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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. 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

  5. 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

  6. 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

  7. Colon cancer

    MedlinePlus

    ... red or processed meats Have colorectal polyps Have inflammatory bowel disease ( Crohn disease or ulcerative colitis ) Have a family history of colon cancer Have a personal history of breast cancer Some inherited diseases also increase the risk ...

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

    PubMed

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

    2015-01-01

    Despite recent progress in the identification of genetic and molecular alternations in colorectal carcinoma, the precise molecular pathogenesis remains unclear. NALP1 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 1) is a member of the nucleotide-binding oligomerization domain-like receptor family of proteins that are key organization proteins in the inflammasome. It is reported that NALP1 plays a central role in cell apoptosis, pyroptosis, inflammatory reactions and autoimmune diseases. DAC (5-aza-2-deoxycytidine) is an antitumor drug useful to lung cancer, myelodysplastic disorders, myelodysplasia and acute myeloid leukemia. In this study, we examined the expression of NALP1 in human normal and cancerous colon tissues using tissue microarray, western blot and quantitative real-time PCR and we measured the expression of NALP1 in three kinds of colon cancer cell lines and animal models before and after treatment with DAC. Furthermore, we examined the treatment effects of DAC on colon cancer in our animal model. Our data indicate that NALP1 is expressed low in human colorectal tumoral tissues relative to paratumoral tissues and was associated with the survival and tumor metastasis of patients. The expression of NALP1 increased after treatment with DAC both in vitro and in vivo. Furthermore, DAC suppressed the growth of colon cancer and increased lifespan in mouse model. Therefore, we conclude that NALP1 is expressed low in colon cancer and associated with the survival and tumor metastasis of patients, and treatment with DAC can restore NALP1 levels to suppress the growth of colon cancer. PMID:25611377

  9. [A case of recurrent pelvic tumor of sigmoid colon cancer showing partial response to lipiodolization].

    PubMed

    Shimoda, K; Hazama, S; Mitsunaga, H; Uchiyama, T; Oka, M; Suzuki, T

    1991-08-01

    We performed lipiodolization and immunochemotherapy for recurrent pelvic tumor of sigmoid colon cancer using an infuserport which was implanted and connected to the catheter placed in the right internal iliac artery. Following lipiodolization, the level of CEA (980 ng/ml) decreased to within the normal range. MRI showed necrotic change and regression (more than 50%) of tumor. DSA revealed disappearance of tumor neovascularity. No serious side effect but skin erosion in the gluteal region was encountered after lipiodolization. This result suggests that lipiodolization is worth performing in further clinical trials for pelvic tumor. PMID:1652230

  10. 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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  13. 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

  14. 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

  15. Liver Colonization Competence Governs Colon Cancer Metastasis

    NASA Astrophysics Data System (ADS)

    Kuo, Tsong-Hong; Kubota, Tetsuro; Watanabe, Masahiko; Furukawa, Toshiharu; Teramoto, Tatuso; Ishibiki, Kyuya; Kitajima, Masaki; Rahim Moosa, A.; Penman, Sheldon; Hoffman, Robert M.

    1995-12-01

    Tumors that metastasize do so to preferred target organs. To explain this apparent specificity, Paget, >100 years ago, formulated his seed and soil hypothesis; i.e., the cells from a given tumor would "seed" only favorable "soil" offered by certain organs. The hypothesis implies that cancer cells must find a suitable "soil" in a target organ-i.e., one that supports colonization-for metastasis to occur. We demonstrate in this report that ability of human colon cancer cells to colonize liver tissue governs whether a particular colon cancer is metastatic. In the model used in this study, human colon tumors are transplanted into the nude mouse colon as intact tissue blocks by surgical orthotopic implantation. These implanted tumors closely simulate the metastatic behavior of the original human patient tumor and are clearly metastatic or nonmetastatic to the liver. Both classes of tumors were equally invasive locally into tissues and blood vessels. However, the cells from each class of tumor behave very differently when directly injected into nude mouse livers. Only cells from metastasizing tumors are competent to colonize after direct intrahepatic injection. Also, tissue blocks from metastatic tumors affixed directly to the liver resulted in colonization, whereas no colonization resulted from nonmetastatic tumor tissue blocks even though some growth occurred within the tissue block itself. Thus, local invasion (injection) and even adhesion to the metastatic target organ (blocks) are not sufficient for metastasis. The results suggest that the ability to colonize the liver is the governing step in the metastasis of human colon cancer.

  16. 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 ...

  17. [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

  18. Establishment of human colon cancer cell lines from fresh tumors versus xenografts: comparison of success rate and cell line features.

    PubMed

    Dangles-Marie, Virginie; Pocard, Marc; Richon, Sophie; Weiswald, Louis-Bastien; Assayag, Franck; Saulnier, Patrick; Judde, Jean-Gabriel; Janneau, Jean-Louis; Auger, Nathalie; Validire, Pierre; Dutrillaux, Bernard; Praz, Françoise; Bellet, Dominique; Poupon, Marie-France

    2007-01-01

    Obtaining representative human colon cancer cell lines from fresh tumors is technically difficult. Using 32 tumor fragments from patients with colon cancer, the present study shows that prior xenograft leads to more efficient cell line establishment compared with direct establishment from fresh tumors (P < 0.05). From 26 tumor specimens, we successfully established 20 tumor xenografts in nude mice (77%); among 19 of these xenografts, 9 (47%) led to cell lines, including four from liver metastases. Only 3 of 31 tumor specimens (9.7%) grew immediately in vitro, and all were derived from primary tumors. To compare major phenotypic and genotypic characteristics of human colon cancer cell lines derived from the same tumor fragment using two protocols, the two pairs of cell lines obtained from 2 of 32 tumor fragments were extensively studied. They displayed similar morphology and were able to form compact spheroids. Chemosensitivity to 5-fluorouracil, CPT11, and L-OHP differed between cell lines obtained from patient tumors and those derived from xenografts. Matched cell lines shared a common core of karyotype alterations and distinctive additional chromosomal aberrations. Expression levels of genes selected for their role in oncogenesis evaluated by real-time quantitative PCR were found to be statistically correlated whatever the in vitro culture model used. In conclusion, xenotransplantation in mice of tumor fragments before establishment of cell lines enables generation of more novel human cancer cell lines for investigation of colon cancer cell biology, opening up the opportunity of reproducing the diversity of this disease. PMID:17210723

  19. 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

  20. Decreased Anti-Tumor Cytotoxic Immunity among Microsatellite-Stable Colon Cancers from African Americans

    PubMed Central

    Li, Shi; Khan, Mohammad W.; Tian, Mengxi; Tejada, Ruth; Hassan, Avan; Washington, Allen; Mukherjee, Bhramar; Carethers, John M.; McGuire, Kathleen L.

    2016-01-01

    Colorectal cancer is a leading cause of cancer related deaths in the U.S., with African-Americans having higher incidence and mortality rates than Caucasian-Americans. Recent studies have demonstrated that anti-tumor cytotoxic T lymphocytes provide protection to patients with colon cancer while patients deficient in these responses have significantly worse prognosis. To determine if differences in cytotoxic immunity might play a role in racial disparities in colorectal cancer 258 microsatellite-stable colon tumors were examined for infiltrating immune biomarkers via immunohistochemistry. Descriptive summary statistics were calculated using two-sample Wilcoxon rank sum tests, while linear regression models with log-transformed data were used to assess differences in race and Pearson and Spearman correlations were used to correlate different biomarkers. The association between different biomarkers was also assessed using linear regression after adjusting for covariates. No significant differences were observed in CD8+ (p = 0.83), CD57+ (p = 0.55), and IL-17-expressing (p = 0.63) cell numbers within the tumor samples tested. When infiltration of granzyme B+ cells was analyzed, however, a significant difference was observed, with African Americans having lower infiltration of cells expressing this cytotoxic marker than Caucasians (p<0.01). Analysis of infiltrating granzyme B+ cells at the invasive borders of the tumor revealed an even greater difference by race (p<0.001). Taken together, the data presented suggest differences in anti-tumor immune cytotoxicity may be a contributing factor in the racial disparities observed in colorectal cancer. PMID:27310868

  1. MiR-9, -31, and -182 Deregulation Promote Proliferation and Tumor Cell Survival in Colon Cancer12

    PubMed Central

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

    2012-01-01

    Several microRNAs (miRNAs) are known to be deregulated in colon cancer, but the mechanisms behind their potential involvement on proliferation and tumor cell survival are unclear. The present study aimed to identify miRNAs with functional implications for development of colon cancer. The cell proliferation and apoptosis were examined following perturbations of miRNA levels by employing a comprehensive miRNA library screen. miRNAs nominated for relevance to colon cancer were validated on expression and functional levels. By integrating the effect of miRNA up-regulation with the endogenous miRNA expression levels within the HT29, HCT116, and SW480 colon cancer cell lines, we identified miRNAs controlling cell proliferation (n = 53) and apoptosis (n = 93). From these functionally nominated miRNAs, we narrowed the list to 10 oncogene- and 20 tumor suppressor-like miRNAs that were also differentially expressed between colon cancer (n = 80) and normal colonic mucosa (n = 20). The differential expressions of miR-9, miR-31, and miR-182 were successfully validated in a series of colon carcinomas (n = 30) and polyps (n = 10) versus normal colonic mucosa (n = 10), whereas the functional effect was confirmed in an in-depth validation using different cell viability and apoptotic markers. Several transcription factors and genes regulating cell proliferation were identified as putative target genes by integrative miRNA/mRNA expression analysis obtained from the same colon cancer patient samples. This study suggests that deregulated expression of miR-9, miR-31, and miR-182 during carcinogenesis plays a significant role in the development of colon cancer by promoting proliferation and tumor cell survival. PMID:23019418

