inhibitor of colon cancer cell proliferation and significantly decreases LEF-1 expression. The LEF-1 regualted genes Cyclin D1 and c-Myc were indirectly repressed by miR-26b and this was consistent with decreased proliferation. miR-26b overexpression in SW480 colon cancer cells also inhibited tumor growth in nude mice and this was due to decreased tumor growth and not apoptosis. Analyses of human colon cancer databases also demonstrated a link between miR-26b and LEF-1 expression. c-Myc expression is associated with multiple cancers and we propose that miR-26b may act as a potential therapeutic agent in reducing cancer cell proliferation through repressing LEF-1 activation of c-Myc and Cyclin D1 expression. PMID:24785257

  7. [Treatment of colonic cancer with laser (Nd-YAG). Our initial experience].

    PubMed

    Meroño, E; Martín de Argila, C; Martín-Scapa, A; García Plaza, A

    1992-11-01

    Laser-therapy represents an acceptable alternative in the palliative treatment of colon cancer. We have treated 25 patients with this pathology, 10 with obstructive tumor, which impeded the insertion of the endoscope, and 15 non-obstructive tumors. Higher technical difficulties on the former, together with a worse clinical situation, due to the fact that the tumor was more invasive, produce a more discrete result and with a higher risk of complications (one patient had a perforation and other an obstructive stenosis after two months of treatment) in comparison with the group of patients with non-obstructive tumors. However the treatment improved their quality of life with the recovery of their intestinal function. Among patients with non-obstructive tumors of the colonic light, prolonged survival (mean 6.8 months) was reached by 73.3% of patients belonging to this group; disappearing after treatment even the endoscopic view of the tumor in 33.3% of the patients.

  8. Physical Activity Counteracts Tumor Cell Growth in Colon Carcinoma C26-Injected Muscles: An Interim Report

    PubMed Central

    Hiroux, Charlotte; Vandoorne, Tijs; Koppo, Katrien; De Smet, Stefan; Hespel, Peter; Berardi, Emanuele

    2016-01-01

    Skeletal muscle tissue is a rare site of tumor metastasis but is the main target of the degenerative processes occurring in cancer-associated cachexia syndrome. Beneficial effects of physical activity in counteracting cancer-related muscle wasting have been described in the last decades. Recently it has been shown that, in tumor xeno-transplanted mouse models, physical activity is able to directly affect tumor growth by modulating inflammatory responses in the tumor mass microenvironment. Here, we investigated the effect of physical activity on tumor cell growth in colon carcinoma C26 cells injected tibialis anterior muscles of BALB/c mice. Histological analyses revealed that 4 days of voluntary wheel running significantly counteracts tumor cell growth in C26-injected muscles compared to the non-injected sedentary controls. Since striated skeletal muscle tissue is the site of voluntary contraction, our results confirm that physical activity can also directly counteract tumor cell growth in a metabolically active tissue that is usually not a target for metastasis. PMID:27478560

  9. Association of Family History with Cancer Recurrence and Survival Among Patients with Stage III Colon Cancer

    PubMed Central

    Chan, Jennifer A.; Meyerhardt, Jeffrey A.; Niedzwiecki, Donna; Hollis, Donna; Saltz, Leonard B.; Mayer, Robert J.; Thomas, James; Schaefer, Paul; Whittom, Renaud; Hantel, Alexander; Goldberg, Richard M.; Warren, Robert S.; Bertagnolli, Monica; Fuchs, Charles S.

    2011-01-01

    Context A family history of colorectal cancer in a first-degree relative increases the risk of developing colorectal cancer. However, the influence of family history on cancer recurrence and survival among patients with established disease remains uncertain. Objective To examine the association of family history of colorectal cancer with cancer recurrence and survival of patients with colon cancer. Design, Setting, and Participants Prospective observational study of 1,087 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803) between April 1999 and May 2001. Patients provided data on family history at baseline and were followed up until March 2007 for disease recurrence and death (median follow-up 5.6 years). In a subset of patients, we assessed microsatellite instability (MSI) and expression of the mismatch repair (MMR) proteins, MLH1 and MSH2, in tumor specimens. Main Outcome Measure Disease-free survival, recurrence-free survival, and overall survival according to the presence or absence of a family history of colorectal cancer. Results Among 1,087 eligible patients, 195 (17.9%) reported a family history of colorectal cancer in a first-degree relative. Cancer recurrence or death occurred in 57/195 patients (29%; 95% confidence interval [CI], 23%-36%) with a family history of colorectal cancer and 343/892 patients (38%; 95% CI, 35%-42%) without a family history. Compared to patients without a family history, the adjusted hazard ratios (HR) among those with ≥1 affected first-degree relatives were 0.72 (95% CI, 0.54-0.96) for disease-free survival (DFS), 0.74 (95% CI, 0.55-0.99) for recurrence-free survival (RFS), and 0.75 (95% CI, 0.54-1.05) for overall survival (OS). This reduction in risk of cancer recurrence or death associated with a family history became stronger with an increasing number of affected first-degree relatives. Compared to participants without a family history of colorectal cancer, those with 1

  10. Impact of in Vivo Ischemic Time on RNA Quality--Experiences from a Colon Cancer Biobank.

    PubMed

    Olsen, Jesper; Kirkeby, Lene T; Eiholm, Susanne; Jess, Per; Troelsen, Jesper T; Gögenür, Ismail; Olsen, Jorgen

    2015-08-01

    Considerable effort has been made to improve differentiated diagnostics as well as personalized treatment for colorectal cancer patients. High-quality fresh frozen tissue is often required to investigate relevant molecular signatures in these patients. In RNA expression studies, the "RNA integrity number" is widely accepted as a reliable marker of RNA quality. Here, we investigate the feasibility of obtaining high-quality tissue from a colon cancer biobank and the impact of in vivo ischemic time and various technical and clinicopathological factors on RNA quality. Biopsies were obtained immediately following the tumor removal. The time from clamping the main arterial supply to resection and removal of the tumor was used to estimate the in vivo ischemic time. We did not observe a significant difference in RNA quality between normal tissue and tumor tissue. We observed a significant correlation between in vivo ischemic time and RNA quality in normal tissue (r = -0.24, p<0.001) but not in tumor tissue. Male gender and laparoscopic procedure were also significantly associated with lower RNA quality in normal tissue only. In tumor tissue, poor differentiation was associated with low RNA quality. In conclusion, in vivo ischemic time, surgical procedure, and gender have minor but significant effects on the quality of RNA from normal colon tissue but not tumor tissue. Poorly differentiated tumors are associated with lower RNA quality. Although its impact is low, it can still be considered to note in vivo ischemic time in colon cancer specimen procurement.

  11. Fiber, intestinal sterols, and colon cancer.

    PubMed

    Huang, C T; Gopalakrishna, G S; Nichols, B L

    1978-03-01

    It has been postulated that dietary fiber's protective effect against the development of colon cancer, diverticular disease, and atherosclerosis may be due to the adsorption and/or dilution of intestinal sterols such as bile acids and neural sterols and their bacterial metabolites by component(s) of fiber. Dietary fiber is made up of four major components-cellulose, hemicellulose, lignin, and pectin. There is evidence that hemicellulose and pectin may induce an increase in fecal bile acid excretion in man which may be accompanied by a decrease in serum cholesterol. Natural fibers, such as rolled oats, alfalfa, guar gum, and Bengal gram have been shown to have hypocholesterolemic properties of alfalfa, wheat straw, and some other fibers found considerable amounts of bile acids in vitro. On the other hand, wheat bran, oat hulls, and all the synthetic fibers tested bound only negligible amounts of bile acids under the same conditions. Vegetarians in the United States have lower plasma lipids and different plasma lipoprotein patterns than those of comparable control populations on regular mixed diet. They also have smaller daily fractional turnover rates of cholic acid and deoxycholic acid pool size. In addition, populations on a mixed Western diet, where the rate of large bowel cancer is high (North American, English, Scottish, etc.) degraded and excreted cholesterol and bile acid metabolites to a greater degree than populations where the rate of colon cancer is comparatively low (Ugandan, Japanese, etc). It cannot be denied that the fiber theory linking fiber deficiency with the development of colon cancer and other diseases, is simple, attractive and appears to be firmly based in common sense. When subjected to research studies, however, the situation appears much more complex than expected. Although some progress is being made, the data are often contradictory and confusing, probably due to lack of adequate documentation of fiber intake (e.g., use of dietary fiber

  12. The organotelluride catalyst LAB027 prevents colon cancer growth in the mice

    PubMed Central

    Coriat, R; Marut, W; Leconte, M; Ba, L B; Vienne, A; Chéreau, C; Alexandre, J; Weill, B; Doering, M; Jacob, C; Nicco, C; Batteux, F

    2011-01-01

    Organotellurides are newly described redox-catalyst molecules with original pro-oxidative properties. We have investigated the in vitro and in vivo antitumoral effects of the organotelluride catalyst LAB027 in a mouse model of colon cancer and determined its profile of toxicity in vivo. LAB027 induced an overproduction of H2O2 by both human HT29 and murine CT26 colon cancer cell lines in vitro. This oxidative stress was associated with a decrease in proliferation and survival rates of the two cell lines. LAB027 triggered a caspase-independent, ROS-mediated cell death by necrosis associated with mitochondrial damages and autophagy. LAB027 also synergized with the cytotoxic drug oxaliplatin to augment its cytostatic and cytotoxic effects on colon cancer cell lines but not on normal fibroblasts. The opposite effects of LAB027 on tumor and on non-transformed cells were linked to differences in the modulation of reduced glutathione metabolism between the two types of cells. In mice grafted with CT26 tumor cells, LAB027 alone decreased tumor growth compared with untreated mice, and synergized with oxaliplatin to further decrease tumor development compared with mice treated with oxaliplatin alone. LAB027 an organotelluride catalyst compound synergized with oxaliplatin to prevent both in vitro and in vivo colon cancer cell proliferation while decreasing the in vivo toxicity of oxaliplatin. No in vivo adverse effect of LAB027 was observed in this model. PMID:21833029

  13. Rectal and colon cancer: Not just a different anatomic site.

    PubMed

    Tamas, K; Walenkamp, A M E; de Vries, E G E; van Vugt, M A T M; Beets-Tan, R G; van Etten, B; de Groot, D J A; Hospers, G A P

    2015-09-01

    Due to differences in anatomy, primary rectal and colon cancer require different staging procedures, different neo-adjuvant treatment and different surgical approaches. For example, neoadjuvant radiotherapy or chemoradiotherapy is administered solely for rectal cancer. Neoadjuvant therapy and total mesorectal excision for rectal cancer might be responsible in part for the differing effect of adjuvant systemic treatment on overall survival, which is more evident in colon cancer than in rectal cancer. Apart from anatomic divergences, rectal and colon cancer also differ in their embryological origin and metastatic patterns. Moreover, they harbor a different composition of drug targets, such as v-raf murine sarcoma viral oncogene homolog B (BRAF), which is preferentially mutated in proximal colon cancers, and the epidermal growth factor receptor (EGFR), which is prevalently amplified or overexpressed in distal colorectal cancers. Despite their differences in metastatic pattern, composition of drug targets and earlier local treatment, metastatic rectal and colon cancer are, however, commonly regarded as one entity and are treated alike. In this review, we focused on rectal cancer and its biological and clinical differences and similarities relative to colon cancer. These aspects are crucial because they influence the current staging and treatment of these cancers, and might influence the design of future trials with targeted drugs.

  14. Cholesterol masks membrane glycosphingolipid tumor-associated antigens to reduce their immunodetection in human cancer biopsies.

    PubMed

    Novak, Anton; Binnington, Beth; Ngan, Bo; Chadwick, Karen; Fleshner, Neil; Lingwood, Clifford A

    2013-11-01

    Glycosphingolipids (GSLs) are neoplastic and normal/cancer stem cell markers and GSL/cholesterol-containing membrane rafts are increased in cancer cell plasma membranes. We define a novel means by which cancer cells can restrict tumor-associated GSL immunoreactivity. The GSL-cholesterol complex reorients GSL carbohydrate to a membrane parallel, rather than perpendicular conformation, largely unavailable for antibody recognition. Methyl-β-cyclodextrin cholesterol extraction of all primary human tumor frozen sections tested (ovarian, testicular, neuroblastoma, prostate, breast, colon, pheochromocytoma and ganglioneuroma), unmasked previously "invisible" membrane GSLs for immunodetection. In ovarian carcinoma, globotriaosyl ceramide (Gb3), the GSL receptor for the antineoplastic Escherichia coli-derived verotoxin, was increased throughout the tumor. In colon carcinoma, Gb3 detection was vastly increased within the neovasculature and perivascular stroma. In tumors considered Gb3 negative (neuroblastoma, Leydig testicular tumor and pheochromocytoma), neovascular Gb3 was unmasked. Tumor-associated GSL stage-specific embryonic antigen (SSEA)-1, SSEA-3, SSEA-4 and globoH were unmasked according to tumor: SSEA-1 in prostate/colon; SSEA-3 in prostate; SSEA-4 in pheochromocytoma/some colon tumors; globoH in prostate/some colon tumors. In colon, anti-SSEA-1 was tumor cell specific. Within the GSL-cholesterol complex, filipin-cholesterol binding was also reduced. These results may relate to the ill-defined benefit of statins on cancer prognosis, for example, prostate carcinoma. We found novel anti-tumor GSL antibodies circulating in 3/5 statin-treated, but not untreated, prostate cancer patients. Lowering tumor membrane cholesterol may permit immune recognition of otherwise unavailable tumor-associated GSL carbohydrate, for more effective immunosurveillance and active/passive immunotherapy. Our results show standard immunodetection of tumor GSLs significantly under assesses

  15. Guanylyl cyclase C signaling axis and colon cancer prevention

    PubMed Central

    Pattison, Amanda M; Merlino, Dante J; Blomain, Erik S; Waldman, Scott A

    2016-01-01

    Colorectal cancer (CRC) is a major cause of cancer-related mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C (GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B), which bind and activate GUCY2C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C’s role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2C ligand linaclotide (Linzess™). Here we review the known contributions of the GUCY2C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention. PMID:27688649

  16. Guanylyl cyclase C signaling axis and colon cancer prevention.

    PubMed

    Pattison, Amanda M; Merlino, Dante J; Blomain, Erik S; Waldman, Scott A

    2016-09-28

    Colorectal cancer (CRC) is a major cause of cancer-related mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C (GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B), which bind and activate GUCY2C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C's role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2C ligand linaclotide (Linzess™). Here we review the known contributions of the GUCY2C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention. PMID:27688649

  17. Guanylyl cyclase C signaling axis and colon cancer prevention

    PubMed Central

    Pattison, Amanda M; Merlino, Dante J; Blomain, Erik S; Waldman, Scott A

    2016-01-01

    Colorectal cancer (CRC) is a major cause of cancer-related mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C (GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B), which bind and activate GUCY2C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C’s role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2C ligand linaclotide (Linzess™). Here we review the known contributions of the GUCY2C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.

  18. The role of IGFBP-5 in mediating the anti-proliferation effect of tetrandrine in human colon cancer cells.

    PubMed

    Wu, Ke; Zhou, Mi; Wu, Qiu-Xiang; Yuan, Shuang-Xu; Wang, Dong-Xu; Jin, Jie-Li; Huang, Jun; Yang, Jun-Qin; Sun, Wen-Juan; Wan, Li-Hua; He, Bai-Cheng

    2015-03-01

    Colon cancer is one of the most common malignancies, causes considerable morbidity and mortality. The current treatment for colon cancer is more modest than had been hoped. There is an urgent clinical need to explore new agents or adjuvants for colon cancer treatment. Natural products and their derivates act as one of the major source for anticancer agent. In the present study, we investigated the anti-proliferation and chemoprevention effects of tetrandrine (Tet) on colon cancer cells to uncover the possible molecular basis of this effect. We found that Tet can inhibit proliferation and induce apoptosis in LoVo cells. With dimethylhydrazine (DMH) and dextran sodium sulfate (DSS) induced colon cancer model, we found that Tet can prevent or inhibit DMH plus DSS induced aberrant crypt foci (ACF) and colon cancer formation, as well as suppress tumor growth in the xenograft colon cancer model. Tet can downregulate the expression of IGFBP-5 in LoVo cells. Exogenous expression of IGFBP-5 can attenuate the anti-cancer activity of Tet, while IGFBP-5 knockdown potentiates this effect of Tet on LoVo cells. Tet can inhibit Wnt/β-catenin signaling transduction, which can be partly reversed by exogenous expression of IGFBP-5, but is enhanced by IGFBP-5 knockdown. Our results demonstrated that the anticancer activity of Tet in colon cancer cells may be mediated partly by downregulating the expression of IGFBP-5, thus inactivating Wnt/β-catenin signaling transduction. PMID:25524807

  19. A novel histone deacetylase inhibitor Chidamide induces apoptosis of human colon cancer cells

    SciTech Connect

    Liu, Lin; Chen, Baoan; Qin, Shukui; Li, Suyi; He, Xiangming; Qiu, Shaomin; Zhao, Wei; Zhao, Hong

    2010-02-05

    Many studies have demonstrated that histone deacetylase (HDAC) inhibitors induce various tumor cells to undergo apoptosis, and such inhibitors have been used in different clinical trials against different human cancers. In this study, we designed and synthesized a novel HDAC inhibitor, Chidamide. We showed that Chidamide was able to increase the acetylation levels of histone H3 and to inhibit the PI3K/Akt and MAPK/Ras signaling pathways, which resulted in arresting colon cancer cells at the G1 phase of the cell cycle and promoting apoptosis. As a result, the proliferation of colon cancer cells was suppressed in vitro. Our data support the potential application of Chidamide as an anticancer agent in treating colon cancer. Future studies are needed to demonstrate its in vivo efficacy.

  20. Influence of gilaburu (Viburnum opulus) juice on 1,2-dimethylhydrazine (DMH)-induced colon cancer.

    PubMed

    Ulger, Harun; Ertekin, Tolga; Karaca, Omur; Canoz, Ozlem; Nisari, Mehtap; Unur, Erdoğan; Elmalı, Ferhan

    2013-10-01

    In this study, the effects of gilaburu (Viburnum opulus) juice on colon tumorogenesis were investigated. Eight weeks old Balb-C male mice received subcutaneous injections of 1,2-dimethylhydrazine (DMH) (20 mg/kg body weight) once a week for 12 weeks. Both the sham control (group 1) and the DMH control (group 2) groups received drinking water alone, whereas the mice of groups 3 and 4 received gilaburu juice for 30 weeks (started with first DMH injection) and for 18 weeks (started after last DMH injection), respectively. Eighteen weeks after the last DMH injection, all mice were killed and the histogenesis of colon tumors was investigated from the paraffin-embedded sections of colon, which were stained with hematoxylin-eosin. The sites and incidences of tumoral lesions (low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma and invasive carcinoma) were analyzed and compared with control. The results showed that the body weights of the mice were similar in all the groups. No tumoral lesions were found in group 1. Colon tumors developed in all DMH-treated mice (groups 2, 3 and 4). In these groups, the greatest numbers of tumor lesions were detected in the distal colon, followed by the mid-colon and only a few in the proximal colon. There was a reduction in the mean total number of tumor lesion in groups 3 (8.5) and 4 (8.3), when compared to group 2 (11.3). The incidence of invasive carcinoma in group 3 was significantly lower than group 2 (p < 0.05). On the basis of these results, we conclude that gilaburu juice may be useful for the prevention of colon cancer at the initiation stage.

  1. Tumor markers used in monitoring the tumor recurrence in patients with colorectal cancer

    PubMed Central

    BURZ, CLAUDIA; AZIZ, BEN YOUSSEF MOHAMED; BĂLĂCESCU, LOREDANA; LELUŢIU, LUMINIŢA; BUIGA, RAREŞ; SAMASCA, GABRIEL; IRIMIE, ALEXANDRU; LISENCU, COSMIN

    2016-01-01

    Background and aims The aim of this study was to investigate the value of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) correlated with some tissue molecules as predictive markers for recurrence in colon cancer. Methods A total of 30 patients diagnosed with colon cancer stage II or III who underwent optimal surgery were enrolled in study. Tumor markers CEA and CA 19-9 were determined before surgery. Tumor samples were prepared using tissue microarray kit (TMA) then stained for different cellular markers (Ki 67, HER2, BCL2, CD56, CD4, CD8) and analyzed using Inforatio programme for quantitative determination. All patients received standard adjuvant treatment, which consisted of eight cycles chemotherapy type XELOX. The patients were followed up for 3 years. Results Upon 3 years follow-up, 67% of patients developed tumor relapse, the most common site of metastasis being the liver. No correlations were observed between either serum or tissue tumor markers and the risk of tumor relapse. Conclusion Over 50% of patients with colon cancer who had optimal treatment developed metastasis. No statistically significant predictive value for investigated molecules was found. Future studies are needed to confirm the use of molecular markers in monitoring patients with colorectal cancer PMID:27547057

  2. Colon cancer prediction with genetic profiles using intelligent techniques.

    PubMed

    Alladi, Subha Mahadevi; P, Shinde Santosh; Ravi, Vadlamani; Murthy, Upadhyayula Suryanarayana

    2008-01-01

    Micro array data provides information of expression levels of thousands of genes in a cell in a single experiment. Numerous efforts have been made to use gene expression profiles to improve precision of tumor classification. In our present study we have used the benchmark colon cancer data set for analysis. Feature selection is done using t-statistic. Comparative study of class prediction accuracy of 3 different classifiers viz., support vector machine (SVM), neural nets and logistic regression was performed using the top 10 genes ranked by the t-statistic. SVM turned out to be the best classifier for this dataset based on area under the receiver operating characteristic curve (AUC) and total accuracy. Logistic Regression ranks as the next best classifier followed by Multi Layer Perceptron (MLP). The top 10 genes selected by us for classification are all well documented for their variable expression in colon cancer. We conclude that SVM together with t-statistic based feature selection is an efficient and viable alternative to popular techniques.

  3. Colon cancer prediction with genetic profiles using intelligent techniques

    PubMed Central

    Alladi, Subha Mahadevi; P, Shinde Santosh; Ravi, Vadlamani; Murthy, Upadhyayula Suryanarayana

    2008-01-01

    Micro array data provides information of expression levels of thousands of genes in a cell in a single experiment. Numerous efforts have been made to use gene expression profiles to improve precision of tumor classification. In our present study we have used the benchmark colon cancer data set for analysis. Feature selection is done using t‐statistic. Comparative study of class prediction accuracy of 3 different classifiers viz., support vector machine (SVM), neural nets and logistic regression was performed using the top 10 genes ranked by the t‐statistic. SVM turned out to be the best classifier for this dataset based on area under the receiver operating characteristic curve (AUC) and total accuracy. Logistic Regression ranks as the next best classifier followed by Multi Layer Perceptron (MLP). The top 10 genes selected by us for classification are all well documented for their variable expression in colon cancer. We conclude that SVM together with t-statistic based feature selection is an efficient and viable alternative to popular techniques. PMID:19238250

  4. Trypanosoma cruzi extracts elicit protective immune response against chemically induced colon and mammary cancers.

    PubMed

    Ubillos, Luis; Freire, Teresa; Berriel, Edgardo; Chiribao, María Laura; Chiale, Carolina; Festari, María Florencia; Medeiros, Andrea; Mazal, Daniel; Rondán, Mariella; Bollati-Fogolín, Mariela; Rabinovich, Gabriel A; Robello, Carlos; Osinaga, Eduardo

    2016-04-01

    Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, has anticancer effects mediated, at least in part, by parasite-derived products which inhibit growth of tumor cells. We investigated whether immunity to T. cruzi antigens could induce antitumor activity, using two rat models which reproduce human carcinogenesis: colon cancer induced by 1,2-dimethylhydrazine (DMH), and mammary cancer induced by N-nitroso-N-methylurea (NMU). We found that vaccination with T. cruzi epimastigote lysates strongly inhibits tumor development in both animal models. Rats immunized with T. cruzi antigens induce activation of both CD4(+) and CD8(+) T cells and splenocytes from these animals showed higher cytotoxic responses against tumors as compared to rats receiving adjuvant alone. Tumor-associated immune responses included increasing number of CD11b/c(+) His48(-) MHC II(+) cells corresponding to macrophages and/or dendritic cells, which exhibited augmented NADPH-oxidase activity. We also found that T. cruzi lysate vaccination developed antibodies specific for colon and mammary rat cancer cells, which were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) in vitro. Anti-T. cruzi antibodies cross-reacted with human colon and breast cancer cell lines and recognized 41/60 (68%) colon cancer and 38/63 (60%) breast cancer samples in a series of 123 human tumors. Our results suggest that T. cruzi antigens can evoke an integrated antitumor response involving both the cellular and humoral components of the immune response and provide novel insights into the understanding of the intricate relationship between parasite infection and tumor growth.

  5. Differential expression of nanog1 and nanogp8 in colon cancer cells

    SciTech Connect

    Ishiguro, Tatsuya; Sato, Ai; Ohata, Hirokazu; Sakai, Hiroaki; Nakagama, Hitoshi; Okamoto, Koji

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Nanog is expressed in a majority of colon cancer cell lines examined. Black-Right-Pointing-Pointer Both nanog1 and nanogp8 are expressed in colon cancer cells with varying ratios. Black-Right-Pointing-Pointer Nanog mediates cell proliferation of colon cancer cells. Black-Right-Pointing-Pointer Nanog predominantly localizes in cytoplasm of colon cancer cells. -- Abstract: Nanog, a homeodomain transcription factor, is an essential regulator for promotion of self-renewal of embryonic stem cells and inhibition of their differentiation. It has been demonstrated that nanog1 as well as nanogp8, a retrogene of nanog1, is preferentially expressed in advanced stages of several types of cancer, suggesting their involvement during cancer progression. Here, we investigated the expression of Nanog in well-characterized colon cancer cell lines. Expression of Nanog was detectable in 5 (HCT116, HT29, RKO, SW48, SW620) out of seven cell lines examined. RNA expression analyses of nanog1 and nanogp8 indicated that, while nanog1 was a major form in SW620 as well as in teratoma cells Tera-2, nanogp8 was preferentially expressed in HT29 and HCT116. In accordance with this, shRNA-mediated knockdown of nanog1 caused the reduction of Nanog in SW620 but not in HT29. Inhibition of Nanog in SW620 cells negatively affected cell proliferation and tumor formation in mouse xenograft. Biochemical subcellular fractionation and immunostaining analyses revealed predominant localization of Nanog in cytoplasm in SW620 and HT29, while it was mainly localized in nucleus in Tera-2. Our data indicate that nanog1 and nanogp8 are differentially expressed in colon cancer cells, and suggest that their expression contributes to proliferation of colon cancer cells.

  6. Variability in the lymph node retrieval after resection of colon cancer

    PubMed Central

    Choi, Jung Pil; Park, In Ja; Lee, Byung Cheol; Hong, Seung Mo; Lee, Jong Lyul; Yoon, Yong Sik; Kim, Chan Wook; Lim, Seok-Byung; Lee, Jung Bok; Yu, Chang Sik; Kim, Jin Cheon

    2016-01-01

    Abstract The purpose of this study was to evaluate variations in the number of retrieved lymph nodes (LNs) over time and to determine the factors that influence the retrieval of <12 LNs during colon cancer resection. Patients with colon cancer who were surgically treated between 1997 and 2013 were identified from our institutional tumor registry. Patient, tumor, and pathologic variables were evaluated. Factors that influenced the retrieval of <12 LNs were evaluated using multivariate logistic regression modeling, including time effects. In total, 6967 patients were identified. The median patient age was 61 years (interquartile range [IQR] = 45–79 years) and 58.4% of these patients were male. The median number of LNs retrieved was 21 (IQR = 14–29), which increased from 14 (IQR = 11–27) in 1997 to 26 (IQR = 19–34) in 2013. The proportion of patients with ≥12 retrieved LNs increased from 72% in 1997 to 98.8% in 2013 (P < 0.00001). This corresponded to the more recent emphasis on a multidisciplinary approach to adequate LN evaluation. The number of retrieved LNs was also found to be associated with age, sex, tumor location, T stage, and operative year. Tumor location and T stage influenced the number of retrieved LNs, irrespective of the operative year (P < 0.05). Factors including a tumor location in the sigmoid/left colon, old age, open resection, earlier operative year, and early T stage were more likely to be associated with <12 recovered LNs (P < 0.5; chi-squared test) (P < 0.001). The total number of retrieved LNs may be influenced by tumor location and T stage of a colon cancer, irrespective of the year of surgery. LN retrieval after colon cancer resection has increased in recent years due to a better awareness of its importance and the use of multidisciplinary approaches. PMID:27495024

  7. MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL.

    PubMed

    Baraniskin, Alexander; Birkenkamp-Demtroder, Karin; Maghnouj, Abdelouahid; Zöllner, Hannah; Munding, Johanna; Klein-Scory, Susanne; Reinacher-Schick, Anke; Schwarte-Waldhoff, Irmgard; Schmiegel, Wolff; Hahn, Stephan A

    2012-04-01

    MicroRNAs (miRNAs) are small non-coding RNAs that are involved in different biological processes by suppressing target gene expression. Altered expression of miR-30a-5p has been reported in colon carcinoma. To elucidate its potential biological role in colon cancer, miR-30a-5p was overexpressed via a lentiviral vector system in two different colon cancer cell lines. This induced in both lines miR-30a-5p-mediated growth inhibition, attributable to a cell cycle arrest at the G(1) phase and an induction of apoptosis. Combining global gene expression analyses of miR-30a-5p transgenic line HCT116 with in silico miRNA target prediction, we identified the denticleless protein homolog (DTL) as a potential miRNA-30a-5p target. Subsequent reporter gene assays confirmed the predicted miR-30a-5p binding site in the 3'untranslated region of DTL. Importantly, overexpression of DTL in HCT116 cells partially rescued these cells from miR-30a-5p-mediated growth suppression. In addition, TP53 and CDKN1A expression were increased in miR-30a-5p-overexpressing HCT116 cells, suggesting that miR-30a-5p is able to modulate the cell cycle via a DTL-TP53-CDKN1A regulatory circuit. Finally, 379 colorectal cancer tissues were screened for DTL expression and DTL was found to be overexpressed in 95.8% of human colorectal cancers compared with normal colon mucosa. In conclusion, our data identified miR-30a-5p as a tumor-suppressing miRNA in colon cancer cells exerting its function via modulation of DTL expression, which is frequently overexpressed in colorectal cancer. Thus, our data suggest that restoring miR-30a-5p function may prove useful as therapeutic strategy for tumors with reduced miR-30a-5p expression.

  8. LINE-1 hypomethylation in normal colon mucosa is associated with poor survival in Chinese patients with sporadic colon cancer

    PubMed Central

    Wu, Yuchen; Li, Yiwei; Nie, Jia; Li, Dawei; Peng, Junjie; Lian, Peng; Li, Bin; Cai, Guoxiang; Li, Xinxiang; Cai, Sanjun

    2015-01-01

    Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients' colon cancer-specific survival (CCSS). Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3–85) months. A mean LINE-1 methylation rate of 64.62% (range, 9.45–86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity at 18q. The LINE-1 methylation level, MSI status, perineural invasion and distant metastases were confirmed as independent prognostic factors for patient CCSS. A stratified survival analysis further revealed that certain subgroups of patients with LINE-1 hypomethylation had significantly worse survival (all p < 0.05). Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer. PMID:26172297

  9. LINE-1 hypomethylation in normal colon mucosa is associated with poor survival in Chinese patients with sporadic colon cancer.

    PubMed

    Zhuo, Changhua; Li, Qingguo; Wu, Yuchen; Li, Yiwei; Nie, Jia; Li, Dawei; Peng, Junjie; Lian, Peng; Li, Bin; Cai, Guoxiang; Li, Xinxiang; Cai, Sanjun

    2015-09-15

    Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients' colon cancer-specific survival (CCSS). Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3-85) months. A mean LINE-1 methylation rate of 64.62% (range, 9.45-86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity at 18q. The LINE-1 methylation level, MSI status, perineural invasion and distant metastases were confirmed as independent prognostic factors for patient CCSS. A stratified survival analysis further revealed that certain subgroups of patients with LINE-1 hypomethylation had significantly worse survival (all p < 0.05). Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer. PMID:26172297

  10. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer.