  2. Let-7a inhibits tumor cell growth and metastasis by directly targeting RTKN in human colon cancer.

    PubMed

    Li, Bin; Chen, Peng; Chang, Yanxiang; Qi, Jingpeng; Fu, Hui; Guo, Huifang

    2016-09-16

    Colorectal cancer (CRC) is the third most common cancer worldwide, with high morbidity. MicroRNAs (miRNAs) are endogenous small RNAs that play important roles in regulating multiple biological and pathologic processes. The differential expression of miRNAs in CRC was first reported in 2003. Accumulated evidence indicates that lethal-7a (let-7a, miRNA) generally functions as a tumor suppressor in several human cancers. However, the role of let-7a in human colon cancer remains unclear. The aim of this study was to investigate the biological functions of let-7a and its potential role in colon cancer. We first discovered that let-7a level was significantly decreased in colon cancer tissues and cell lines (HT-29, HCT-116, LoVo, SW480, and SW620). To explore the effects of let-7a on colon cancer, let-7a over-expressed HCT-116 and SW620 cells were constructed. Further studies demonstrated that over-expressed let-7a could remarkably inhibit HCT-116 and SW620 cell growth and metastasis by directly down-regulating Rhotekin (RTKN). When RTKN was reintroduced into let-7a mimic transfected HCT-116 or SW620 cells, the inhibition effects of let-7a on colon cancer cell growth and metastasis were markedly reversed. In conclusion, our research shows that let-7a can inhibit tumor cell growth and metastasis by directly targeting RTKN in human colon cancer. PMID:27498032

  3. 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

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

    PubMed Central

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

    2015-01-01

    Increasing evidence reveals that aberrant expression of microRNA contributes to the development and progression of colon cancer, but the roles of microRNA-506 (miR-506) in colon cancer remain elusive. Here, we demonstrated that miR-506 was down-regulated in colon cancer tissue and cells and that miR-506 expression was inversely correlated with EZH2 expression, tumor size, lymph node invasion, TNM stage and metastasis. A high level of miR-506 identified patients with a favorable prognosis. In vitro and in vivo experiments confirmed that miR-506 inhibits the proliferation and metastasis of colon cancer, and a luciferase reporter assay confirmed that EZH2 is a direct and functional target of miR-506 via the 3′UTR of EZH2. The restoration of EZH2 expression partially reversed the proliferation and invasion of miR-506-overexpressing colon cancer cells. Moreover, we confirmed that the miR-506-EZH2 axis inhibits proliferation and metastasis by activating/suppressing specific downstream tumor-associated genes and the Wnt/β-catenin signaling pathway. Taking together, our study sheds light on the role of miR-506 as a suppressor for tumor growth and metastasis and raises the intriguing possibility that miR-506 may serve as a new potential marker for monitoring and treating colon cancer. PMID:26452129

  5. Analysis of surgical complications of primary tumor resection after neoadjuvant treatment in stage IV colon cancer

    PubMed Central

    Martínez, Patricia; Baixauli, Jorge; Pastor, Carlos; Rodríguez, Javier; Pardo, Fernando; Rotellar, Fernando; Chopitea, Ana; Hernández-Lizoáin, José Luís

    2014-01-01

    Purpose Assess the surgical complications of primary tumor resection in stage IV colon cancer patients previously treated with neoadjuvant chemotherapy. Methods Between July 2001 and September 2010, 67 consecutive patients received preoperative chemotherapy. Clinical and surgical complications were obtained from the medical records. This study was retrospective in design. Results All patients were affected with liver metastasis, and 29.8% had metastasis in additional organs. Three different schemes of preoperative chemotherapy were employed, based on FOLFIRI, XELOXIRI or XELOX plus cetuximab. Eighteen patients (26.8%) reported some side effects to the chemotherapy, without contraindicating any intervention. All patients underwent colon surgery and within those, eight patients (11.9%), underwent liver surgery simultaneously. Median hospital admission was 8 [3-29] days. The perioperative complication rate was 16.2%, when the estimated physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) was 58.3%. There was not perioperative mortality, despite the mortality prediction for Portsmouth-POSSUM (P-POSSUM) being 5.07%. No differences were observed between the chemotherapy regimen (P=0.72) or the kind of the surgery—simple or combined (P=0.58). Conclusions Neoadjuvant chemotherapy as a systemic treatment for stage IV colon cancer does not indicate surgery contraindication nor increases postoperative morbimortality by a significant amount. PMID:24772343

  6. 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

  7. [A case of esophageal cancer with sigmoid colon tumor treated by laparoscopic surgery].

    PubMed

    Arita, Tomohiro; Shiozaki, Atsushi; Fujiwara, Hitoshi; Kokuba, Yukihito; Kuriu, Yoshiaki; Kubota, Takeshi; Ichikawa, Daisuke; Okamoto, Kazuma; Ishii, Hiromichi; Ikoma, Hisashi; Nakanishi, Masayoshi; Ochiai, Toshiya; Sakakura, Chohei; Sonoyama, Teruhisa; Otsuji, Eigo

    2010-11-01

    We performed a subtotal esophagectomy with gastric tube reconstruction by hand assisted laparoscopic surgery and laparoscopic sigmoidectomy simultaneously for the patient with middle thoracic esophageal cancer and lateral spreading tumor in the sigmoid colon. Upper abdominal and transumbilical incisions were made and Lap Discs (regular, mini) were set respectively. Two 12 mm ports were inserted in the right flank and lower quadrant, and two 5 mm ports were inserted in the left flank and lower quadrant. First, by using video-scope from upper Lap Disc, laparoscopic sigmoidectomy was performed. Anastomosis was performed via lower Lap Disc. For the gastric tube reconstruction, upper Lap Disc was used for hand assistance, and video-scope was inserted from lower Lap Disc. The patient was discharged at 26 days after surgery without complications. In conclusion, our surgical procedure provided a good surgical view and decreased a surgical stress. PMID:21224582

  8. 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

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

    PubMed

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

    2007-02-19

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

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

    PubMed Central

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

    2007-01-01

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

  11. Tumor Initiating Cells and Chemoresistance: Which Is the Best Strategy to Target Colon Cancer Stem Cells?

    PubMed Central

    Paldino, Emanuela; Tesori, Valentina; Casalbore, Patrizia; Gasbarrini, Antonio

    2014-01-01

    There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called “cancer stem cells” (CSCs). In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics. PMID:24527460

  12. 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

  13. Colon cancer - Series (image)

    MedlinePlus

    Colon cancer is the third most common cancer in the United States. Risk factors include a diet low ... The treatment of colon cancer depends on the stage of the disease. Stage I cancer is limited to the inner lining of the colon; ...

  14. Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition

    PubMed Central

    2010-01-01

    Background Activating transcription factor-3 (ATF3) is involved in the complex process of cellular stress response. However, its exact role in cancer is discussed controversially because both tumor suppressive and oncogenic effects have been described. Here we followed-up on our previous observation that inhibition of Hsp90 may increase ATF3 expression and sought to determine the role of ATF3 in colon cancer. Methods Regulation of ATF3 was determined in cancer cells using signaling inhibitors and a heat-shock protein-90 (Hsp90) antagonist. Human HCT116 cancer cells were stably transfected with an ATF3-shRNA or a luciferase-shRNA expression plasmid and alterations in cell motility were assessed in migration assays. The impact of ATF3 down-regulation on cancer growth and metastasis were investigated in a subcutaneous tumor model, a model of hepatic tumor growth and in a model of peritoneal carcinomatosis. Human colon cancer tissues were analyzed for ATF3 expression. Results The results show that therapeutic Hsp90 inhibition substantially up-regulates the expression of ATF3 in various cancer cells, including colon, gastric and pancreatic cancer. This effect was evident both in vitro and in vivo. RNAi mediated knock-down of ATF3 in HCT116 colon cancer cells significantly increased cancer cell migration in vitro. Moreover, in xenogenic mouse models, ATF3 knock-down promoted subcutaneous tumor growth and hepatic metastasis, as well as peritoneal carcinomatosis. Importantly, ATF3 expression was lower in human colon cancer specimens, as compared to corresponding normal surrounding tissues, suggesting that ATF3 may represent a down-regulated tumor suppressor in colon cancer. Conclusion In conclusion, ATF3 down-regulation in colon cancer promotes tumor growth and metastasis. Considering that blocking Hsp90 induces ATF3 expression, Hsp90 inhibition may represent a valid strategy to treat metastatic colon cancer by up-regulating this anti-metastatic transcription factor. PMID

  15. Hydroxycamptothecin induces apoptosis and inhibits tumor growth in colon cancer by the downregulation of survivin and XIAP expression

    PubMed Central

    2013-01-01

    Background 10-Hydroxycamptothecin (10-HCPT), isolated from a Chinese tree Camptotheca acuminate, inhibits the activity of topoisomerase I and has a broad spectrum of anticancer activity in vitro and in vivo. It has been shown that HCPT is more active and less toxic than conventional camptothecins and can induce cancer cell apoptosis. However, the mechanisms of HCPT-induced apoptosis in colon cancer cells remain unclear. In this study, we investigated the effects of HCPT on apoptosis of colon cancer and underlying mechanism. Methods Cell proliferation was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, and apoptosis was measured using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Expression of genes was detected using real-time reverse transcription-polymerase chain reaction (real time-PCR) and Western blot. Tumor growth in vivo was evaluated using a nude mouse xenograft model. Results HCPT could significantly inhibit cell proliferation and induce apoptosis in colon cancer SW1116 and Colo 205 cells in dose- and time-dependent manners. HCPT treatment activated the activities of caspase 3, 7, 8 and 9, downregulated the expression of survivin, survivinΔEx3, survivin-3B and XIAP, and upregulated expression of surviving 2B. Moreover, the combination of HCPT and 5-fluorouracial (5-FU) synergistically induced apoptosis and downregulated the expression of survivin and XIAP. Knockdown of survivin and XIAP by siRNA sensitized colon cancer to HCTP-induced apoptosis. Furthermore, HCPT treatment significantly inhibited SW1116 xenograft tumor growth. Conclusions Our results elucidate new mechanisms of HCPT antitumor by the downregulation of survivin and XIAP expression. The combination of HCPT with 5-FU or IAP inhibitors may be a potential strategy for colon cancer treatment. PMID:23721525

  16. Colon cancer - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100157.htm Colon cancer - Series To use the sharing features on ... 5 out of 5 Normal anatomy Overview The colon, or large intestine, is a muscular tube that ...