    PubMed

    Slattery, M L; Potter, J D; Samowitz, W; Schaffer, D; Leppert, M

    1999-06-01

    Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12. PMID:10385141

  11. HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation

    SciTech Connect

    Al-Haidari, Amr A.; Syk, Ingvar; Thorlacius, Henrik

    2014-03-28

    Highlights: • Simvastatin blocked CCL17-induced and CCR4-dependent RhoA activation in HT29 cells. • CCL17/CCR4-mediated migration of colon cancer cells was antagonised by simvastatin. • Cell migration recovered by adding Mevalonate and geranylgeranyl pyrophosphate. • Targeting HMG-CoA reductase might be useful to inhibit colon cancer metastasis. - Abstract: Background: Simvastatin is widely used to lower cholesterol levels in patients with cardiovascular diseases, although accumulating evidence suggests that statins, such as simvastatin, also exert numerous anti-tumoral effects. Aim: The aim of this study was to examine the effect of simvastatin on colon cancer cell migration. Methods: Migration assays were performed to evaluate CCL17-induced colon cancer cell (HT-29) chemotaxis. In vitro tumor growth and apoptosis were assessed using a proliferation assay and annexin V assay, respectively. Active RhoA protein levels in CCL17-stimulated colon cancer cells were quantified using a G-LISA assay. Results: We found that simvastatin dose-dependently decreased CCL17-induced colon cancer cell migration. Simvastatin had no effect on colon cancer cell proliferation or apoptosis. Inhibition of beta chemokine receptor 4, CCR4, reduced CCL17-evoked activation of RhoA in colon cancer cells. Moreover, administration of mevalonate reversed the inhibitory effect of simvastatin on CCL17-induced colon cancer cell migration. Interestingly, co-incubation with geranylgeranyl pyrophosphate (GGPP) antagonized the inhibitory impact of simvastatin on colon cancer cell migration triggered by CCL17. Moreover, we observed that simvastatin decreased CCL17-induced activation of RhoA in colon cancer cells. Administration of mevalonate and GGPP reversed the inhibitory effect of simvastatin on CCL17-provoked RhoA activation in colon cancer cells. Conclusions: Taken together, our findings show for the first time that HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via

  12. Isolated metachronous splenic metastasis from synchronous colon cancer

    PubMed Central

    Gencosmanoglu, Rasim; Aker, Fugen; Kir, Gozde; Tozun, Nurdan

    2006-01-01

    Background Isolated splenic metastases from colorectal cancer are very rare and there are only 13 cases reported in the English literature so far. Most cases are asymptomatic and the diagnosis is usually made by imaging studies during the evaluation of rising CEA level postoperatively. Case presentation A 76-year-old man underwent an extended left hemicolectomy for synchronous colon cancers located at the left flexure and the sigmoid colon. The tumors were staged as IIIC (T3N2M0) clinically and the patient received adjuvant chemotherapy. During the first year follow-up period, the patient remained asymptomatic with normal levels of laboratory tests including CEA measurement. However, a gradually rising CEA level after the 14th postoperative month necessitated further imaging studies including computed tomography of the abdomen which revealed a mass in the spleen that was subsequently confirmed by 18FDG- PET scanning to be an isolated metastasis. The patient underwent splenectomy 17 months after his previous cancer surgery. Histological diagnosis confirmed a metastatic adenocarcinoma with no capsule invasion. After an uneventful postoperative period, the patient has been symptom-free during the one-year of follow-up with normal blood CEA levels, although he did not accept to receive any further adjuvant therapy. To the best of our knowledge, this 14th case of isolated splenic metastasis from colorectal carcinoma is also the first reported case of splenic metastasis demonstrated preoperatively by 18FDG PET-CT fusion scanning which revealed its solitary nature as well. Conclusion Isolated splenic metastasis is a rare finding in the follow-up of colorectal cancer patients and long-term survival can be achieved with splenectomy. PMID:16824207

  13. Vertebral Metastasis as the Initial Manifestation of Colon Cancer

    PubMed Central

    Jain, Tushina; Williams, Renee; Liechty, Benjamin

    2016-01-01

    Oncology guidelines currently recommend against performing colonoscopies in the workup of adenocarcinoma of unknown primary unless colonic malignancy is otherwise suggested by clinical signs or symptoms. We present 2 cases of metastatic colonic adenocarcinoma that presented only with neurologic symptoms from vertebral metastasis. Although bony metastases are a rare presentation of colon cancer and colonoscopy is not warranted in the initial workup of adenocarcinoma of unknown primary, we describe these cases as a reminder that bony metastases do not rule out a colon cancer diagnosis. PMID:27807574

  14. Cancers of the colon and rectum: identical or fraternal twins?

    PubMed

    Hong, Theodore S; Clark, Jeffrey W; Haigis, Kevin M

    2012-02-01

    Colorectal cancer represents a major cause of cancer morbidity and mortality, with approximately 1.2 million cases and 600,000 deaths worldwide each year. Because of the anatomic continuity of the colon into the rectum, cancers affecting these organs have historically been considered equivalent. In this Prospective, we discuss the clinical and experimental data suggesting that colon cancer and rectal cancer are highly related, but distinct, diseases. Reconsidering the relationship between these cancers has implications for the development of new therapeutic paradigms. PMID:22585856

  15. A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy

    PubMed Central

    Sánchez-Martínez, Ruth; Álvarez-Fernández, Mónica; Vargas, Teodoro; Molina, Susana; García, Belén; Herranz, Jesús; Moreno-Rubio, Juan; Reglero, Guillermo; Pérez-Moreno, Mirna; Feliu, Jaime; Malumbres, Marcos; de Molina, Ana Ramírez

    2015-01-01

    The alterations in carbohydrate metabolism that fuel tumor growth have been extensively studied. However, other metabolic pathways involved in malignant progression, demand further understanding. Here we describe a metabolic acyl-CoA synthetase/stearoyl-CoA desaturase ACSL/SCD network causing an epithelial-mesenchymal transition (EMT) program that promotes migration and invasion of colon cancer cells. The mesenchymal phenotype produced upon overexpression of these enzymes is reverted through reactivation of AMPK signaling. Furthermore, this network expression correlates with poorer clinical outcome of stage-II colon cancer patients. Finally, combined treatment with chemical inhibitors of ACSL/SCD selectively decreases cancer cell viability without reducing normal cells viability. Thus, ACSL/SCD network stimulates colon cancer progression through conferring increased energetic capacity and invasive and migratory properties to cancer cells, and might represent a new therapeutic opportunity for colon cancer treatment. PMID:26451612

  16. Aesculetin suppresses proliferation of human colon cancer cells by directly targeting β-catenin

    PubMed Central

    Lee, Sung-Young; Lim, Tae-Gyu; Chen, Hanyong; Jung, Sung Keun; Lee, Hyo-Jeong; Lee, Mee-Hyun; Kim, Dong Joon; Shin, Aram; Lee, Ki Won; Bode, Ann M.; Surh, Young-Joon; Dong, Zigang

    2013-01-01

    The Wnt pathway is a promising therapeutic and preventive target in various human cancers. The transcriptional complex of β-catenin/Tcf, a key mediator of canonical Wnt signaling, has been implicated in human colon cancer development. Current treatment of colon cancer depends on traditional cytotoxic agents with limited effects. Therefore, the identification of natural compounds that can disrupt the β–catenin/TcF complex to suppress cancer cell growth with fewer adverse side effects is needed. To identify compounds that inhibit the association between β-catenin and Tcf, we used computer docking to screen a natural compound library. Aesculetin, also known as 6,7-dihydroxycoumarin, is a derivative of coumarin and was identified as a potential small molecule inhibitor of the Wnt/β-catenin pathway. We then evaluated the effect of aesculetin on the growth of various human colon cancer cell lines and its effect on Wnt/β-catenin signaling in cells and in an embryonic model. Aesculetin disrupted the formation of the β-catenin/Tcf complex through direct binding with the Lys312, Gly307, Lys345 and Asn387 residues of β-catenin in colon cancer cells. Additionally, aesculetin effectively decreased viability and inhibited anchorage-independent growth of colon cancer cells. Aesculetin potently antagonized the cellular effects of β-catenin-dependent activity and in vivo treatment with aesculetin suppressed tumor growth in a colon cancer xenograft mouse model. Our data indicate that the interaction between aesculetin and β-catenin inhibits the formation of the β-catenin/Tcf complex, which could contribute to aesculetin’s positive therapeutic and preventive effects against colon carcinogenesis. PMID:24104353

  17. Upregulation of activin A gene by butyrate in human colon cancer cell lines.

    PubMed

    Sonoyama, Kei; Pholnukulkit, Pimara; Toyoda, Masahiko; Rutatip, Suriya; Kasai, Takanori

    2003-06-01

    Activin A has been reported to play a role in the progression of colorectal cancer. Because dietary fiber protects against colorectal cancer, we hypothesized that butyrate, a fermentation product of dietary fiber, may affect the expression of activin A in colon cancer cells. Semiquantitative RT-PCR demonstrated that the activin A gene was upregulated by sodium butyrate in the human colon cancer cell lines HT-29 and Caco-2 in a concentration- and time-dependent manner. However, the activin A gene did not respond to sodium butyrate in the human normal colonic cell line FHC, rat normal intestinal epithelial cell (IEC) line IEC-6, and the explant of rat colon. Flow cytometry and agarose gel electrophoresis of genomic DNA revealed that cell cycle arrest and apoptosis were induced by sodium butyrate but not exogenous activin A in HT-29 cells, indicating that activin A could not act as an autocrine factor in colon cancer cells. By assuming that activin A promotes colorectal cancer spread as a paracrine factor, our findings suggest that butyrate could act as a tumor promoter in some circumstances.

  18. Colon tumors with the simultaneous induction of driver mutations in APC, KRAS, and PIK3CA still progress through the adenoma-to-carcinoma sequence

    PubMed Central

    Hadac, Jamie N.; Leystra, Alyssa A.; Olson, Terrah J. Paul; Maher, Molly E.; Payne, Susan N; Yueh, Alexander E.; Schwartz, Alexander R.; Albrecht, Dawn M.; Clipson, Linda; Pasch, Cheri A.; Matkowskyj, Kristina A.; Halberg, Richard B.; Deming, Dustin A.

    2015-01-01

    Human colorectal cancers often possess multiple mutations, including 3–6 driver mutations per tumor. The timing of when these mutations occur during tumor development and progression continues to be debated. More advanced lesions carry a greater number of driver mutations, indicating that colon tumors might progress from adenomas to carcinomas through the stepwise accumulation of mutations following tumor initiation. However, mutations that have been implicated in tumor progression have been identified in normal-appearing epithelial cells of the colon, leaving the possibility that these mutations might be present prior to the initiation of tumorigenesis. We utilized mouse models of colon cancer to investigate whether tumorigenesis still occurs through the adenoma-to-carcinoma sequence when multiple mutations are present at the time of tumor initiation. To create a model in which tumors could concomitantly possess mutations in Apc, Kras, and Pik3ca, we developed a novel minimally invasive technique to administer an adenovirus expressing Cre recombinase to a focal region of the colon. Here we demonstrate that the presence of these additional driver mutations at the time of tumor initiation results in increased tumor multiplicity and an increased rate of progression to invasive adenocarcinomas. These cancers can even metastasize to retroperitoneal lymph nodes or the liver. However, despite having as many as three concomitant driver mutations at the time of initiation, these tumors still proceed through the adenoma-to-carcinoma sequence. PMID:26276752

  19. Withaferin-A Inhibits Colon Cancer Cell Growth by Blocking STAT3 Transcriptional Activity

    PubMed Central

    Choi, Bu Young; Kim, Bong-Woo

    2015-01-01

    Background: Withania somnifera (known as Ashwagandha) is a medicinal plant used in the ayurvedic medicines in India. Withaferin-A, a withanolide derived from the leaf extract of W. somnifera, has been reported to exhibit anti-tumor activity against various cancer cells, such as leukemia, breast cancer and colon cancer cells. Methods: We investigated the anti-cancer effects of withaferin-A on the proliferation and migration of human colorectal cancer (HCT116) cells. And we evaluated the effects of withaferin-A on the transcriptional activity of STAT3 and the growth of HCT116 cells in xenograft mouse tumor model. Results: In the present study, we found that withaferin-A inhibited the proliferation and migration of HCT116 cells in a concentration-dependent manner. Treatment of HCT116 cells with withaferin-A attenuated interleukin-6-induced activation of STAT3, which has been implicated in the development and progression of colon cancer. To examine the effect of withaferin-A on HCT116 cells proliferation in vivo, we generated HCT116 cells xenograft tumors in Balb/c nude mice and treated the tumor bearing mice with or without withaferin-A intraperitoneally. Treatment with withaferin-A exhibited significant decrease in the volume and weight of tumors as compared to untreated controls. Conclusions: The present study suggests that withaferin-A holds the potential to be developed as a small molecule inhibitor of STAT3 for the treatment of HCT116. PMID:26473157

  20. Association of Global DNA Hypomethylation with Clinicopathological Variables in Colonic Tumors of Iraqi Patients

    PubMed Central

    Qasim, Ban J.; Al-Wasiti, Estabraq A.; Azzal, Hayder S.

    2016-01-01

    Background/Aim: Colorectal cancer (CRC) ranks sixth among the most common 10 cancers in Iraq. It is a foremost public health dilemma and there is improved interest in understanding the fundamental principles of its molecular biology. DNA methylation in cancer has become the issue of passionate investigation. As compared with normal cells, the malignant cells show major disruptions in their DNA methylation patterns. We aimed to assess the association of global DNA hypomethylation in colonic adenomas and carcinomas of Iraqi patients, measured by immunohistochemistry of 5-methylcytosin, with different clinicopathological variables. Patients and Methods: Thirty tissue paraffin blocks from patients with colorectal adenomas, 30 tissue paraffin blocks from patients with colorectal adenocarcinomas, and 30 samples of apparently normal colonic tissue taken from autopsy cases as a control group were included in the present study. From each block, two sections of 5 μm thickness were taken, one section was stained with Hematoxylin and Eosin for revision of histopathological diagnosis and one section was immunohistochemically stained for 5-methylcytosine (5mC) and digitally analyzed by AperioImageScope software. Results: The mean digital value of 5mC immunohistochemical expression was sequentially decreased during neoplastic progression from normal colonic tissue into adenoma and then to carcinoma. The mean digital value of 5mC expression was significantly lower in large size adenomas (≥1 cm), and those with severe dysplasia. Concerning carcinoma cases, 5mC expression was significantly lower in stage C2. Conclusions: The immunohistochemical evaluation of 5mC yields refined information on colorectal tumor biology in adenoma and carcinoma. Global DNA hypomethylation reflected by low immunohistochemical expression of 5-mC is associated with advanced colorectal adenomatous polyps suggesting that it is an early event in colorectal carcinogenesis. Also this hypomethylation can

  1. Chemopreventive effect of apple and berry fruits against colon cancer

    PubMed Central

    Jaganathan, Saravana Kumar; Vellayappan, Muthu Vignesh; Narasimhan, Gayathri; Supriyanto, Eko; Octorina Dewi, Dyah Ekashanti; Narayanan, Aqilah Leela T; Balaji, Arunpandian; Subramanian, Aruna Priyadarshini; Yusof, Mustafa

    2014-01-01

    Colon cancer arises due to the conversion of precancerous polyps (benign) found in the inner lining of the colon. Prevention is better than cure, and this is very true with respect to colon cancer. Various epidemiologic studies have linked colorectal cancer with food intake. Apple and berry juices are widely consumed among various ethnicities because of their nutritious values. In this review article, chemopreventive effects of these fruit juices against colon cancer are discussed. Studies dealing with bioavailability, in vitro and in vivo effects of apple and berry juices are emphasized in this article. A thorough literature survey indicated that various phenolic phytochemicals present in these fruit juices have the innate potential to inhibit colon cancer cell lines. This review proposes the need for more preclinical evidence for the effects of fruit juices against different colon cancer cells, and also strives to facilitate clinical studies using these juices in humans in large trials. The conclusion of the review is that these apple and berry juices will be possible candidates in the campaign against colon cancer. PMID:25493015

  2. Chemopreventive effect of apple and berry fruits against colon cancer.

    PubMed

    Jaganathan, Saravana Kumar; Vellayappan, Muthu Vignesh; Narasimhan, Gayathri; Supriyanto, Eko; Octorina Dewi, Dyah Ekashanti; Narayanan, Aqilah Leela T; Balaji, Arunpandian; Subramanian, Aruna Priyadarshini; Yusof, Mustafa

    2014-12-01

    Colon cancer arises due to the conversion of precancerous polyps (benign) found in the inner lining of the colon. Prevention is better than cure, and this is very true with respect to colon cancer. Various epidemiologic studies have linked colorectal cancer with food intake. Apple and berry juices are widely consumed among various ethnicities because of their nutritious values. In this review article, chemopreventive effects of these fruit juices against colon cancer are discussed. Studies dealing with bioavailability, in vitro and in vivo effects of apple and berry juices are emphasized in this article. A thorough literature survey indicated that various phenolic phytochemicals present in these fruit juices have the innate potential to inhibit colon cancer cell lines. This review proposes the need for more preclinical evidence for the effects of fruit juices against different colon cancer cells, and also strives to facilitate clinical studies using these juices in humans in large trials. The conclusion of the review is that these apple and berry juices will be possible candidates in the campaign against colon cancer.

  3. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.

    PubMed

    Keerthivasan, Shilpa; Aghajani, Katayoun; Dose, Marei; Molinero, Luciana; Khan, Mohammad W; Venkateswaran, Vysak; Weber, Christopher; Emmanuel, Akinola Olumide; Sun, Tianjao; Bentrem, David J; Mulcahy, Mary; Keshavarzian, Ali; Ramos, Elena M; Blatner, Nichole; Khazaie, Khashayarsha; Gounari, Fotini

    2014-02-26

    The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/β-catenin signaling in T cells promotes expression of RORγt. Expression of β-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/β-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.

  4. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.

    PubMed

    Keerthivasan, Shilpa; Aghajani, Katayoun; Dose, Marei; Molinero, Luciana; Khan, Mohammad W; Venkateswaran, Vysak; Weber, Christopher; Emmanuel, Akinola Olumide; Sun, Tianjao; Bentrem, David J; Mulcahy, Mary; Keshavarzian, Ali; Ramos, Elena M; Blatner, Nichole; Khazaie, Khashayarsha; Gounari, Fotini

    2014-02-26

    The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/β-catenin signaling in T cells promotes expression of RORγt. Expression of β-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/β-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer. PMID:24574339

  5. Antitumor effects of calgranulin B internalized in human colon cancer cells

    PubMed Central

    Yoo, Byong Chul; Ku, Ja-Lok; Shin, Young-Kyoung; Cho, Jae Youl; Kim, Minjae; Kwon, Myung-Hee; Goh, Sung Ho; Chang, Hee Jin; Oh, Jae Hwan

    2016-01-01

    Calgranulin B is a small, calcium-binding protein expressed in neutrophils that is secreted into the tumor microenvironment in cancer cases. We previously showed that calgranulin B levels are increased in the stools of colorectal cancer patients. In patient tumor tissues, calgranulin B protein levels correlated with the presence of stromal inflammatory cells surrounding tumor cells, and calgranulin B promoter methylation was observed in both paired human tissues and colon cancer cell lines. Cell lines did not express calgranulin B, but in vitro studies showed that colon cancer cells internalized extracellular calgranulin B, while other types of cancer cells did not. Calgranulin B internalization led to reduced cell proliferation and increased apoptotic cell death. AKT and ERK signals were also increased after calgranulin B treatment, as were p53, β-catenin, E-cadherin and cleaved caspase-3 levels. Additionally, a human protein microarray identified aurora A kinase as a calgranulin B binding partner, and binding inhibited aurora A kinase activity in a dose-dependent manner. Our findings demonstrate the antitumor effects of calgranulin B in the inflammatory microenvironment and suggest that calgranulin B could be potentially efficacious in the treatment of colon cancer. PMID:26933915

  6. Possible mechanisms by which pro- and prebiotics influence colon carcinogenesis and tumor growth.

    PubMed

    Reddy, B S

    1999-07-01

    Oligofructose and inulin, selective fermentable chicory fructans, have been shown to stimulate the growth of bifidobacteria, which are regarded as beneficial strains in the colon. Studies were designed to evaluate inulin (Raftiline) and oligofructose (Raftilose) for their potential inhibitory properties against the development of colonic aberrant crypt foci (ACF) in rats. ACF are putative preneoplastic lesions from which adenomas and carcinomas may develop in the colon. The results of this study indicate that dietary administration of oligofructose and inulin inhibits the development of ACF in the colon, suggesting the potential colon tumor inhibitory properties of chicory fructans. The degree of ACF inhibition was more pronounced in animals given inulin than in those fed oligofructose. Because these prebiotics selectively stimulate the growth of bifidobacteria, ornithine decarboxylase (ODC) activities, ras-p21 ontoprotein expressions and tumor inhibitory activity of lyophilized cultures of Bifidobacterium longum against chemically induced colon and mammary carcinogenesis and against colonic tumor cell proliferation were examined. Dietary administration of lyophilized cultures of B. longum strongly suppressed colon and mammary tumor development and tumor burden. Inhibition of colon carcinogenesis was associated with a decrease in colonic mucosal cell proliferation and activities of colonic mucosal and tumor ornithine decarboxylase and ras-p21. Human clinical trials are likely to broaden our insight into the importance of the pre- and probiotics in health and disease.

  7. A simple, quantitative method using alginate gel to determine rat colonic tumor volume in vivo.

    PubMed

    Irving, Amy A; Young, Lindsay B; Pleiman, Jennifer K; Konrath, Michael J; Marzella, Blake; Nonte, Michael; Cacciatore, Justin; Ford, Madeline R; Clipson, Linda; Amos-Landgraf, James M; Dove, William F

    2014-04-01

    Many studies of the response of colonic tumors to therapeutics use tumor multiplicity as the endpoint to determine the effectiveness of the agent. These studies can be greatly enhanced by accurate measurements of tumor volume. Here we present a quantitative method to easily and accurately determine colonic tumor volume. This approach uses a biocompatible alginate to create a negative mold of a tumor-bearing colon; this mold is then used to make positive casts of dental stone that replicate the shape of each original tumor. The weight of the dental stone cast correlates highly with the weight of the dissected tumors. After refinement of the technique, overall error in tumor volume was 16.9% ± 7.9% and includes error from both the alginate and dental stone procedures. Because this technique is limited to molding of tumors in the colon, we utilized the Apc(Pirc/+) rat, which has a propensity for developing colonic tumors that reflect the location of the majority of human intestinal tumors. We have successfully used the described method to determine tumor volumes ranging from 4 to 196 mm³. Alginate molding combined with dental stone casting is a facile method for determining tumor volume in vivo without costly equipment or knowledge of analytic software. This broadly accessible method creates the opportunity to objectively study colonic tumors over time in living animals in conjunction with other experiments and without transferring animals from the facility where they are maintained.

  8. A Simple, Quantitative Method Using Alginate Gel to Determine Rat Colonic Tumor Volume In Vivo

    PubMed Central

    Irving, Amy A; Young, Lindsay B; Pleiman, Jennifer K; Konrath, Michael J; Marzella, Blake; Nonte, Michael; Cacciatore, Justin; Ford, Madeline R; Clipson, Linda; Amos-Landgraf, James M; Dove, William F

    2014-01-01

    Many studies of the response of colonic tumors to therapeutics use tumor multiplicity as the endpoint to determine the effectiveness of the agent. These studies can be greatly enhanced by accurate measurements of tumor volume. Here we present a quantitative method to easily and accurately determine colonic tumor volume. This approach uses a biocompatible alginate to create a negative mold of a tumor-bearing colon; this mold is then used to make positive casts of dental stone that replicate the shape of each original tumor. The weight of the dental stone cast correlates highly with the weight of the dissected tumors. After refinement of the technique, overall error in tumor volume was 16.9% ± 7.9% and includes error from both the alginate and dental stone procedures. Because this technique is limited to molding of tumors in the colon, we utilized the ApcPirc/+ rat, which has a propensity for developing colonic tumors that reflect the location of the majority of human intestinal tumors. We have successfully used the described method to determine tumor volumes ranging from 4 to 196 mm3. Alginate molding combined with dental stone casting is a facile method for determining tumor volume in vivo without costly equipment or knowledge of analytic software. This broadly accessible method creates the opportunity to objectively study colonic tumors over time in living animals in conjunction with other experiments and without transferring animals from the facility where they are maintained. PMID:24674588

  9. Proteogenomic characterization of human colon and rectal cancer

    PubMed Central

    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 R.; Wang, Sean; Wang, Pei; Kinsinger, Christopher R.; Rivers, Robert C.; Rodriguez, Henry; Townsend, R. Reid; Ellis, Matthew J.C.; Carr, Steven A.; Tabb, David L.; Coffey, Robert J.; Slebos, Robbert J.C.; Liebler, Daniel C.

    2014-01-01

    Summary We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. mRNA transcript abundance did not reliably predict protein abundance differences between tumors. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA “MSI/CIMP” transcriptomic subtype, but had distinct mutation, methylation, and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates including HNF4A, TOMM34 and SRC. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology. PMID:25043054

  10. [A CASE OF ASCENDING COLON CANCER RECURRENCE WITH INTRALUMINAL URETERAL DISSEMINATION MIMICKING PRIMARY URETERAL CANCER, DETECTED DURING INVESTIGATION FOR FEVER].

    PubMed

    Nishiyama, Ryuichi; Kubota, Masashi; Kanno, Toru; Okada, Takashi; Higashi, Yoshihito; Yamada, Hitoshi

    2015-10-01

    A 69-year-old woman visited our hospital with a chief complaint of fever. Five years ago, she was diagnosed as ascending colon cancer and received right hemi-colectomy. One year later, local recurrence with right hydronephrosis was detected, and she received chemotherapy -4 cycles of modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus bevacizumab, and 12 cycles of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab- for two years. Local recurrence and right hydronephrosis disappeared on positron emission tomography performed 4 years postoperatively. This time, abdominal computed tomography for investigation of fever showed a relapse of right hydronephrosis and pyonephrosis. Cystoscopy revealed non-papillary tumor from the right ureteral orifice. Pelvic magnetic resonance imaging showed multiple tumors in the right ureter, and the distal lesion projecting into the bladder. After the general condition became well by right nephrostomy for infection control, transurethral resection of bladder tumor was performed. Histological examination of the specimen revealed a metastatic tubular adenocarcinoma (colon origin). Although right nephrectomy was performed for pyonephrosis control, she died of local progression of ascending colon cancer 10 months after first visit. Intraluminal ureteral progression of carcinoma originating from organs other than urinary tract is very rare. To our knowledge, this is the 9th report in the English or Japanese literature. In this case we could not rule out primary ureteral cancer preoperatively, and histological examination revealed intraluminal ureteral dissemination of ascending colon cancer.

  11. PGE{sub 2}-induced colon cancer growth is mediated by mTORC1

    SciTech Connect

    Dufour, Marc Faes, Seraina Dormond-Meuwly, Anne Demartines, Nicolas Dormond, Olivier

    2014-09-05

    Highlights: • PGE{sub 2} activates mTORC1 in colon cancer cells. • Inhibition of mTORC1 blocks PGE{sub 2} induced colon cancer cell growth. • mTORC1 is a signaling intermediary in PGE{sub 2} induced colon cancer cell responses. - Abstract: The inflammatory prostaglandin E{sub 2} (PGE{sub 2}) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE{sub 2} directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE{sub 2}-induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE{sub 2} increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE{sub 2} EP{sub 4} receptor was responsible for transducing the signal to mTORC1. Moreover, PGE{sub 2} increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE{sub 2}-induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE{sub 2} increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE{sub 2} mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth.

  12. Thyroid, Renal, and Breast Carcinomas, Chondrosarcoma, Colon Adenomas, and Ganglioneuroma: A New Cancer Syndrome, FAP, or Just Coincidence.

    PubMed

    Atta, Ihab Shafek; AlQahtani, Fahd Nasser

    2016-01-01

    We are presenting a case associated with papillary thyroid carcinoma, renal cell carcinoma, invasive mammary carcinoma, chondrosarcoma, benign ganglioneuroma, and numerous colon adenomas. The patient had a family history of colon cancer, kidney and bladder cancers, lung cancer, thyroid cancer, leukemia, and throat and mouth cancers. She was diagnosed with colonic villous adenoma at the age of 41 followed by thyroid, renal, and breast cancers and chondrosarcoma at the ages of 48, 64, 71, and 74, respectively. Additionally, we included a table with the most common familial cancer syndromes with one or more benign or malignant tumors diagnosed in our case, namely, FAP, HNPCC, Cowden, Peutz-Jeghers, renal cancer, tuberous sclerosis, VHL, breast/other, breast/ovarian, Carney, Werner's, Bloom, Li-Fraumeni, xeroderma pigmentosum, ataxia-telangiectasia, osteochondromatosis, retinoblastoma, and MEN2A. PMID:27087812

  13. Thyroid, Renal, and Breast Carcinomas, Chondrosarcoma, Colon Adenomas, and Ganglioneuroma: A New Cancer Syndrome, FAP, or Just Coincidence

    PubMed Central

    Atta, Ihab Shafek; AlQahtani, Fahd Nasser

    2016-01-01

    We are presenting a case associated with papillary thyroid carcinoma, renal cell carcinoma, invasive mammary carcinoma, chondrosarcoma, benign ganglioneuroma, and numerous colon adenomas. The patient had a family history of colon cancer, kidney and bladder cancers, lung cancer, thyroid cancer, leukemia, and throat and mouth cancers. She was diagnosed with colonic villous adenoma at the age of 41 followed by thyroid, renal, and breast cancers and chondrosarcoma at the ages of 48, 64, 71, and 74, respectively. Additionally, we included a table with the most common familial cancer syndromes with one or more benign or malignant tumors diagnosed in our case, namely, FAP, HNPCC, Cowden, Peutz-Jeghers, renal cancer, tuberous sclerosis, VHL, breast/other, breast/ovarian, Carney, Werner's, Bloom, Li-Fraumeni, xeroderma pigmentosum, ataxia-telangiectasia, osteochondromatosis, retinoblastoma, and MEN2A. PMID:27087812

  14. Liver X receptor β activation induces pyroptosis of human and murine colon cancer cells

    PubMed Central

    Derangère, V; Chevriaux, A; Courtaut, F; Bruchard, M; Berger, H; Chalmin, F; Causse, S Z; Limagne, E; Végran, F; Ladoire, S; Simon, B; Boireau, W; Hichami, A; Apetoh, L; Mignot, G; Ghiringhelli, F; Rébé, C

    2014-01-01

    Liver X receptors (LXRs) have been proposed to have some anticancer properties, through molecular mechanisms that remain elusive. Here we report for the first time that LXR ligands induce caspase-1-dependent cell death of colon cancer cells. Caspase-1 activation requires Nod-like-receptor pyrin domain containing 3 (NLRP3) inflammasome and ATP-mediated P2 × 7 receptor activation. Surprisingly, LXRβ is mainly located in the cytoplasm and has a non-genomic role by interacting with pannexin 1 leading to ATP secretion. Finally, LXR ligands have an antitumoral effect in a mouse colon cancer model, dependent on the presence of LXRβ, pannexin 1, NLRP3 and caspase-1 within the tumor cells. Our results demonstrate that LXRβ, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis. PMID:25124554

  15. Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro.

    PubMed

    Yang, Zi-Rong; Liu, Meng; Peng, Xiu-Lan; Lei, Xiao-Fei; Zhang, Ji-Xiang; Dong, Wei-Guo

    2012-05-11

    Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC(50)=75 μM). This cytotoxicity was reflected by cell cycle arrest at G(2)/M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase-9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer. PMID:22546556

  16. PUMA mediates the combinational therapy of 5-FU and NVP-BEZ235 in colon cancer.

    PubMed

    Wang, Huanan; Zhang, Lingling; Yang, Xu; Jin, Yipeng; Pei, Shimin; Zhang, Di; Zhang, Hong; Zhou, Bin; Zhang, Yingjie; Lin, Degui

    2015-06-10

    Colon cancer is the third most common cancer in humans which has a high mortality rate, and 5-Fluorouracil (5-FU) is one of the most widely used drugs in colon cancer therapy. However, acquired chemoresistance is becoming the major challenges for patients, and the molecular mechanism underlying the development of 5-FU resistance is still poorly understood. In this study, a newly designed therapy in combination with 5-FU and NVP-BEZ235 in colon cancer cells (HCT-116 and RKO) was established, to investigate the mechanism of 5-FU resistance and optimize drug therapy to improve outcome for patients. Our results show 5-FU induced cell apoptosis through p53/PUMA pathway, with aberrant Akt activation, which may well explain the mechanism of 5-FU resistance. NVP-BEZ235 effectively up-regulated PUMA expression, mainly through inactivation of PI3K/Akt and activation of FOXO3a, leading to cell apoptosis even in the p53-/- HCT-116 cells. Combination treatment of 5-FU and NVP-BEZ235 further increased cell apoptosis in a PUMA/Bax dependent manner. Moreover, significantly enhanced anti-tumor effects were observed in combination treatment in vivo. Together, these results demonstrated that the combination treatment of 5-FU and NVP-BEZ235 caused PUMA-dependent tumor suppression both in vitro and in vivo, which may promise a more effective strategy for colon cancer therapy.

  17. MicroRNA Profiles Discriminate among Colon Cancer Metastasis

    PubMed Central

    Drusco, Alessandra; Nuovo, Gerard J.; Zanesi, Nicola; Di Leva, Gianpiero; Pichiorri, Flavia; Volinia, Stefano; Fernandez, Cecilia; Antenucci, Anna; Costinean, Stefan; Bottoni, Arianna; Rosito, Immacolata A.; Liu, Chang-Gong; Burch, Aaron; Acunzo, Mario; Pekarsky, Yuri; Alder, Hansjuerg; Ciardi, Antonio; Croce, Carlo M.

    2014-01-01

    MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC). In most cases, metastatic disease is difficult to predict and to prevent with adequate therapies. The aim of our study was to identify a microRNA signature for metastatic CRC that could predict and differentiate metastatic target organ localization. Normal and cancer tissues of three different groups of CRC patients were analyzed. RNA microarray and TaqMan Array analysis were performed on 66 Italian patients with or without lymph nodes and/or liver recurrences. Data obtained with the two assays were analyzed separately and then intersected to identify a primary CRC metastatic signature. Five differentially expressed microRNAs (hsa-miR-21, -103, -93, -31 and -566) were validated by qRT-PCR on a second group of 16 American metastatic patients. In situ hybridization was performed on the 16 American patients as well as on three distinct commercial tissues microarray (TMA) containing normal adjacent colon, the primary adenocarcinoma, normal and metastatic lymph nodes and liver. Hsa-miRNA-21, -93, and -103 upregulation together with hsa-miR-566 downregulation defined the CRC metastatic signature, while in situ hybridization data identified a lymphonodal invasion profile. We provided the first microRNAs signature that could discriminate between colorectal recurrences to lymph nodes and liver and between colorectal liver metastasis and primary hepatic tumor. PMID:24921248

  18. 5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits

    PubMed Central

    Calvani, Maura; Taddei, Maria Letizia; Giannoni, Elisa; Kopetz, Scott; Kazmi, Syed Mohammad Ali; Pia, Morelli Maria; Pettazzoni, Piergiorgio; Sacco, Elena; Caselli, Anna; Vanoni, Marco; Landriscina, Matteo; Cirri, Paolo; Chiarugi, Paola

    2015-01-01

    Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stem-like phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer. PMID:26527315

  19. The Homeobox Gene MEIS1 Is Methylated in BRAFp.V600E Mutated Colon Tumors

    PubMed Central

    Dihal, Ashwin A.; Boot, Arnoud; van Roon, Eddy H.; Schrumpf, Melanie; Fariña-Sarasqueta, Arantza; Fiocco, Marta; Zeestraten, Eliane C. M.; Kuppen, Peter J. K.; Morreau, Hans; van Wezel, Tom; Boer, Judith M.