  17. Acute blockade of IL-25 in a colitis associated colon cancer model leads to increased tumor burden.

    PubMed

    Thelen, Tennille D; Green, Ryan M; Ziegler, Steven F

    2016-01-01

    Chronic inflammation within the gastrointestinal tract results in an increased risk for developing colorectal cancer. Epithelial cytokines, including interleukin-25 (IL-25), are produced in the colon and are critical for protection from parasites, but can also be pathogenic in the context of inflammatory bowel diseases and allergy. Whether IL-25 is involved in the progression from inflammation to cancer is still largely unexplored. Using a well-established murine model for colitis-induced colon cancer; we aimed to determine the role of IL-25 in this process. We found that acute IL-25 blockade resulted in greater tumor burdens compared to isotype control treated mice. Histologically, α-IL-25 treated mice had increased colitis scores compared to mice receiving isotype control antibody, as well as decreased eosinophilia. This is the first study to explore the therapeutic potential of using an IL-25 blocking antibody during a chronic inflammatory setting. Taken together these data suggest that IL-25 plays an inhibitory role in the growth and development of colonic tumors. PMID:27165713

  18. Acute blockade of IL-25 in a colitis associated colon cancer model leads to increased tumor burden

    PubMed Central

    Thelen, Tennille D.; Green, Ryan M.; Ziegler, Steven F.

    2016-01-01

    Chronic inflammation within the gastrointestinal tract results in an increased risk for developing colorectal cancer. Epithelial cytokines, including interleukin-25 (IL-25), are produced in the colon and are critical for protection from parasites, but can also be pathogenic in the context of inflammatory bowel diseases and allergy. Whether IL-25 is involved in the progression from inflammation to cancer is still largely unexplored. Using a well-established murine model for colitis-induced colon cancer; we aimed to determine the role of IL-25 in this process. We found that acute IL-25 blockade resulted in greater tumor burdens compared to isotype control treated mice. Histologically, α-IL-25 treated mice had increased colitis scores compared to mice receiving isotype control antibody, as well as decreased eosinophilia. This is the first study to explore the therapeutic potential of using an IL-25 blocking antibody during a chronic inflammatory setting. Taken together these data suggest that IL-25 plays an inhibitory role in the growth and development of colonic tumors. PMID:27165713

  19. PRDM1, a Tumor-Suppressor Gene, is Induced by Genkwadaphnin in Human Colon Cancer SW620 Cells.

    PubMed

    Kang, Ho-Bum; Lee, Ha-Reum; Jee, Da Jung; Shin, Su-Hyun; Nah, Seong-Su; Yoon, Sun Young; Kim, Jae Wha

    2016-01-01

    Genkwadaphnin (GD-1) is isolated from the flower buds of Daphne genkwa Siebold et Zuccarini (Thymelaeaceae), and it has been used as a traditional Korean and Chinese medicine. In this study, the authors observe that GD-1 inhibits the growth of the colon cancer cell line, SW620, through the up-regulation of p21 expression in a PRDM1-dependent manner. After treatment with GD-1, the transcriptional repressor PRDM1 is prominently induced in SW620 cells. Furthermore, GD-1 induce the phosphorylation of PKD1 and MEK and subsequently provide PRDM1 enhancement, resulting in the suppression of c-Myc expression and the up-regulation of p21. PKD1 knockdown using siRNA abrogates PRDM1 expression by GD-1 and subsequently disrupts the regulation of c-Myc and p21 expression. Treating SW620 cells with GD-1 inhibits cell-cycle progression and is characterized by the down-regulation of c-Myc followed by the up-regulation of p21 expression. The up-regulation of p21 by GD-1 induces the growth arrest of the SW620 colon cancer cell line. Based on these data, the authors propose that GD-1 has tumor-suppressor activity that may contribute to the anti-tumor effects of PRDM1 in colon cancer. PMID:26096175

  20. 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

  1. Persistent STAT3 Activation in Colon Cancer Is Associated with Enhanced Cell Proliferation and Tumor Growth1

    PubMed Central

    Corvinus, Florian M; Orth, Carina; Moriggl, Richard; Tsareva, Svetlana A; Wagner, Stefan; Pfitzner, Edith B; Baus, Daniela; Kaufmann, Roland; Huberb, Lukas A; Zatloukal, Kurt; Beug, Hartmut; Öhlschläger, Peter; Schütz, Alexander; Halbhuber, Karl-Jürgen; Friedrich, Karlheinz

    2005-01-01

    Abstract Colorectal carcinoma (CRC) is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6-driven proliferation. Blockade of STAT3 activation in CRC-derived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth. PMID:16036105

  2. Regulation of APC and AXIN2 expression by intestinal tumor suppressor CDX2 in colon cancer cells.

    PubMed

    Olsen, Anders Krüger; Coskun, Mehmet; Bzorek, Michael; Kristensen, Michael Holmsgaard; Danielsen, Erik Thomas; Jørgensen, Steffen; Olsen, Jørgen; Engel, Ulla; Holck, Susanne; Troelsen, Jesper Thorvald

    2013-06-01

    Wnt signaling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found to be transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signaling-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression of APC, AXIN2 and GSK3β in migrating colon cancer cells at the invasive front. CDX2-bound promoter and enhancer regions from APC, AXIN2 and GSK3β were analyzed for gene regulatory activity and the expression pattern of APC and GSK3β at the invasive front was evaluated by immunohistochemical procedures. Transfection of intestinal and non-intestinal cell lines demonstrated that CDX2 activated APC and AXIN2 promoter activities via intestinal cell-specific enhancer elements. Suppressed CDX2 expression was associated with endogenous downregulation of APC and AXIN2 expression in Caco-2 cells but did not affect GSK3β expression. Furthermore, elevated levels of nuclear β-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cells in vivo. These results suggest that a low CDX2 level has influence on the Wnt signaling in invasive colon cancer cells possibly promoting cellular migration. PMID:23393221

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

    PubMed Central

    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

    2013-01-01

    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

  4. 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

  5. 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

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

    PubMed Central

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

    2014-01-01

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

  7. Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells

    PubMed Central

    Yang, Xuguang; Li, Bingji; Liu, Jie; He, Rui

    2016-01-01

    Thymic stromal lymphopoietin (TSLP) has recently been suggested in several epithelial cancers, either pro-tumor or anti-tumor. However, the role of TSLP in colon cancer remains unknown. We here found significantly decreased TSLP levels in tumor tissues compared with tumor-surrounding tissues of patients with colon cancer and TSLP levels negatively correlated with the clinical staging score of colon cancer. TSLPR, the receptor of TSLP, was expressed in all three colon cancer cell lines investigated and colon tumor tissues. The addition of TSLP significantly enhanced apoptosis of colon cancer cells in a TSLPR-dependent manner. Interestingly, TSLP selectively induced the apoptosis of colon cancer cells, but not normal colonic epithelial cells. Furthermore, we demonstrated that TSLP induced JNK and p38 activation and initiated apoptosis mainly through the extrinsic pathway, as caspase-8 inhibitor significantly reversed the apoptosis-promoting effect of TSLP. Finally, using a xenograft mouse model, we demonstrated that peritumoral administration of TSLP greatly reduced tumor growth accompanied with extensive tumor apoptotic response, which was abolished by tumor cell-specific knockdown of TSLPR. Collectively, our study reveals a novel anti-tumor effect of TSLP via direct promotion of the apoptosis of colon cancer cells, and suggests that TSLP could be of value in treating colon cancer. PMID:26919238

  8. 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

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

    PubMed Central

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

    2013-01-01

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

  10. 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

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

    PubMed

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

    2016-09-01

    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

  12. Priming and potentiation of DNA damage response by fibronectin in human colon cancer cells and tumor-derived myofibroblasts

    PubMed Central

    DE WEVER, OLIVIER; SOBCZAK-THÉPOT, JOËLLE; VERCOUTTER-EDOUART, ANNE-SOPHIE; MICHALSKI, JEAN-CLAUDE; OUELAA-BENSLAMA, RADIA; STUPACK, DWAYNE G.; BRACKE, MARC; EMAMI, SHAHIN

    2016-01-01

    We have previously shown that the genotoxin-induced apoptosis in mouse embryo fibroblasts was enhanced by the extracellular matrix protein fibronectin (FN). In the present study, we tested the hypothesis that FN regulates the DNA damage response (DDR) signaling pathways in HCT116 (p53-wt) and HT29 (p53-mut) human colon cancer cells and tumor-derived myofibroblasts. DNA damage recognition mechanisms were analyzed by immunofluorescence staining, cell cycle analysis and immunoblotting addressed at specific molecular sensors and executors involved in the DDR pathways. The results show that FN, but not collagen type IV or Matrigel, initiates and potentiates the DDR to the anticancer drug cisplatin in an α5 integrin and cell cycle-dependent manner (S and G2/M phases) in human colon cancer cells. Accordingly, we demonstrate that adhesion of HCT116 cells to FN upregulated the expression of α5 integrin FN receptors at the cell surface. These FN-induced DDR pathways include the concerted phosphorylation of histone H2AX on Ser139 detected as nuclear foci (γ-H2AX, 15 and 25 kDa forms), of ataxia telangiectasia mutated (ATM-Ser1981), checkpoint kinase 2 (CHK2-Thr68, 62 and 67 kDa) and p53-Ser15. These FN-induced γ-H2AX signals were interrupted or attenuated by selective inhibitors acting on the DDR pathway kinases, including wortmannin (targeting the phosphatidylinositol-3-kinase-related protein kinases, PIKK), KU55933 (ATM), NU7026 (DNA-dependent protein kinase catalytic subunit, DNA-PK-cs) and SP600125 (JNK2, stress activated protein kinase/c-Jun N-terminal kinase-2). Adhesion to FN also potentiated the γ-H2AX signals and the cytotoxic effects of cisplatin in human colon tumor-derived myofibroblasts. These data provide evidence that FN promotes DNA damage recognition and chemosensitization to cisplatin via the potentiation of the DNA damage signaling responses in human colon cancer cells and tumor-derived myofibroblasts. PMID:21567080

  13. 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

  14. Colon cancer screening

    MedlinePlus

    ... screening; Sigmoidoscopy - screening; Virtual colonoscopy - screening; Fecal immunochemical test; Stool DNA test; sDNA test ... death and complications caused by colorectal cancer. SCREENING TESTS There are several ways to screen for colon ...

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

    PubMed

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

    2015-10-01

    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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Colon Cancer Metastatic to the Biliary Tree.

    PubMed

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

    2016-04-01

    Metastasis of colon adenocarcinoma is commonly found in the lung, liver, or peritoneum. Common bile duct (CBD) tumors related to adenomas from familial adenomatous polyposis metastasizing from outside of the gastrointestinal tract have been reported. We report a case of biliary colic due to metastatic colon adenocarcinoma to the CBD. Obstructive jaundice with signs of acalculous cholecystitis on imaging in a patient with a history of colon cancer should raise suspicion for metastasis to CBD. PMID:27144209

  1. 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

  2. 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. PMID:25866291

  3. Sphingolipids in colon cancer

    PubMed Central

    García-Barros, Mónica; Coant, Nicolas; Truman, Jean-Philip; Snider, Ashley J.

    2013-01-01

    Colorectal cancer is one of the major causes of death in the western world. Despite increasing knowledge of the molecular signaling pathways implicated in colon cancer, therapeutic outcomes are still only moderately successful. Sphingolipids, a family of N-acyl linked lipids, have not only structural functions but are also implicated in important biological functions. Ceramide, sphingosine and sphingosine-1-phosphate are the most important bioactive lipids, and they regulate several key cellular functions. Accumulating evidence suggests that many cancers present alterations in sphingolipids and their metabolizing enzymes. The aim of this review is to discuss the emerging roles of sphingolipids, both endogenous and dietary, in colon cancer and the interaction of sphingolipids with WNT/β-catenin pathway, one of the most important signaling cascades that regulate development and homeostasis in intestine PMID:24060581

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

    PubMed Central

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

    2013-01-01

    Purpose Discovery transcriptomic analyses suggest eukaryotic initiation factor 3b (eIF3b) is elevated in human bladder and prostate cancer, yet its role as a prognostic factor or its requirement in the maintenance or progression of human cancer is not established. Here we determine the therapeutic potential of eIF3b by examining the clinical relevance of its expression in human cancer tissues and its role in experimental tumor models. Experimental Design We examined mRNA expression of eIF3b in bladder (N=317) and prostate (N=566) tissue samples and protein expression by immunohistochemistry in 143 bladder tumor samples as a function of clinicopathologic features. The impact of eIF3b depletion by siRNA in human cancer lines was evaluated in regards to in vitro cell growth, cell cycle, migration, in vivo subcutaneous tumor growth and lung colonization. Results eIF3b mRNA expression correlated to tumor grade, stage and survival in human bladder and prostate cancer. eIF3b protein expression stratified survival in human bladder cancer. eIF3b depletion reduced in vitro cancer cell growth; inhibited G1/S cell cycle transition by changing protein but not RNA expression of Cyclin A, E, Rb and p27Kip1; inhibited migration and disrupted actin cytoskeleton and focal adhesions. These changes were associated with decreased protein expression of integrin α5. Integrin α5 depletion phenocopied effects observed with eIF3b. eIF3b depleted bladder cancer cells formed fewer subcutaneous tumors that grew more slowly and had reduced lung colonization. Conclusion eIF3b expression relates to human bladder and prostate cancer prognosis, is required for tumor growth and thus a candidate therapeutic target. PMID:23575475

  5. MC32 tumor cells acquire Ag-specific CTL resistance through the loss of CEA in a colon cancer model

    PubMed Central

    Lee, Sang-Yeul; Sin, Jeong-Im

    2015-01-01

    We previously reported that MC32 cells resist carcinoembryonic antigen (CEA) DNA vaccination by losing their antigen presentation to Ag-specific CTLs in the context of MHC class I antigens in a colon cancer therapeutic model. In this study, we selected 2 tumor cells, MC32-S2–2 and MC32-S4–2, which have the ability to form tumors in CEA DNA vaccine-immunized mice. Wild type MC32 cells grew significantly less in CEA-immunized mice (with Ag-specific CTL lytic activity) than in control mice (with no Ag-specific CTL lytic activity). However, MC32-S2–2 and MC32-S4–2 cells grew at a similar rate in both control and CEA-immunized mice, confirming their resistant status against CEA DNA vaccination. MC32-S2–2 and MC32-S4–2 cells were not susceptible to lysis by CEA-specific CD8+ T cells. Moreover, when MC32-S2–2 and MC32-S4–2 cells were used as stimulating agents of CEA-specific immune cells for IFN-γ production, these cells failed to stimulate the induction of Ag-specific IFN-γ, suggesting a loss of tumor cell recognition by Ag-specific immune cells. However, MC32-S2–2 and MC32-S4–2 cells expressed MHC class I antigens in a manner similar to that of wild type MC32 cells. Finally, Western blot assay confirmed that in MC32-S2–2 and MC32-S4–2 cells, CEA expression remained absent but mouse CEA was expressed. Taken together, these data show that MC32 cells may also be able to achieve resistance to CEA-specific CTLs by antigen loss in this model. PMID:25902414

  6. 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

  7. 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

  8. 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

  9. 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. PMID:24740923

  10. Anti-tumor effect of SLPI on mammary but not colon tumor growth.

    PubMed

    Amiano, Nicolás O; Costa, María J; Reiteri, R Macarena; Payés, Cristian; Guerrieri, Diego; Tateosian, Nancy L; Sánchez, Mercedes L; Maffia, Paulo C; Diament, Miriam; Karas, Romina; Orqueda, Andrés; Rizzo, Miguel; Alaniz, Laura; Mazzolini, Guillermo; Klein, Slobodanka; Sallenave, Jean-Michel; Chuluyan, H Eduardo

    2013-02-01

    Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor that was related to cancer development and metastasis dissemination on several types of tumors. However, it is not known the effect of SLPI on mammary and colon tumors. The aim of this study was to examine the effect of SLPI on mammary and colon tumor growth. The effect of SLPI was tested on in vitro cell apoptosis and in vivo tumor growth experiments. SLPI over-expressing human and murine mammary and colon tumor cells were generated by gene transfection. The administration of murine mammary tumor cells over-expressing high levels of SLPI did not develop tumors in mice. On the contrary, the administration of murine colon tumor cells over-expressing SLPI, developed faster tumors than control cells. Intratumoral, but not intraperitoneal administration of SLPI, delayed the growth of tumors and increased the survival of mammary but not colon tumor bearing mice. In vitro culture of mammary tumor cell lines treated with SLPI, and SLPI producer clones were more prone to apoptosis than control cells, mainly under serum deprivation culture conditions. Herein we demonstrated that SLPI induces the apoptosis of mammary tumor cells in vitro and decreases the mammary but not colon tumor growth in vivo. Therefore, SLPI may be a new potential therapeutic tool for certain tumors, such as mammary tumors. PMID:22767220

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  12. 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. PMID:27470345

  13. 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

  14. 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

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

    PubMed

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

    2015-10-01

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

  16. 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. PMID:16129820

  17. Virus-Like Particles Displaying Recombinant Short-Chain Fragment Region and Interleukin 2 for Targeting Colon Cancer Tumors and Attracting Macrophages.