    2013-01-01

    Development of colorectal cancer (CRC) can occur both via gene mutations in tumor suppressor genes and oncogenes, as well as via epigenetic changes, including DNA methylation. Site-specific methylation in CRC regulates expression of tumor-associated genes. Right-sided colon tumors more frequently have BRAFp.V600E mutations and have higher methylation grades when compared to left-sided malignancies. The aim of this study was to identify DNA methylation changes associated with BRAFp.V600E mutation status. We performed methylation profiling of colon tumor DNA, isolated from frozen sections enriched for epithelial cells by macro-dissection, and from paired healthy tissue. Single gene analyses comparing BRAFp.V600E with BRAF wild type revealed MEIS1 as the most significant differentially methylated gene (log2 fold change: 0.89, false discovery rate-adjusted P-value 2.8*10-9). This finding was validated by methylation-specific PCR that was concordant with the microarray data. Additionally, validation in an independent cohort (n=228) showed a significant association between BRAFp.V600E and MEIS1 methylation (OR: 13.0, 95% CI: 5.2 - 33.0, P<0.0001). MEIS1 methylation was associated with decreased MEIS1 gene expression in both patient samples and CRC cell lines. The same was true for gene expression of a truncated form of MEIS1, MEIS1D27, which misses exon 8 and has a proposed tumor suppression function. To trace the origin of MEIS1 promoter methylation, 14 colorectal tumors were flow-sorted. Four out of eight BRAFp.V600E tumor epithelial fractions (50%) showed MEIS1 promoter methylation, as well as three out of eight BRAFp.V600E stromal fractions (38%). Only one out of six BRAF wild type showed MEIS1 promoter methylation in both the epithelial tumor and stromal fractions (17%). In conclusion, BRAFp.V600E colon tumors showed significant MEIS1 promoter methylation, which was associated with decreased MEIS1 gene expression. PMID:24244575

  20. Prognostic impact of mutation profiling in patients with stage II and III colon cancer

    PubMed Central

    Shen, Yinchen; Han, Xiaohong; Wang, Jianfei; Wang, Shuai; Yang, Hongying; Lu, Shih-Hsin; Shi, Yuankai

    2016-01-01

    Development of colorectal cancer (CRC) associates with accumulation of genetic mutations include the epidermal growth factor receptor (EGFR) signaling pathway. However, whether mutations in KRAS together with downstream factors BRAF, PIK3CA and NRAS impact prognosis is still unclear for stage II-III colon cancer. In the present study a total of 228 stage II-III colon cancer samples were retrospectively collected, KRAS (codons 12, 13 and 61), BRAF (exon 11 and exon 15), PIK3CA (exon 9 and exon 20) and NRAS (codons 12, 13 and 61) status was detected by Sanger sequencing, 37.89% (86/227) tumors harbored a KRAS mutation, 7.02% (16/228) harbored a BRAF mutation, 13.18% (29/220) harbored a PIK3CA mutation and 0.89% (2/224) harbored a NRAS mutation. NRAS mutations existed only in stage II colon cancer. Older groups harbored a higher KRAS and BRAF mutation (P < 0.05), PIK3CA (exon9) mutations appeared more common in worse differentiation tumors (P = 0.032). Moreover, PIK3CA (E545K) mutation was significantly associated with tumor recurrence (P = 0.031) and acted independently prognostic for poor OS (P = 0.044), while only in stage III colon cancer. KRAS, BRAF and NRAS mutations do not have major prognostic value in stage II and III colon cancer, subtypes of gene mutations should be further investigated for a better understanding in CRC. PMID:27074743

  1. A transcriptional regulatory role of the THAP11-HCF-1 complex in colon cancer cell function.

    PubMed

    Parker, J Brandon; Palchaudhuri, Santanu; Yin, Hanwei; Wei, Jianjun; Chakravarti, Debabrata

    2012-05-01

    The recently identified Thanatos-associated protein (THAP) domain is an atypical zinc finger motif with sequence-specific DNA-binding activity. Emerging data suggest that THAP proteins may function in chromatin-dependent processes, including transcriptional regulation, but the roles of most THAP proteins in normal and aberrant cellular processes remain largely unknown. In this work, we identify THAP11 as a transcriptional regulator differentially expressed in human colon cancer. Immunohistochemical analysis of human colon cancers revealed increased THAP11 expression in both primary tumors and metastases. Knockdown of THAP11 in SW620 colon cancer cells resulted in a significant decrease in cell proliferation, and profiling of gene expression in these cells identified a novel gene set composed of 80 differentially expressed genes, 70% of which were derepressed by THAP11 knockdown. THAP11 was found to associate physically with the transcriptional coregulator HCF-1 (host cell factor 1) and recruit HCF-1 to target promoters. Importantly, THAP11-mediated gene regulation and its chromatin association require HCF-1, while HCF-1 recruitment at these genes requires THAP11. Collectively, these data provide the first characterization of THAP11-dependent gene expression in human colon cancer cells and suggest that the THAP11-HCF-1 complex may be an important transcriptional and cell growth regulator in human colon cancer. PMID:22371484

  2. Paraneoplastic Erythrocytosis of Colon Cancer, with Serum Erythropoietin within the Normal Reference Range

    PubMed Central

    Kitayama, Hiromitsu; Kondo, Tomohiro; Sugiyama, Junko; Hirayama, Michiaki; Oyamada, Yumiko; Tsuji, Yasushi

    2016-01-01

    Patient: Female, 75 Final Diagnosis: Erythropoietin-secreting colon cancer Symptoms: None Medication: — Clinical Procedure: Immunohistochemistry Specialty: Hematology Objective: Rare disease Background: Paraneoplastic erythrocytosis can be brought on by ectopic erythropoietin production usually in kidney, brain, and liver tumor with increase of serum erythropoietin level. We report here a paraneoplastic erythrocytosis of colon cancer with serum erythropoietin within the normal reference, which required an immunohistologic test for erythropoietin-antibody to be diagnosed. Case Report: Our case report was of a 75-year-old woman with erythrocytosis. Her hemoglobin and serum erythropoietin levels were 191 g/dL and 12.6 IU/L (reference range, 9.1–32.8), respectively. Colonoscopy revealed an advanced sigmoid colon tumor 20 mm in diameter. She underwent colectomy, and immunohistochemical examination showed the colon adenocarcinoma was focally positive for erythropoietin-antibody. One month after the surgery, her hemoglobin level decreased to 117 g/L. Conclusions: Colon cancer can cause paraneoplastic erythrocytosis, and it is important to consider not simply the absolute serum erythropoietin level but also the serum erythropoietin level relative to simultaneously measured hemoglobin level. We should include paraneoplastic erythrocytosis as a differential diagnosis in cases of high hemoglobin level unexplained by other diseases. PMID:27318703

  3. Cancer immunotherapy using tumor cryoablation.

    PubMed

    Sidana, Abhinav

    2014-01-01

    Cryoablation is increasingly being used as a primary treatment for localized cancers and as a salvage therapy for metastatic cancers. Anecdotal clinical reports and animal experiments have confirmed an induction of systemic antitumor immune response by tumor cryoablation. To capitalize on the stimulatory effects of cryoablation for cancer immunotherapy, this response must be intensified using other immunomodulatory agents. This article reviews the preclinical and clinical evidence and discusses the mechanism of the antitumor immune response generated by cryoablation. The rationale and evidence behind several immunotherapy approaches that can be combined with cryoablation to devise a cryoimmunotherapeutic strategy with a potential to impact the progression of metastatic disease are described.

  4. Colorectal (Colon) Cancer: What Are the Risk Factors?

    MedlinePlus

    ... What Are the Risk Factors for Colorectal Cancer? Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir ... Cancer Institute) Learning About Colon Cancer Stay Informed Language: English Español (Spanish) File Formats Help: How do I ...

  5. Laparoscopic surgery for colon cancer: a systematic review

    PubMed Central

    Kahnamoui, Kamyar; Cadeddu, Margherita; Farrokhyar, Forough; Anvari, Mehran

    2007-01-01

    Introduction Colorectal cancer is the second leading cause of cancer-related death in western countries. The objective of this systematic review was to show that laparoscopic-assisted colon resection for cancer is not inferior to open colectomy with respect to cancer survival and perioperative outcomes. Method We performed a comprehensive literature review. Inclusion criteria were adults aged over 16 years with a colon resection for documented colon cancer and randomized controlled trials with laparoscopic-assisted or open resections. We excluded studies that did not document colon cancer recurrence in their article. We assessed data extraction and study quality and performed a quantitative data analysis. Results Six published and 4 unpublished studies fulfilled our inclusion criteria, with a total of 1262 patients. All primary and secondary outcomes showed good homogeneity, except for morbidity, which was described heterogeneously between the studies. There was no disadvantage to laparoscopic colon resection in any of these primary and secondary outcomes, compared with the conventional open technique. Conclusion The results of this study suggest that, although there is no definitive answer, present evidence indicates that laparoscopic colon cancer resection is as safe and efficacious as the conventional open technique. PMID:17391617

  6. Aged garlic extract inhibits 1,2-dimethylhydrazine-induced colon tumor development by suppressing cell proliferation.

    PubMed

    Jikihara, Hiroshi; Qi, Guangying; Nozoe, Koichiro; Hirokawa, Mayumi; Sato, Hiromi; Sugihara, Yuka; Shimamoto, Fumio

    2015-03-01

    Garlic and its constituents are reported to have a preventive effect against colorectal cancer in animal models. Aged garlic extract (AGE), which is produced by natural extraction from fresh garlic for more than 10 months in aqueous ethanol, also has reputed chemopreventive effects on colon carcinogenesis, but has never been studied for its effects on colon cancer development. We investigated the antitumor effects of AGE in rats with 1,2-dimethylhydrazine (DMH)-induced carcinogenesis, and the mechanism of AGE in human colon cancer cell proliferation. F344 rats randomly divided into three groups were administered DMH (20 mg/kg weight) subcutaneously once a week for 8 weeks in a basal diet. After the last injection, one group of rats was then moved onto a basal diet containing 3% wt/wt AGE, and rats were sacrificed at 8 or 31 weeks. The number of aberrant crypt foci (ACF), histological type of tumor and proliferative activity of the tumor lesions were analyzed by macroscopic, pathological and immunohistochemical methods. DLD-1 human colon cancer cells were utilized to investigate the effect of AGE on anti-cell proliferation. AGE decreased the number of ACF but had no effect on gross tumor pathology. AGE showed a lower number of adenoma and adenocarcinoma lesions by histological analysis. Immunohistochemical staining indicated that AGE suppressed the proliferative activity in adenoma and adenocarcinoma lesions, but showed no effect on normal colon mucosa. Moreover, we demonstrated that AGE delayed cell cycle progression by downregulating cyclin B1 and cdk1 expression via inactivation of NF-κB in the human colorectal cancer cells but did not induce apoptosis. These findings suggest that AGE has an antitumor effect through suppression of cell proliferation. PMID:25573280

  7. Modulators affecting the immune dialogue between human immune and colon cancer cells

    PubMed Central

    Djaldetti, Meir; Bessler, Hanna

    2014-01-01

    The link between chronic inflammation and colorectal cancer has been well established. The events proceeding along tumorigenesis are complicated and involve cells activated at the cancer microenvironment, tumor infiltrating polymorphonuclears, immune cells including lymphocyte subtypes and peripheral blood mononuclear cells (PBMC), as well as tumor-associated macrophages. The immune cells generate inflammatory cytokines, several of them playing a crucial role in tumorigenesis. Additional factors, such as gene expression regulated by cytokines, assembling of tumor growth- and transforming factors, accelerated angiogenesis, delayed apoptosis, contribute all to initiation, development and migration of tumor cells. Oxygen radical species originating from the inflammatory area promote cell mutation and cancer proliferation. Tumor cells may over-express pro-inflammatory mediators that in turn activate immune cells for inflammatory cytokines production. Consequently, an immune dialogue emerges between immune and cancer cells orchestrated through a number of activated molecular pathways. Cytokines, encompassing migration inhibitory factor, transforming growth factor beta 1, tumor necrosis factor-α, Interleukin (IL)-6, IL-10, IL-12, IL-17, IL-23 have been reported to be involved in human cancer development. Some cytokines, namely IL-5, IL-6, IL-10, IL-22 and growth factors promote tumor development and metastasis, and inhibit apoptosis via activation of signal transducer activator transcription-3 transcription factor. Colon cancer environment comprises mesenchymal, endothelial and immune cells. Assessment of the interaction between components in the tumor environment and malignant cells requires a reconsideration of a few topics elucidating the role of chronic inflammation in carcinogenesis, the function of the immune cells expressed by inflammatory cytokine production, the immunomodulation of cancer cells and the existence of a cross-talk between immune and malignant

  8. Feedback - Colon Cancer Conference and Workshop 2010 —

    Cancer.gov

    This document contains feedback given by the participants of the Colon Cancer Conference and the Histopathology workshop. The meetings took place in October 2010 at the Jackson Laboratory in Bar Harbor, Maine.

  9. Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer.

    PubMed

    Aliper, Alexander M; Frieden-Korovkina, Victoria P; Buzdin, Anton; Roumiantsev, Sergey A; Zhavoronkov, Alex

    2014-11-30

    In solid cancers, myeloid derived suppressor cells (MDSC) infiltrate (peri)tumoral tissues to induce immune tolerance and hence to establish a microenvironment permissive to tumor growth. Importantly, the mechanisms that facilitate such infiltration or a subsequent immune suppression are not fully understood. Hence, in this study, we aimed to delineate disparate molecular pathways which MDSC utilize in murine models of colon or breast cancer. Using pathways enrichment analysis, we completed interactome maps of multiple signaling pathways in CD11b+/Gr1(high/low) MDSC from spleens and tumor infiltrates of mice with c26GM colon cancer and tumor infiltrates of MDSC in 4T1 breast cancer. In both cancer models, infiltrating MDSC, but not CD11b+ splenic cells, have been found to be enriched in multiple signaling molecules suggestive of their enhanced proliferative and invasive phenotypes. The interactome data has been subsequently used to reconstruct a previously unexplored regulation of MDSC cell cycle by the c-myc transcription factor which was predicted by the analysis. Thus, this study represents a first interactome mapping of distinct multiple molecular pathways whereby MDSC sustain cancer progression. PMID:25294811

  10. SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk

    PubMed Central

    Mullany, Lila E.; Wolff, Roger K.; Herrick, Jennifer S.; Buas, Matthew F.; Slattery, Martha L.

    2015-01-01

    Introduction MicroRNAs (miRNAs) regulate messenger RNAs (mRNAs) and as such have been implicated in a variety of diseases, including cancer. MiRNAs regulate mRNAs through binding of the miRNA 5’ seed sequence (~7–8 nucleotides) to the mRNA 3’ UTRs; polymorphisms in these regions have the potential to alter miRNA-mRNA target associations. SNPs in miRNA genes as well as miRNA-target genes have been proposed to influence cancer risk through altered miRNA expression levels. Methods MiRNA-SNPs and miRNA-target gene-SNPs were identified through the literature. We used SNPs from Genome-Wide Association Study (GWAS) data that were matched to individuals with miRNA expression data generated from an Agilent platform for colon tumor and non-tumor paired tissues. These samples were used to evaluate 327 miRNA-SNP pairs for associations between SNPs and miRNA expression levels as well as for SNP associations with colon cancer. Results Twenty-two miRNAs expressed in non-tumor tissue were significantly different by genotype and 21 SNPs were associated with altered tumor/non-tumor differential miRNA expression across genotypes. Two miRNAs were associated with SNP genotype for both non-tumor and tumor/non-tumor differential expression. Of the 41 miRNAs significantly associated with SNPs all but seven were significantly differentially expressed in colon tumor tissue. Two of the 41 SNPs significantly associated with miRNA expression levels were associated with colon cancer risk: rs8176318 (BRCA1), ORAA 1.31 95% CI 1.01, 1.78, and rs8905 (PRKAR1A), ORGG 2.31 95% CI 1.11, 4.77. Conclusion Of the 327 SNPs identified in the literature as being important because of their potential regulation of miRNA expression levels, 12.5% had statistically significantly associations with miRNA expression. However, only two of these SNPs were significantly associated with colon cancer. PMID:26630397

  11. Brain-derived neurotrophic factor regulates cell motility in human colon cancer.

    PubMed

    Huang, Ssu-Ming; Lin, Chingju; Lin, Hsiao-Yun; Chiu, Chien-Ming; Fang, Chia-Wei; Liao, Kuan-Fu; Chen, Dar-Ren; Yeh, Wei-Lan

    2015-06-01

    Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominant-negative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.

  12. Evaluation of the left-to-right shift of colon tumors in Iran: Is the trend changing?

    PubMed Central

    Kashfi, Seyed Mohammad Hossein; Nazemalhosseini Mojarad, Ehsan; Pourhoseingholi, Mohamad Amin; Asadzadeh Aghdaei, Hamid; Anaraki, Fakhrialsadat; Zali, Mohammad Reza

    2015-01-01

    Background: Colorectal cancer (CRC) is the second cause of cancer-related deaths worldwide. There have been several studies reporting the proximal tumor shift, especially in Western countries. In the present study, we investigated the clinicopathologic and anatomical distributions of colorectal tumors in Iranian CRC patients. Materials and Methods: In this retrospective cohort study, 258 patients with CRC from 2008 to 2013 were evaluated. Comparison of variables was performed using Pearson's chi-square test and Fisher's exact test depending on the nature of the data. Results: A total of 258 patients including 124 (48.1%) females and 134 (51.9%) males enrolled in this study. The majority of cancers were detected in the rectosigmoid, i.e., 98 (38%) followed by the left colon, i.e., 84 (32.6%) and the right colon, i.e., 76 (29.5%). In the present study, we observed the significant association between metastases, adjuvant therapy, family history, and history of inflammatory bowel disease (IBD) with tumor, node, and metastasis (TNM) staging (P < 0.001). In univariate analysis, there was a strong association between overall survival (OS) and stage II CRC (P = 0.03). However, the predictive value was lost in multivariate analysis (P = 0.145). Conclusion: Unlike the majority of previous studies on Iranian CRC patients, we observed a considerably higher occurrence of right-sided colon cancers (84 versus 76). Although this phenomenon did not reach the statistical significance rate, based on recent studies on Iranian population including the present one, the pattern of anatomical distribution of colorectal tumors has been changed toward the proximal colon. This requires an urgent need to provide other strategies and complementary detecting approaches in order to identify proximal tumors in Iranian CRC patients. PMID:26929764

  13. Vaccine Therapy in Treating Patients With Colon, Pancreatic, or Lung Cancer

    ClinicalTrials.gov

    2015-04-27

    Recurrent Colon Cancer; Extensive Stage Small Cell Lung Cancer; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Limited Stage Small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Stage III Non-small Cell Lung Cancer; Stage I Pancreatic Cancer; Stage II Non-small Cell Lung Cancer; Stage IVB Pancreatic Cancer; Stage II Pancreatic Cancer; Stage III Colon Cancer; Stage IVA Pancreatic Cancer

  14. Glucocorticoid receptor (GR) immunohistochemical expression is correlated with cell cycle-related molecules in human colon cancer.

    PubMed

    Theocharis, Stamatios; Kouraklis, Gregorios; Margeli, Alexandra; Agapitos, Emmanuel; Ninos, Sotirios; Karatzas, Gabriel; Koutselinis, Antonios

    2003-09-01

    The aim of this study was to examine glucocorticoid receptor (GR) immunohistochemical expression in colon cancer histopathological specimens and to correlate it with clinicopathological parameters, tumor proliferative capacity, cell cycle-related molecule expression, and patients' survival. Primary tumoral samples from 91 colon cancer patients were immunostained for the detection of GR, cyclins D1 and E, Rb protein (pRb), p16, p21, and Ki-67, using the streptavidin-biotin-peroxidase technique. GR expression was correlated with tumor histopathological characteristics and proliferative capacity, cell cycle-related molecule expression, and patients' survival. GR positivity was prominent in 44 of 91 (48%) colon cancer cases and was positively correlated with the expression of cell cycle-related molecules pRb (P = 0.008) and p16 (P = 0.002), while lack of correlation was noted with cyclins D1 and E and p21. GR expression was not correlated with tumor location, grade of differentiation, Dukes' stage, lymph node and liver metastasis, venous invasion, tumor proliferative capacity (evident by Ki-67-labeling status) and patient survival. Our findings support evidence for GR participation in the biological mechanisms underlying the carcinogenic evolution in the colon, implying the use of glucocorticoids as an adjuvant treatment for cell cycle modulation in colon cancer cells.

  15. Natural products and colon cancer: current status and future prospects

    PubMed Central

    Rajamanickam, Subapriya; Agarwal, Rajesh

    2008-01-01

    Carcinogenesis is a multistage process consisting of initiation, promotion and progression phases. Thus, the multistage sequence of events has many phases for prevention and intervention. Chemoprevention, a novel approach for controlling cancer, involves the use of specific natural products or synthetic chemical agents to reverse, suppress or prevent premalignancy before the development of invasive cancer. Several natural products, such as, grains, nuts, cereals, spices, fruits, vegetables, beverages, medicinal plants and herbs and their various phytochemical constituents including, phenolics, flavonoids, carotenoids, alkaloids, nitrogen containing as well as organosulfur compounds confer protective effects against wide range of cancers including colon cancer. Since diet has an important role in the etiology of colon cancer, dietary chemoprevention received attention for colon cancer prevention. However, identification of an agent with chemopreventive potential requires in vitro studies, efficacy and toxicity studies in animal models before embarking on human clinical trials. A brief introduction about colon cancer and the role of some recent natural products in colon cancer chemoprevention with respect to multiple molecular mechanisms in various in vitro, in vivo and clinical studies are described in this review. PMID:19884979

  16. Irinotecan-Eluting Beads in Treating Patients With Refractory Metastatic Colon or Rectal Cancer That Has Spread to the Liver

    ClinicalTrials.gov

    2016-01-22

    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 IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

  17. Post-translational glycoprotein modifications regulate colon cancer stem cells and colon adenoma progression in Apc(min/+) mice through altered Wnt receptor signaling.

    PubMed

    Guo, Huabei; Nagy, Tamas; Pierce, Michael

    2014-11-01

    Deletion of GnT-V (MGAT5), which synthesizes N-glycans with β(1,6)-branched glycans, reduced the compartment of cancer stem cells (CSC) in the her-2 mouse model of breast cancer, leading to delay of tumor onset. Because GnT-V levels are also commonly up-regulated in colon cancer, we investigated their regulation of colon CSC and adenoma development. Anchorage-independent cell growth and tumor formation induced by injection of colon tumor cells into NOD/SCID mice were positively associated with GnT-V levels, indicating regulation of proliferation and tumorigenicity. Using Apc(min/+) mice with different GnT-V backgrounds, knock-out of GnT-V had no significant effect on the number of adenoma/mouse, but adenoma size was significantly reduced and accompanied increased survival of Apc(min/+) mice with GnT-V deletion (p < 0.01), suggesting an inhibition in the progression of colon adenoma caused by deletion of GnT-V. Decreased expression levels of GnT-V down-regulated the population of colon (intestine) CSC, affecting their ability for self-renewal and tumorigenicity in NOD/SCID mice. Furthermore, altered nuclear translocation of β-catenin and expression of Wnt target genes were positively associated with expression levels of GnT-V, indicating the regulation of canonical Wnt/β-catenin signaling. By overexpressing the Wnt receptor, FZD-7, in colon cancer cells, we found that FZD-7 receptors expressed N-linked β(1,6) branching, indicating that FZD-7 can be modified by GnT-V. The aberrant Wnt signaling observed after modulating GnT-V levels is likely to result from altered N-linked β(1,6) branching on FZD-7, thereby affecting Wnt signaling, the compartment of CSC, and tumor progression.

  18. Knockdown of PFTAIRE Protein Kinase 1 (PFTK1) Inhibits Proliferation, Invasion, and EMT in Colon Cancer Cells.

    PubMed

    Zhu, Jiankang; Liu, Chongzhong; Liu, Fengyue; Wang, Yadong; Zhu, Min

    2016-01-01

    PFTK1 is a member of the cyclin-dependent kinase (CDK) family and is upregulated in many types of tumors. However, its expression and role in colon cancer remain unclear. In this study, we aimed to investigate the expression and function of PFTK1 in colon cancer. Our results showed that PFTK1 was highly expressed in colon cancer cell lines. The in vitro experiments demonstrated that knockdown of PFTK1 inhibited the proliferation, migration, and invasion of colon cancer cells as well as the epithelial-to-mesenchymal transition (EMT) progress. Furthermore, knockdown of PFTK1 suppressed the expression of Shh as well as Smo, Ptc, and Gli-1 in colon cancer cells. Taken together, these results suggest that knockdown of PFTK1 inhibited the proliferation and invasion of colon cancer cells as well as the EMT progress by suppressing the Sonic hedgehog signaling pathway. Therefore, these findings reveal that PFTK1 may be a potential therapeutic target for the treatment of colon cancer. PMID:27458094

  19. Complete mesocolic excision and central vascular ligation for colon cancer: Principle, anatomy, surgical technique, and outcomes.

    PubMed

    Kim, Nam Kyu; Kim, Young Wan; Han, Yoon Dae; Cho, Min Soo; Hur, Hyuk; Min, Byung Soh; Lee, Kang Young

    2016-09-01

    Classic colon cancer surgery refers to a wide resection of the tumor-bearing segment and the lymphatics draining along the named artery. The concept of TME has been applied to colon cancer and complete mesocolic excision (CME) in conjuction with central vascular ligation (CVL) has been introduced as the surgical treatment for colon cancer. Here, we discuss appropriate CME procedure with regard to the oncologic backgrounds, essential components, applied anatomy, laparoscopic technique, short-term, and oncologic outcomes. The introduction of CME has improved oncologic outcomes greatly in patients with colon cancer. The improved outcomes with CME can be attributed to underlying sound oncologic principles such as dissection through the proper plane of mesocolic excision, central vascular ligation, and sufficient length of proximal and distal margins. Thereby, CME technique can achieve en bloc removal of the diseased lesion with the increased amount of the colonic mesentery even though the length of for both bowel and mesentery resection remains a matter of debate. CME is a technically demanding operation thus, comprehensive understanding of the applied vascular anatomy is essential for successful CME. Favorable outcomes of open CME have been replicated with a laparoscopic approach. In future perspective, incorporating a structured education program on minimally invasive (laparoscopy or robot) CME would be beneficial. PMID:27566031

  20. Colonic manifestations of PTEN hamartoma tumor syndrome: Case series and systematic review

    PubMed Central

    Stanich, Peter P; Pilarski, Robert; Rock, Jonathan; Frankel, Wendy L; El-Dika, Samer; Meyer, Marty M

    2014-01-01

    AIM: To investigate our clinical experience with the colonic manifestations of phosphatase and tensin homolog on chromosome ten (PTEN) hamartoma tumor syndrome (PHTS) and to perform a systematic literature review regarding the same. METHODS: This study was approved by the appropriate institutional review board prior to initiation. A clinical genetics database was searched for patients with PHTS or a component syndrome that received gastrointestinal endoscopy or pathology interpretation at our center. These patient’s records were retrospectively reviewed for clinical characteristics (including family history and genetic testing), endoscopy results and pathology findings. We also performed a systematic review of the literature for case series of PHTS or component syndromes that reported gastrointestinal manifestations and investigations published after consensus diagnostic criteria were established in 1996. These results were compiled and reported. RESULTS: Eight patients from our institution met initial inclusion criteria. Of these, 5 patients underwent 4.2 colonoscopies at mean age 45.8 ± 10.8 years. All were found to have colon polyps during their clinical course and polyp histology included adenoma, hyperplastic, ganglioneuroma and juvenile. No malignant lesions were identified. Two had multiple histologic types. One patient underwent colectomy due to innumerable polyps and concern for future malignant potential. Systematic literature review of PHTS patients undergoing endoscopy revealed 107 patients receiving colonoscopy at mean age 37.4 years. Colon polyps were noted in 92.5% and multiple colon polyp histologies were reported in 53.6%. Common polyp histologies included hyperplastic (43.6%), adenoma (40.4%), hamartoma (38.3%), ganglioneuroma (33%) and inflammatory (24.5%) polyps. Twelve (11.2%) patients had colorectal cancer at mean age 46.7 years (range 35-62). Clinical outcomes secondary to colon polyposis and malignancy were not commonly reported

  1. Antitumor Activity of Human Hydatid Cyst Fluid in a Murine Model of Colon Cancer

    PubMed Central

    Russo, Sofía; Berois, Nora; Fernández, Gabriel; Freire, Teresa; Osinaga, Eduardo

    2013-01-01

    This study evaluates the antitumor immune response induced by human hydatic cyst fluid (HCF) in an animal model of colon carcinoma. We found that anti-HCF antibodies were able to identify cell surface and intracellular antigens in CT26 colon cancer cells. In prophylactic tumor challenge experiments, HCF vaccination was found to be protective against tumor formation for 40% of the mice (P = 0.01). In the therapeutic setting, HCF vaccination induced tumor regression in 40% of vaccinated mice (P = 0.05). This vaccination generated memory immune responses that protected surviving mice from tumor rechallenge, implicating the development of an adaptive immune response in this process. We performed a proteomic analysis of CT26 antigens recognized by anti-HCF antibodies to analyze the immune cross-reactivity between E. granulosus (HCF) and CT26 colon cancer cells. We identified two proteins: mortalin and creatine kinase M-type. Interestingly, CT26 mortalin displays 60% homology with E. granulosus hsp70. In conclusion, our data demonstrate the capacity of HCF vaccination to induce antitumor immunity which protects from tumor growth in an animal model. This new antitumor strategy could open new horizons in the development of highly immunogenic anticancer vaccines. PMID:24023528

  2. The anti-cancer effects of poi (Colocasia esculenta) on colonic adenocarcinoma cells In vitro.

    PubMed

    Brown, Amy C; Reitzenstein, Jonathan E; Liu, Jessie; Jadus, Martin R

    2005-09-01

    Hawaiians tend to have lower incidence rates of colorectal cancer and it was hypothesized that this may be due to ethnic differences in diet, specifically, their consumption of poi, a starchy paste made from the taro (Colocasia esulenta L.) plant corm. Soluble extracts of poi were incubated at 100 mg/mL in vitro for antiproliferative activity against the rat YYT colon cancer cell line. (3)H-thymidine incorporation studies were conducted to demonstrate that the poi inhibited the proliferation of these cancer cells in a dose-dependent manner. The greatest suppression of YYT colon cancer growth occurred when 25% concentration was used. When poi was incubated with the YYT cells after 2 days, the YYT cells underwent apoptotic changes as evidenced by a positive terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) stain. Poi enhanced the proliferation of normal mouse splenocyte control cells, suggesting that poi is not simply toxic to all cells but even has a positive immunostimulatory role. By flow cytometry, T cells (CD4+ and CD8+) were predominantly activated by the poi. Although numerous factors can contribute to the risk of colon cancer, perhaps poi consumption may contribute to the lower colon cancer rates among Hawaiians by two distinct mechanisms. First, by inducing apoptosis within colon cancer cells; second, by non-specifically activating lymphocytes, which in turn can lyse cancerous cells. Our results suggest for the first time that poi may have novel tumor specific anti-cancer activities and future research is suggested with animal studies and human clinical trials.

  3. In vitro and in vivo anti-colon cancer effects of Garcinia mangostana xanthones extract

    PubMed Central

    2012-01-01

    Background Xanthones are a group of oxygen-containing heterocyclic compounds with remarkable pharmacological effects such as anti-cancer, antioxidant, anti-inflammatory, and antimicrobial activities. Methods A xanthones extract (81% α-mangostin and 16% γ-mangostin), was prepared by crystallization of a toluene extract of G. mangostana fruit rinds and was analyzed by LC-MS. Anti-colon cancer effect was investigated on HCT 116 human colorectal carcinoma cells including cytotoxicity, apoptosis, anti-tumorigenicity, and effect on cell signalling pathways. The in vivo anti-colon cancer activity was also investigated on subcutaneous tumors established in nude mice. Results The extract showed potent cytotoxicity (median inhibitory concentration 6.5 ± 1.0 μg/ml), due to induction of the mitochondrial pathway of apoptosis. Three key steps in tumor metastasis including the cell migration, cell invasion and clonogenicity, were also inhibited. The extract and α-mangostin up-regulate the MAPK/ERK, c-Myc/Max, and p53 cell signalling pathways. The xanthones extract, when fed to nude mice, caused significant growth inhibition of the subcutaneous tumor of HCT 116 colorectal carcinoma cells. Conclusions Our data suggest new mechanisms of action of α-mangostin and the G. mangostana xanthones, and suggest the xanthones extract of as a potential anti-colon cancer candidate. PMID:22818000

  4. Development of an oral nanotherapeutics using redox nanoparticles for treatment of colitis-associated colon cancer.

    PubMed

    Vong, Long Binh; Yoshitomi, Toru; Matsui, Hirofumi; Nagasaki, Yukio

    2015-07-01

    Oral chemotherapy is the preferred treatment for colon cancer. However, this strategy faces many challenges, including instability in the gastrointestinal (GI) tract, insufficient bioavailability, low tumor targeting, and severe adverse effects. In this study, we designed a novel redox nanoparticle (RNP(O)) that is an ideal oral therapeutics for colitis-associated colon cancer treatment. RNP(O) possesses nitroxide radicals in the core, which act as reactive oxygen species (ROS) scavengers. Orally administered RNP(O) highly accumulated in colonic mucosa, and specifically internalized in cancer tissues, but less in normal tissues. Despite of long-term oral administration of RNP(O), no noticeable toxicities were observed in major organs of mice. Because RNP(O) effectively scavenged ROS, it significantly suppressed tumor growth after accumulation at tumor sites. Combination of RNP(O) with the conventional chemotherapy, irinotecan, led to remarkably improved therapeutic efficacy and effectively suppressed its adverse effects on GI tract. Therefore, RNP(O) is promising oral nanotherapeutics for cancer therapies. PMID:25934452

  5. Development of an oral nanotherapeutics using redox nanoparticles for treatment of colitis-associated colon cancer.

    PubMed

    Vong, Long Binh; Yoshitomi, Toru; Matsui, Hirofumi; Nagasaki, Yukio

    2015-07-01

    Oral chemotherapy is the preferred treatment for colon cancer. However, this strategy faces many challenges, including instability in the gastrointestinal (GI) tract, insufficient bioavailability, low tumor targeting, and severe adverse effects. In this study, we designed a novel redox nanoparticle (RNP(O)) that is an ideal oral therapeutics for colitis-associated colon cancer treatment. RNP(O) possesses nitroxide radicals in the core, which act as reactive oxygen species (ROS) scavengers. Orally administered RNP(O) highly accumulated in colonic mucosa, and specifically internalized in cancer tissues, but less in normal tissues. Despite of long-term oral administration of RNP(O), no noticeable toxicities were observed in major organs of mice. Because RNP(O) effectively scavenged ROS, it significantly suppressed tumor growth after accumulation at tumor sites. Combination of RNP(O) with the conventional chemotherapy, irinotecan, led to remarkably improved therapeutic efficacy and effectively suppressed its adverse effects on GI tract. Therefore, RNP(O) is promising oral nanotherapeutics for cancer therapies.

  6. MicroRNA-320a suppresses human colon cancer cell proliferation by directly targeting {beta}-catenin

    SciTech Connect

    Sun, Jian-Yong; Huang, Yi; Li, Ji-Peng; Zhang, Xiang; Wang, Lei; Meng, Yan-Ling; Yan, Bo; Bian, Yong-Qian; Zhao, Jing; Wang, Wei-Zhong; and others

    2012-04-20

    Highlights: Black-Right-Pointing-Pointer miR-320a is downregulated in human colorectal carcinoma. Black-Right-Pointing-Pointer Overexpression of miR-320a inhibits colon cancer cell proliferation. Black-Right-Pointing-Pointer {beta}-Catenin is a direct target of miR-320a in colon cancer cells. Black-Right-Pointing-Pointer miR-320a expression inversely correlates with mRNA expression of {beta}-catenin's target genes in human colon carcinoma. -- Abstract: Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-320a) in human colorectal carcinoma. However, its expression pattern and underlying mechanisms in the development and progression of colorectal carcinoma has not been elucidated clearly. Here, we performed real-time PCR to examine the expression levels of miR-320a in colon cancer cell lines and tumor tissues. And then, we investigated its biological functions in colon cancer cells by a gain of functional strategy. Further more, by the combinational approaches of bioinformatics and experimental validation, we confirmed target associations of miR-320a in colorectal carcinoma. Our results showed that miR-320a was frequently downregulated in cancer cell lines and colon cancer tissues. And we demonstrated that miR-320a restoration inhibited colon cancer cell proliferation and {beta}-catenin, a functionally oncogenic molecule was a direct target gene of miR-320a. Finally, the data of real-time PCR showed the reciprocal relationship between miR-320a and {beta}-catenin's downstream genes in colon cancer tissues. These findings indicate that miR-320a suppresses the growth of colon cancer cells by directly targeting {beta}-catenin, suggesting its application in prognosis prediction and cancer treatment.

  7. Experimental radioimmunotherapy of a xenografted human colonic tumor (GW-39) producing carcinoembryonic antigen

    SciTech Connect

    Goldenberg, D.M.; Gaffar, S.A.; Bennett, S.J.; Beach, J.L.

    1981-11-01

    Experiments were undertaken to evaluate the antitumor effects of 131I-labeled goat antibody immunoglobulin G prepared against carcinoembryonic antigen in hamsters bearing the carcinoembryonic antigen-producing GW-39 human colonic carcinoma. At a single injection of 1 mCi 131I and higher, a marked growth inhibition of GW-39 tumors, as well as a considerable increase in the survival time of the tumor-bearing hamsters, could be achieved. At a dose of 1 mCi, the radioactive affinity-purified antibody appeared to be superior to radioactive normal goat immunoglobulin G in influencing tumor growth and survival time, but no significant difference could be seen at the higher dose of 2 mCi given. Radiobiological calculations indicated that the tumors received, at up to 20 days after therapy, 1325 rads for the specific antibody and only 411 rads for the normal immunoglobulin G preparation. These findings encourage the further evaluation of antibodies to tumor markers for isotopic cancer therapy.

  8. The mRNA of L-Type Calcium Channel Elevated in Colon Cancer

    PubMed Central

    Wang, Xi-Tao; Nagaba, Yasushi; Cross, Heide S.; Wrba, Fritz; Zhang, Lin; Guggino, Sandra E.

    2000-01-01

    Previous reports indicate that the mRNA for the cardiac isoform of the voltage-gated L-type calcium channel (α1C) is elevated in colon cancer. The aim of these experiments was to verify that the mRNA for α1C was significantly increased in tumors of two separate populations of patients when compared to normal adjacent mucosa. The second aim was to measure the distribution of α1C using immunocytochemistry in normal human colon and in colon cancer and to determine what might regulate the channel expression. Biopsies were taken from patients with various stages of colon cancer and nearby normal mucosa were used as control. RNA was prepared and mRNA level measured by semiquantitative reverse transcriptase-polymerase chain reaction. The mRNA of the calcium channel was compared with other markers including β-actin. The mRNA for α1C was increased significantly in colon cancers compared to nearby adjacent mucosa. Using confocal microscopy α1C was localized mainly at the apical membrane in the surface epithelium of normal human colon with less distribution on the lateral and basal membranes. The channel was localized on the lateral and basal membranes in crypt cells. Calcium channel localization appeared to be nearer nuclei in colon cancer samples, in part because of the smaller size of the cells. Likewise, cultured Caco-2 and T84 cells showed a membrane distribution. Western blotting indicated that α1C protein was increased in nonconfluent cultures of colonic carcinoma cells compared to confluent cells and immunocytochemistry confirms that there is more calcium channel protein in cells that are nonconfluent. We conclude that the increase in mRNA of α1 subunit of the cardiac isoform of the L-type calcium channel may be a useful marker of colon cancer compared to other markers because the increase is large and this increase can be documented on small samples using a simple semiquantitative reverse transcriptase-polymerase chain reaction. We found that α1C protein is

  9. Trefoil factor-3 expression in human colon cancer liver metastasis.

    PubMed

    Babyatsky, Mark; Lin, Jing; Yio, Xianyang; Chen, Anli; Zhang, Jie-yu; Zheng, Yan; Twyman, Christina; Bao, Xiuliang; Schwartz, Myron; Thung, Swan; Lawrence Werther, J; Itzkowitz, Steven

    2009-01-01

    Deaths from colorectal cancer are often due to liver metastasis. Trefoil factor-3 (TFF3) is expressed by normal intestinal epithelial cells and its expression is maintained throughout the colon adenoma-carcinoma sequence. Our previous work demonstrated a correlation between TFF3 expression and metastatic potential in an animal model of colon cancer. The aim of this study was to determine whether TFF3 is expressed in human colon cancer liver metastasis (CCLM) and whether inhibiting TFF3 expression in colon cancer cells would alter their invasive potential in vitro. Human CCLMs were analyzed at the mRNA and protein level for TFF3 expression. Two highly metastatic rat colon cancer cell lines that either natively express TFF3 (LN cells) or were transfected with TFF3 (LPCRI-2 cells), were treated with two rat TFF3 siRNA constructs (si78 and si365), and analyzed in an in vitro invasion assay. At the mRNA and protein level, TFF3 was expressed in 17/17 (100%) CCLMs and 10/11 (91%) primary colon cancers, but not in normal liver tissue. By real time PCR, TFF3 expression was markedly inhibited by both siRNA constructs in LN and LPCRI-2 cells. The si365 and si78 constructs inhibited invasion by 44% and 53%, respectively, in LN cells, and by 74% and 50%, respectively, in LPCRI-2 cells. These results provide further evidence that TFF3 contributes to the malignant behavior of colon cancer cells. These observations may have relevance for designing new diagnostic and treatment approaches to colorectal cancer.

  10. Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro

    SciTech Connect

    Yang, Zi-Rong; Liu, Meng; Peng, Xiu-Lan; Lei, Xiao-Fei; Zhang, Ji-Xiang; Dong, Wei-Guo

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer Noscapine inhibited cell viability of colon cancer in a time- and dose- dependent manner. Black-Right-Pointing-Pointer G{sub 2}/M phase arrest and chromatin condensation and nuclear fragmentation were induced. Black-Right-Pointing-Pointer Noscapine promoted apoptosis via mitochondrial pathways. Black-Right-Pointing-Pointer Tumorigenicity was inhibited by noscapine. -- Abstract: Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC{sub 50} = 75 {mu}M). This cytotoxicity was reflected by cell cycle arrest at G{sub 2}/M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase-9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer.

  11. Induction of apoptosis in colon cancer cells by a novel topoisomerase I inhibitor TopIn

    SciTech Connect

    Bae, Soo Kyung; Gwak, Jungsug; Song, Im-Sook; Park, Hyung-Soon; Oh, Sangtaek

    2011-05-27

    Highlights: {yields} TopIn activates p53-dependent transcription in colon cancer cells. {yields} TopIn induces apoptosis in colon cancer cells. {yields} TopIn selectively inhibits topoisomerase I activity. {yields} TopIn does not affect the activity of BCRP and MDR-1. -- Abstract: The tumor suppressor p53 plays an important role in cellular emergency mechanisms through regulating the genes involved in cell cycle arrest and apoptosis. To identify small molecules that can activate p53-responsive transcription, we performed chemical screening using genetically engineered HCT116 reporter cells. We found that TopIn (7-phenyl-6H-[1,2,5]oxadiazolo[3,4-e]indole 3-oxide) efficiently activated p53-mediated transcriptional activity and induced phosphorylation of p53 at Ser15, thereby stabilizing the p53 protein. Furthermore, TopIn upregulated the expression of p21{sup WAF1/CIP1}, a downstream target of p53, and suppressed cellular proliferation in various colon cancer cells. Additionally, TopIn induced DNA fragmentation, caspase-3/7 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis, in p53 wild-type and mutated colon cancer cells. Finally, we found that TopIn inhibited topoisomerase I activity, but not topoisomerase II, in vitro and induced the formation of the topoisomerase I-DNA complex in HCT116 colon cancer cells. Unlike camptothecin (CPT) and its derivative SN38, TopIn did not affect the activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP) or multidrug-resistant protein-1 (MDR-1). These results suggest that TopIn may present a promising new topoisomerase I-targeting anti-tumor therapeutics.

  12. Acidic microenvironment and bone pain in cancer-colonized bone

    PubMed Central

    Yoneda, Toshiyuki; Hiasa, Masahiro; Nagata, Yuki; Okui, Tatsuo; White, Fletcher A

    2015-01-01

    Solid cancers and hematologic cancers frequently colonize bone and induce skeletal-related complications. Bone pain is one of the most common complications associated with cancer colonization in bone and a major cause of increased morbidity and diminished quality of life, leading to poor survival in cancer patients. Although the mechanisms responsible for cancer-associated bone pain (CABP) are poorly understood, it is likely that complex interactions among cancer cells, bone cells and peripheral nerve cells contribute to the pathophysiology of CABP. Clinical observations that specific inhibitors of osteoclasts reduce CABP indicate a critical role of osteoclasts. Osteoclasts are proton-secreting cells and acidify extracellular bone microenvironment. Cancer cell-colonized bone also releases proton/lactate to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Thus, extracellular microenvironment of cancer-colonized bone is acidic. Acidosis is algogenic for nociceptive sensory neurons. The bone is densely innervated by the sensory neurons that express acid-sensing nociceptors. Collectively, CABP is evoked by the activation of these nociceptors on the sensory neurons innervating bone by the acidic extracellular microenvironment created by bone-resorbing osteoclasts and bone-colonizing cancer cells. As current treatments do not satisfactorily control CABP and can elicit serious side effects, new therapeutic interventions are needed to manage CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and by which the expression and function of the acid-sensing nociceptors on the sensory neurons are regulated would facilitate to develop novel therapeutic approaches for the management of CABP. PMID:25987988

  13. Patterns of metastasis in colon and rectal cancer

    PubMed Central

    Riihimäki, Matias; Hemminki, Akseli; Sundquist, Jan; Hemminki, Kari

    2016-01-01

    Investigating epidemiology of metastatic colon and rectal cancer is challenging, because cancer registries seldom record metastatic sites. We used a population based approach to assess metastatic spread in colon and rectal cancers. 49,096 patients with colorectal cancer were identified from the nationwide Swedish Cancer Registry. Metastatic sites were identified from the National Patient Register and Cause of Death Register. Rectal cancer more frequently metastasized into thoracic organs (OR = 2.4) and the nervous system (1.5) and less frequently within the peritoneum (0.3). Mucinous and signet ring adenocarcinomas more frequently metastasized within the peritoneum compared with generic adenocarcinoma (3.8 [colon]/3.2 [rectum]), and less frequently into the liver (0.5/0.6). Lung metastases occurred frequently together with nervous system metastases, whereas peritoneal metastases were often listed with ovarian and pleural metastases. Thoracic metastases are almost as common as liver metastases in rectal cancer patients with a low stage at diagnosis. In colorectal cancer patients with solitary metastases the survival differed between 5 and 19 months depending on T or N stage. Metastatic patterns differ notably between colon and rectal cancers. This knowledge should help clinicians to identify patients in need for extra surveillance and gives insight to further studies on the mechanisms of metastasis. PMID:27416752

  14. DDA1 promotes stage IIB–IIC colon cancer progression by activating NFκB/CSN2/GSK-3β signaling

    PubMed Central

    Sun, Hongcheng; Wen, Yugang; Yu, Fudong; Cui, Feifei; Zhang, Dongyuan; Xue, Yingming; Liu, Chenchen; Yue, Ben; Chen, Jian; Wang, Jingtao; Wang, Xiao; Zhang, Meng; Yu, Yang; Jiang, Weiliang; Liu, Xisheng; Mi, Yushuai; Zhou, Zongguang; Qin, Xuebin; Peng, Zhihai

    2016-01-01

    Conventional high-recurrence risk factors are not sufficient to predict post-operative risk of tumor recurrence or sensitivity to 5-fluorouracil (5-FU)-based chemotherapy for stage II colon cancer. DDA1, an evolutionarily conserved gene located at 19p13.11, may be involved in the activation of nuclear factor kappaB (NFκB). This study aimed to investigate whether DDA1 contributes to tumorigenesis and progression of stage II colon cancer via activation of the NFκB pathway. We found that positive expression of DDA1 alone or in combination with p65 nuclear translocation correlated with increased risk of tumor recurrence in patients with stage IIB–IIC colon cancer. DDA1 overexpression in colon cancer lines promoted cell proliferation, facilitated cell cycle progression, inhibited 5-FU-induced apoptosis, enhanced invasion, and induced the epithelial-mesenchymal transition. Suppression of DDA1 inhibited tumor progression, and reduced tumor growth in vivo. We also demonstrated that DDA1-mediated tumor progression is associated with the activation of the NFκB/COP9 signalosome 2(CSN2)/glycogen synthase kinase3β (GSK3β) pathway. These results indicate that DDA1 promotes colon cancer progression through activation of NFκB/CSN2/GSK3β signaling. DDA1, together with NFκB activation status, may serve as a sensitive biomarker for tumor recurrence risk and prognosis in patients with stage IIB–IIC colon cancers. PMID:26942699

  15. Synthesis, Structure-Activity Relationship, and Mechanistic Investigation of Lithocholic Acid Amphiphiles for Colon Cancer Therapy

    PubMed Central

    Bhargava, Priyanshu; Singh, Ashima; Motiani, Rajender K.; Shyam, Radhey; Sreekanth, Vedagopuram; Sengupta, Sagar; Bajaj, Avinash

    2014-01-01

    We report a structure-activity relationship of lithocholic acid amphiphiles for their anticancer activities against colon cancer. We synthesized ten cationic amphiphiles differing in nature of cationic charged head groups using lithocholic acid. We observed that anticancer activities of these amphiphiles against colon cancer cell lines are contingent on nature of charged head group. Lithocholic acid based amphiphile possessing piperidine head group (LCA-PIP1) is ~10 times more cytotoxic as compared to its precursor. Biochemical studies revealed that enhanced activity of LCA-PIP1 as compared to lithocholic acid is due to greater activation of apoptosis.LCA-PIP1 induces sub G0 arrest and causes cleavage of caspases. A single dose of lithocholic acid-piperidine derivative is enough to reduce the tumor burden by 75% in tumor xenograft model. PMID:25685308

  16. Endoscopic ultrasound for staging of colonic cancer proximal to the rectum: A systematic review and meta-analysis

    PubMed Central

    Malmstrøm, Marie Louise; Săftoiu, Adrian; Vilmann, Peter; Klausen, Tobias Wirenfeldt; Gögenur, Ismail

    2016-01-01

    Background and Objectives: Treatment of colonic cancer patients is highly dependent on the depth of tumor invasion (T-stage) as well as the extension of lymph node involvement (N-stage). We aimed to systematically review the accuracy of endoscopic ultrasound (EUS) for staging of colonic cancer proximal to the rectum. Patients and Methods: Men and women with colonic adenocarcinomas were included in the study. EUS staging was compared to histopathology as the gold standard. Outcome measures were T- and N-staging accuracies. Articles were searched in PubMed, Web of Science, The Cochrane Library, and EMBASE. Results: Six studies were identified comparing EUS staging of colonic cancer to histopathology. The pooled-staging sensitivity and specificity were 0.90 and 0.98 for T1 tumors, 0.67 and 0.96 for T2 tumors, and 0.97 and 0.83 for T3/T4 tumors, respectively. Sensitivity and specificity for N + disease were 0.59 and 0.78, respectively. Conclusions: EUS is a feasible method for T-staging of cancers of the colon proximal to the rectum. The accuracy of lymph node staging needs to be verified by prospective multicenter studies including larger patient populations. PMID:27803903

  17. Multimodal nonlinear optical microscopy used to discriminate human colon cancer

    NASA Astrophysics Data System (ADS)

    Adur, Javier; Pelegati, Vitor B.; Bianchi, Mariana; de Thomaz, André A.; Baratti, Mariana O.; Carvalho, Hernandes F.; Casco, Víctor H.; Cesar, Carlos L.

    2013-02-01

    Colon cancer is one of the most diffused cancers in the Western World, ranking third worldwide in frequency of incidence after lung and breast cancers. Even if it is curable when detected and treated early, a more accurate premature diagnosis would be a suitable aim for both cancer prognostic and treatment. Combined multimodal nonlinear optical (NLO) microscopies, such as two-photon excitation fluorescence (TPEF), second-harmonic generation (SHG), third harmonic generation (THG), and fluorescence lifetime imaging microscopy (FLIM) can be used to detect morphological and metabolic changes associated with stroma and epithelial transformation in colon cancer disease. NLO microscopes provide complementary information about tissue microstructure, showing distinctive patterns between normal and malignant human colonic mucosa. Using a set of scoring methods significant differences both in the content, distribution and organization of stroma collagen fibrils, and lifetime components of NADH and FAD cofactors of human colon mucosa biopsies were found. Our results provide a framework for using NLO techniques as a clinical diagnostic tool for human colon cancer, and also suggest that the SHG and FLIM metrics could be applied to other intestinal disorders, which are characterized by abnormal cell proliferation and collagen assembly.

  18. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

    PubMed Central

    Dalerba, Piero; Sahoo, Debashis; Paik, Soonmyung; Guo, Xiangqian; Yothers, Greg; Song, Nan; Wilcox-Fogel, Nate; Forgó, Erna; Rajendran, Pradeep S.; Miranda, Stephen P.; Hisamori, Shigeo; Hutchison, Jacqueline; Kalisky, Tomer; Qian, Dalong; Wolmark, Norman; Fisher, George A.; van de Rijn, Matt; Clarke, Michael F.

    2016-01-01

    Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P = 0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein–negative colon cancers than among the 276 (87.9%) with CDX2 protein–positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P = 0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P = 0.003) and in the validation data set (51% among 15 patients with CDX2

  19. In vitro effects of extracts of extra virgin olive oil on human colon cancer cells.

    PubMed

    Pampaloni, Barbara; Mavilia, Carmelo; Fabbri, Sergio; Romani, Annalisa; Ieri, Francesca; Tanini, Annalisa; Tonelli, Francesco; Brandi, Maria Luisa

    2014-01-01

    The Mediterranean diet is associated with a lower incidence of atherosclerosis, cardiovascular diseases, and some types of cancer. Recent interest has been focused on the biological activity of phenolic compounds present in extra virgin olive oils (EVOOs). Both in vivo and in vitro studies have shown that EVOO components have positive effects on metabolic parameters, such as plasma lipoproteins, oxidative damage, inflammatory markers, platelet function, and antimicrobial activity. We have investigated the possible interactions between 2 extracts of extra virgin olive oil and estrogen receptor β (ERβ) in an in vitro model of colon cancer. The qualification and quantification of the components of the 2 samples tested showed that phenolic compounds-hydroxytyrosol, secoiridoids, and lignans-are the major represented compounds. EVOO extracts were tested on a colon cancer cell line engineered to overexpress ERβ (HCT8-β8). By using custom made Oligo microarray, gene expression profiles of colon cancer cells challenged with EVOO-T extracts when compared with those of cells exposed to 17β-estradiol (17β-E2). This study demonstrated that the EVOO extracts tested showed an antiproliferative effect on colon cancer cells through the interaction with estrogen-dependent signals involved in tumor cell growth. Specifically, the ability of EVOO extracts to inhibit cell proliferation was superimposable to the activation of the ERβ receptor, similar to what was observed after 17β-E2 challenge. PMID:25207387

  20. Label-free detection of tumor markers in a colon carcinoma tumor progression model by confocal Raman microspectroscopy

    NASA Astrophysics Data System (ADS)

    Scalfi-Happ, Claudia; Rück, Angelika; Udart, Martin; Hauser, Carmen; Dürr, Christine; Kriebel, Martin

    2013-06-01

    Living colon carcinoma cells were investigated by confocal Raman microspectroscopy. An in vitro model of tumor progression was established. Evaluation of data sets by cluster analysis reveals that lipid bodies might be a valuable diagnostic parameter for early carcinogenesis.

  1. Volvulus of the Sigmoid Colon Associated With Rectal Cancer: A Case Report

    PubMed Central

    Lee, Seung-Hyun; Ahn, Byung-Kwon; Baek, Sung-Uhn

    2015-01-01

    Sigmoid volvulus is one of the three most common causes of acute colonic obstruction. Predisposing factors include chronic constipation, adhesion from a prior abdominal surgery, and megacolon. However, concomitant presentation of volvulus of the sigmoid colon and rectal cancer is extremely rare. We report a case of a 50-year-old woman with coexisting volvulus of the sigmoid colon and rectal cancer. The patient presented with abdominal distension and pain for 2 days. On computed tomography, the whole colon was dilated with gas and feces. A whirl sign with rotation of the inferior mesenteric vessel was identified. The rectum had irregular wall thickening. Colonoscopy showed a circumscribed, ulcerofungating mass approximately 6 cm from the anal verge. The sigmoid colon was obstructed at a point approximately 25 cm from the anal verge. The mucosa was hyperemic and edematous with the pathognomonic spiral pattern. Endoscopic reduction was not successful. On laparotomy, the sigmoid colon was rotated around its mesentery. It was severely distended with edematous, hyperemic serosa. A tumor of the rectum was identified in the mid-rectum. The patient underwent low anterior resection and protective ileostomy. Pathologic findings confirmed adenocarcinoma of the rectum. The postoperative course was complicated by an ileus, which was managed with conservative treatment.

  2. Induction of pyroptosis in colon cancer cells by LXRβ

    PubMed Central

    Rébé, Cédric; Derangère, Valentin; Ghiringhelli, François

    2015-01-01

    Liver X receptors (LXRs) have been proposed to have some anticancer properties. We recently identified a new non-genomic role of LXRβ in colon cancer cells. Under LXR agonist treatment, LXRβ induces pyroptosis of these cells in vitro and in vivo, raising the possibility of targeting this isoform in cancer treatment. PMID:27308405

  3. Unique DNA methylome profiles in CpG island methylator phenotype colon cancers.

    PubMed

    Xu, Yaomin; Hu, Bo; Choi, Ae-Jin; Gopalan, Banu; Lee, Byron H; Kalady, Matthew F; Church, James M; Ting, Angela H

    2012-02-01

    A subset of colorectal cancers was postulated to have the CpG island methylator phenotype (CIMP), a higher propensity for CpG island DNA methylation. The validity of CIMP, its molecular basis, and its prognostic value remain highly controversial. Using MBD-isolated genome sequencing, we mapped and compared genome-wide DNA methylation profiles of normal, non-CIMP, and CIMP colon specimens. Multidimensional scaling analysis revealed that each specimen could be clearly classified as normal, non-CIMP, and CIMP, thus signifying that these three groups have distinctly different global methylation patterns. We discovered 3780 sites in various genomic contexts that were hypermethylated in both non-CIMP and CIMP colon cancers when compared with normal colon. An additional 2026 sites were found to be hypermethylated in CIMP tumors only; and importantly, 80% of these sites were located in CpG islands. These data demonstrate on a genome-wide level that the additional hypermethylation seen in CIMP tumors occurs almost exclusively at CpG islands and support definitively that these tumors were appropriately named. When these sites were examined more closely, we found that 25% were adjacent to sites that were also hypermethylated in non-CIMP tumors. Thus, CIMP is also characterized by more extensive methylation of sites that are already prone to be hypermethylated in colon cancer. These observations indicate that CIMP tumors have specific defects in controlling both DNA methylation seeding and spreading and serve as an important first step in delineating molecular mechanisms that control these processes. PMID:21990380

  4. Receptor and enzyme expression for prostanoid metabolism in colorectal cancer related to tumor tissue PGE2.

    PubMed

    Gustafsson, Annika; Andersson, Marianne; Lagerstedt, Kristina; Lönnroth, Christina; Nordgren, Svante; Lundholm, Kent

    2010-02-01

    Prostaglandins support progression of colorectal cancer by several mechanisms. This conclusion is based on epidemiological and drug intervention long-term studies or retrieved from animal and cell culture experiments. The aim of the present study was to map receptor and enzyme expression for prostanoid metabolism in the presence of high or low PGE2 content within colon cancer tissue at primary tumor operation and after short-term preoperative provision of non-steroidal anti-inflammatory drug (NSAID). Twenty-three unselected patients with colon cancer were randomly selected to receive indomethacin (NSAID) or sham treatment for 3 days before surgery. Normal colon and tumor tissue were collected at operation for RNA extraction. Tissue PGE2 levels were measured by radioimmunoassay. Gene expression was quantified by microarray and real-time PCR. COX-1 expression increased proportionally to COX-2 expression in colon cancer tissue from untreated patients. Indomethacin reduced PGE2 content in normal and tumor tissue with subsequently decreased IP, HPGD and PPARgamma receptor expression in both tumor and normal colon tissue, while subtype EP1-4 receptors were not significantly influenced by indomethacin treatment. MPGES-1 expression was not related to overall PGE2 content in tumor and colon tissue, but decreased significantly in normal tissue during indomethacin exposure. Reduction of tumor tissue PGE2 was related to significant alteration in expression of several hundred genes indicating decreased cell cycling and increased apoptosis during indomethacin treatment, probably related to upregulation of acute phase reactants in tumor tissue. Increased prostanoid activity in colon cancer tissue is related to cross-talk between tumor and stroma cells. PMID:20043083

  5. MicroRNA-145 Targets YES and STAT1 in Colon Cancer Cells

    PubMed Central

    Gregersen, Lea H.; Jacobsen, Anders B.; Frankel, Lisa B.; Wen, Jiayu; Krogh, Anders; Lund, Anders H.

    2010-01-01

    Background MicroRNAs (miRNAs) have emerged as important gene regulators and are recognized as key players in tumorigenesis. miR-145 is reported to be down-regulated in several cancers, but knowledge of its targets in colon cancer remains limited. Methodology/Principal Findings To investigate the role of miR-145 in colon cancer, we have employed a microarray based approach to identify miR-145 targets. Based on seed site enrichment analyses and unbiased word analyses, we found a significant enrichment of miRNA binding sites in the 3′-untranslated regions (UTRs) of transcripts down-regulated upon miRNA overexpression. Gene Ontology analysis showed an overrepresentation of genes involved in cell death, cellular growth and proliferation, cell cycle, gene expression and cancer. A number of the identified miRNA targets have previously been implicated in cancer, including YES, FSCN1, ADAM17, BIRC2, VANGL1 as well as the transcription factor STAT1. Both YES and STAT1 were verified as direct miR-145 targets. Conclusions/Significance The study identifies and validates new cancer-relevant direct targets of miR-145 in colon cancer cells and hereby adds important mechanistic understanding of the tumor-suppressive functions of miR-145. PMID:20098684

  6. Efficacy of photothermal ablation using intravenously delivered NIR-absorbing nanorods in colon cancer

    NASA Astrophysics Data System (ADS)

    Goodrich, Glenn P.; Payne, J. Donald; Sharp, Kelly; Bao, LiLi; Sang, Kristina L.

    2009-02-01

    The use of near-infrared absorbing nanoparticles recently has been proposed for the minimally invasive photothermal ablation of solid tumors, and this approach currently is being investigated in the clinic. One class of nanoparticles, gold nanorods, has been investigated for the ablation of various cancer types using both direct injection and systemic delivery. Here we investigate the photothermal ablation of colon cancer in an animal model using intravenously delivered gold nanorods. Nanorods with an aspect ratio of ~3.2 and an extinction peak of 774 nm were PEGylated, suspended in an isotonic solution, and infused into the tail vein of BALB/c mice bearing subcutaneous CT26.wt murine colon cancer tumors. After 24 hrs, an isotropic laser fiber was inserted through a small incision in the skin to a point proximate to and beneath the tumor. The area was illuminated with 3.5 W average power for 3 minutes. Control groups consisted of laser-only, nanorod-only and untreated tumored animals. The survival of the animals receiving nanorod-based photothermal ablation was statistically longer than the control groups with >44% complete response. This work demonstrates the promise of systemically delivering nanoparticles to tumors for thermal ablation

  7. Cancer-related multiple brain infarctions caused by Trousseau syndrome in a patient with metastatic colon cancer: a case report.

    PubMed

    Akiyama, Takahiko; Miyamoto, Yuji; Sakamoto, Yasuo; Tokunaga, Ryuma; Kosumi, Keisuke; Shigaki, Hironobu; Kurashige, Junji; Iwatsuki, Masaaki; Baba, Yoshifumi; Yoshida, Naoya; Baba, Hideo

    2016-12-01

    Thromboembolism that occurs in association with a malignant tumor is known as Trousseau syndrome. We herein present a case of Trousseau syndrome during systemic chemotherapy for metastatic colon cancer. A 65-year-old man with multiple liver metastases underwent primary tumor resection and systemic chemotherapy. Multiple brain infarctions were detected by magnetic resonance imaging immediately after first-line chemotherapy, which was deemed ineffective. There was no evidence of cardioembolic stroke or carotid atherosclerosis. Although the patient was initially asymptomatic, he subsequently developed paralysis. Despite anticoagulant treatment, he developed repeated recurrences of the infarction, and the area of the infarction spread as the liver metastases progressed. The patient's condition showed no response to an alternative treatment regimen for advanced colon carcinoma. He died approximately 11 months after tumor discovery. PMID:27595586

  8. Ex Vivo Sentinel Node Mapping in Colon Cancer Combining Blue Dye Staining and Fluorescence Imaging

    PubMed Central

    Schaafsma, Boudewijn E.; Verbeek, Floris P.R.; van der Vorst, Joost R.; Hutteman, Merlijn; Kuppen, Peter J.K.; Frangioni, John V.; van de Velde, Cornelis J.H.; Vahrmeijer, Alexander L.

    2013-01-01

    Background The sentinel lymph node procedure has been proposed to improve nodal staging in colon cancer patients. The aim of this study was to assess the added value of near-infrared fluorescence imaging to conventional blue dye staining for ex vivo sentinel lymph node mapping. Materials and Methods Twenty-two consecutive patients undergoing surgery for colon cancer were included. After tumor resection, a premixed cocktail of the near-infrared lymphatic tracer HSA800 and blue dye was submucosally injected around the tumor for detection of sentinel lymph nodes. The Mini-FLARE imaging system was used for fluorescence imaging. Results In 95% of the patients, at least one sentinel lymph node was identified. Overall, a total of 77 sentinel lymph nodes were identified, of which 77 were fluorescent (100%) and 70 (91%) were blue. Sentinel lymph nodes that were located deeper in the mesenteric fat could easily be located by NIR fluorescence. In 4 out of 5 patients with lymph node metastases, tumor cells were present in at least 1 of the sentinel lymph nodes. Conclusions This study shows the successful use and added value of the near-infrared fluorescence tracer HSA800 to conventional blue dye for the ex vivo sentinel lymph node procedure in colon cancer. PMID:23391167

  9. Near-infrared Mueller matrix imaging for colonic cancer detection

    NASA Astrophysics Data System (ADS)

    Wang, Jianfeng; Zheng, Wei; Lin, Kan; Huang, Zhiwei

    2016-03-01

    Mueller matrix imaging along with polar decomposition method was employed for the colonic cancer detection by polarized light in the near-infrared spectral range (700-1100 nm). A high-speed (<5s) Muller matrix imaging system with dual-rotating waveplates was developed. 16 (4 by 4) full Mueller matrices of the colonic tissues (i.e., normal and caner) were acquired. Polar decomposition was further implemented on the 16 images to derive the diattentuation, depolarization, and the retardance images. The decomposed images showed clear margin between the normal and cancerous colon tissue samples. The work shows the potential of near-infrared Mueller matrix imaging for the early diagnosis and detection of malignant lesions in the colon.