    PubMed

    Deo, Vipin Kumar; Kato, Tatsuya; Park, Enoch Y

    2016-05-01

    Functionalized virus-like particles (VLPs) can target with specificity as drug delivery systems and can attract macrophages for the destruction of cancer cells. Here, the group antigen capsid protein from the Rous sarcoma virus was used to prepare VLPs, functionalized by displaying glycol-inositol phosphate-anchored recombinant single chain fragment variable (rscFv) and hemagglutinin transmembrane region anchored recombinant human interleukin-2 (rhIL2) (designated as VLP-rscFv-rhIL2s) in silkworms. The rscFv specifically binds the tumor-associated glycoprotein 72 that is expressed at the surface of colon cancer cells. VLP-rscFv-rhIL2 was affinity purified and had a smooth particle size with a diameter of 50 nm. Calcein-AM-packaged VLP-rscFv-rhIL2s successfully targeted cancer cells as a model for drug delivery system. VLP-rscFv-rhIL2 bound with colon cancer cells that attracted macrophages (human monocytic cell line-1 cells) in chemotaxis chamber assays compared with negative controls. The macrophages secreted tumor necrosis factor-α, a cytokine that is necessary to destroy cancer cells. These results demonstrate the potential of VLP-rscFv-rhIL2 as an intelligent nano biomaterial that is capable of attracting macrophages. PMID:27037014

  18. Preoperative Serum Levels of Mesothelin in Patients with Colon Cancer

    PubMed Central

    Bostancı, Özgür; Kemik, Özgür; Kemik, Ahu; Battal, Muharrem; Demir, Uygar; Purisa, Sevim; Mihmanlı, Mehmet

    2014-01-01

    Background. Screening for biochemical markers is important for diagnosing colon cancer. In this study, the reliability of serum mesothelin levels as a potential diagnostic and screening instrument was evaluated concerning colon cancer. Methods. Ninety-five patients who had undergone colonoscopic examination and who were diagnosed with colon cancer were included in the study. The serum mesothelin levels were measured with the ELISA kits and were evaluated in terms of significant difference when compared between colon cancer and control group. Results. Patients with colon cancer had significantly higher mesothelin serum levels (P < 0.001) than the control groups. We found significant associations between serum levels and tumor grade, perineural invasion, and vascular invasion (resp., P < 0.001). Conclusion. Evaluating the serum levels of mesothelin has a potential to detect and screen the colon cancer in affected patients. Our data suggest that mesothelin exhibits effects towards colon cancer and serves as a biomarker for this deadly disease. PMID:25477701

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

    PubMed Central

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

    2014-01-01

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

  20. Hereditary and Familial Colon Cancer

    PubMed Central

    Jasperson, Kory W.; Tuohy, Thérèse M.; Neklason, Deborah W.; Burt, Randall W.

    2011-01-01

    Between 2% to 5% of all colon cancers arise in the setting of well defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance. A number of less penetrant, but possibly more frequent susceptibility genes have been identified for this level of inheritance. Clarification of predisposing genes allows for accurate risk assessment and more precise screening approaches. This review examines the colon cancer syndromes, their genetics and management, and also the common familial colon cancers with current genetic advances and screening guidelines. PMID:20420945

  1. Colon polyps and cancer.

    PubMed

    Kronborg, O

    2004-01-01

    Screening for colorectal neoplasia still is the best method of reducing the mortality due to colorectal cancer, and it is to be hoped that fecal occult blood test programs will expand in the near future and be combined with appropriate endoscopy. There are substantial problems with compliance in large programs with occult blood tests as well as endoscopy. Colonography and DNA testing in feces are not yet suitable for population screening. Diagnostic strategies in symptomatic patients are becoming more selective, in the hope of avoiding many superfluous examinations without increasing the risk of missing cancers. New results have confirmed the preventive effect of long-term aspirin use on adenoma recurrence, but the most cost-effective dosage is not clear; the mechanism of action is also uncertain, but seems to involve cyclooxygenase-2. The risk of adenomas does not appear to be associated with low consumption of folate, but with low intake of fiber. A number of biomarkers have been evaluated in polyp patients, but so far surveillance is still based on endoscopic experience, which is less than optimal. Attempts have been made to restrict the number of surveillance endoscopies and reduce the pathologist's workload. The place of argon plasma coagulation has been clearly defined in connection with piecemeal removal of large sessile adenomas. Advances have been achieved in surgery and radiotherapy for rectal cancer, and acute surgery for colonic cancer with severe obstruction will be less common after the introduction of the metal stent. PMID:14722849

  2. Novel Piperazine-based Compounds Inhibit Microtubule Dynamics and Sensitize Colon Cancer Cells to Tumor Necrosis Factor-induced Apoptosis*

    PubMed Central

    Chopra, Avijeet; Anderson, Amy; Giardina, Charles

    2014-01-01

    We recently identified a series of mitotically acting piperazine-based compounds that potently increase the sensitivity of colon cancer cells to apoptotic ligands. Here we describe a structure-activity relationship study on this compound class and identify a highly active derivative ((4-(3-chlorophenyl)piperazin-1-yl)(2-ethoxyphenyl)methanone), referred to as AK301, the activity of which is governed by the positioning of functional groups on the phenyl and benzoyl rings. AK301 induced mitotic arrest in HT29 human colon cancer cells with an ED50 of ≈115 nm. Although AK301 inhibited growth of normal lung fibroblast cells, mitotic arrest was more pronounced in the colon cancer cells (50% versus 10%). Cells arrested by AK301 showed the formation of multiple microtubule organizing centers with Aurora kinase A and γ-tubulin. Employing in vitro and in vivo assays, tubulin polymerization was found to be slowed (but not abolished) by AK301. In silico molecular docking suggests that AK301 binds to the colchicine-binding domain on β-tubulin, but in a novel orientation. Cells arrested by AK301 expressed elevated levels of TNFR1 on their surface and more readily activated caspases-8, -9, and -3 in the presence of TNF. Relative to other microtubule destabilizers, AK301 was the most active TNF-sensitizing agent and also stimulated Fas- and TRAIL-induced apoptosis. In summary, we report a new class of mitosis-targeting agents that effectively sensitizes cancer cells to apoptotic ligands. These compounds should help illuminate the role of microtubules in regulating apoptotic ligand sensitivity and may ultimately be useful for developing agents that augment the anti-cancer activities of the immune response. PMID:24338023

  3. Right colon cancer presenting as hemorrhagic shock.

    PubMed

    Iwata, Tomoyuki; Konishi, Kazuo; Yamazaki, Takahisa; Kitamura, Katsuya; Katagiri, Atsushi; Muramoto, Takashi; Kubota, Yutaro; Yano, Yuichiro; Kobayashi, Yoshiya; Yamochi, Toshiko; Ohike, Nobuyuki; Murakami, Masahiko; Gokan, Takehiko; Yoshikawa, Nozomi; Imawari, Michio

    2011-02-15

    A 67-year-old man visited our hospital with a history of continuous hematochezia leading to hemorrhagic shock. An abdominal computed tomography scan revealed a large mass in the ascending colon invading the duodenum and pancreatic head as well as extravasation of blood from the gastroduodenal artery (GDA) into the colon. Colonoscopy revealed an irregular ulcerative lesion and stenosis in the ascending colon. Therefore, right hemicolectomy combined with pylorus-preserving pancreaticoduodenectomy was performed. Histologically, the tumor was classified as a moderately differentiated adenocarcinoma. Moreover, cancer cells were mainly located in the colon but had also invaded the duodenum and pancreas and involved the GDA. Immunohistochemically, the tumor cells were positive for cytokeratin (CK)20 and carcinoembryonic antigen (CEA) but not for CK7 and carbohydrate antigen (CA)19-9. The patient died 23 d after the surgery because he had another episode of arterial bleeding from the anastomosis site. Although En bloc resection of the tumor with pancreaticoduodenectomy and colectomy performed for locally advanced colon cancer can ensure long-term survival, patients undergoing these procedures should be carefully monitored, particularly when the tumor involves the main artery. PMID:21607161

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

    PubMed

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

    2015-11-01

    Recent studies have implicated ARMc8 in promoting tumor formation in non-small cell lung cancer and breast cancer; however, so far, no studies have revealed the expression pattern or cellular function of ARMc8 in colon cancer. In this study, we used immunohistochemical staining to measure ARMc8 expression in 206 cases of colon cancer and matched adjacent normal colon tissue. Clinically important behaviors of cells, including invasiveness and migration, were evaluated after upregulation of ARMc8 expression in HT29 cells through gene transfection or downregulation of expression in LoVo cells using RNAi. We found that ARMc8 was primarily located in the membrane and cytoplasm of tumor cells, and its expression level was significantly higher in colon cancer in comparison to that in the adjacent normal colon tissues (p < 0.001). ARMc8 expression was closely related to TNM stage (p = 0.006), lymph node metastasis (p = 0.001), and poor prognosis (p = 0.002) of colon cancer. The invasiveness and migration capacity of HT29 cells transfected with ARMc8 were significantly greater than those of control cells (p < 0.001), while ARMc8 siRNA treatment significantly reduced cell invasion and migration in LoVo cells (p < 0.001). Furthermore, we demonstrated that ARMc8 could upregulate the expression of MMP7 and snail and downregulate the expression of p120ctn and α-catenin. Therefore, ARMc8 probably enhanced invasiveness and metastatic capacity by affecting these tumor-associated factors, thereby playing a role in enhancing the tumorigenicity of colon cancer cells. ARMc8 is likely to become a potential therapeutic target for colon cancer. PMID:26081621

  5. Colon tumor cells grown in NASA Bioreactor

    NASA Technical Reports Server (NTRS)

    2001-01-01

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

  6. A Case of Sigmoid Colon Tuberculosis Mimicking Colon Cancer

    PubMed Central

    Yu, Seong-Min; Kim, Min-Dae; Lee, Hee-Ryong; Jung, Peel; Ryu, Tae-Hyun; Choi, Seung-Ho; Lee, Il-Seon

    2012-01-01

    Tuberculosis of the sigmoid colon is a rare disorder. An 80-year-old man visited Bongseng Memorial Hospital for medical examination. A colonoscopy was performed, and a lesion in the sigmoid colon that was suspected to be colon cancer was found. A biopsy was performed, and tuberculous enteritis with chronic granulomatous inflammation was diagnosed. Intestinal tuberculosis is most frequent in the ileocecal area, followed by the ascending colon, transverse colon, duodenum, stomach, and sigmoid colon, in descending order. Hence, we report a case of intestinal tuberculosis in the sigmoid colon, which is rare and almost indistinguishable from colon cancer. PMID:23185709

  7. 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.