  10. Piwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity.

    PubMed

    Li, Dawei; Sun, Xing; Yan, Dongwang; Huang, Jianfeng; Luo, Qiongzhen; Tang, Huamei; Peng, Zhihai

    2012-10-01

    Piwi-like protein 2 (Piwil2) has recently emerged as a putative oncogene which is amplified in several human malignancies. However, the role of Piwil2 in colon cancer remains poorly understood. The aim of this study was to investigate the clinical and pathological significance of Piwil2, and the possible role in the proliferation and metastasis of colon cancer. Primary colon cancer paired with adjacent normal colon tissue and lymph node metastasis (LNM) lesions in 66 patients' tissue microarrays (TMA) were used to determine the expression of Piwil2. Knocked down Piwil2 expression in SW620 and SW480 colon cancer cell lines was performed to evaluate the role of Piwil2 in cell proliferation, invasion, metastasis in vitro and tumorigenicity in vivo. The possible roles of Piwil2 in the regulation of a 2 kb matrix metallopeptidase 9 (MMP9) promoter fragment and on the regulation of apoptotic pathways were evaluated by using a luciferase reporter construct and Western blots, respectively. Significantly higher expression levels of Piwil2 were observed in primary colon cancer tissue and in LNM in comparison with normal colon mucosa. Piwil2 expression significantly correlated with more aggressive clinical and pathological parameters with poorer five-year metastasis-free survival and overall survival. Piwil2 silencing significantly reduced cancer cell proliferation, colony formation ability and increased apoptosis in vitro and inhibited tumor growth in vivo. Piwil2 knockdown also attenuated migration and invasion of colon cancer cells via modulation of MMP9 transcriptional activities. Our results indicate that Piwil2 moderates the proliferation and metastasis potential of colon cancer.

  11. [Cases of Obstructive Colon Cancer for Which Elective Surgery Was Performed after Colonic Stent Placement].

    PubMed

    Maruo, Hirotoshi; Nakamura, Koichi; Higashi, Yukihiro; Shoji, Tsuyoshi; Yamazaki, Masanori; Nishiyama, Raisuke; Koike, Kota; Kubota, Hiroyuki

    2015-11-01

    The present study investigated the short-term outcomes of 20 patients with obstructive colon cancer who underwent colonic stent placement as a bridge to surgery (BTS) during the 3-year period between April 2012 and March 2015. Subjects comprised 13 men and 7 women, with a mean age of 68.3 years. Placement and decompression were successfully achieved in all of the patients. Oral ingestion became possible from a mean of 2.7 days after placement. No serious complications associated with placement were encountered. Total colonoscopy was performed after placement in 17 patients (85%), and independent advanced cancer was seen in the proximal portion of the colon in 1 patient. Elective surgery was performed for all of the patients after placement. Excluding the 2 patients for whom preoperative chemotherapy or treatment of another disease was prioritized, the mean interval to surgery for the remaining 18 patients was 23.2 days. The operative procedure performed was laparoscopic surgery in 8 patients (40%). Although minor leakage (n=1) and abdominal wall abscess (n=1) were observed as postoperative complications, the patients generally had an uneventful course. Colonic stent placement for obstructive colon cancer is relatively easy and safe, and may be considered as an effective treatment method that enables favorable intestinal decompression preoperatively and one-stage resection. PMID:26805323

  12. Dietary resistant starch type 3 prevents tumor induction by 1,2-dimethylhydrazine and alters proliferation, apoptosis and dedifferentiation in rat colon.

    PubMed

    Bauer-Marinovic, Morana; Florian, Simone; Müller-Schmehl, Katrin; Glatt, Hansruedi; Jacobasch, Gisela

    2006-09-01

    Some epidemiological and experimental studies suggest that consumption of resistant starch is preventive against colon cancer. Resistant starch leads to a fermentation-mediated increase in the formation of short-chain fatty acids, with a particularly high butyrate fraction in large bowel. Butyrate is considered to be protective against colon cancer because it causes growth arrest and apoptosis and regulates expression of proteins involved in cellular dedifferentiation in various tumor cell lines in culture. We sought to investigate these processes under conditions of a carcinogenicity experiment in vivo. In the present study, 1,2-dimethylhydrazine-treated Sprague-Dawley rats were fed standard diet (n=12) or diet with 10% hydrothermally modified Novelose 330, a resistant starch type 3 (RS3), replacing digestible starch (n=8). After 20 weeks tumor number, epithelial proliferation, apoptosis, immunoreactivity of carcinogenesis-related proteins [protein kinase C-delta (PKC-delta), heat shock protein 25 (HSP25) and gastrointestinal glutathione peroxidase (GI-GPx)], as well as mucin properties were evaluated in proximal and distal colon in situ. No tumors developed under RS3 diet, compared to a tumor incidence of 0.6+/-0.6 (P<0.05) under the standard diet. RS3 decreased the number of proliferating cells, the length of the proliferation zone and the total length of the crypt in the distal colon, but not proximal colon, and enhanced apoptosis in both colonic segments. It induced PKC-delta and HSP25 expression, but inhibited GI-GPx expression in the epithelium of distal colon. RS3 increased the number of predominantly acidic mucin containing goblet cells in the distal colon, but had no effect on the goblet cell count. We conclude that hydrothermally treated RS3 prevented colon carcinogenesis, and that this effect was mediated by enhanced apoptosis of damaged cells accompanied by changes in parameters of dedifferentiation in colonic mucosa.

  13. Rural-Urban Differences in Colon Cancer Risk in Blacks and Whites: The North Carolina Colon Cancer Study

    ERIC Educational Resources Information Center

    Yeomans Kinney, Anita; Harrell, Janna; Slattery, Marty; Martin, Christopher; Sandler, Robert S.

    2006-01-01

    Context: Geographic and racial variations in cancer incidence have been observed. Studies of colorectal carcinoma indicate a higher incidence and mortality rate for blacks than for whites in the United States. Purpose: We evaluated the effect of rural versus urban residence on colon cancer risk and stage of disease at diagnosis in blacks and…

  14. Pseudo-Meigs' syndrome secondary to metachronous ovarian metastases from transverse colon cancer.

    PubMed

    Kyo, Kennoki; Maema, Atsushi; Shirakawa, Motoaki; Nakamura, Toshio; Koda, Kenji; Yokoyama, Hidetaro

    2016-05-14

    Pseudo-Meigs' syndrome associated with colorectal cancer is extremely rare. We report here a case of pseudo-Meigs' syndrome secondary to metachronous ovarian metastases from colon cancer. A 65-year-old female with a history of surgery for transverse colon cancer and peritoneal dissemination suffered from metachronous ovarian metastases during treatment with systemic chemotherapy. At first, neither ascites nor pleural effusion was observed, but she later complained of progressive abdominal distention and dyspnea caused by rapidly increasing ascites and pleural effusion and rapidly enlarging ovarian metastases. Abdominocenteses were repeated, and cytological examinations of the fluids were all negative for malignant cells. We suspected pseudo-Meigs' syndrome, and bilateral oophorectomies were performed after thorough informed consent. The patient's postoperative condition improved rapidly after surgery. We conclude that pseudo-Meigs' syndrome should be included in the differential diagnosis of massive or rapidly increasing ascites and pleural effusion associated with large or rapidly enlarging ovarian tumors.

  15. Pseudo-Meigs’ syndrome secondary to metachronous ovarian metastases from transverse colon cancer

    PubMed Central

    Kyo, Kennoki; Maema, Atsushi; Shirakawa, Motoaki; Nakamura, Toshio; Koda, Kenji; Yokoyama, Hidetaro

    2016-01-01

    Pseudo-Meigs’ syndrome associated with colorectal cancer is extremely rare. We report here a case of pseudo-Meigs’ syndrome secondary to metachronous ovarian metastases from colon cancer. A 65-year-old female with a history of surgery for transverse colon cancer and peritoneal dissemination suffered from metachronous ovarian metastases during treatment with systemic chemotherapy. At first, neither ascites nor pleural effusion was observed, but she later complained of progressive abdominal distention and dyspnea caused by rapidly increasing ascites and pleural effusion and rapidly enlarging ovarian metastases. Abdominocenteses were repeated, and cytological examinations of the fluids were all negative for malignant cells. We suspected pseudo-Meigs’ syndrome, and bilateral oophorectomies were performed after thorough informed consent. The patient’s postoperative condition improved rapidly after surgery. We conclude that pseudo-Meigs’ syndrome should be included in the differential diagnosis of massive or rapidly increasing ascites and pleural effusion associated with large or rapidly enlarging ovarian tumors. PMID:27182170

  16. Colon cancer: association of histopathological parameters and patients' survival with clinical presentation.

    PubMed

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

    2013-10-01

    Available data correlating symptoms of colon cancer patients with the severity of the disease are very limited. In a population-based setting, we correlated information on symptoms of colon cancer patients with several pathological tumor parameters and survival. Information on all patients diagnosed with colon cancer in Iceland in 1995-2004 for this retrospective, population-based study was obtained from the Icelandic Cancer Registry. Information on symptoms of patients and blood hemoglobin was collected from patients' files. Pathological parameters were obtained from a previously performed standardized tumor review. A total of 768 patients entered this study; the median age was 73 years. Tumors in patients presenting at diagnosis with visible blood in stools were significantly more likely to be of lower grade, having pushing border, conspicuous peritumoral lymphocytic infiltration, and lower frequency of vessel invasion. Patients with abdominal pain and anemia were significantly more likely to have vessel invasion. Logistic regression showed that visible blood in stools was significantly associated with protecting pathological factors (OR range 0.38-0.83, p < 0.05). Tumors in patients presenting with abdominal pain were strongly associated with infiltrative margin and scarce peritumoral lymphocytic infiltration (OR = 1.95; 2.18 respectively, p < 0.05). Changes in bowel habits were strongly associated with vessel invasion (OR = 2.03, p < 0.05). Cox regression showed that blood in stools predicted survival (HR = 0.54). In conclusion, visible blood in stools correlates significantly with all the beneficial pathological parameters analyzed and with better survival of patients. Anemia, general symptoms, changes in bowel habits, acute symptoms, and abdominal pain correlate with more aggressive tumor characteristics and adverse outcome for patients.

  17. KRAS Mutation in Stage III Colon Cancer and Clinical Outcome Following Intergroup Trial CALGB 89803

    PubMed Central

    Ogino, Shuji; Meyerhardt, Jeffrey A.; Irahara, Natsumi; Niedzwiecki, Donna; Hollis, Donna; Saltz, Leonard B.; Mayer, Robert J.; Schaefer, Paul; Whittom, Renaud; Hantel, Alexander; Benson, Al B.; Goldberg, Richard M.; Bertagnolli, Monica M.; Fuchs, Charles S.

    2009-01-01

    Purpose Alterations in the RAS and RAF pathway relate to epigenetic and epigenomic aberrations, and are important in colorectal carcinogenesis. KRAS mutation in metastatic colorectal cancer predicts resistance to anti-EGFR targeted therapy (cetuximab or panitumumab). However, it remains uncertain whether KRAS mutation predicts prognosis or clinical outcome of colon cancer patients independent of anti-EGFR therapy. Methods We conducted a study of 508 cases identified among 1264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) in 1999–2001 (CALGB 89803). KRAS mutations were detected in 178 tumors (35%) by Pyrosequencing. Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age, sex, tumor location, tumor/node stage, performance status, adjuvant chemotherapy arm and microsatellite instability (MSI) status. Results Compared to patients with KRAS-wild-type tumors, patients with KRAS-mutated tumors did not experience any difference in disease-free (DFS), recurrence-free (RFS), or overall survival (OS). Five-year DFS, RFS and OS (KRAS-mutated vs. KRAS-wild-type patients) were: 62% vs. 63% (log-rank p=0.89); 64% vs. 66% (p=0.84); and 75% vs. 73% (p=0.56), respectively. The effect of KRAS mutation on patient survival did not significantly differ according to clinical features, chemotherapy arm or MSI status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status. Conclusions In this large trial of chemotherapy in stage III colon cancer patients, KRAS mutational status was not associated with any significant influence on disease-free or overall survival. PMID:19934290

  18. PRL-3 promotes cell adhesion by interacting with JAM2 in colon cancer

    PubMed Central

    Lian, Shenyi; Meng, Lin; Xing, Xiaofang; Yang, Yongyong; Qu, Like; Shou, Chengchao

    2016-01-01

    Phosphatase of regenerating liver-3 (PRL-3), also termed PTP4A3, is a metastasis-related protein tyrosine phosphatase. Its expression levels are significantly correlated with the progression and survival of a wide range of malignant tumors. However, the mechanism by which PRL-3 promotes tumor invasion and metastasis is not clear. In the present study, the functions of PRL-3 were systemically analyzed in the key events of metastasis including, motility and adhesion. A cell wounding assay, cell spread assay and cell-matrix adhesion assay were carried out to analyze the cell movement and cell adhesion ability of colon cancer, immunoprecipitation and immunofluorescence assay was confirmed the interaction of PRL-3 and JAM2. It was demonstrated that PRL-3 promoted the motility of Flp-In-293 and LoVo colon cancer cells and increased the distribution of cell skeleton proteins on the cell protrusions. In addition, stably expressing PRL-3 reduced the spreading speed of colon cancer cells and cell adhesion on uncoated, fibronectin-coated and collagen I-coated plates. Mechanistically, junction adhesion molecular 2 (JAM2) was identified as a novel interacting protein of PRL-3. The findings of the present study revealed the roles of PRL-3 in cancer cell motility and adhesion process, and provided information on the possibility of PRL-3 increase cell-cell adhesion by associating with JAM2. PMID:27588115

  19. Methylsulfonylmethane Induces p53 Independent Apoptosis in HCT-116 Colon Cancer Cells

    PubMed Central

    Karabay, Arzu Zeynep; Koc, Asli; Ozkan, Tulin; Hekmatshoar, Yalda; Sunguroglu, Asuman; Aktan, Fugen; Buyukbingol, Zeliha

    2016-01-01

    Methylsulfonylmethane (MSM) is an organic sulfur-containing compound which has been used as a dietary supplement for osteoarthritis. MSM has been shown to reduce oxidative stress and inflammation, as well as exhibit apoptotic or anti-apoptotic effects depending on the cell type or activating stimuli. However, there are still a lot of unknowns about the mechanisms of actions of MSM. In this study, MSM was tested on colon cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis revealed that MSM inhibited cell viability and increased apoptotic markers in both HCT-116 p53 +/+ and HCT-116 p53 −/− colon cancer cells. Increased poly (ADP-ribose) polymerase (PARP) fragmentation and caspase-3 activity by MSM also supported these findings. MSM also modulated the expression of various apoptosis-related genes and proteins. Moreover, MSM was found to increase c-Jun N-terminal kinases (JNK) phosphorylation in both cell lines, dose-dependently. In conclusion, our results show for the first time that MSM induces apoptosis in HCT-116 colon cancer cells regardless of their p53 status. Since p53 is defective in >50% of tumors, the ability of MSM to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy. Moreover, the remarkable effect of MSM on Bim, an apoptotic protein, also suggests its potential use as a novel chemotherapeutic agent for Bim-targeted anti-cancer therapies. PMID:27428957

  20. Methylsulfonylmethane Induces p53 Independent Apoptosis in HCT-116 Colon Cancer Cells.

    PubMed

    Karabay, Arzu Zeynep; Koc, Asli; Ozkan, Tulin; Hekmatshoar, Yalda; Sunguroglu, Asuman; Aktan, Fugen; Buyukbingol, Zeliha

    2016-01-01

    Methylsulfonylmethane (MSM) is an organic sulfur-containing compound which has been used as a dietary supplement for osteoarthritis. MSM has been shown to reduce oxidative stress and inflammation, as well as exhibit apoptotic or anti-apoptotic effects depending on the cell type or activating stimuli. However, there are still a lot of unknowns about the mechanisms of actions of MSM. In this study, MSM was tested on colon cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis revealed that MSM inhibited cell viability and increased apoptotic markers in both HCT-116 p53 +/+ and HCT-116 p53 -/- colon cancer cells. Increased poly (ADP-ribose) polymerase (PARP) fragmentation and caspase-3 activity by MSM also supported these findings. MSM also modulated the expression of various apoptosis-related genes and proteins. Moreover, MSM was found to increase c-Jun N-terminal kinases (JNK) phosphorylation in both cell lines, dose-dependently. In conclusion, our results show for the first time that MSM induces apoptosis in HCT-116 colon cancer cells regardless of their p53 status. Since p53 is defective in >50% of tumors, the ability of MSM to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy. Moreover, the remarkable effect of MSM on Bim, an apoptotic protein, also suggests its potential use as a novel chemotherapeutic agent for Bim-targeted anti-cancer therapies. PMID:27428957

  1. Antitumor Effects of Fucoidan on Human Colon Cancer Cells via Activation of Akt Signaling

    PubMed Central

    Han, Yong-seok; Lee, Jun Hee; Lee, Sang Hun

    2015-01-01

    We identified a novel Akt signaling mechanism that mediates fucoidan-induced suppression of human colon cancer cell (HT29) proliferation and anticancer effects. Fucoidan treatment significantly inhibited growth, induced G1-phase-associated upregulation of p21WAF1 expression, and suppressed cyclin and cyclin-dependent kinase expression in HT29 colon cancer cells. Additionally, fucoidan treatment activated the Akt signaling pathway, which was inhibited by treatment with an Akt inhibitor. The inhibition of Akt activation reversed the fucoidan-induced decrease in cell proliferation, the induction of G1-phase-associated p21WAF1 expression, and the reduction in cell cycle regulatory protein expression. Intraperitoneal injection of fucoidan reduced tumor volume; this enhanced antitumor efficacy was associated with induction of apoptosis and decreased angiogenesis. These data suggest that the activation of Akt signaling is involved in the growth inhibition of colon cancer cells treated with fucoidan. Thus, fucoidan may serve as a potential therapeutic agent for colon cancer. PMID:25995820

  2. Antitumor Effects of Fucoidan on Human Colon Cancer Cells via Activation of Akt Signaling.

    PubMed

    Han, Yong-Seok; Lee, Jun Hee; Lee, Sang Hun

    2015-05-01

    We identified a novel Akt signaling mechanism that mediates fucoidan-induced suppression of human colon cancer cell (HT29) proliferation and anticancer effects. Fucoidan treatment significantly inhibited growth, induced G1-phase-associated upregulation of p21WAF1 expression, and suppressed cyclin and cyclin-dependent kinase expression in HT29 colon cancer cells. Additionally, fucoidan treatment activated the Akt signaling pathway, which was inhibited by treatment with an Akt inhibitor. The inhibition of Akt activation reversed the fucoidan-induced decrease in cell proliferation, the induction of G1-phase-associated p21WAF1 expression, and the reduction in cell cycle regulatory protein expression. Intraperitoneal injection of fucoidan reduced tumor volume; this enhanced antitumor efficacy was associated with induction of apoptosis and decreased angiogenesis. These data suggest that the activation of Akt signaling is involved in the growth inhibition of colon cancer cells treated with fucoidan. Thus, fucoidan may serve as a potential therapeutic agent for colon cancer.

  3. Inhibition of SW620 human colon cancer cells by upregulating miRNA-145

    PubMed Central

    Li, Chen; Xu, Na; Li, Yu-Qiang; Wang, Yu; Zhu, Zhi-Tu

    2016-01-01

    inhibiting colon cancer cell proliferation and migration. This is a good foundation for development of colon cancer therapy by targeting tumor suppressor miR-145. PMID:26973415

  4. Cancer Research Repository for Individuals With Cancer Diagnosis and High Risk Individuals.

    ClinicalTrials.gov

    2014-12-12

    Pancreatic Cancer; Thyroid Cancer; Lung Cancer; Esophageal Cancer; Thymus Cancer; Colon Cancer; Rectal Cancer; GIST; Anal Cancer; Bile Duct Cancer; Duodenal Cancer; Gallbladder Cancer; Gastric Cancer; Liver Cancer; Small Intestine Cancer; Peritoneal Surface Malignancies; Familial Adenomatous Polyposis; Lynch Syndrome; Bladder Cancer; Kidney Cancer; Penile Cancer; Prostate Cancer; Testicular Cancer; Ureter Cancer; Urethral Cancer; Hypopharyngeal Cancer; Laryngeal Cancer; Lip Cancer; Oral Cavity Cancer; Nasopharyngeal Cancer; Oropharyngeal Cancer; Paranasal Sinus Cancer; Nasal Cavity Cancer; Salivary Gland Cancer; Skin Cancer; CNS Tumor; CNS Cancer; Mesothelioma

  5. Implication of STAT3 signaling in human colonic cancer cells during intestinal trefoil factor 3 (TFF3) -- and vascular endothelial growth factor-mediated cellular invasion and tumor growth.

    PubMed

    Rivat, Christine; Christine, Rivat; Rodrigues, Sylvie; Sylvie, Rodrigues; Bruyneel, Erik; Erik, Bruyneel; Piétu, Geneviève; Geneviève, Piétu; Robert, Amélie; Amélie, Robert; Redeuilh, Gérard; Gérard, Redeuilh; Bracke, Marc; Marc, Bracke; Gespach, Christian; Christian, Gespach; Attoub, Samir; Samir, Attoub

    2005-01-01

    Signal transducer and activator of transcription (STAT) 3 is overexpressed or activated in most types of human tumors and has been classified as an oncogene. In the present study, we investigated the contribution of the STAT3s to the proinvasive activity of trefoil factors (TFF) and vascular endothelial growth factor (VEGF) in human colorectal cancer cells HCT8/S11 expressing VEGF receptors. Both intestinal trefoil peptide (TFF3) and VEGF, but not pS2 (TFF1), activate STAT3 signaling through Tyr(705) phosphorylation of both STAT3alpha and STAT3beta isoforms. Blockade of STAT3 signaling by STAT3beta, depletion of the STAT3alpha/beta isoforms by RNA interference, and pharmacologic inhibition of STAT3alpha/beta phosphorylation by cucurbitacin or STAT3 inhibitory peptide abrogates TFF- and VEGF-induced cellular invasion and reduces the growth of HCT8/S11 tumor xenografts in athymic mice. Differential gene expression analysis using DNA microarrays revealed that overexpression of STAT3beta down-regulates the VEGF receptors Flt-1, neuropilins 1 and 2, and the inhibitor of DNA binding/differentiation (Id-2) gene product involved in the neoplastic transformation. Taken together, our data suggest that TFF3 and the essential tumor angiogenesis regulator VEGF(165) exert potent proinvasive activity through STAT3 signaling in human colorectal cancer cells. We also validate new therapeutic strategies targeting STAT3 signaling by pharmacologic inhibitors and RNA interference for the treatment of colorectal cancer patients.

  6. Fetal programming of colon cancer in adult rats: correlations with altered neonatal trajectory, circulating IGF-I and IGFPBs, and testosterone

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lifelong consumption of soy protein isolate (SPI) reduces the incidence of azoxymethane (AOM)-induced colon tumors in adult male Sprague-Dawley rats. We determined if a maternal SPI diet during pregnancy could protect against colon cancer in progeny. Four groups of male rats were used: a lifetime ...

  7. [Clinical Response of Metastatic Colon Cancer to Chemotherapy with S-1 and Oxaliplatin - A Case Report].

    PubMed

    Morimoto, Tomonori; Yata, Yoshihiro; Yonenaga, Yoshikuni; Hanaki, Kouji; Mise, Masahiro; Higaside, Shunichi; Kanda, Yuuji; Noda, Hideki

    2015-06-01

    Chemotherapy with S-1 and oxaliplatin is a new treatment for metastatic colorectal cancer. We present the first case of S-1, oxaliplatin, and bevacizumab therapy in our hospital. The patient was a 69-year-old woman with ascending colon cancer and multiple lung and liver metastases. She tended to suffer from constipation; stenoses at the cecum and colon cancer were detected by colon fiberscopy. Following surgical resection of the primary tumor, the patient received systemic chemotherapy with S-1, oxaliplatin, and bevacizumab. Following chemotherapy, CT showed no cancer in the lung and cancer reduction in the liver or dissemination. The patient had diarrhea and no appetite at first, so we reduced the oxaliplatin dose by 80%. After reduction of the oxaliplatin dose, we could treat the patient with S-1 and oxaliplatin continuously with no toxicity. S-1 and oxaliplatin chemotherapy is cost-effective, and has less toxicity than other chemotherapies, if proper measures are taken. It seemed to have a non-inferior response rate and disease control compared to other chemotherapies, such as FOLFOX. Thus, this chemotherapy is a valid choice for metastatic colorectal cancer.

  8. Antitumor activity of 2-hydroxycinnamaldehyde for human colon cancer cells through suppression of β-catenin signaling.

    PubMed

    Lee, Min Ai; Park, Hyen Joo; Chung, Hwa-Jin; Kim, Won Kyung; Lee, Sang Kook

    2013-07-26

    The antiproliferative and antitumor activities of 2-hydroxycinnamaldehyde (1), a phenylpropanoid isolated from the bark of Cinnamomum cassia, were investigated using human colorectal cancer cells. Compound 1 exhibited antiproliferative effects in HCT116 colon cancer cells, accompanied by modulation of the Wnt/β-catenin cell signaling pathway. This substance was found also to inhibit β-catenin/T-cell factor (TCF) transcriptional activity in HEK293 cells and HCT116 colon cancer cells. Further mechanistic investigations in human colon cancer cells with aberrantly activated Wnt/β-catenin signaling showed that 1 significantly suppressed the binding of β-catenin/TCF complexes to their specific genomic targets in the nucleus and led to the down-regulation of Wnt target genes such as c-myc and cyclin D1. In an in vivo xenograft model, the intraperitoneal administration of 1 (10 or 20 mg/kg body weight, three times/week) for four weeks suppressed tumor growth in athymic nude mice implanted with HCT116 colon cancer cells significantly, without any apparent toxicity. In an ex vivo biochemical analysis of the tumors, compound 1 was also found to suppress Wnt target genes associated with tumor growth including β-catenin, c-myc, cyclin D1, and survivin. The suppression of the Wnt/β-catenin signaling pathway is a plausible mechanism of action underlying the antiproliferative and antitumor activity of 1 in human colorectal cancer cells. PMID:23855266

  9. RPM peptide conjugated bioreducible polyethylenimine targeting invasive colon cancer.

    PubMed

    Lee, Yeong Mi; Lee, Duhwan; Kim, Jihoon; Park, Hansoo; Kim, Won Jong

    2015-05-10

    CPIEDRPMC (RPM) peptide is a peptide that specifically targets invasive colorectal cancer, which is one of the leading causes of cancer-related deaths worldwide. In this study, we exploited RPM peptide as a targeting ligand to produce a novel and efficient gene delivery system that could potentially be used to treat invasive colon cancer. In order to achieve enhanced specificity to colon cancer cells, the RPM peptide was conjugated to a bioreducible gene carrier consisting of a reducible moiety of disulfide-crosslinked low molecular weight polyethylenimine, IR820 dye, and polyethylene glycol. Here, we examined the physiochemical properties, cytotoxicity, in vitro transfection efficiency, and in vivo biodistribution of the RPM-conjugated polyplex. Our results showed that the RPM-conjugated gene carrier formed a compact polyplex with pDNA that had low toxicity. Furthermore, the RPM-conjugated polymer not only had higher cellular uptake in invasive colon cancer than the non-targeted polymer, but also showed enhanced transfection efficiency in invasive colon cancer cells in vitro and in vivo.

  10. Western diet enhances benzo(a)pyrene-induced colon tumorigenesis in a polyposis in rat coli (PIRC) rat model of colon cancer

    PubMed Central

    Harris, Kelly L.; Pulliam, Stephanie R.; Okoro, Emmanuel; Guo, Zhongmao; Washington, Mary K.; Adunyah, Samuel E.; Amos-Landgraf, James M.; Ramesh, Aramandla

    2016-01-01

    Consumption of Western diet (WD), contaminated with environmental toxicants, has been implicated as one of the risk factors for sporadic colon cancer. Our earlier studies using a mouse model revealed that compared to unsaturated dietary fat, the saturated dietary fat exacerbated the development of colon tumors caused by B(a)P. The objective of this study was to study how WD potentiates B(a)P-induced colon carcinogenesis in the adult male rats that carry a mutation in the Apc locus - the polyposis in the rat colon (PIRC) rats. Groups of PIRC rats were fed with AIN-76A standard diet (RD) or Western diet (WD) and received 25, 50, or 100 μg B(a)P/kg body weight (wt) via oral gavage for 60 days. Subsequent to exposure, rats were euthanized; colons were retrieved and preserved in 10% formalin for counting the polyp numbers, measuring the polyp size, and histological analyses. Blood samples were collected and concentrations of cholesterol, triglycerides, glucose, insulin and leptin were measured. Rats that received WD + B(a)P showed increased levels of cholesterol, triglycerides, and leptin in comparison to RD + B(a)P groups or controls. The colon tumor numbers showed a B(a)P dose-response relationship. Adenomas with high grade dysplasia were prominent in B(a)P + WD rats compared to B(a)P + RD rats and controls (p < 0.05). The larger rat model system used in this study allows for studying more advanced tumor phenotypes over a longer duration and delineating the role of diet - toxicant interactions in sporadic colon tumor development. PMID:26959117

  11. Pretargeted immuno-PET of CEA-expressing intraperitoneal human colonic tumor xenografts: a new sensitive detection method

    PubMed Central

    2012-01-01

    Background In this study, pretargeted immuno-positron-emission tomography [PET] with a bispecific monoclonal anti-carcinoembryonic antigen [CEA] (CEACAM5) × anti-hapten antibody (bispecific monoclonal antibody [bsmAb]) and a small (1.5 kD) peptide labeled with 68Ga was compared to fludeoxyglucose [18F-FDG]-PET for detecting intraperitoneal [i.p.] CEA-expressing human colonic tumor xenografts in nude mice. Methods Two groups of female BALB/c nude mice were inoculated with LS174T human colonic tumor cells i.p. One group received 5 MBq 18F-FDG, and the other received intravenous injections of the bsmAb, followed 16 h later with 5 MBq of 68Ga-labeled peptide. One hour after the radiolabeled peptide or FDG was given, micro-PET/computed tomography images were acquired. Thereafter, the uptake of the 68Ga or 18F in dissected tissue was determined. Results Within 1 h, high uptake of the 68Ga-labeled peptide in the tumor lesions (23.4 ± 7.2% ID/g) and low background activity levels were observed (e.g., tumor-to-intestine ratio, 58 ± 22). This resulted in a clear visualization of all intra-abdominal tumor lesions ≥ 10 μL and even some tumors as small as 5 μL (2 mm diameter). 18F-FDG efficiently localized in the tumors (8.7 ± 3.1% ID/g) but also showed physiological uptake in various normal tissues (e.g., tumor-to-intestine ratio, 3.9 ± 1.1). Conclusions Pretargeted immuno-PET with bsmAb and a 68Ga-labeled peptide could be a very sensitive imaging method for imaging colonic cancer, disclosing occult lesions. PMID:22284761

  12. Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention.

    PubMed

    Zeng, Huawei; Lazarova, Darina L; Bordonaro, Michael

    2014-02-15

    Many epidemiological and experimental studies have suggested that dietary fiber plays an important role in colon cancer prevention. These findings may relate to the ability of fiber to reduce the contact time of carcinogens within the intestinal lumen and to promote healthy gut microbiota, which modifies the host's metabolism in various ways. Elucidation of the mechanisms by which dietary fiber-dependent changes in gut microbiota enhance bile acid deconjugation, produce short chain fatty acids, and modulate inflammatory bioactive substances can lead to a better understanding of the beneficial role of dietary fiber. This article reviews the current knowledge concerning the mechanisms via which dietary fiber protects against colon cancer.

  13. STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH{sup +}/CD133{sup +} stem cell-like human colon cancer cells

    SciTech Connect

    Lin, Li; Fuchs, James; Li, Chenglong; Olson, Veronica; Bekaii-Saab, Tanios; Lin, Jiayuh

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells. Black-Right-Pointing-Pointer STAT3 inhibitor, FLLL32 inhibits P-STAT3 and STAT3 target genes in colon cancer stem-like cells. Black-Right-Pointing-Pointer Inhibition of STAT3 resulted in decreased cell viability and reduced numbers of tumorspheres. Black-Right-Pointing-Pointer STAT3 is required for survival and tumorsphere forming capacity in colon cancer stem-like cells. Black-Right-Pointing-Pointer Targeting STAT3 in cancer stem-like cells may offer a novel treatment approach for colon cancer. -- Abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existence of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH{sup +}/CD133{sup +}). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower

  14. Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer.

    PubMed

    Vasudevan, Anita; Yu, Yingjie; Banerjee, Sanjeev; Woods, James; Farhana, Lulu; Rajendra, Sindhu G; Patel, Aamil; Dyson, Gregory; Levi, Edi; Maddipati, Krishna Rao; Majumdar, Adhip P N; Nangia-Makker, Pratima

    2014-11-01

    Increasing evidence supports the contention that many malignancies, including sporadic colorectal cancer, are driven by the self-renewing, chemotherapy-resistant cancer stem/stem-like cells (CSC/CSLC), underscoring the need for improved preventive and therapeutic strategies targeting CSCs/CSLCs. Omega-3 polyunsaturated fatty acids (ω-3 PUFA), have been reported to inhibit the growth of primary tumors, but their potential as a preventive agent for recurring cancers is unexplored. The primary objectives of this investigation are (i) to examine whether eicosapentaenoic acid (EPA; one of the ω-3 PUFA) synergizes with FuOx (5-FU+Oxaliplatin), the backbone of colon cancer chemotherapy, and (ii) whether EPA by itself or in combination with conventional chemotherapy prevents the recurrence of colon cancer via eliminating/suppressing CSCs/CSLCs. FuOx-resistant (chemoresistant; CR) colon cancer cells, highly enriched in CSCs, were used for this study. Although EPA alone was effective, combination of EPA and FuOx was more potent in (i) inhibiting cell growth, colonosphere formation, and sphere-forming frequency, (ii) increasing sphere disintegration, (iii) suppressing the growth of SCID mice xenografts of CR colon cancer cells, and (iv) decreasing proinflammatory metabolites in mice. In addition, EPA + FuOx caused a reduction in CSC/CSLC population. The growth reduction by this regimen is the result of increased apoptosis as evidenced by PARP cleavage. Furthermore, increased pPTEN, decreased pAkt, normalization of β-catenin expression, localization, and transcriptional activity by EPA suggests a role for the PTEN-Akt axis and Wnt signaling in regulating this process. Our data suggest that EPA by itself or in combination with FuOx could be an effective preventive strategy for recurring colorectal cancer.

  15. Schlafen-3 decreases cancer stem cell marker expression and autocrine/juxtacrine signaling in FOLFOX-resistant colon cancer cells.

    PubMed

    Oh, Phil-Sun; Patel, Vaishali B; Sanders, Matthew A; Kanwar, Shailender S; Yu, Yingjie; Nautiyal, Jyoti; Patel, Bhaumik B; Majumdar, Adhip P N

    2011-08-01

    We have previously demonstrated that expression of the novel gene schlafen-3 (Slfn-3) correlates with intestinal epithelial cell differentiation (Patel VB, Yu Y, Das JK, Patel BB, Majumdar AP. Biochem Biophys Res Commun 388: 752-756, 2009). The present investigation was undertaken to examine whether Slfn-3 plays a role in regulating differentiation of FOLFOX-resistant (5-fluorouracil + oxaliplatin) colon cancer cells that are highly enriched in cancer stem cells (CSCs). Transfection of Slfn-3 in FOLFOX-resistant colon cancer HCT-116 cells resulted in increase of alkaline phosphatase activity, a marker of intestinal differentiation. Additionally, Slfn-3 transfection resulted in reduction of mRNA and protein levels of the CSC markers CD44, CD133, CD166, and aldehyde dehydrogenase 1 in both FOLFOX-resistant HCT-116 and HT-29 cells. This was accompanied by decreased formation of tumorosphere/colonosphere (an in vitro model of tumor growth) in stem cell medium and inhibition of expression of the chemotherapeutic drug transporter protein ABCG2. Additionally, Slfn-3 transfection of FOLFOX-resistant HCT-116 and HT-29 cells reduced Hoechst 33342 dye exclusion. Finally, Slfn-3 transfection inhibited the expression of transforming growth factor-α in both FOLFOX-resistant colon cancer cells, but stimulated apoptosis in response to additional FOLFOX treatment. In summary, our data demonstrate that Slfn-3 expression inhibits multiple characteristics of CSC-enriched, FOLFOX-resistant colon cancer cells, including induction of differentiation and reduction in tumorosphere/colonosphere formation, drug transporter activity, and autocrine stimulation of proliferation. Thus Slfn-3 expression may render colon CSCs more susceptible to cancer chemotherapeutics.

  16. Cancer Progression and Tumor Growth Kinetics

    NASA Astrophysics Data System (ADS)

    Blagoev, Krastan; Kalpathy-Cramer, Jayashree; Wilkerson, Julia; Sprinkhuizen, Sara; Song, Yi-Qiao; Bates, Susan; Rosen, Bruce; Fojo, Tito

    2013-03-01

    We present and analyze tumor growth data from prostate and brain cancer. Scaling the data from different patients shows that early stage prostate tumors show non-exponential growth while advanced prostate and brain tumors enter a stage of exponential growth. The scaling analysis points to the existence of cancer stem cells and/or massive apoptosis in early stage prostate cancer and that late stage cancer growth is not dominated by cancer stem cells. Statistical models of these two growth modes are discussed. Work supported by the National Science Foundation and the National Institutes of Health

  17. Five New Genes Linked to Colon Cancer

    MedlinePlus

    ... More Health News on: Colorectal Cancer Genes and Gene Therapy Recent Health News Related MedlinePlus Health Topics Colorectal Cancer Genes and Gene Therapy About MedlinePlus Site Map FAQs Contact Us Get ...

  18. Treatment with Insulin Analog X10 and IGF-1 Increases Growth of Colon Cancer Allografts

    PubMed Central

    Hvid, Henning; Blouin, Marie-José; Birman, Elena; Damgaard, Jesper; Poulsen, Fritz; Fels, Johannes Josef; Fledelius, Christian; Hansen, Bo Falck; Pollak, Michael

    2013-01-01

    Obesity and type 2 diabetes are associated with an increased risk for development of certain forms of cancer, including colon cancer. The publication of highly controversial epidemiological studies in 2009 raised the possibility that use of the insulin analog glargine increases this risk further. However, it is not clear how mitogenic effects of insulin and insulin analogs measured in vitro correlate with tumor growth-promoting effects in vivo. The aim of this study was to examine possible growth-promoting effects of native human insulin, insulin X10 and IGF-1, which are considered positive controls in vitro, in a short-term animal model of an obesity- and diabetes-relevant cancer. We characterized insulin and IGF-1 receptor expression and the response to treatment with insulin, X10 and IGF-1 in the murine colon cancer cell line (MC38 cells) in vitro and in vivo. Furthermore, we examined pharmacokinetics and pharmacodynamics and monitored growth of MC38 cell allografts in mice with diet-induced obesity treated with human insulin, X10 and IGF-1. Treatment with X10 and IGF-1 significantly increased growth of MC38 cell allografts in mice with diet-induced obesity and we can therefore conclude that supra-pharmacological doses of the insulin analog X10, which is super-mitogenic in vitro and increased the incidence of mammary tumors in female rats in a 12-month toxicity study, also increase growth of tumor allografts in a short-term animal model. PMID:24260289

  19. Sasa quelpaertensis Leaf Extract Inhibits Colon Cancer by Regulating Cancer Cell Stemness in Vitro and in Vivo

    PubMed Central

    Min, Soo Jin; Lim, Ji Ye; Kim, Haeng Ran; Kim, Se-Jae; Kim, Yuri

    2015-01-01

    A rare subpopulation of cancer cells, termed cancer stem cells (CSCs), may be responsible for tumor relapse and resistance to conventional chemotherapy. The development of a non-toxic, natural treatment for the elimination of CSCs is considered a strategy for cancer treatment with minimal side effects. In the present study, the potential for Sasa quelpaertensis leaf extract (SQE) and its two bioactive compounds, tricin and p-coumaric acid, to exert anti-CSC effects by suppressing cancer stemness characteristics were evaluated in colon cancer cells. CD133+CD44+ cells were isolated from HT29 and HCT116 cell lines using flow-activated cell sorting (FACs). SQE treatment was found to significantly suppress the self-renewal capacity of both cell lines. SQE treatment was also associated with the down-regulation of β-catenin and phosphorylated GSK3β, while significantly enhancing cell differentiation by up-regulating CK20 expression and blocking the expression of several stem cell markers, including DLK1, Notch1, and Sox-2. In vivo, SQE supplementation suppressed tumor growth in a xenograft model by down-regulating stem cell markers and β-catenin as well as HIF-1α signaling. Compared with two bioactive compounds of SQE, SQE exhibited the most effective anti-CSC properties. Taken together, these results provide evidence that SQE inhibits colon cancer by regulating the characteristics of CSCs. PMID:25941936

  20. Validation of methylation biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer.

    PubMed

    Cesaroni, Matteo; Powell, Jasmine; Sapienza, Carmen

    2014-07-01

    We have validated differences in DNA methylation levels of candidate genes previously reported to discriminate between normal colon mucosa of patients with colon cancer and normal colon mucosa of individuals without cancer. Here, we report that CpG sites in 16 of the 30 candidate genes selected show significant differences in mean methylation level in normal colon mucosa of 24 patients with cancer and 24 controls. A support vector machine trained on these data and data for an additional 66 CpGs yielded an 18-gene signature, composed of ten of the validated candidate genes plus eight additional candidates. This model exhibited 96% sensitivity and 100% specificity in a 40-sample training set and classified all eight samples in the test set correctly. Moreover, we found a moderate-strong correlation (Pearson coefficients r = 0.253-0.722) between methylation levels in colon mucosa and methylation levels in peripheral blood for seven of the 18 genes in the support vector model. These seven genes, alone, classified 44 of the 48 patients in the validation set correctly and five CpGs selected from only two of the seven genes classified 41 of the 48 patients in the discovery set correctly. These results suggest that methylation biomarkers may be developed that will, at minimum, serve as useful objective and quantitative diagnostic complements to colonoscopy as a cancer-screening tool. These data also suggest that it may be possible to monitor biomarker methylation levels in tissues collected much less invasively than by colonoscopy.

  1. Streptococcus pneumoniae pharyngeal colonization in school-age children and adolescents with cancer

    PubMed Central

    Principi, Nicola; Preti, Valentina; Gaspari, Stefania; Colombini, Antonella; Zecca, Marco; Terranova, Leonardo; Cefalo, Maria Giuseppina; Ierardi, Valentina; Pelucchi, Claudio; Esposito, Susanna

    2016-01-01

    Patients with cancer, particularly those with hematologic malignancies, are at an increased risk of invasive pneumococcal disease (IPD) and they are included in the list of subjects for whom pneumococcal vaccination is recommended. The main aim of this study was to evaluate Streptococcus pneumoniae colonization in school-aged children and adolescents with cancer to determine the potential protective efficacy of 13-valent pneumococcal conjugate vaccine (PCV13). An oropharyngeal swab was obtained from 277 patients (age range 6-17 years) with cancer during routine clinical visits and analyzed for S. pneumoniae using real-time polymerase chain reaction. S. pneumoniae was identified in 52 patients (18.8%), including 47/235 (20.0%) with hematologic malignancies and 5/42 (11.9%) with solid tumors. Colonization declined significantly with an increase in age (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.16-0.71, and OR 0.30, 95% CI 0.11-0.82 in children aged 10-14 and ≥15 years, respectively, as compared to those <10 years). Carriage was more common among patients with leukemia or lymphoma than in children with solid tumors. Co-trimoxazole prophylaxis was significantly associated with reduced pneumococcal carriage (OR 0.41, 95% CI 0.19–0.89). A total of 15/58 (25.9%) and 26/216 (12.0%) children were colonized by PCV13 serotypes among cancer patients previously vaccinated and not vaccinated with 7-valent pneumococcal conjugate vaccine (PCV7), respectively. In conclusion, this study indicates that children and adolescents with cancer are frequently colonized by S. pneumoniae. Because most of the carried serotypes are included in PCV13, this vaccine is presently the best solution to reduce the risk of IPD in these patients. PMID:26367101

  2. Targeted deletion of the metastasis-associated phosphatase Ptp4a3 (PRL-3) suppresses murine colon cancer.

    PubMed

    Zimmerman, Mark W; Homanics, Gregg E; Lazo, John S

    2013-01-01

    Ptp4a3 (commonly known as PRL-3) is an enigmatic member of the Ptp4a family of prenylated protein tyrosine phosphatases that are highly expressed in many human cancers. Despite strong correlations with tumor metastasis and poor patient prognosis, there is very limited understanding of this gene family's role in malignancy. Therefore, we created a gene-targeted murine knockout model for Ptp4a3, the most widely studied Ptp4a family member. Mice deficient for Ptp4a3 were grossly normal. Fewer homozygous-null males were observed at weaning, however, and they maintained a decreased body mass. Although Ptp4a3 is normally associated with late-stage cancer and metastasis, we observed increased Ptp4a3 expression in the colon of wildtype mice immediately following treatment with the carcinogen azoxymethane. To investigate the role of Ptp4a3 in malignancy, we used the most commonly studied murine colitis-associated colon cancer model. Wildtype mice treated with azoxymethane and dextran sodium sulfate developed approximately 7-10 tumors per mouse in the distal colon. The resulting tumor tissue had 4-fold more Ptp4a3 mRNA relative to normal colon epithelium and increased PTP4A3 protein. Ptp4a3-null mice developed 50% fewer colon tumors than wildtype mice after exposure to azoxymethane and dextran sodium sulfate. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with Ptp4a3, suggesting an enhanced cell signaling pathway engagement in the absence of the phosphatase. These results provide the first definitive evidence implicating Ptp4a3 in colon tumorigenesis and highlight the potential value of the phosphatase as a therapeutic target for early stage malignant disease.

  3. Hyaluronic acid-tagged silica nanoparticles in colon cancer therapy: therapeutic efficacy evaluation

    PubMed Central

    Liu, Kai; Wang, Zhi-qi; Wang, Shi-jiang; Liu, Ping; Qin, Yue-hong; Ma, Yan; Li, Xiao-Chen; Huo, Zhi-Jun

    2015-01-01

    Colon cancer is one of the leading causes of cancer-related death worldwide, and the therapeutic application of 5-fluorouracil (5-FU) is limited due to its nonspecificity, low bioavailability, and overdose. The present study is an attempt to improve the chemotherapeutic efficacy of 5-FU in colon cancers. Therefore, we have prepared 5-FU-loaded hyaluronic acid (HA)-conjugated silica nanoparticles (SiNPs) to target to colon cancer cells. In this study, we have showed the specific binding and intracellular accumulation of targeted nanoparticles based on HA surface modifications in colon carcinoma cells. The particles had spherical shapes with sizes of approximately 130 nm. HA-conjugated nanoparticles showed a sustained release pattern for 5-FU and continuously released for 120 hours. We have further investigated the cytotoxicity potential of targeted and nontargeted nanoparticles in colo-205 cancer cells. IC50 value of 5-FU/hyaluronic acid-conjugated silica nanoparticles (HSNP) was 0.65 µg/mL compared with ~2.8 µg/mL for 5-FU/SNP after 24 hours of incubation. The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. The 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/silica nanoparticles (SNP)-treated group. The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model. The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs. Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy. Thus, 5-FU/HSNP could be a promising drug delivery system for colon cancer

  4. Hyaluronic acid-tagged silica nanoparticles in colon cancer therapy: therapeutic efficacy evaluation.

    PubMed

    Liu, Kai; Wang, Zhi-qi; Wang, Shi-jiang; Liu, Ping; Qin, Yue-hong; Ma, Yan; Li, Xiao-Chen; Huo, Zhi-Jun

    2015-01-01

    Colon cancer is one of the leading causes of cancer-related death worldwide, and the therapeutic application of 5-fluorouracil (5-FU) is limited due to its nonspecificity, low bioavailability, and overdose. The present study is an attempt to improve the chemotherapeutic efficacy of 5-FU in colon cancers. Therefore, we have prepared 5-FU-loaded hyaluronic acid (HA)-conjugated silica nanoparticles (SiNPs) to target to colon cancer cells. In this study, we have showed the specific binding and intracellular accumulation of targeted nanoparticles based on HA surface modifications in colon carcinoma cells. The particles had spherical shapes with sizes of approximately 130 nm. HA-conjugated nanoparticles showed a sustained release pattern for 5-FU and continuously released for 120 hours. We have further investigated the cytotoxicity potential of targeted and nontargeted nanoparticles in colo-205 cancer cells. IC50 value of 5-FU/hyaluronic acid-conjugated silica nanoparticles (HSNP) was 0.65 µg/mL compared with ~2.8 µg/mL for 5-FU/SNP after 24 hours of incubation. The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. The 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/silica nanoparticles (SNP)-treated group. The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model. The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs. Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy. Thus, 5-FU/HSNP could be a promising drug delivery system for colon cancer

  5. Clinical significance of aberrant mammalian target of rapamycin expression in stage IIIB colon cancer

    PubMed Central

    WEN, MEILING; LI, BAOXIU; CAO, XIAOFEI; WENG, CHENGYIN; WU, YONG; FANG, XISHENG; ZHANG, XIAOSHI; LIU, GUOLONG

    2014-01-01

    The aim of the present study was to investigate the significance of aberrant expression of mammalian target of rapamycin (mTOR) and the activated form of mTOR kinase, phosphorylated mTOR (pmTOR), in human stage IIIB colon cancer. The expression of mTOR and pmTOR was detected by immunohistochemistry in the tumor tissue of stage IIIB colon cancer patients. The association between the expression of mTOR, pmTOR and clinicopathological parameters of patients was analyzed. The positive expression of mTOR and pmTOR was observed to be higher in 75.5% (80/106) and 76.4% (81/106) of the 106 colon cancer specimens, compared with the adjacent normal tissues. The high level of pmTOR expression was found to be significantly higher in the invasive tumor front cells and resulted in a higher risk of mortality. The results suggested that mTOR and pmTOR may be promising clinical markers and present novel molecular targets for designing novel therapeutic strategies to treat this malignancy. PMID:25120661

  6. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

    PubMed

    Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

    2003-01-01

    Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.

  7. Inhibition of cyclooxygenase-1 lowers proliferation and induces macroautophagy in colon cancer cells

    SciTech Connect

    Wu, William Ka Kei; Wu, Ya Chun; Li, Hai To

    2009-04-24

    Evolving evidence supports that cyclooxygenase-1 (COX-1) takes part in colon carcinogenesis. The effects of COX-1 inhibition on colon cancer cells, however, remains obscured. In this study, we demonstrate that COX-1 inhibitor sc-560 inhibited colon cancer cell proliferation with concomitant G{sub 0}/G{sub 1}-phase cell cycle arrest. The anti-proliferative effect was associated with down-regulation of c-Fos, cyclin E{sub 2} and E{sub 2}F-1 and up-regulation of p21{sup Waf1/Cip1} and p27{sup Kip1}. In addition, sc-560 induced macroautophagy, an emerging mechanism of tumor suppression, as evidenced by the formation of LC3{sup +} autophagic vacuoles, enhanced LC3 processing, and the accumulation of acidic vesicular organelles and autolysosomes. In this connection, 3-methyladenine, a Class III phosphoinositide 3-kinase inhibitor, significantly abolished the formation of LC3{sup +} autophagic vacuoles and the processing of LC3 induced by sc-560. To conclude, this study reveals the unreported relationship between COX-1 and proliferation/macroautophagy of colon cancer cells.

  8. Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis.

    PubMed

    Valdés, Alberto; García-Cañas, Virginia; Rocamora-Reverte, Lourdes; Gómez-Martínez, Angeles; Ferragut, José Antonio; Cifuentes, Alejandro

    2013-01-01

    In this work, the effect of rosemary extracts rich on polyphenols obtained using pressurized fluids was investigated on the gene expression of human SW480 and HT29 colon cancer cells. The application of transcriptomic profiling and functional enrichment analysis was done via two computational approaches, Ingenuity Pathway Analysis and Gene Set Enrichment Analysis. These two approaches were used for functional enrichment analysis as a previous step for a reliable interpretation of the data obtained from microarray analysis. Reverse transcription quantitative-PCR was used to confirm relative changes in mRNA levels of selected genes from microarrays. The selection of genes was based on their expression change, adjusted p value, and known biological function. According to genome-wide transcriptomics analysis, rosemary polyphenols altered the expression of ~4 % of the genes covered by the Affymetrix Human Gene 1.0ST chip in both colon cancer cells. However, only ~18 % of the differentially expressed genes were common to both cell lines, indicating markedly different expression profiles in response to the treatment. Differences in induction of G2/M arrest observed by rosemary polyphenols in the two colon adenocarcinoma cell lines suggest that the extract may be differentially effective against tumors with specific mutational pattern. From our results, it is also concluded that rosemary polyphenols induced a low degree of apoptosis indicating that other multiple signaling pathways may contribute to colon cancer cell death.

  9. MUC1-C ACTIVATES THE TAK1 INFLAMMATORY PATHWAY IN COLON CANCER

    PubMed Central

    Takahashi, Hidekazu; Jin, Caining; Rajabi, Hasan; Pitroda, Sean; Alam, Maroof; Ahmad, Rehan; Raina, Deepak; Hasegawa, Masanori; Suzuki, Yozo; Tagde, Ashujit; Bronson, Roderick T.; Weichselbaum, Ralph; Kufe, Donald

    2015-01-01

    The mucin 1 (MUC1) oncoprotein has been linked to the inflammatory response by promoting cytokine-mediated activation of the NF-κB pathway. The TGF-β-activated kinase 1 (TAK1) is an essential effector of proinflammatory NF-κB signaling that also regulates cancer cell survival. The present studies demonstrate that the MUC1-C transmembrane subunit induces TAK1 expression in colon cancer cells. MUC1 also induces TAK1 in a MUC1+/−/IL-10−/− mouse model of colitis and colon tumorigenesis. We show that MUC1-C promotes NF-κB-mediated activation of TAK1 transcription and, in a positive regulatory loop, MUC1-C contributes to TAK1-induced NF-κB signaling. In this way, MUC1-C binds directly to TAK1 and confers the association of TAK1 with TRAF6, which is necessary for TAK1-mediated activation of NF-κB. Targeting MUC1-C thus suppresses the TAK1→NF-κB pathway, downregulates BCL-XL, and in turn sensitizes colon cancer cells to MEK inhibition. Analysis of colon cancer databases further indicates that MUC1, TAK1 and TRAF6 are upregulated in tumors associated with decreased survival and that MUC1-C-induced gene expression patterns predict poor outcomes in patients. These results support a model in which MUC1-C-induced TAK1→NF-κB signaling contributes to intestinal inflammation and colon cancer progression. PMID:25659581

  10. The B-cell tumor promoter Bcl-3 suppresses inflammation-associated colon tumorigenesis in epithelial cells

    PubMed Central

    Tang, Wanhu; Wang, Hongshan; Ha, Hye-lin; Tassi, Ilaria; Bhardwaj, Reetika; Claudio, Estefania; Siebenlist, Ulrich

    2016-01-01

    Bcl-3 is an atypical member of the IκB family. It associates with p50/NF-κB1 and p52/NF-κB2 homodimers in nuclei where it modulates transcription in a context-dependent manner. A subset of B cell tumors exhibits recurrent translocations of Bcl-3, resulting in overexpression. Elevated expression without translocations is also observed in various B cell lymphomas and even some solid tumors. Here we investigated the role of Bcl-3 in AOM/DSS-induced colon tumors, a mouse model for colitis-associated colorectal cancers in humans. Contrary to expectations, Bcl-3 suppressed colorectal tumor formation: Bcl-3-deficient mice were relatively protected from DSS-induced epithelial damage and developed more polyps after AOM/DSS treatment, though polyp size was unaffected. DSS-challenged mutant mice exhibited increased recruitment of myeloid-derived suppressor cells (MDSCs), consistent with protection of the epithelium. Loss of Bcl-3 in intestinal epithelial cells was sufficient to increase tumorigenesis. The added tumor burden in mutant mice was dependent on TNFα, a tumorigenic, NF-κB-mediated signaling pathway that was dampened by Bcl-3. These findings reveal a tumor-suppressive role for Bcl-3 in this inflammation-associated cancer model. Bcl-3 thus functions as a tumor promoter or suppressor, depending on the cellular and environmental context. PMID:27132515

  11. Dietary fibre and colon cancer: epidemiologic and experimental evidence.

    PubMed Central

    Reddy, B S

    1980-01-01

    Epidemiologic studies have identified two dietary factors, a relatively high intake of fat and a relatively low intake of fibre, that are associated with colon cancer in humans. However, a recent study has shown a low risk of large bowel cancer in a rural Finnish population with a high dietary intake of fat, but also a high intake of fibre. Observations in humans and studies in animals have indicated that dietary fibre may protect against colon carcinogenesis by binding bile acids in the intestinal tract, by a direct effect on the colonic mucosa and by an indirect effect on the metabolism of carcinogens. The strength of protection varies with the type of fibre. PMID:6254626

  12. Three cases of endoscopic resection for synchronous early colon cancers after self-expandable metallic stent placement for obstructive colon cancer

    PubMed Central

    Moroi, Rintaro; Endo, Katsuya; Ichikawa, Ryo; Takahashi, So; Shiroki, Takeharu; Shinkai, Hirohiko; Ishiyama, Fumitake; Kayaba, Shoichi

    2016-01-01

    Background and study aims: The feasibility of endoscopic resection for synchronous early colon cancer after placement of self-expandable metallic stents (SEMS) for malignant colorectal obstruction is unknown. Herein we evaluated 3 cases of endoscopic resection for synchronous early colorectal cancers after SEMS placement. Patient 1 was an 82-year-old man with obstructive sigmoid colon cancer. We curatively treated the synchronous descending colon cancer with endoscopic submucosal dissection (ESD) and the rectal cancer with endoscopic mucosal resection (EMR) after SEMS placement. This is the first reported case of a successful ESD for synchronous early colon cancer via the use of a colonic stent. Patient 2 was an 81-year-old man with obstructive ascending colon cancer. We resected the synchronous transverse colon cancer via ESD. Histologic findings indicated that the carcinoma cells had invaded the submucosal layer. Therefore, we immediately performed expanded right-hemicolectomy. Patient 3 was an 81-year-old man with obstructive sigmoid colon cancer. We curatively treated the synchronous transverse colon cancer with EMR after SEMS placement. There were no complications associated with the endoscopic treatments in any of the cases. Our results indicate that preoperative endoscopic resection combined with the ESD technique for synchronous colorectal cancer after SEMS placement could be effective as a surgical strategy for patients with malignant colorectal obstruction. PMID:27652303

  13. Three cases of endoscopic resection for synchronous early colon cancers after self-expandable metallic stent placement for obstructive colon cancer

    PubMed Central

    Moroi, Rintaro; Endo, Katsuya; Ichikawa, Ryo; Takahashi, So; Shiroki, Takeharu; Shinkai, Hirohiko; Ishiyama, Fumitake; Kayaba, Shoichi

    2016-01-01

    Background and study aims: The feasibility of endoscopic resection for synchronous early colon cancer after placement of self-expandable metallic stents (SEMS) for malignant colorectal obstruction is unknown. Herein we evaluated 3 cases of endoscopic resection for synchronous early colorectal cancers after SEMS placement. Patient 1 was an 82-year-old man with obstructive sigmoid colon cancer. We curatively treated the synchronous descending colon cancer with endoscopic submucosal dissection (ESD) and the rectal cancer with endoscopic mucosal resection (EMR) after SEMS placement. This is the first reported case of a successful ESD for synchronous early colon cancer via the use of a colonic stent. Patient 2 was an 81-year-old man with obstructive ascending colon cancer. We resected the synchronous transverse colon cancer via ESD. Histologic findings indicated that the carcinoma cells had invaded the submucosal layer. Therefore, we immediately performed expanded right-hemicolectomy. Patient 3 was an 81-year-old man with obstructive sigmoid colon cancer. We curatively treated the synchronous transverse colon cancer with EMR after SEMS placement. There were no complications associated with the endoscopic treatments in any of the cases. Our results indicate that preoperative endoscopic resection combined with the ESD technique for synchronous colorectal cancer after SEMS placement could be effective as a surgical strategy for patients with malignant colorectal obstruction.

  14. Variability in the lymph node retrieval after resection of colon cancer: Influence of operative period and process.

    PubMed

    Choi, Jung Pil; Park, In Ja; Lee, Byung Cheol; Hong, Seung Mo; Lee, Jong Lyul; Yoon, Yong Sik; Kim, Chan Wook; Lim, Seok-Byung; Lee, Jung Bok; Yu, Chang Sik; Kim, Jin Cheon

    2016-08-01

    The purpose of this study was to evaluate variations in the number of retrieved lymph nodes (LNs) over time and to determine the factors that influence the retrieval of <12 LNs during colon cancer resection.Patients with colon cancer who were surgically treated between 1997 and 2013 were identified from our institutional tumor registry. Patient, tumor, and pathologic variables were evaluated. Factors that influenced the retrieval of <12 LNs were evaluated using multivariate logistic regression modeling, including time effects.In total, 6967 patients were identified. The median patient age was 61 years (interquartile range [IQR] = 45-79 years) and 58.4% of these patients were male. The median number of LNs retrieved was 21 (IQR = 14-29), which increased from 14 (IQR = 11-27) in 1997 to 26 (IQR = 19-34) in 2013. The proportion of patients with ≥12 retrieved LNs increased from 72% in 1997 to 98.8% in 2013 (P < 0.00001). This corresponded to the more recent emphasis on a multidisciplinary approach to adequate LN evaluation. The number of retrieved LNs was also found to be associated with age, sex, tumor location, T stage, and operative year. Tumor location and T stage influenced the number of retrieved LNs, irrespective of the operative year (P < 0.05). Factors including a tumor location in the sigmoid/left colon, old age, open resection, earlier operative year, and early T stage were more likely to be associated with <12 recovered LNs (P < 0.5; chi-squared test) (P < 0.001).The total number of retrieved LNs may be influenced by tumor location and T stage of a colon cancer, irrespective of the year of surgery. LN retrieval after colon cancer resection has increased in recent years due to a better awareness of its importance and the use of multidisciplinary approaches. PMID:27495024

  15. Detection of colon and rectum cancers by terahertz techniques

    NASA Astrophysics Data System (ADS)

    Wahaia, Faustino; Valusis, Gintaras; Bernardo, Luis M.; Oliveira, Albino; Macutkevic, Jan; Kasalynas, Irmantas; Seliuta, Dalius

    2010-04-01

    Based on experimental analyses of colon and rectal tissues by THz spectroscopy and THz imaging, we show it is possible to distinguish between healthy and cancerous zones. Plots of the absorption coefficient and the index of refraction of the healthy and cancer affected tissues as well as 2-D transmission THz images will be presented. The experimental results will be discussed and the conditions for the tissues discrimination will be established.

  16. The Tumor Microenvironment in Esophageal Cancer

    PubMed Central

    Lin, Eric W.; Karakasheva, Tatiana A.; Hicks, Philip D.; Bass, Adam J.; Rustgi, Anil K.

    2016-01-01

    Esophageal cancer is a deadly disease, ranking sixth among all cancers in mortality. Despite incremental advances in diagnostics and therapeutics, esophageal cancer still carries a poor prognosis, and thus there remains a need to elucidate the molecular mechanisms underlying this disease. There is accumulating evidence that a comprehensive understanding of the molecular composition of esophageal cancer requires attention to not only tumor cells but also the tumor microenvironment, which contains diverse cell populations, signaling factors, and structural molecules that interact with tumor cells and support all stages of tumorigenesis. In esophageal cancer, environmental exposures can trigger chronic inflammation, which leads to constitutive activation of pro-inflammatory signaling pathways that promote survival and proliferation. Anti-tumor immunity is attenuated by cell populations such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), as well as immune checkpoints like programmed death-1 (PD-1). Other immune cells such as tumor-associated macrophages can have other pro-tumorigenic functions, including the induction of angiogenesis and tumor cell invasion. Cancer-associated fibroblasts secrete growth factors and alter the extracellular matrix (ECM) to create a tumor niche and enhance tumor cell migration and metastasis. Further study of how these TME components relate to the different stages of tumor progression in each esophageal cancer subtype will lead to development of novel and specific TME-targeting therapeutic strategies, which offer considerable potential especially in the setting of combination therapy. PMID:26923327

  17. Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many epidemiological and experimental studies have suggested that dietary fiber plays an important role in colon cancer prevention. These findings may relate to the ability of fiber to reduce the contact time of carcinogens within the intestinal lumen and to promote healthy gut microbiota, which mod...

  18. Downregulation of microRNA-1 and microRNA-145 contributes synergistically to the development of colon cancer.

    PubMed

    Xu, Xuehu; Wu, Xiaobing; Jiang, Qingping; Sun, Yan; Liu, Haibo; Chen, Rong; Wu, Shangbiao

    2015-12-01

    The aim of the present study was to identify the differentially expressed microRNAs (miRNAs or miRs) in patients with colon cancer and examine their roles in the pathogenesis of the disease. The expression profiles of miRNAs were examined in tumor tissue samples collected from 20 patients with histologically confirmed colon cancer and in the adjacent non-cancerous control tissues using microarray analysis. We found that numerous miRNAs were differentially expressed in the colon cancer tissues compared with the control tissues. Following functional analysis, we noted that three miRNAs which were significantly downregulated, miR-145, miR-451 and miR-1, shared the same target gene, [NLR family, apoptosis inhibitory protein (NAIP)], which has previously been reported to be involved in the development of colon cancer. We then confirmed that NAIP is a target gene of miR-145 and miR-1, but not of miR-451, using a luceriferase assay, and we confirmed the expression patterns of these miRNAs and NAIP in the tumor tissue, as well as in the adjacent non-cancerous control tissues. Additionally, in order to examine the function of miR-145 and miR-1 in human colon cancer, we transiently transfected a human colon cancer cell line with miR-145 and miR-1 mimics or inhibitors, and the results of MTT assay revealed that the re-expression of miR-145 and miR-1 inhibited the survival of colon cancer cells, which may be attributed to the inhibition of the anti-apoptotic activity of NAIP. Our findings demonstrated that miR-145 and miR-1 play a negative regulatory role in the proliferation of colon cancer by targeting NAIP; thus, miR-145 and miR-1 may prove to be novel therapeutic targets in the treatment of colon cancer. PMID:26459459

  19. Knee pain and swelling: An atypical presentation of metastatic colon cancer to the patella

    PubMed Central

    Gasagranda, Bethany; Leeman, Kimberly; Heller, Matthew T.