  8. 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

  9. 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

  10. 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

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

    PubMed Central

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

    2015-01-01

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

  12. 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

  13. 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 ( ...

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

    PubMed Central

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

    2016-01-01

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

  15. [The tip of the iceberg: multiple cutaneous sebaceous tumor in colon cancer. Muir-Torre syndrome--case report].

    PubMed

    Herr, Gyula; Szenes, Mária; Hohl, Györgyi; Vinkler, Márta Erzsébet; Tüske, György; Horváth, János; Nagy, Gyöngyi; Tihanyi, Mariann; Széll, Márta; Nagy, Nikoletta; Gasztonyi, Beáta

    2015-06-14

    Muir-Torre syndrome is a rare genodermatosis with autosomal dominant inheritance. The syndrome is considered to be a subtype of the hereditary nonpolyposis colorectal cancer (or Lynch-syndrome). In two-third of the cases, it develops as the consequence of germline mutations in mismatch-repair genes--most commonly MutS Homolog-2 and MutL Homolog-1. Its diagnosis can be established if at least one sebaceous tumor (sebaceoma, sebaceous adenoma, epithelioma, carcinoma or basal-cell carcinoma with sebaceous differentiation) and/or keratoacanthoma and at least one internal neoplasm are present. Here the authors present the history of a 52-year-old man with multiple sebaceous carcinomas on his back. Immunohistochemical analysis showed the lack of MutL Homolog-1 protein expression in the tumor cells. Detailed clinical workup in order to identify internal malignancy found malignant coecum tumor. Histopathological evaluation of the sample from the right hemicolectomy revealed mid-grade adenocarcinoma with MutL Homolog-1 and postmeiotic segregation increased-2 deficiency. The detection of the cutaneous sebaceous carcinoma and the application of the modern diagnostic methods resulted in identification of the associated colorectal cancer in an early stage; hence, definitive treatment was available for the patient. PMID:26051134

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. Terahertz polarization imaging for colon cancer detection

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  1. Proteins and an Inflammatory Network Expressed in Colon Tumors

    PubMed Central

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

    2011-01-01

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

  2. Colon Cancer Rising in People Under 50

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159004.html Colon Cancer Rising in People Under 50 Incidence up ... TUESDAY, May 24, 2016 (HealthDay News) -- Although overall colon cancer rates are declining, the rates among Americans ...

  3. Vitamin E metabolite 13'-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice.

    PubMed

    Jang, Yumi; Park, Na-Young; Rostgaard-Hansen, Agnetha Linn; Huang, Jianjie; Jiang, Qing

    2016-06-01

    Vitamin E forms are substantially metabolized to various carboxychromanols including 13'-carboxychromanols (13'-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13'-COOH and δTE-13'-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13'-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13'-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13'-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13'-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13'-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13'-COOH-induced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13'-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13'-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents. PMID:27016075

  4. Colon Cancer

    Cancer.gov

    From 2000 until 2010 with the support from the National Cancer Institute, the Mouse Models for Human Cancer Consortium, and the Howard Hughes Medical Institute workshops and conferences to advance the understanding and use of animal models in colorectal cancer research have been organized .

  5. Tumor-specific Th2 responses inhibit growth of CT26 colon-cancer cells in mice via converting intratumor regulatory T cells to Th9 cells.

    PubMed

    Liu, Jiang-Qi; Li, Xing-Yong; Yu, Hai-Qiong; Yang, Gui; Liu, Zhi-Qiang; Geng, Xiao-Rui; Wang, Shuai; Mo, Li-Hua; Zeng, Lu; Zhao, Miao; Fu, Yun-Ting; Sun, Hong-Zhi; Liu, Zhi-Gang; Yang, Ping-Chang

    2015-01-01

    The abnormality of immune regulation plays a critical role in the pathogenesis of cancer; the underlying mechanism has not been fully understood yet. This study aims to investigate the role of cancer specific T helper (Th)2 response in the inhibition of colon cancer (Cca) cell growth. The results showed that with Cca cell (CT26 cell) extracts as an antigen, the Cca-extract specific Th2 response was induced in the Cca-bearing mice. The Cca mass size was significantly reduced, or radically disappeared (5 out of 10; or 50%); the survival rate was markedly improved in mice immunized with Cca-extract, but not in those immunized with another tumor cell (U87 cell) extracts or to bovine serum albumin. The immunization with Cca-extract also induced Cca cell apoptosis and converted the intra-Cca Tregs to T helper (Th) 9 cells. In conclusion, Cca-specific Th2 responses inhibit Cca growth in a mouse model via inducing Cca cell apoptosis and converting intra-Cca Tregs to Th9 cells. PMID:26035423

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

    PubMed

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

    2016-07-15

    Colon cancer is one of the major causes of cancer-related death in the world. Understanding the molecular mechanism underlying this malignancy will facilitate the diagnosis and treatment. Serine-arginine protein kinase 2 (SRPK2) has been reported to be upregulated in several cancer types. However, its expression and functions in colon cancer remains unknown. In this study, it was found that the expression of SRPK2 was up-regulated in the clinical colon cancer samples. Overexpression of SRPK2 promoted the growth and migration of colon cancer cells, while knocking down the expression of SRPK2 inhibited the growth, migration and tumorigenecity of colon cancer cells. Molecular mechanism studies revealed that SRPK2 activated ERK signaling in colon cancer cells. Taken together, our study demonstrated the tumor promoting roles of SRPK2 in colon cancer cells and SRPK2 might be a promising therapeutic target for colon cancer. PMID:27041240

  7. 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.

  8. Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors

    PubMed Central

    Papaioannou, Marilena; Lopez-Casas, Pedro Pablo; Llonch, Elisabet; Hidalgo, Manuel; Gorgoulis, Vassilis G.; Nebreda, Angel R.

    2015-01-01

    Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment. PMID:25890501

  9. Five New Genes Linked to Colon Cancer

    MedlinePlus

    ... nih.gov/medlineplus/news/fullstory_159556.html Five New Genes Linked to Colon Cancer But researchers say ... 24, 2016 (HealthDay News) -- Scientists have identified five new gene mutations that may be tied to colon ...

  10. STUDIES OF DBP-INDUCED COLON CANCER

    EPA Science Inventory

    Induction of colon carcinomas by trihalomethanes in rats may be relevant to epidemiological findings of increased incidences of colon-rectal cancer associated with exposure to chlorination byproducts. These studies have demonstrated that the brominated THMs in drinking water ind...

  11. Five New Genes Linked to Colon Cancer

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_159556.html Five New Genes Linked to Colon Cancer But researchers say ... 24, 2016 (HealthDay News) -- Scientists have identified five new gene mutations that may be tied to colon ...

  12. 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

  13. 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.

  14. 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

  15. XFM demonstrates preferential accumulation of a vanadyl-based MRI contrast agent in murine colonic tumors

    PubMed Central

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

    2016-01-01

    Contrast agents that specifically enhance cancers on MRI would allow earlier detection. Vanadyl-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 I.V.; 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 5 normal mice and 4 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 2-fold higher in cancers vs. normal tissue (p<0.002). Cancers also contained numerous ‘hot spots’ with intracellular VC concentrations 6-fold higher than the concentration in normal colon (p<0.0001). 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. PMID:25813904

  16. Bacterial Responses to a Simulated Colon Tumor Microenvironment*

    PubMed Central

    Boleij, Annemarie; Dutilh, Bas E.; Kortman, Guus A. M.; Roelofs, Rian; Laarakkers, Coby M.; Engelke, Udo F.; Tjalsma, Harold

    2012-01-01

    One of the few bacteria that have been consistently linked to colorectal cancer (CRC) is the opportunistic pathogen Streptococcus gallolyticus. Infections with this bacterium are generally regarded as an indicator for colonic malignancy, while the carriage rate of this bacterium in the healthy large intestine is relatively low. We speculated that the physiological changes accompanying the development of CRC might favor the colonization of this bacterium. To investigate whether colon tumor cells can support the survival of S. gallolyticus, this bacterium was grown in spent medium of malignant colonocytes to simulate the altered metabolic conditions in the CRC microenvironment. These in vitro simulations indicated that S. gallolyticus had a significant growth advantage in these spent media, which was not observed for other intestinal bacteria. Under these conditions, bacterial responses were profiled by proteome analysis and metabolic shifts were analyzed by 1H-NMR-spectroscopy. In silico pathway analysis of the differentially expressed proteins and metabolite analysis indicated that this advantage resulted from the increased utilization of glucose, glucose derivates, and alanine. Together, these data suggest that tumor cell metabolites facilitate the survival of S. gallolyticus, favoring its local outgrowth and providing a possible explanation for the specific association of S. gallolyticus with colonic malignancy. PMID:22713208

  17. Colon Cancer After Acute Diverticulitis Treatment

    PubMed Central

    Oh, Kwang Hoon; Kim, Eun Jung; Lee, Je Hoon; Choi, Kyu Un; Han, Myung Sik; Ahn, Jae Hong; Cheon, Gab Jin

    2013-01-01

    Diverticulitis is the most common clinical complication of diverticular disease, affecting 10-25% of the patients with diverticula. The prevalences of diverticulitis and colon cancer tend to increase with age and are higher in industrialized countries. Consequently, diverticulitis and colon cancer have been reported to have similar epidemiological characteristics. However, the relationship between these diseases remains controversial, as is the performance of routine colonoscopy after an episode of diverticulitis to exclude colon cancer. Recently, we experienced three cases of colon cancer after treating acute diverticulitis, based on which we suggest the importance of follow-up colonoscopy after acute diverticulitis. PMID:24032118