    2015-01-01

    Knee pain is a common reason for a patient to seek medical evaluation. Of the many causes of knee pain, malignancy is one of the least common. When malignancy is the etiology of the pain, it is usually due to a primary tumor of the osseous structures or soft tissues of the knee joint. Metastatic disease involving the knee joint is uncommon, with few cases reported in the literature. Of these reported cases, metastatic colon cancer is exceedingly rare. However, in a patient with new onset knee pain and the proper clinical history, metastatic disease should be considered as a potential explanation of symptoms. We report a case of knee pain and swelling due to metastatic colon cancer to the patella. PMID:27141244

  20. Solitary mediastinal lymph node recurrence after curative resection of colon cancer.

    PubMed

    Matsuda, Yasuhiro; Yano, Masahiko; Miyoshi, Norikatsu; Noura, Shingo; Ohue, Masayuki; Sugimura, Keijiro; Motoori, Masaaki; Kishi, Kentaro; Fujiwara, Yoshiyuki; Gotoh, Kunihito; Marubashi, Shigeru; Akita, Hirofumi; Takahashi, Hidenori; Sakon, Masato

    2014-08-27

    We report two cases of solitary mediastinal lymph node recurrence after colon cancer resection. Both cases had para-aortic lymph node metastasis at the time of initial surgery and received adjuvant chemotherapy for 4 years in case 1 and 18 mo in case 2. The time to recurrence was more than 8 years in both cases. After resection of the recurrent tumor, the patient is doing well with no recurrence for 6 years in case 1 and 4 mo in case 2. Patients should be followed up after colon cancer surgery considering the possibility of solitary mediastinal lymph node recurrence if they had para-aortic node metastasis at the time of initial surgery. PMID:25161766

  1. N-end rule pathway inhibition assists colon tumor regression via necroptosis

    PubMed Central

    Agarwalla, Pritha; Banerjee, Rajkumar

    2016-01-01

    Recent study has shown that N-end rule pathway, an ubiquitin dependent proteolytic system, counteracts cell death by degrading many antisurvival protein fragments like BCLxL, BRCA1, RIPK1, etc. Inhibition of the N-end rule pathway can lead to metabolic stabilization of proapoptotic protein fragments like RIPK1, thereby sensitizing cells to programmed cell death. Receptor interacting serine-threonine protein kinase-1 (RIPK1) is one of the upstream regulators of programmed necrosis known as necroptosis. Necroptosis is particularly gaining attention of cancer biologists as it provides an alternate therapeutic modality to kill cancer cells, which often evolve multiple strategies to circumvent growth inhibition by apoptosis. Utilizing the over expression of biotin receptor in cancer cells, herein, we report that coadministration of synthetic hetero-bivalent N-end rule inhibitor RFC11 and anticancer drug shikonin solubilized in a stable biotin receptor-targeted liposome exhibited significant synergistic antitumor effect in both subcutaneous and orthotopic mouse colon tumor model through induction of necroptosis with distinctive upregulation of RIPK1. Besides developing a newly targeted formulation for necroptosis induction, this report is the first in vivo evidence demonstrating that potent inhibition of N-end rule pathway can enhance therapeutic efficacy of conventional chemotherapeutics. PMID:27556106

  2. N-end rule pathway inhibition assists colon tumor regression via necroptosis.

    PubMed

    Agarwalla, Pritha; Banerjee, Rajkumar

    2016-01-01

    Recent study has shown that N-end rule pathway, an ubiquitin dependent proteolytic system, counteracts cell death by degrading many antisurvival protein fragments like BCLxL, BRCA1, RIPK1, etc. Inhibition of the N-end rule pathway can lead to metabolic stabilization of proapoptotic protein fragments like RIPK1, thereby sensitizing cells to programmed cell death. Receptor interacting serine-threonine protein kinase-1 (RIPK1) is one of the upstream regulators of programmed necrosis known as necroptosis. Necroptosis is particularly gaining attention of cancer biologists as it provides an alternate therapeutic modality to kill cancer cells, which often evolve multiple strategies to circumvent growth inhibition by apoptosis. Utilizing the over expression of biotin receptor in cancer cells, herein, we report that coadministration of synthetic hetero-bivalent N-end rule inhibitor RFC11 and anticancer drug shikonin solubilized in a stable biotin receptor-targeted liposome exhibited significant synergistic antitumor effect in both subcutaneous and orthotopic mouse colon tumor model through induction of necroptosis with distinctive upregulation of RIPK1. Besides developing a newly targeted formulation for necroptosis induction, this report is the first in vivo evidence demonstrating that potent inhibition of N-end rule pathway can enhance therapeutic efficacy of conventional chemotherapeutics. PMID:27556106

  3. Bone morphogenetic protein signaling and growth suppression in colon cancer

    PubMed Central

    Beck, Stayce E.; Jung, Barbara H.; Fiorino, Antonio; Gomez, Jessica; Del Rosario, Eunice; Cabrera, Betty L.; Huang, Sherry C.; Chow, Jimmy Y. C.; Carethers, John M.

    2014-01-01

    Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β superfamily, which utilize BMP receptors and intracellular SMADs to transduce their signals to regulate cell differentiation, proliferation, and apoptosis. Because mutations in BMP receptor type IA (BMPRIA) and SMAD4 are found in the germline of patients with the colon cancer predisposition syndrome juvenile polyposis, and because the contribution of BMP in colon cancers is largely unknown, we examined colon cancer cells and tissues for evidence of BMP signaling and determined its growth effects. We determined the presence and functionality of BMPR1A by examining BMP-induced phosphorylation and nuclear translocation of SMAD1; transcriptional activity via a BMP-specific luciferase reporter; and growth characteristics by cell cycle analysis, cell growth, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide metabolic as-says. These assays were also performed after transfection with a dominant negative (DN) BMPR1A construct. In SMAD4-null SW480 cells, we examined BMP effects on cellular wound assays as well as BMP-induced transcription in the presence of transfected SMAD4. We also determined the expression of BMPR1A, BMP ligands, and phospho-SMAD1 in primary human colon cancer specimens. We found intact BMP signaling and modest growth suppression in HCT116 and two derivative cell lines and, surprisingly, growth suppression in SMAD4-null SW480 cells. BMP-induced SMAD signaling and BMPR1A-mediated growth suppression were reversed with DN BMPR1A transfection. BMP2 slowed wound closure, and transfection of SMAD4 into SW480 cells did not change BMP-specific transcriptional activity over controls due to receptor stimulation by endogenously produced ligand. We found no cell cycle alterations with BMP treatment in the HCT116 and derivative cell lines, but there was an increased G1 fraction in SW480 cells that was not due to increased p21 transcription. In human colon cancer

  4. MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

    PubMed

    Ogawa, Hisataka; Wu, Xin; Kawamoto, Koichi; Nishida, Naohiro; Konno, Masamitsu; Koseki, Jun; Matsui, Hidetoshi; Noguchi, Kozou; Gotoh, Noriko; Yamamoto, Tsuyoshi; Miyata, Kanjiro; Nishiyama, Nobuhiro; Nagano, Hiroaki; Yamamoto, Hirofumi; Obika, Satoshi; Kataoka, Kazunori; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

    2015-01-01

    Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR) 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors. PMID:25970424

  5. Colon Cancer Screening in North Carolina.

    PubMed

    Harvin, Glenn

    2016-01-01

    Colorectal cancer (CRC) is the 2nd leading cause of cancer death both in North Carolina and in the United States. The goal of CRC screening is early detection and prevention. This commentary reviews the evidence for screening, discusses current screening options, and explores which options are best suited for use in North Carolina. PMID:27154885

  6. Cyclooxygenase-2 knockdown using retinoic acid chalcone (RAC), a promising therapeutic strategy for colon cancer

    PubMed Central

    Jiang, Chao; Wang, Qiong; Xu, Zhe; Li, Wei-Su; Chen, Che; Yao, Xue-Quan; Liu, Fu-Kun

    2015-01-01

    Retinoic acid is an effective agent in the treatment of epithelial and hematological malignancies. The present study demonstrates that retinoic acid chalcone (RAC), an analogue of retinoic acid inhibits cell proliferation and induces apoptosis in HCT-15 and CT26.WT colon cancer cell lines. In HCT-15 cells the percentage of apoptotic cells increased from 32.4 ± 3, 45.0 ± 3 to 72.6 ± 5% respectively at 10, 15 and 20 μg/mL compared to 3.7% in control. Similarly in CT26.WT cells the percentage increased from 28.6 ± 3, 41.2 ± 3 to 65.4 ± 5% on treatment with 10, 15 and 20 μg/mL concentrations of RAC after 72 h compared to 2.9 ± 1% in control. Western blotting, fluorescence-activated cell sorting analysis and reverse transcription-PCR assays were used to investigate these effects. RAC inhibited the overexpression of COX-2, PGE2 and PGE2 receptor (EP1 and EP4) in the colon cancer cell lines. RAC mediated inhibition of cell growth and induction of apoptosis through COX-2 inhibition was also confirmed by treating the HCT-15 and CT26.WT colon cancer cells with COX-2 inhibitor, indomethacin and transfection of cells with COX-2 small interfering RNA. In nude mice with tumor xenografts, treatment with RAC-supplemented diet caused inhibition of COX-2, PGE2, and PGE2 receptors (EP1, EP3, and EP4) in tumors. Thus RAC can be a potential candidate for the treatment of colon cancer through the inhibition of COX-2 expression and subsequent inhibition of PGE2 and PGE2 receptors. PMID:26269760

  7. The Osteogenic Niche Promotes Early-Stage Bone Colonization of Disseminated Breast Cancer Cells

    PubMed Central

    Wang, Hai; Yu, Cuijuan; Gao, Xia; Welte, Thomas; Muscarella, Aaron M.; Tian, Lin; Zhao, Hong; Zhao, Zhen; Du, Shiyu; Tao, Jianning; Lee, Brendan; Westbrook, Thomas F.; Wong, Stephen T. C.; Jin, Xin; Rosen, Jeffrey M.; Osborne, C. Kent; Zhang, Xiang H.-F.

    2014-01-01

    Summary Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. Significance In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases. PMID:25600338

  8. Personalized medicine approaches for colon cancer driven by genomics and systems biology: OncoTrack

    PubMed Central

    Henderson, David; Ogilvie, Lesley A; Hoyle, Nicholas; Keilholz, Ulrich; Lange, Bodo; Lehrach, Hans

    2014-01-01

    The post-genomic era promises to pave the way to a personalized understanding of disease processes, with technological and analytical advances helping to solve some of the world's health challenges. Despite extraordinary progress in our understanding of cancer pathogenesis, the disease remains one of the world's major medical problems. New therapies and diagnostic procedures to guide their clinical application are urgently required. OncoTrack, a consortium between industry and academia, supported by the Innovative Medicines Initiative, signifies a new era in personalized medicine, which synthesizes current technological advances in omics techniques, systems biology approaches, and mathematical modeling. A truly personalized molecular imprint of the tumor micro-environment and subsequent diagnostic and therapeutic insight is gained, with the ultimate goal of matching the “right” patient to the “right” drug and identifying predictive biomarkers for clinical application. This comprehensive mapping of the colon cancer molecular landscape in tandem with crucial, clinical functional annotation for systems biology analysis provides unprecedented insight and predictive power for colon cancer management. Overall, we show that major biotechnological developments in tandem with changes in clinical thinking have laid the foundations for the OncoTrack approach and the future clinical application of a truly personalized approach to colon cancer theranostics. PMID:25074435

  9. Effect of siRNA-mediated knockdown of eIF3c gene on survival of colon cancer cells

    PubMed Central

    Song, Ning; Wang, Yan; Gu, Xiao-dong; Chen, Zong-you; Shi, Liu-bin

    2013-01-01

    Eukaryotic initiation factor subunit c (eIF3c) has been identified as an oncogene that is over-expressed in tumor cells and, therefore, is a potential therapeutic target for gene-based cancer treatment. This study was focused on investigating the effect of small interfering RNA (siRNA)-mediated eIF3c gene knockdown on colon cancer cell survival. The eIF3c gene was observed to be highly expressed in colon cancer cell models. The expression levels of the gene in eIF3c siRNA infected and control siRNA infected cells were compared via real-time polymerase chain reaction (PCR) and western blotting analysis. Cell proliferation levels were analyzed employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Furthermore, the effects of eIF3c gene knockdown on the cell cycle and apoptosis were analyzed using flow cytometry. The results showed that suppression of eIF3c expression significantly (P<0.001) reduced cell proliferation and colony formation of RKO colon cancer cells. The cell cycle was arrested by decreasing the number of cells entering S phase. Further, apoptosis was induced as a result of eIF3c knockdown. Collectively, eIF3c deletion effectively reduced the survival of colon cancer cells and could be used as a therapeutic tool for colon cancer therapy. PMID:23733421

  10. The influence of hormone therapies on colon and rectal cancer.

    PubMed

    Mørch, Lina Steinrud; Lidegaard, Øjvind; Keiding, Niels; Løkkegaard, Ellen; Kjær, Susanne Krüger

    2016-05-01

    Exogenous sex hormones seem to play a role in colorectal carcinogenesis. Little is known about the influence of different types or durations of postmenopausal hormone therapy (HT) on colorectal cancer risk. A nationwide cohort of women 50-79 years old without previous cancer (n = 1,006,219) were followed 1995-2009. Information on HT exposures was from the National Prescription Register and updated daily, while information on colon (n = 8377) and rectal cancers (n = 4742) were from the National Cancer Registry. Potential confounders were obtained from other national registers. Poisson regression analyses with 5-year age bands included hormone exposures as time-dependent covariates. Use of estrogen-only therapy and combined therapy were associated with decreased risks of colon cancer (adjusted incidence rate ratio 0.77, 95 % confidence interval 0.68-0.86 and 0.88, 0.80-0.96) and rectal cancer (0.83, 0.72-0.96 and 0.89, 0.80-1.00), compared to never users. Transdermal estrogen-only therapy implied more protection than oral administration, while no significant influence was found of regimen, progestin type, nor of tibolone. The benefit of HT was stronger for long-term hormone users; and hormone users were at lower risk of advanced stage of colorectal cancer, which seems supportive for a causal association between hormone therapy and colorectal cancer. PMID:26758900

  11. Prodigiosin-induced apoptosis in human colon cancer cells.

    PubMed

    Montaner, B; Pérez-Tomás, R

    2001-03-16

    Prodigiosin is a red pigment produced by various bacteria including Serratia marcescens. Colorectal cancer is one of the most frequent malignancies and one of the most frequent causes of cancer death in the Western world. Its treatment is far from satisfactory and the challenge to oncologists is to find novel chemical entities with less toxicity and greater effectiveness than those used in current chemotherapy. Here we characterize the apoptotic action of prodigiosin in colon cancer cells. DLD-1 and SW-620 human colon adenocarcinoma cells, NRK and Swiss-3T3 nonmalignant cells were assayed by the MTT assay, fragmentation pattern of DNA, Hoechst 33342 staining and study of PARP cleavage by Western blot, in order to characterize the prodigiosin-induced apoptosis. Prodigiosin was purified and its structure was confirmed. Metastatic SW-620 cells were more sensitive to prodigiosin (IC50: 275 nM) than DLD-1. We did not observe a significant decrease in the viability of NRK cells. We confirmed that prodigiosin induces apoptosis in both cancer cell lines by the characteristic DNA laddering pattern and condensed nuclei or apoptotic bodies identified by fluorescence microscopy. These results indicate that prodigiosin induces apoptosis in colon cancer cells.

  12. Omega-3 Eicosapentaenoic Acid Decreases CD133 Colon Cancer Stem-Like Cell Marker Expression While Increasing Sensitivity to Chemotherapy

    PubMed Central

    De Carlo, Flavia; Witte, Theodore R.; Hardman, W. Elaine; Claudio, Pier Paolo

    2013-01-01

    Colorectal cancer is the third leading cause of cancer-related death in the western world. In vitro and in vivo experiments showed that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can attenuate the proliferation of cancer cells, including colon cancer, and increase the efficacy of various anticancer drugs. However, these studies address the effects of n-3 PUFAs on the bulk of the tumor cells and not on the undifferentiated colon cancer stem-like cells (CSLCs) that are responsible for tumor formation and maintenance. CSLCs have also been linked to the acquisition of chemotherapy resistance and to tumor relapse. Colon CSLCs have been immunophenotyped using several antibodies against cellular markers including CD133, CD44, EpCAM, and ALDH. Anti-CD133 has been used to isolate a population of colon cancer cells that retains stem cells properties (CSLCs) from both established cell lines and primary cell cultures. We demonstrated that the n-3 PUFA, eicosapentaenoic acid (EPA), was actively incorporated into the membrane lipids of COLO 320 DM cells. 25 uM EPA decreased the cell number of the overall population of cancer cells, but not of the CD133 (+) CSLCs. Also, we observed that EPA induced down-regulation of CD133 expression and up-regulation of colonic epithelium differentiation markers, Cytokeratin 20 (CK20) and Mucin 2 (MUC2). Finally, we demonstrated that EPA increased the sensitivity of COLO 320 DM cells (total population) to both standard-of-care chemotherapies (5-Fluorouracil and oxaliplatin), whereas EPA increased the sensitivity of the CD133 (+) CSLCs to only 5-Fluorouracil. PMID:23874993

  13. Functional and genetic analysis of the colon cancer network.

    PubMed

    Emmert-Streib, Frank; de Matos Simoes, Ricardo; Glazko, Galina; McDade, Simon; Haibe-Kains, Benjamin; Holzinger, Andreas; Dehmer, Matthias; Campbell, Frederick

    2014-01-01

    Cancer is a complex disease that has proven to be difficult to understand on the single-gene level. For this reason a functional elucidation needs to take interactions among genes on a systems-level into account. In this study, we infer a colon cancer network from a large-scale gene expression data set by using the method BC3Net. We provide a structural and a functional analysis of this network and also connect its molecular interaction structure with the chromosomal locations of the genes enabling the definition of cis- and trans-interactions. Furthermore, we investigate the interaction of genes that can be found in close neighborhoods on the chromosomes to gain insight into regulatory mechanisms. To our knowledge this is the first study analyzing the genome-scale colon cancer network. PMID:25079297

  14. Correlation of trace elements in hair with colon cancer

    SciTech Connect

    Kwiatek, W.M.; Cholewa, M.; Kajfosz, J.; Jones, K.W.; Shore, R.E.; Redrick, A.L.

    1986-01-01

    The trace element content of 116 hair samples from patients with colon cancer and from referent series of patients who had a variety of other diseases were measured using proton-induced x-ray emission (PIXE). The patients had been on largely uncontrolled diets, and the interest was whether there were differences in trace element concentrations attributable to the effects of colon cancer. The concentrations of K, Ca, Mn, Fe, Cu, Zn, Se, Br, and Rb were determined using a beam of 2.5-MeV protons. Minimum detectable limits (MDL) of 0.3 ppM were obtained for Zn and Se. Cluster analysis of the data set did not reveal any significant differences between the cancer and control groups. Mean values and ranges obtained for the elemental concentrations show good agreement with other published determinations. 20 refs., 3 figs., 3 tabs.

  15. Recurrent R-spondin fusions in colon cancer.

    PubMed

    Seshagiri, Somasekar; Stawiski, Eric W; Durinck, Steffen; Modrusan, Zora; Storm, Elaine E; Conboy, Caitlin B; Chaudhuri, Subhra; Guan, Yinghui; Janakiraman, Vasantharajan; Jaiswal, Bijay S; Guillory, Joseph; Ha, Connie; Dijkgraaf, Gerrit J P; Stinson, Jeremy; Gnad, Florian; Huntley, Melanie A; Degenhardt, Jeremiah D; Haverty, Peter M; Bourgon, Richard; Wang, Weiru; Koeppen, Hartmut; Gentleman, Robert; Starr, Timothy K; Zhang, Zemin; Largaespada, David A; Wu, Thomas D; de Sauvage, Frederic J

    2012-08-30

    Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

  16. Get Tested for Colon Cancer: Here's How

    MedlinePlus

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  17. Integrin β6 can be translationally regulated by eukaryotic initiation factor 4E: Contributing to colonic tumor malignancy.

    PubMed

    Enyu, Liu; Zhengchuan, Niu; Jiayong, Wang; Benjia, Liang; Qi, Sun; Ruixi, Qin; Cheng, Peng; Khan, Abdul Qadir; Wei, Song; Jun, Niu

    2015-08-01

    It is well known that both eukaryotic initiation factor 4E (eIF4E) and integrin αvβ6 can contribute to malignant behavior of colon cancer. We have found that integrin αvβ6 and eIF4E were co-expressed and positively correlated in colon cancer tissues. Recently, deregulation of the protein synthesis apparatus has begun to gain attention as a major participant in cancer development and progression. However, the regulation of integrin β6 expression at translational level has never been investigated before. In present study, gene-silencing technique for eIF4E by small interfering RNA (siRNA) was used in all the subsequent experiments, in order to investigate whether eIF4E could translationally regulate expression of integrin β6 in colon cancer SW480 and HT-29 cell lines. Additionally, the subsequent effects of eIF4E knockdown on cellular malignant behavior were observed. siRNA in SW480 and HT-29 transfectants. Subsequently, protein expression of β6 was markedly suppressed, while mRNA expression of β6 showed no significant variation before and after eIF4E RNA interfering. Therefore, it could be seen that eIF4E could upregulate the expression of β6, without effect on β6 mRNA expression. More importantly, after treated with eIF4E siRNA, cellular migratory capacity on fibronectin of HT-29 and β6-transfected SW480 as well as their survival to 5-FU was decreased distinctly. Expression of integrin β6 could be translationally regulated by eIF4E, which subsequently contributed to tumor malignancy through enhancing cellular migration, survival, anti-apoptosis, and chemoresistance of colon cancer in vitro. Thus, targeting eIF4E in integrin αvβ6 expressing tumors can be a potential therapeutic strategy for patients with colon cancer.

  18. Reduction in promotor methylation utilizing EGCG (epigallocatechin-3-gallate) restores RXRα expression in human colon cancer cells.

    PubMed

    Morris, Jay; Moseley, Vondina R; Cabang, April B; Coleman, Katie; Wei, Wei; Garrett-Mayer, Elizabeth; Wargovich, Michael J

    2016-06-01

    Silencing of regulatory genes through hypermethylation of CpG islands is an important mechanism in tumorigenesis. In colon cancer, RXRα, an important dimerization partner with other nuclear transcription factors, is silenced through this mechanism. We previously found that colon tumors in ApcMin/+ mice had diminished levels of RXRα protein and expression levels of this gene were restored by treatment with a green tea intervention, due to reduced promoter methylation of RXRα. We hypothesized that CIMP+ cell lines, which epigenetically silence key regulatory genes would also evidence silencing of RXRα and EGCG treatment would restore its expression. We indeed found EGCG to restore RXRα activity levels in the human cell lines, in a dose dependent manner and reduced RXRα promoter methylation. EGCG induced methylation changes in several other colon cancer related genes but did not cause a decrease in global methylation. Numerous epidemiological reports have shown the benefits of green tea consumption in reducing colon cancer risk but to date no studies have shown that the risk reduction may be related to the epigenetic restoration by tea polyphenols. Our results show that EGCG modulates the reversal of gene silencing involved in colon carcinogenesis providing a possible avenue for colon cancer prevention and treatment. PMID:27167203

  19. Reduction in promotor methylation utilizing EGCG (epigallocatechin-3-gallate) restores RXRα expression in human colon cancer cells

    PubMed Central

    Morris, Jay; Moseley, Vondina R.; Cabang, April B.; Coleman, Katie; Wei, Wei; Garrett-Mayer, Elizabeth; Wargovich, Michael J.

    2016-01-01

    Silencing of regulatory genes through hypermethylation of CpG islands is an important mechanism in tumorigenesis. In colon cancer, RXRα, an important dimerization partner with other nuclear transcription factors, is silenced through this mechanism. We previously found that colon tumors in ApcMin/+ mice had diminished levels of RXRα protein and expression levels of this gene were restored by treatment with a green tea intervention, due to reduced promoter methylation of RXRα. We hypothesized that CIMP+ cell lines, which epigenetically silence key regulatory genes would also evidence silencing of RXRα and EGCG treatment would restore its expression. We indeed found EGCG to restore RXRα activity levels in the human cell lines, in a dose dependent manner and reduced RXRα promoter methylation. EGCG induced methylation changes in several other colon cancer related genes but did not cause a decrease in global methylation. Numerous epidemiological reports have shown the benefits of green tea consumption in reducing colon cancer risk but to date no studies have shown that the risk reduction may be related to the epigenetic restoration by tea polyphenols. Our results show that EGCG modulates the reversal of gene silencing involved in colon carcinogenesis providing a possible avenue for colon cancer prevention and treatment. PMID:27167203

  20. Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

    PubMed Central

    Rentoft, Matilda; Lindell, Kristoffer; Tran, Phong; Chabes, Anna Lena; Watt, Danielle L.; Marjavaara, Lisette; Nilsson, Anna Karin; Melin, Beatrice; Trygg, Johan; Johansson, Erik

    2016-01-01

    Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells. PMID:27071091

  1. Roles of Probiotics and Prebiotics in Colon Cancer Prevention: Postulated Mechanisms and In-vivo Evidence

    PubMed Central

    Liong, Min-Tze

    2008-01-01

    Probiotics are live bacteria that could exert health beneficial effects upon consumption. In additional to their conventional use as gut modulators, probiotics are investigated for their role to prevent cancer. In-vivo and molecular studies have demonstrated encouraging outcomes, mainly attributed to its antimicrobial effects against carcinogen-producing microorganisms, antimutagenic properties, and alteration of the tumor differentiation processes. Prebiotics are indigestible food components that could promote the growth of beneficial bacteria including probiotics. Present studies have suggested that prebiotics also possess protective effect against colon carcinogenesis, mainly attributed to the production of short chain fatty acids upon its fermentation by gut microflora, and alteration of gene-expressions in tumor cells. Synbiotic (combination of probiotic and prebiotic) has been found to exert a synergistic effect in improving colon carcinogenesis compared to when both were used individually. This paper highlights the colon cancer preventive effects by probiotics, prebiotics and synbiotics. In addition, the controversial outcomes on the insignificant effect of these food adjuncts will be discussed. PMID:19325789

  2. Ex vivo expanded human circulating Vδ1 γδT cells exhibit favorable therapeutic potential for colon cancer

    PubMed Central

    Wu, Dang; Wu, Pin; Wu, Xianguo; Ye, Jun; Wang, Zhen; Zhao, Shuai; Ni, Chao; Hu, Guoming; Xu, Jinghong; Han, Yuehua; Zhang, Ting; Qiu, Fuming; Yan, Jun; Huang, Jian

    2015-01-01

    Gamma delta T (γδT) cells are innate-like lymphocytes with strong, MHC-unrestricted cytotoxicity against cancer cells and show a promising prospect in adoptive cellular immunotherapy for various malignancies. However, the clinical outcome of commonly used Vγ9Vδ2 γδT (Vδ2 T) cells in adoptive immunotherapy for most solid tumors is limited. Here, we demonstrate that freshly isolated Vδ1 γδT (Vδ1 T) cells from human peripheral blood (PB) exhibit more potent cytotoxicity against adherent and sphere-forming human colon cancer cells than Vδ2 T cells in vitro. We also develop an optimized protocol to preferentially expand Vδ1 T cells isolated from PB of both healthy donors and colon cancer patients by in vitro short-term culture with phytohemagglutinin (PHA) and interleukin-7 (IL-7). Expanded Vδ1 T cells highly expressed cytotoxicity-related molecules, chemokine receptors and cytokines with enhanced cytolytic effect against adherent and sphere-forming colon cancer cells in a cell-to-cell contact dependent manner. In addition, PHA and IL-7 expanded Vδ1 T cells showed proliferation and survival advantage partly through an IL-2 signaling pathway. Furthermore, ex vivo expanded Vδ1 T cells also restrained the tumor growth and prolonged the tumor-burdened survival of human colon carcinoma xenografted mice. Our findings suggest that human PB Vδ1 T cells expanded by PHA and IL-7 are a promising candidate for anticancer adoptive immunotherapy for human solid tumors such as colon cancer. PMID:25949914

  3. Targeting tumor suppressor networks for cancer therapeutics.

    PubMed

    Guo, Xuning Emily; Ngo, Bryan; Modrek, Aram Sandaldjian; Lee, Wen-Hwa

    2014-01-01

    Cancer is a consequence of mutations in genes that control cell proliferation, differentiation and cellular homeostasis. These genes are classified into two categories: oncogenes and tumor suppressor genes. Together, overexpression of oncogenes and loss of tumor suppressors are the dominant driving forces for tumorigenesis. Hence, targeting oncogenes and tumor suppressors hold tremendous therapeutic potential for cancer treatment. In the last decade, the predominant cancer drug discovery strategy has relied on a traditional reductionist approach of dissecting molecular signaling pathways and designing inhibitors for the selected oncogenic targets. Remarkable therapies have been developed using this approach; however, targeting oncogenes is only part of the picture. Our understanding of the importance of tumor suppressors in preventing tumorigenesis has also advanced significantly and provides a new therapeutic window of opportunity. Given that tumor suppressors are frequently mutated, deleted, or silenced with loss-of-function, restoring their normal functions to treat cancer holds tremendous therapeutic potential. With the rapid expansion in our knowledge of cancer over the last several decades, developing effective anticancer regimens against tumor suppressor pathways has never been more promising. In this article, we will review the concept of tumor suppression, and outline the major therapeutic strategies and challenges of targeting tumor suppressor networks for cancer therapeutics.

  4. Overexpression of OATP1B3 confers apoptotic resistance in colon cancer

    PubMed Central

    Lee, Wooin; Belkhiri, Abbes; Lockhart, A. Craig; Merchant, Nipun; Glaeser, Hartmut; Harris, Elizabeth I.; Washington, M. Kay; Brunt, Elizabeth M.; Zaika, Alex; Kim, Richard B.; El-Rifai, Wael

    2008-01-01

    Organic anion transporting polypeptide 1B3 (OATP1B3, SLCO1B3) is normally expressed in hepatocytes. In this study, we demonstrated frequent overexpression of OATP1B3 in colorectal adenocarcinomas. Quantitative RT-PCR analysis of 17 colon tumors indicated tumoral overexpression of OATP1B3 by ~100 fold, compared to 20 normal colon samples (p<0.0001). Using immunohistochemistry on a tissue microarray containing 93 evaluable colon tumor specimens, we detected immunostaining of OATP1B3 in 75 colon adenocarcinomas (81%) and no immunostaining in normal samples. To determine the functional effects of OATP1B3 expression on drug-induced apoptosis, we used camptothecin and oxaliplatin on a panel of colorectal cancer cell lines stably overexpressing OATP1B3. The results indicated that OATP1B3 overexpression enhanced cell survival in RKO, HCT-8 and HCT116p53+/+ cells that harbor wildtype p53 but not in Caco-2 and HCT116p53-/- cells that lack p53, compared to the respective empty vector controls (p<0.01). The TUNEL assay confirmed that HCT116p53+/+ cells overexpressing OATP1B3 had significantly lower apoptotic levels compared to empty vector control (P<0.001). The overexpression of OATP1B3 reduced the transcriptional activity of p53, with subsequent reductions in transcript and protein levels of its downstream transcription targets (P21WAF1 and PUMA). Overexpression of a point mutation (G583E) variant of OATP1B3 lacking transport activity did not confer an antiapoptotic effect or affect p53 transcriptional activity, suggesting that the antiapoptotic effect of OATP1B3 may be associated with its transport activity. Taken together, our results suggest that OATP1B3 overexpression in colorectal cancer cells may provide a survival advantage by altering p53-dependent pathways. PMID:19074900

  5. Solitary Fibrous Tumor of the Sigmoid Colon Masquerading as an Adnexal Neoplasm

    PubMed Central

    Bratton, Laura; Salloum, Rabih; Cao, Wenqing

    2016-01-01

    Solitary fibrous tumor is a rare, benign spindle cell neoplasm that was first described in the thoracic pleura. This tumor is now known to occur at many extrapleural sites. There are established criteria for the diagnosis of malignant solitary fibrous tumor including ≥4 mitotic figures per 10 high-power fields, increased cellularity, cytologic atypia, infiltrative margins, and/or necrosis. Although all solitary fibrous tumors have the potential to recur or metastasize, those with malignant histologic features tend to behave more aggressively. We report a case of solitary fibrous tumor, with malignant histologic features, in a 21-year-old woman which arose from the serosal surface of the sigmoid colon.

  6. Hypoxic Tumor Microenvironment and Cancer Cell Differentiation

    PubMed Central

    Kim, Yuri; Lin, Qun; Glazer, Peter M.; Yun, Zhong

    2010-01-01

    Hypoxia or oxygen deficiency is a salient feature of solid tumors. Hypoxic tumors are often resistant to conventional cancer therapies, and tumor hypoxia correlates with advanced stages of malignancy. Hypoxic tumors appear to be poorly differentiated. Increasing evidence suggests that hypoxia has the potential to inhibit tumor cell differentiation and thus plays a direct role in the maintenance of cancer stem cells. Studies have also shown that hypoxia blocks differentiation of mesenchymal stem/progenitor cells, a potential source of tumor-associated stromal cells. It is therefore likely that hypoxia may have a profound impact on the evolution of the tumor stromal microenvironment. These observations have led to the emergence of a novel paradigm for a role of hypoxia in facilitating tumor progression. Hypoxia may help create a microenvironment enriched in poorly differentiated tumor cells and undifferentiated stromal cells. Such an undifferentiated hypoxic microenvironment may provide essential cellular interactions and environmental signals for the preferential maintenance of cancer stem cells. This hypothesis suggests that effectively targeting hypoxic cancer stem cells is a key to successful tumor control. PMID:19519400

  7. A case of leptospirosis simulating colon cancer with liver metastases

    PubMed Central

    Granito, Alessandro; Ballardini, Giorgio; Fusconi, Marco; Volta, Umberto; Muratori, Paolo; Sambri, Vittorio; Battista, Giuseppe; Bianchi, Francesco B.