  18. Up-regulation of CNDP2 facilitates the proliferation of colon cancer

    PubMed Central

    2014-01-01

    Background Cytosolic nonspecific dipetidase (CN2) belongs to the family of M20 metallopeptidases. It was stated in previous articles that higher expression levels of CN2 were observed in renal cell carcinoma and breast cancer. Our study explored the correlation between CN2 and colon carcinogenesis. Methods We analysed the relationship between 183 patients clinicopathological characteristics and its CN2 expression. To detect the levels of CN2 in colon cancer cell lines and colon cancer tissues by western blot. To verify cell proliferation in colon cancer cells with knockdown of CNDP2 and explore the causes of these phenomena. Results The expression levels of CN2 in clinical colon tumors and colon cancer cell lines were significantly higher than that in normal colon mucosa and colon cell lines. The difference in CN2 levels was associated with tumor location (right- and left-sided colon cancer), but there was no significant association with age, gender, tumor size, tumor grade, tumor stage or serum carcinoembryonic antigen (CEA). Knockdown of CNDP2 inhibited cell proliferation, blocked cell cycle progression and retarded carcinogenesis in an animal model. The signaling pathway through which knockdown of CNDP2 inhibited cell proliferation and tumorigenesis involved in EGFR, cyclin B1 and cyclin E. Conclusions Knockdown of CNDP2 can inhibit the proliferation of colon cancer in vitro and retarded carcinogenesis in vivo. PMID:24885395

  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. PMID:26437221

  1. Regular Doctor Visits Can Help Spot Colon Cancer

    MedlinePlus

    ... 159699.html Regular Doctor Visits Can Help Spot Colon Cancer Early detection improves likelihood of survival, researchers ... increases the odds you'll be screened for colon cancer, a new study says. Colon cancer is ...

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

    PubMed Central

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

    2013-01-01

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

  3. Microbes, Microbiota and Colon Cancer

    PubMed Central

    Sears, Cynthia L.; Garrett, Wendy S.

    2014-01-01

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

  4. Colon Cancer Rising in People Under 50

    MedlinePlus

    ... fullstory_159004.html Colon Cancer Rising in People Under 50 Incidence up more than 10 percent in ... cancer rates are declining, the rates among Americans under 50 have jumped more than 11 percent in ...

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

    MedlinePlus Videos and Cool Tools

    ... explains the most commonly used screening methods, including test preparation, in simple language. View video Narrator : If ... cancer or even going for a colon cancer test can be frightening to you. “What if they ...

  6. 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.

  7. Metastatic cancer to the lung

    MedlinePlus

    ... Bladder cancer Breast cancer Colon cancer Kidney cancer Neuroblastoma Prostate cancer Sarcoma Wilms tumor Symptoms Symptoms may ... Breast cancer Cancer Chemotherapy Colon cancer Lung cancer Neuroblastoma Prostate cancer Radiation therapy Wilms tumor Update Date ...

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

    PubMed Central

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

    2015-01-01

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

  9. 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

  10. Inhibition of azoxymethane-induced colon cancer by orange juice.

    PubMed

    Miyagi, Y; Om, A S; Chee, K M; Bennink, M R

    2000-01-01

    Previous research has shown that hesperidin, a flavanone glycoside in orange juice, inhibits colon carcinogenesis and that feeding double-strength orange juice delays the onset of chemically induced mammary cancer in rats. This study determined whether feeding single-strength, pasteurized orange juice would inhibit azoxymethane (AOM)-induced colon cancer in male Fischer 344 rats. Colon cancer was initiated by injecting AOM (15 mg/kg body wt) at 22 and 29 days of age. One week after the second AOM injection, orange juice replaced drinking water for the experimental group (n = 30). The rats were killed 28 weeks later, and tumors were removed for histological analysis. Feeding orange juice reduced tumor incidence by 22% (p < 0.05). Tumor reduction was associated with a decreased labeling index and proliferation zone in the colonic mucosa. Hesperidin, other flavonoids, limonin 17-beta-D-glucopyranoside, and other limonoid glucosides are potential chemopreventive agents in orange juice that could account for the decreased colon tumorigenesis associated with feeding orange juice. PMID:10890034

  11. Regional and systemic distribution of anti-tumor x anti-CD3 heteroaggregate antibodies and cultured human peripheral blood lymphocytes in a human colon cancer xenograft

    SciTech Connect

    Nelson, H.; Ramsey, P.S.; Kerr, L.A.; McKean, D.J.; Donohue, J.H. )

    1990-11-15

    Anti-tumor antibody (317G5) covalently coupled to an anti-CD3 antibody (OKT3) produces a heteroaggregate (HA) antibody that can target PBL to lyse tumor cells expressing the appropriate tumor Ag. The i.v. and i.p. distribution of radiolabeled HA antibody 317G5 x OKT3 and of radiolabeled cultured human PBL were studied in athymic nude mice bearing solid intraperitoneal tumor established from the human colon tumor line, LS174T. Mice were injected with 125I-labeled HA antibody, 125I-labeled anti-tumor mAb, or 111In-labeled PBL, and at designated timepoints tissues were harvested and measured for radioactivity. 125I-317G5 x OKT3 localized specifically to tumor sites. Tumor radioactivity levels (percent injected dose/gram) were lower with 125I-317G5 x OKT3 HA antibody than with 125I-317G5 anti-tumor mAb, but were similar to levels reported for other anti-tumor mAb. The major difference in radioactivity levels observed between i.v. and i.p. administration of 125I-317G5 x OKT3 was an increase in hepatic radioactivity after i.v. HA antibody administration. HA antibodies produced from F(ab')2 fragments, which exhibit decreased m. w. and decreased Fc receptor-mediated binding, demonstrated improved tumor:tissue ratios as compared to intact antibody HA. 125I-317G5 F(ab')2 x OKT3 F(ab')2 antibody levels were equivalent to intact HA antibody levels in tumor, but were lower than intact HA antibody levels in the blood, bowel, and liver. Tumor:bowel ratios (20:1 at 48 h) were highest when 317G5 F(ab')2 x OKT3 F(ab')2 was injected i.p. Autoradiography confirmed that anti-tumor x anti-CD3 HA antibodies localized specifically to intraperitoneal tumor; that i.p. administered HA antibodies penetrated tumor directly; and that i.v. administered HA antibodies distributed along tumor vasculature.

  12. [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

  13. Treatment of colon cancer with oncolytic herpes simplex virus in preclinical models.

    PubMed

    Yang, H; Peng, T; Li, J; Wang, Y; Zhang, W; Zhang, P; Peng, S; Du, T; Li, Y; Yan, Q; Liu, B

    2016-05-01

    Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients. PMID:26871935

  14. NDC80 promotes proliferation and metastasis of colon cancer cells.

    PubMed

    Xing, X K; Wu, H Y; Chen, H L; Feng, H G

    2016-01-01

    Chromosome instability is a common feature of tumor cells, and may be an important mechanism in tumor formation. Nuclear division cycle 80 (NDC80) is closely associated with the stability of chromosomes. Therefore, we investigated the relationship between NDC80 and development of colon cancer using a range of methods. Western blotting and immunohistochemistry were employed to determine the expression of this protein in different colon cells and tissues, cell proliferation was measured with an MTT assay, levels of proliferating cell nuclear antigen were examined by immunofluorescence, and cell migration was observed using wound healing tests. Our results showed that the expression of NDC80 in colon cancer cells (CACO2, HCT8, HCT116, and SW480) and tissues (from 20 patients) was higher than that in controls. Moreover, cell proliferation and migration rates were elevated in cells transfected with NDC80 compared to control groups. In summary, NDC80 promotes the proliferation and metastasis of colon cancer cells, and may constitute a new target for gene therapy in treating this disease. Combined with clinicopathological grading, measurement of positive NDC80 expression may be helpful in diagnosing and estimating the prognosis of colon cancer patients. PMID:27173328

  15. Nutrients and Risk of Colon Cancer

    PubMed Central

    Hu, Jinfu; La Vecchia, Carlo; Negri, Eva; Mery, Les

    2010-01-01

    Dietary fats are thought to be important in the etiology of colon cancer. However, the evidence linking them is inconclusive. Studies on dietary protein, cholesterol and carbohydrate and the risk of colon cancer are also inconsistent. This study examined the association between dietary intake of protein, fats, cholesterol and carbohydrates, and the risk of colon cancer. Mailed questionnaires were completed by 1731 individuals with histologically confirmed cases of colon cancer and 3097 population controls between 1994 and 1997 in seven Canadian provinces. Measurements included socio-economic status, lifestyle habits and diet. A 69-item food frequency questionnaire was used to provide data on eating habits from two years before the study. Odds ratios (OR) and 95% confidence intervals (CI) were computed using unconditional logistic regression. The nutrients were categorized by quartiles based on the distributions among the controls. Intake of polyunsaturated fat, trans-fat and cholesterol were significantly associated with the risk of colon cancer; the ORs for the highest quartiles were 1.36 (95% CI, 1.02–1.80), 1.37 (95% CI, 1.10–1.71) and 1.42 (95% CI, 1.10–1.84), respectively. The association was stronger with proximal colon cancer (PCC). An increased risk was also observed with increasing intake of sucrose for both proximal and distal colon cancers; the ORs for the highest quartiles were 1.67 (95% CI, 1.22–2.29) for PCC and 1.58 (95% CI, 1.18–2.10) for distal colon cancer (DCC). An elevated risk of PCC was also found with increased lactose intake. Our findings provide evidence that a diet low in fat and sucrose could reduce the risk of various colon cancers. PMID:24281033

  16. 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

  17. 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

  18. 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...