    2004-01-01

    We report a case of a 61-year-old man who presented with fatigue, abdominal pain and hepatomegaly. Computed tomography (CT) of the abdomen showed hepatomegaly and multiple hepatic lesions highly suggestive of metastatic diseases. Due to the endoscopic finding of colon ulcer, colon cancer with liver metastases was suspected. Biochemically a slight increase of transaminases, alkaline phosphatase and gammaglutamyl transpeptidase were present; α - fetoprotein, carcinoembryogenic antigen and carbohydrate 19-9 antigen serum levels were normal. Laboratory and instrumental investigations, including colon and liver biopsies revealed no signs of malignancy. In the light of spontaneous improvement of symptoms and CT findings, his personal history was revaluated revealing direct contact with pigs and their tissues. Diagnosis of leptospirosis was considered and confirmed by detection of an elevated titer of antibodies to leptospira. After two mo, biochemical data, CT and colonoscopy were totally normal. PMID:15285043

  8. Limitations of tissue micro array in Duke's B colon cancer.

    PubMed

    Kjaer-Frifeldt, Sanne; Lindebjerg, Jan; Brünner, Nils; Garm Spindler, Karen-Lise; Jakobsen, Anders

    2012-10-01

    Tissue micro array (TMA) is widely used in cancer research in search of new predictive and prognostic markers. Colon cancer is known to be heterogeneous and the present study addresses some methodological aspects using cores of different size and analysing markers with different cellular distribution. We selected 61 paraffin-embedded tissue blocks representing patients diagnosed with Dukes B colon cancer. Two 1 mm and two 2 mm cores were taken from both the centre and the invasive front of the tumour respectively. The immunostaining included MLH1, MSH2, PMS2, p53, COX-2, TIMP and Betacatenin. Twenty-five percent of the cores taken from paraffin blocks less than 0.5 cm was lost and the total loss was 8%. The homogeneous stains (MLH1, MSH2 and PMS2) all showed high agreement between TMA and whole tissue stains (kappa = 0.96,1 and 1 respectively). The COX-2, p53 and Betacatenin illustrated moderate to high agreement (kappa = 0.54-0.9) whereas TIMP-1 had the lowest score (kappa 0.19-0.25). The application of TMA in Dukes B colon cancer has several pitfalls and depends substantially on the immunohistochemical marker in question. Therefore a validation study seems justified before applying large scale TMA in this setting.

  9. L-Ascorbic acid can abrogate SVCT-2-dependent cetuximab resistance mediated by mutant KRAS in human colon cancer cells.

    PubMed

    Jung, Soo-A; Lee, Dae-Hee; Moon, Jai-Hee; Hong, Seung-Woo; Shin, Jae-Sik; Hwang, Ih Yeon; Shin, Yu Jin; Kim, Jeong Hee; Gong, Eun-Yeung; Kim, Seung-Mi; Lee, Eun Young; Lee, Seul; Kim, Jeong Eun; Kim, Kyu-Pyo; Hong, Yong Sang; Lee, Jung Shin; Jin, Dong-Hoon; Kim, TaeWon; Lee, Wang Jae

    2016-06-01

    Colon cancer patients with mutant KRAS are resistant to cetuximab, an antibody directed against the epidermal growth factor receptor, which is an effective clinical therapy for patients with wild-type KRAS. Numerous combinatorial therapies have been tested to overcome the resistance to cetuximab. However, no combinations have been found that can be used as effective therapeutic strategies. In this study, we demonstrate that L-ascorbic acid partners with cetuximab to induce killing effects, which are influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human colon cancer cells with a mutant KRAS. L-Ascorbic acid treatment of human colon cancer cells that express a mutant KRAS differentially and synergistically induced cell death with cetuximab in a SVCT-2-dependent manner. The ectopic expression of SVCT-2 induced sensitivity to L-ascorbic acid treatment in human colon cancer cells that do not express SVCT-2, whereas the knockdown of endogenous SVCT-2 induced resistance to L-ascorbic acid treatment in SVCT-2-positive cells. Moreover, tumor regression via the administration of L-ascorbic acid and cetuximab in mice bearing tumor cell xenografts corresponded to SVCT-2 protein levels. Interestingly, cell death induced by the combination of L-ascorbic acid and cetuximab resulted in both apoptotic and necrotic cell death. These cell death mechanisms were related to a disruption of the ERK pathway and were represented by the impaired activation of RAFs and the activation of the ASK-1-p38 pathway. Taken together, these results suggest that resistance to cetuximab in human colon cancer patients with a mutant KRAS can be bypassed by L-ascorbic acid in an SVCT-2-dependent manner. Furthermore, SVCT-2 in mutant KRAS colon cancer may act as a potent marker for potentiating L-ascorbic acid co-treatment with cetuximab.

  10. MiR-126 suppresses colon cancer cell proliferation and invasion via inhibiting RhoA/ROCK signaling pathway.

    PubMed

    Li, Nan; Tang, Anliu; Huang, Shuo; Li, Zeng; Li, Xiayu; Shen, Shourong; Ma, Jian; Wang, Xiaoyan

    2013-08-01

    Recent data strongly suggests the profound role of miRNAs in cancer progression. Here, we showed miR-126 expression was much lower in HCT116, SW620 and HT-29 colon cancer cells with highly metastatic potential and miR-126 downregulation was more frequent in colorectal cancers with metastasis. Restored miR-126 expression inhibited HT-29 cell growth, cell-cycle progression and invasion. Mechanically, microarray results combined with bioinformatic and experimental analysis demonstrated miR-126 exerted cancer suppressor role via inhibiting RhoA/ROCK signaling pathway. These results suggest miR-126 function as a potential tumor suppressor in colon cancer progression and miR-126/RhoA/ROCK may be a novel candidate for developing rational therapeutic strategies.

  11. Use of Aspirin postdiagnosis improves survival for colon cancer patients

    PubMed Central

    Bastiaannet, E; Sampieri, K; Dekkers, O M; de Craen, A J M; van Herk-Sukel, M P P; Lemmens, V; van den Broek, C B M; Coebergh, J W; Herings, R M C; van de Velde, C J H; Fodde, R; Liefers, G J

    2012-01-01

    Background: The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients. Methods: Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998–2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure. Results: In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63–0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50–0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46–0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79–1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70–2.20; P<0.001). Conclusion: Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of

  12. MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism

    PubMed Central

    Pereira, Diane M.; Simões, André E. S.; Gomes, Sofia E.; Castro, Rui E.; Carvalho, Tânia; Rodrigues, Cecília M. P.; Borralho, Pedro M.

    2016-01-01

    The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity. Using genetic and pharmacological approaches, we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure. Mechanistically, this was further associated with increased p53 transcriptional activation of p21 and PUMA. In addition, ERK5 inhibition increased the response of HCT116 p53+/+ cells to 5-FU, but failed to sensitize HCT116 p53−/− cells to the cytotoxic effects of this chemotherapeutic agent, suggesting a p53-dependent axis mediating 5-FU sensitization. Finally, ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model, enhancing apoptosis while markedly reducing tumor growth. Collectively, our results suggest that ERK5-targeted in hibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment. PMID:27144434

  13. A Transcriptional Regulatory Role of the THAP11–HCF-1 Complex in Colon Cancer Cell Function

    PubMed Central

    Parker, J. Brandon; Palchaudhuri, Santanu; Yin, Hanwei; Wei, Jianjun

    2012-01-01

    The recently identified Thanatos-associated protein (THAP) domain is an atypical zinc finger motif with sequence-specific DNA-binding activity. Emerging data suggest that THAP proteins may function in chromatin-dependent processes, including transcriptional regulation, but the roles of most THAP proteins in normal and aberrant cellular processes remain largely unknown. In this work, we identify THAP11 as a transcriptional regulator differentially expressed in human colon cancer. Immunohistochemical analysis of human colon cancers revealed increased THAP11 expression in both primary tumors and metastases. Knockdown of THAP11 in SW620 colon cancer cells resulted in a significant decrease in cell proliferation, and profiling of gene expression in these cells identified a novel gene set composed of 80 differentially expressed genes, 70% of which were derepressed by THAP11 knockdown. THAP11 was found to associate physically with the transcriptional coregulator HCF-1 (host cell factor 1) and recruit HCF-1 to target promoters. Importantly, THAP11-mediated gene regulation and its chromatin association require HCF-1, while HCF-1 recruitment at these genes requires THAP11. Collectively, these data provide the first characterization of THAP11-dependent gene expression in human colon cancer cells and suggest that the THAP11–HCF-1 complex may be an important transcriptional and cell growth regulator in human colon cancer. PMID:22371484

  14. Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α*

    PubMed Central

    Shan, Jian-zhen; Xuan, Yan-yan; Zhang, Qi; Huang, Jian-jin

    2016-01-01

    Objective: To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. Methods: Three colon cancer cell lines (RKO, LoVo, and SW480) were used as in vitro models. 5-Fluorouracil (5-FU) and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and expression levels of hypoxia-inducible factor-1α (HIF-1α), multidrug resistance gene 1 (MDR1), and vascular endothelial growth factors (VEGF) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis. Results: We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-1α. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis. Conclusions: Ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-1α accumulation and the subsequent expression of the MDR1 and VEGF. PMID:27604859

  15. MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism.

    PubMed

    Pereira, Diane M; Simões, André E S; Gomes, Sofia E; Castro, Rui E; Carvalho, Tânia; Rodrigues, Cecília M P; Borralho, Pedro M

    2016-06-01

    The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity. Using genetic and pharmacological approaches, we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure. Mechanistically, this was further associated with increased p53 transcriptional activation of p21 and PUMA. In addition, ERK5 inhibition increased the response of HCT116 p53+/+ cells to 5-FU, but failed to sensitize HCT116 p53-/- cells to the cytotoxic effects of this chemotherapeutic agent, suggesting a p53-dependent axis mediating 5-FU sensitization. Finally, ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model, enhancing apoptosis while markedly reducing tumor growth. Collectively, our results suggest that ERK5-targeted inhibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment. PMID:27144434

  16. Validation of methylation biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer.

    PubMed

    Cesaroni, Matteo; Powell, Jasmine; Sapienza, Carmen

    2014-07-01

    We have validated differences in DNA methylation levels of candidate genes previously reported to discriminate between normal colon mucosa of patients with colon cancer and normal colon mucosa of individuals without cancer. Here, we report that CpG sites in 16 of the 30 candidate genes selected show significant differences in mean methylation level in normal colon mucosa of 24 patients with cancer and 24 controls. A support vector machine trained on these data and data for an additional 66 CpGs yielded an 18-gene signature, composed of ten of the validated candidate genes plus eight additional candidates. This model exhibited 96% sensitivity and 100% specificity in a 40-sample training set and classified all eight samples in the test set correctly. Moreover, we found a moderate-strong correlation (Pearson coefficients r = 0.253-0.722) between methylation levels in colon mucosa and methylation levels in peripheral blood for seven of the 18 genes in the support vector model. These seven genes, alone, classified 44 of the 48 patients in the validation set correctly and five CpGs selected from only two of the seven genes classified 41 of the 48 patients in the discovery set correctly. These results suggest that methylation biomarkers may be developed that will, at minimum, serve as useful objective and quantitative diagnostic complements to colonoscopy as a cancer-screening tool. These data also suggest that it may be possible to monitor biomarker methylation levels in tissues collected much less invasively than by colonoscopy. PMID:24806665

  17. Cathelicidin, an antimicrobial peptide produced by macrophages, promotes colon cancer by activating the Wnt/β-catenin pathway

    PubMed Central

    Wang, Xuan; Wu, Junlu; Quan, Wenqiang; Yao, Yiwen; Bals, Robert; Ji, Shurong; Wu, Kaiyin; Guo, Jia; Wan, Haiying

    2015-01-01

    Here we found that levels of cathelicidin, an antimicrobial peptide, were increased in colon cancer tissues compared to noncancerous tissues. Importantly, cathelicidin was mainly expressed in immune cells. Contact with tumor cells caused macrophages to secrete cathelicidin. Neutralization of cathelicidin, in vivo, significantly reduced the engraftment of macrophages into colon tumors, as well as proliferation of tumor cells, resulting in an inhibition of tumor growth. Furthermore, treatment with cathelicidin neutralizing antibody de-activated the Wnt/β-catenin signaling pathway in tumor cells both in vivo and in vitro. Cathelicidin activated Wnt/β-catenin signaling by inducing phosphorylation of PTEN, leading to activation of PI3K/Akt signaling and subsequent phosphorylation of GSK3β, resulting in stabilization and nuclear translocation of β-catenin. These data indicate that cathelicidin, expressed by immune cells in the tumor microenvironment, promotes colon cancer growth through activation of the PTEN/PI3K/Akt and Wnt/β-catenin signaling pathways. PMID:25596747

  18. Predictive and Prognostic Roles of BRAF Mutation in Stage III Colon Cancer: Results from Intergroup Trial CALGB 89803

    PubMed Central

    Ogino, Shuji; Shima, Kaori; Meyerhardt, Jeffrey A.; McCleary, Nadine J.; Ng, Kimmie; Hollis, Donna; Saltz, Leonard B.; Mayer, Robert J.; Schaefer, Paul; Whittom, Renaud; Hantel, Alexander; Benson, Al B.; Spiegelman, Donna; Goldberg, Richard M.; Bertagnolli, Monica M.; Fuchs, Charles S.

    2011-01-01

    Purpose Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colon and rectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. Methods We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm and MSI status. Results Compared to 431 BRAF-wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank p=0.015; multivariate hazard ratio (HR)=1.66; 95% confidence interval (CI), 1.05-2.63]. By assessing combined status of BRAF and MSI, it appeared that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, while BRAF-wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF-wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a non-significant trend toward improved OS was observed for IFL vs. FU/LV arm (multivariate HR=0.52; 95% CI, 0.25-1.10). Among patients with BRAF-wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR=1.02; 95% CI, 0.72-1.46). Conclusions BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy. PMID:22147942

  19. Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study.

    PubMed

    Sasaki, Kazuhito; Tsuno, Nelson H; Sunami, Eiji; Kawai, Kazushige; Hongo, Kumiko; Hiyoshi, Masaya; Kaneko, Manabu; Murono, Koji; Tada, Noriko; Nirei, Takako; Takahashi, Koki; Kitayama, Joji

    2012-08-01

    Autophagy is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemotherapy. Recently, chloroquine diphosphate (CQ), a widely used antimalarial drug, has been studied as a potential inhibitor of autophagy. Here, we aimed to investigate the role of CQ in potentiating the effect of 5-fluorouracil (5-FU), the chemotherapeutic agent of first choice for the treatment of colorectal cancer, in an animal model of colon cancer. The mouse colon cancer cell line colon26 was used. For the in-vivo study, colon26 cells were injected subcutaneously into BALB/c mice, which were treated with saline as a control, CQ (50 mg/kg/day), 5-FU (30 mg/kg/day), or the combination therapy (CQ plus 5-FU). The tumor volume ratio and body weight were monitored. After the sacrifice, tumor tissue protein extracts and tumor sections were prepared and subjected to immunoblotting for the analysis of autophagy-related and apoptosis-related proteins, and the terminal transferase uridyl end labeling assay. The combination of CQ resulted in the inhibition of 5-FU-induced autophagy and a significant enhancement in the 5-FU-induced inhibition of tumor growth. Furthermore, the combination treatment of CQ and 5-FU resulted in a significant increase in the ratio of apoptotic cells compared with other treatments. The expression levels of the proapoptotic proteins, namely Bad and Bax, were increased by the CQ treatment in the protein extracts from tumors. Our findings suggest that the combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of colorectal cancer. PMID:22561420

  20. Identifying Molecular Targets of Lifestyle Modifications in Colon Cancer Prevention

    PubMed Central

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

    2013-01-01

    One in four deaths in the United States is cancer-related, and colorectal cancer (CRC) is the second leading cause of cancer-associated deaths. Screening strategies are utilized but have not reduced disease incidence or mortality. In this regard, there is an interest in cancer preventive strategies focusing on lifestyle intervention, where specific etiologic factors involved in cancer initiation, promotion, and progression could be targeted. For example, exposure to dietary carcinogens, such as nitrosamines and polycyclic aromatic hydrocarbons influences colon carcinogenesis. Furthermore, dietary deficiencies could alter sensitivity to genetic damage and influence carcinogen metabolism contributing to CRC. High alcohol consumption increases the risk of mutations including the fact that acetaldehyde, an ethanol metabolite, is classified as a group 1 carcinogen. Tobacco smoke exposure is also a risk factor for cancer development; approximately 20% of CRCs are associated with smoking. Additionally, obese patients have a higher risk of cancer development, which is further supported by the fact that physical activity decreases CRC risk by 55%. Similarly, chronic inflammatory conditions also increase the risk of CRC development. Moreover, the circadian clock alters digestion and regulates other biochemical, physiological, and behavioral processes that could influence CRC. Taken together, colon carcinogenesis involves a number of etiological factors, and therefore, to create effective preventive strategies, molecular targets need to be identified and beleaguered prior to disease progression. With this in mind, the following is a comprehensive review identifying downstream target proteins of the above lifestyle risk factors, which are modulated during colon carcinogenesis and could be targeted for CRC prevention by novel agents including phytochemicals. PMID:23675573

  1. Robotic complete mesocolic excision for right-sided colon cancer.

    PubMed

    Ozben, Volkan; Baca, Bilgi; Atasoy, Deniz; Bayraktar, Onur; Aghayeva, Afag; Cengiz, Turgut Bora; Erguner, Ilknur; Karahasanoglu, Tayfun; Hamzaoglu, Ismail

    2016-10-01

    Complete mesocolic excision (CME) with central vascular ligation for right-sided colon cancer has been proven to provide superior oncologic outcomes and survival advantage when compared to standard lymphadenectomy [1]. A number of studies comparing conventional laparoscopic versus open CME have shown feasibility and safety of the laparoscopic approach with acceptable oncological profile and postoperative outcomes [2, 3]. The introduction of robotic systems with its technical advantages, including improved vision, better ergonomics and precise dissection, has further revolutionized minimally invasive approach in colorectal surgery. However, there seems to be a relatively slow adoption of robotic approach in the CME technique for right-sided colon cancer. This video demonstrates our detailed operative technique and feasibility for performing right-sided CME robotically. The surgical procedure is performed with a medial-to-lateral approach through four 8-mm robotic and one assistant ports. First, the ileocolic vessels are isolated, clipped and transected near their origins. Cephalad dissection continues along the ventral aspect of the superior mesenteric vein. Staying in the embryological planes between the mesocolon and retroperitoneal structures, mesenteric dissection is extended up to the root of the right colic vessels, if present, and the middle colic vessels, which are clipped and divided individually near their origins. After the terminal ileum is transected using an endolinear staple, the colon is mobilized fully from gastrocolic tissue and then from its lateral attachments. The transverse colon is transected under the guidance of near-infrared fluorescence imaging. Creation of an intracorporeal side-to-side ileotransversostomy anastomosis and extraction of the specimen complete the operation. We consider robotic CME to be feasible, safe and oncologically adequate for the treatment of right-sided colon cancer. Its technical advantages may lead to further

  2. Diagnostic microRNA markers to screen for sporadic human colon cancer in stool: I. Proof of principle.

    PubMed

    Ahmed, Farid E; Ahmed, Nancy C; Vos, Paul W; Bonnerup, Chris; Atkins, James N; Casey, Michelle; Nuovo, Gerard J; Naziri, Wade; Wiley, John E; Mota, Helvecio; Allison, Ron R

    2013-01-01

    To present proof-of-principle application for employing micro(mi)RNAs as diagnostic markers for colon cancer, we carried out global microarray expression studies on stool samples obtained from fifteen individuals (three controls, and three each with TNM stage 0-1, stage 2, stage 3, and stage 4 colon cancer), using Affymetrix GeneChip miRNA 3.0 Array, to select for a panel of miRNA genes for subsequent focused semi-quantitative polymerase chain reaction (PCR) analysis studies. Microarray results showed 202 preferentially expressed miRNA genes that were either increased (141 miRNAs), or reduced (61 miRNAs) in expression. We then conducted a stem-loop reverse transcriptase (RT)-TaqMan® minor groove binding (MGB) probes, followed by a modified qPCR expression study on 20 selected miRNAs. Twelve of the miRNAs exhibited increased and 8 decreased expression in stool from 60 individuals (20 controls, 20 with tumor-lymph node-metastatic (TNM) stage 0-1, 10 with stage 2, five with stage 3, and 5 with stage 4 colon cancer) to quantitatively monitor miRNA changes at various TNM stages of colon cancer progression. We also used laser-capture microdissection (LCM) of colon mucosal epithelial tissue samples (three control samples, and three samples from each of the four stages of colon cancer, for a total of 15 samples) to find concordance or lack thereof with stool findings. The reference housekeeping pseudogene-free ribosomal gene (18S rRNA), which shows little variation in expression, was employed as a normalization standard for relative PCR quantification. Results of the PCR analyses confirmed that twelve miRNAs (miR-7, miR-17, miR-20a, miR-21, miR-92a, miR-96, miR-106a, miR-134, miR-183, miR-196a, miR-199a-3p and miR214) had an increased expression in the stool of patients with colon cancer, and that later TNM carcinoma stages exhibited a more pronounced expression than did adenomas. On the other hand, eight miRNAs (miR-9, miR-29b, miR-127-5p, miR-138, miR-143, miR-146a, mi

  3. Copper Cu 64 Anti-CEA Monoclonal Antibody M5A PET in Diagnosing Patients With CEA Positive Cancer

    ClinicalTrials.gov

    2016-09-12

    Breast Cancer; Colon Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastrointestinal Cancer; Liver and Intrahepatic Biliary Tract Cancer; Lung Cancer; Metastatic Cancer; Pancreatic Cancer; Rectal Cancer; Thyroid Gland Medullary Carcinoma; Unspecified Adult Solid Tumor, Protocol Specific

  4. Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes

    PubMed Central

    Coe, Genevieve L.; Redd, Priscilla S.; Paschall, Amy V.; Lu, Chunwan; Gu, Lilly; Cai, Houjian; Albers, Thomas; Lebedyeva, Iryna O.; Liu, Kebin

    2016-01-01

    FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF-κB, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy. PMID:27487939

  5. Ex-vivo characterization of human colon cancer by Mueller polarimetric imaging.

    PubMed

    Pierangelo, Angelo; Benali, Abdelali; Antonelli, Maria-Rosaria; Novikova, Tatiana; Validire, Pierre; Gayet, Brice; De Martino, Antonello

    2011-01-17

    Cancerous and healthy human colon samples have been analyzed ex-vivo using a multispectral imaging Mueller polarimeter operated in the visible (from 500 to 700 nm) in a backscattering configuration with diffuse light illumination. Three samples of Liberkühn colon adenocarcinomas have been studied: common, mucinous and treated by radiochemotherapy. For each sample, several specific zones have been chosen, based on their visual staging and polarimetric responses, which have been correlated to the histology of the corresponding cuts. The most relevant polarimetric images are those quantifying the depolarization for incident linearly polarized light. The measured depolarization depends on several factors, namely the presence or absence of tumor, its exophytic (budding) or endophytic (penetrating) nature, its thickness (its degree of ulceration) and its level of penetration in deeper layers (submucosa, muscularis externa and serosa). The cellular density, the concentration of stroma, the presence or absence of mucus and the light penetration depth, which increases with wavelength, are also relevant parameters. Our data indicate that the tissues with the lowest and highest depolarizing powers are respectively mucus-free tumoral tissue with high cellular density and healthy serosa, while healthy submucosa, muscularis externa as well as mucinous tumor probably feature intermediate values. Moreover, the specimen coming from a patient treated successfully with radiochemotherapy exhibited a uniform polarimetric response typical of healthy tissue even in the initially pathological zone. These results demonstrate that multi-spectral Mueller imaging can provide useful contrasts to quickly stage human colon cancer ex-vivo and to distinguish between different histological variants of tumor. PMID:21263698

  6. Infrared spectral imaging as a novel approach for histopathological recognition in colon cancer diagnosis

    NASA Astrophysics Data System (ADS)

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

    2012-11-01

    Innovative diagnostic methods are the need of the hour that could complement conventional histopathology for cancer diagnosis. In this perspective, we propose a new concept based on spectral histopathology, using IR spectral micro-imaging, directly applied to paraffinized colon tissue array stabilized in an agarose matrix without any chemical pre-treatment. In order to correct spectral interferences from paraffin and agarose, a mathematical procedure is implemented. The corrected spectral images are then processed by a multivariate clustering method to automatically recover, on the basis of their intrinsic molecular composition, the main histological classes of the normal and the tumoral colon tissue. The spectral signatures from different histological classes of the colonic tissues are analyzed using statistical methods (Kruskal-Wallis test and principal component analysis) to identify the most discriminant IR features. These features allow characterizing some of the biomolecular alterations associated with malignancy. Thus, via a single analysis, in a label-free and nondestructive manner, main changes associated with nucleotide, carbohydrates, and collagen features can be identified simultaneously between the compared normal and the cancerous tissues. The present study demonstrates the potential of IR spectral imaging as a complementary modern tool, to conventional histopathology, for an objective cancer diagnosis directly from paraffin-embedded tissue arrays.

  7. Spraying quantum dot conjugates in the colon of live animals enabled rapid and multiplex cancer diagnosis using endoscopy.

    PubMed

    Park, Youngrong; Ryu, Yeon-Mi; Jung, Yebin; Wang, Taejun; Baek, Yeonggyeong; Yoon, Yeoreum; Bae, Sang Mun; Park, Joonhyuck; Hwang, Sekyu; Kim, Jaeil; Do, Eun-Ju; Kim, Sang-Yeob; Chung, Euiheon; Kim, Ki Hean; Kim, Sungjee; Myung, Seung-Jae

    2014-09-23

    The detection of colon cancer using endoscopy is widely used, but the interpretation of the diagnosis is based on the clinician's naked eye. This is subjective and can lead to false detection. Here we developed a rapid and accurate molecular fluorescence imaging technique using antibody-coated quantum dots (Ab-QDs) sprayed and washed simultaneously on colon tumor tissues inside live animals, subsequently excited and imaged by endoscopy. QDs were conjugated to matrix metalloproteinases (MMP) 9, MMP 14, or carcinoembryonic antigen (CEA) Abs with zwitterionic surface coating to reduce nonspecific bindings. The Ab-QD probes can diagnose tumors on sectioned mouse tissues, fresh mouse colons stained ex vivo and also in vivo as well as fresh human colon adenoma tissues in 30 min and can be imaged with a depth of 100 μm. The probes successfully detected not only cancers that are readily discernible by bare eyes but also hyperplasia and adenoma regions. Sum and cross signal operations provided postprocessed images that can show complementary information or regions of high priority. This multiplexed quantum dot, spray-and-wash, and endoscopy approach provides a significant advantage for detecting small or flat tumors that may be missed by conventional endoscopic examinations and bestows a strategy for the improvement of cancer diagnosis.

  8. (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol inhibits growth of colon tumors in mice

    PubMed Central

    Son, Dong Ju; Choi, Min Gi; Choi, Jeong Soon; Nam, Kyung Tak; Kim, Hae Deun; Rodriguez, Kevin; Gann, Benjamin; Ham, Young Wan; Han, Sang Bae; Hong, Jin Tae

    2015-01-01

    In our previous study, we found that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal showed anti-cancer effect, but it showed lack of stability and drug likeness. We have prepared several (E)-2,4-bis(p-hydroxyphenyl)-2-butenal analogues by Heck reaction. We selected two compounds which showed significant inhibitory effect of colon cancer cell growth. Thus, we evaluated the anti-cancer effects and possible mechanisms of one compound (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol in vitro and in vivo. In this study, we found that (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol induced apoptotic cell death in a dose dependent manner (0-15 μg/ml) through activation of Fas and death receptor (DR) 3 in HCT116 and SW480 colon cancer cell lines. Moreover, the combination treatment with (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol and nuclear factor κB (NF-κB) inhibitor, phenylarsine oxide (0.1 μM) or signal transducer and activator of transcription 3 (STAT3) inhibitor, Stattic (50 μM) increased the expression of Fas and DR3 more significantly. In addition, (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol suppressed the DNA binding activity of both STAT3 and NF-κB. Knock down of STAT3 or NF-κB p50 subunit by STAT3 small interfering RNA (siRNA) or p50 siRNA magnified (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol-induced inhibitory effect on colon cancer cell growth. Besides, the expression of Fas and DR3 was increased in STAT3 siRNA or p50 siRNA transfected cells. Moreover, docking model and pull-down assay showed that (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol directly bound to STAT3 and NF-κB p50 subunit. Furthermore, (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol inhibited colon tumor growth in a dose dependent manner (2.5 mg/kg-5 mg/kg) in mice. Therefore, these findings indicated that (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol may be a promising anti-cancer agent for colon cancer with more advanced research. PMID

  9. Food-grade titanium dioxide exposure exacerbates tumor formation in colitis associated cancer model.

    PubMed

    Urrutia-Ortega, Ismael M; Garduño-Balderas, Luis G; Delgado-Buenrostro, Norma L; Freyre-Fonseca, Verónica; Flores-Flores, José O; González-Robles, Arturo; Pedraza-Chaverri, José; Hernández-Pando, Rogelio; Rodríguez-Sosa, Miriam; León-Cabrera, Sonia; Terrazas, Luis I; van Loveren, Henk; Chirino, Yolanda I

    2016-07-01

    Colorectal cancer is the fourth worldwide cause of death and even if some dietary habits are consider risk factors, the contribution of food additives including foodgrade titanium dioxide (TiO2), designated as E171, has been poorly investigated. We hypothesized that oral E171 intake could have impact on the enhancement of colorectal tumor formation and we aimed to investigate if E171 administration could enhance tumor formation in a colitis associated cancer (CAC) model. BALB/c male mice were grouped as follows: a) control, b) E171, c) CAC and d) CAC + E171 group (n = 6). E171 used in this study formed agglomerates of 300 nm in water. E171 intragastric administration (5 mg/kg body weight/5 days/10 weeks) was unable to induce tumor formation but dysplastic alterations were observed in the distal colon but enhanced the tumor formation in distal colon (CAC + E171 group) measured by tumor progression markers. Some E171 particles were internalized in colonic cells of the E171 and CAC + E171 groups and both groups showed a decrease in goblet cells in the distal colon. However the CAC + E171 group showed a higher decrease of these cells that act as protection barrier in colon. These results suggest that E171 could worsen pre-existent intestinal diseases.

  10. Niacin alleviates TRAIL-mediated colon cancer cell death via autophagy flux activation

    PubMed Central

    Kim, Sung-Wook; Lee, Ju-Hee; Moon, Ji-Hong; Nazim, Uddin M.D.; Lee, You-Jin; Seol, Jae-Won; Hur, Jin; Eo, Seong-Kug; Lee, John-Hwa; Park, Sang-Youel

    2016-01-01

    Niacin, also known as vitamin B3 or nicotinamide is a water-soluble vitamin that is present in black beans and rice among other foods. Niacin is well known as an inhibitor of metastasis in human breast carcinoma cells but the effect of niacin treatment on TRAIL-mediated apoptosis is unknown. Here, we show that niacin plays an important role in the regulation of autophagic flux and protects tumor cells against TRAIL-mediated apoptosis. Our results indicated that niacin activated autophagic flux in human colon cancer cells and the autophagic flux activation protected tumor cells from TRAIL-induced dysfunction of mitochondrial membrane potential and tumor cell death. We also demonstrated that ATG5 siRNA and autophagy inhibitor blocked the niacin-mediated inhibition of TRAIL-induced apoptosis. Taken together, our study is the first report demonstrating that niacin inhibits TRAIL-induced apoptosis through activation of autophagic flux in human colon cancer cells. And our results also suggest that autophagy inhibitors including genetic and pharmacological tools may be a successful therapeutics during anticancer therapy using TRAIL. PMID:26517672

  11. Wnt/β-catenin signaling in T-cells drives epigenetic imprinting of pro-inflammatory properties and promotes colitis and colon cancer

    PubMed Central

    Keerthivasan, Shilpa; Aghajani, Katayoun; Dose, Marei; Molinero, Luciana; Khan, Mohammad W.; Venkatesvaran, Vysak; Weber, Christopher; Emmanuel, Akinola Olumide; Sun, Tianjao; Ramos, Elena M.; Keshavarzian, Ali; Mulcahy, Mary; Blatner, Nichole; Khazaie, Khashayarsha; Gounari, Fotini

    2014-01-01

    The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of TH17 cells and inflammation predict poor outcome, while infiltration by Tregs that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become pro-inflammatory and tumor promoting. These properties were directly linked with their expression of RORγt, the signature transcription factor of TH17 cells. Here, we report that Wnt/β-catenin signaling in T-cells promotes expression of RORγt. Expression of β-catenin was elevated in T-cells and Tregs of patients with colitis and colon cancer. Genetically engineered activation of β-catenin in mouse T-cells resulted in enhanced chromatin accessibility in the proximity of Tcf-1 binding sites genome-wide, induced expression of TH17 signature genes including RORγt, and promoted TH17-mediated inflammation. Strikingly, the mice had inflammation of intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. Based on these findings we conclude that activation of Wnt/β-catenin signaling in T-cells and/or Tregs is causatively linked with the imprinting of pro-inflammatory properties and the promotion of colon cancer. PMID:24574339

  12. An irreducible left scrotal hernia containing a sigmoid colon tumor (adenocarcinoma) – Case report

    PubMed Central

    Gnaś, Jarosław; Bulsa, Marek; Czaja-Bulsa, Grażyna

    2014-01-01

    INTRODUCTION In relation to all inguinal hernias, large irreducible scrotal hernias are quite rare, while such hernias containing colon tumors in the sac have so far been described in fewer than 30 cases. PRESENTATION OF CASE A 61-year-old patient was admitted for a planned surgery because of a large irreducible left-sided scrotal hernia. Intraoperatively, a large tumor of the sigmoid colon was found in the hernial sac. In a hist