  19. Sigmoid colonic metastasis by lymphatic spread occurring with unilateral Krukenberg tumor considered to be caused by stage IA early gastric cancer: A case report

    PubMed Central

    FUJIMOTO, DAISUKE; HIRONO, YASUO; GOI, TAKANAORI; YAMAGUCHI, AKIO

    2016-01-01

    Gastric cancer is one of the most common malignancies in Asia, and the second most common cause of cancer-associated mortality in Japan. Colorectal metastases originating from gastric adenocarcinoma are extremely rare. The present study reports an unusual case of lymphogenous sigmoid metastasis of gastric adenocarcinoma occurring in a 58-year-old female patient. Endoscopic and radiological findings were indicative of 0-IIc+IIa early gastric cancer, and radical distal gastrectomy with D2 lymph node dissection was performed. The pathological diagnosis was stage IA gastric adenocarcinoma (T1bN0M0), according to the Japanese classification of gastric cancer. A follow-up examination at 18 months post surgery revealed a recurrence of paraaortic lymph node metastasis, detected by abdominal computed tomography (CT) and positron emission tomography (PET)/CT. The patient received chemotherapy with S-1 and cisplatin. Subsequently, radiotherapy was administered to the paraaortic lymph nodes at levels Th11-L3. Follow-up abdominal CT and PET/CT revealed an enlarged left ovary, and abnormal uptake in the left ovary and sigmoid colon. An oophorectomy and sigmoidectomy with D3 lymph node dissection were performed. The pathological diagnosis was metastatic adenocarcinoma; this was identical to the gastric pathology in the previous pathological report. The patient continued treatment with chemotherapy. Although sigmoid colonic metastasis from gastric cancer is extremely rare, metastasis from gastric cancer must be considered during the differential diagnosis of cases involving a colorectal mass and a previous history of gastric cancer. PMID:26870264

  20. 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

  1. 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

  2. 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 ...

  3. 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.

  4. 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. PMID:25659576

  5. 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.

  6. 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

  7. 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal kinase

    PubMed Central

    Lei, Ping; Abdelrahim, Maen; Cho, Sung Dae; Liu, Shengxi; Chintharlapalli, Sudhakar; Safe, Stephen

    2008-01-01

    1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) activate the orphan receptors peroxisome proliferator-activated receptor γ (PPARγ) and Nur77 and induce receptor-dependent and -independent apoptotic pathways in colon and other cancer cells. Structure-activity studies show that the p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) analogs, which exhibit minimal activation of Nur77 and PPARγ, induce expression of CCAAT/enhancer-binding protein homologous protein (CHOP/GADD153) in colon cancer cells. Moreover, among a series of bromo and fluoro C-DIM analogs, their induction of CHOP was dependent on the position of the phenyl substituents (para ≥ meta ≥ ortho) and required a free indole group. DIM-C-pPhBr and DIM-C-pPhF not only induced CHOP but also activated death receptor 5 (CHOP dependent), cleavage of caspase 8 and poly (ADP ribose) polymerase (PARP) that is consistent with activation of the extrinsic pathway of apoptosis. These responses were associated with the activation of c-jun N-terminal kinase (JNK) pathway since inhibition of JNK inhibited induction of the extrinsic apoptotic pathway by these C-DIMs. However, in contrast to classical inducers of endoplasmic reticulum (ER) stress such as tunicamycin and thapsigargin, the C-DIM compounds did not induce glucose-related protein 78 that is a marker of ER stress. Proapoptotic and anticarcinogenic effects were also observed in athymic nude mice bearing RKO cell xenografts and treated with 30 mg/kg/day DIM-C-pPhBr and this was accompanied by increased JNK phosphorylation in the tumors. Thus, the anticarcinogenic activity of DIM-C-pPhBr in colon cancer cells and tumors is related to a novel ER stress-independent activation of JNK. PMID:18460448

  8. Mucin production by human colonic carcinoma cells correlates with their metastatic potential in animal models of colon cancer metastasis.

    PubMed Central

    Bresalier, R S; Niv, Y; Byrd, J C; Duh, Q Y; Toribara, N W; Rockwell, R W; Dahiya, R; Kim, Y S

    1991-01-01

    Patients with mucinous colorectal cancers characteristically present with advanced disease, however, the relationship between mucin production by colon cancer cells and their metastatic potential remains unclear. We therefore sought to define the relationship between mucin production by human colon cancer cells and metastatic ability by employing animal models of colon cancer metastasis. LS LiM 6, a colon carcinoma cell line with high liver metastasizing ability during cecal growth in nude mice produced twofold more metabolically labeled intracellular mucin and secreted four- to fivefold more mucin into the culture medium compared to poorly metastatic parental line LS174T. This was accompanied by a similar elevation in poly(A)+ RNA detected by blot hybridization with a human intestinal mucin cDNA probe, and increases in mucin core carbohydrate antigens determined immunohistochemically. Variants of LS174T selected for high (HM 7) or low (LM 12) mucin synthesizing capacity also yielded metastases after cecal growth and colonized the liver after splenic-portal injection in proportion to their ability to produce mucin. Inhibition of mucin glycosylation by the arylglycoside benzyl-alpha-N-acetyl-galactosamine greatly reduced liver colonization after splenic-portal injection of the tumor cells. These data suggest that mucin production by human colon cancer cells correlates with their metastatic potential and affects their ability to colonize the liver in experimental model systems. Images PMID:1999484

  9. Collection of Biospecimen & Clinical Information in Patients w/ Gastrointestinal Cancers

    ClinicalTrials.gov

    2012-05-24

    Gastrointestinal Neoplasms; Gynecologic Cancers; Gynecologic Cancers Cervical Cancer; Gastric (Stomach) Cancer; Gastro-Esophageal(GE) Junction Cancer; Gastrointenstinal Stromal Tumor (GIST); Colon/Rectal Cancer; Colon/Rectal Cancer Colon Cancer; Colon/Rectal Cancer Rectal Cancer; Colon/Rectal Cancer Anal Cancer; Anal Cancer; Hepatobiliary Cancers; Hepatobiliary Cancers Liver; Pancreatic Cancer

  10. Endoscopic management of polypoid early colon cancer.

    PubMed

    Williams, C B; Saunders, B P; Talbot, I C

    2000-09-01

    Endoscopic management of polypoid early colonic cancer (malignant polyps and polypoid carcinomas) is no longer controversial. When the endoscopist is satisfied that excision is complete and histology is "favorable" (a resection margin of 2 mm and well or moderately well differentiated tumor), surgery is unnecessary. When histology show "unfavorable" characteristics (which a few histologists still take to include invasion into lymphatics), surgical or laparoscopic resection may be indicated, providing the patient is considered at suitable risk. Surgery kills some patients without finding residual cancer and cannot save others with metastases, so it should be recommended only with due clinical consideration. Sessile or broad-based polyps, especially those in the rectum, are more likely to be "high risk" and merit specialist management if local removal is to be attempted and to allow proper histologic assessment. Endoscopic approaches such as saline injection polypectomy, india-ink tattooing, and use of the argon beam coagulator are applicable in some cases. New approaches that still require trials include ultrasonographic probes, which occasionally clarify the degree of invasion, and prototype stapling devices to allow full-thickness histologic specimens to be obtained. PMID:11036280

  11. 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

  12. Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation

    PubMed Central

    Le Rolle, Anne-France; Chiu, Thang K.; Zeng, Zhaoshi; Shia, Jinru; Weiser, Martin R.; Paty, Philip B.; Chiu, Vi K.

    2016-01-01

    Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer. PMID:26744320

  13. 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

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

    PubMed

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

    2016-05-01

    Tumor invasion and metastasis are closely associated with epithelial‑mesenchymal transition (EMT). EMT refers to epithelial cells under physiological and pathological conditions that are specific to mesenchymal transition. Curcumin inhibits EMT progression via Wnt signaling. The Wnt signaling pathway is a conservative EMT‑related signaling pathway that is involved in the development of various tumors. In the present study, MTS assays were employed to analyze the proliferation of curcumin‑treated cells. Naked cuticle homolog 2 (NKD2), chemokine receptor 4 (CXCR4) and antibodies associated with EMT were examined in SW620 colorectal cancer cell lines using western blot analysis and real‑time qPCR. NKD2 small‑interfering RNA (siRNA) and CXCR4 expression plasmid was synthesized and transfected into the colorectal cancer cell lines, and NKD2 and CXCR4 expression levels were detected. The results showed that curcumin significantly inhibited the proliferation of colorectal cancer cells and upregulated the expression of NKD2 in SW620 colorectal cancer cells and in the xenograft, resulting in the downregulation of key markers in the Wnt signaling. In addition, the progression of ETM was inhibited due to the overexpression of E‑cadherin as well as the downregulation of vimentin. Curcumin also inhibited tumor metastasis by downregulating the expression of CXCR4 significantly. The results suggested involvement of the NKD2‑Wnt‑CXCR4 signaling pathway in colorectal cancer cells. In addition, curcumin is inhibit this signaling and the development of colorectal cancer. PMID:26985708

  15. Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells

    PubMed Central

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

    2016-01-01

    The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. PMID:26927179

  16. 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

    2016-01-01

    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. 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

  18. Tumor-Associated Macrophage (TAM) and Angiogenesis in Human Colon Carcinoma

    PubMed Central

    Badawi, Manal A.; Abouelfadl, Dalia M.; El-Sharkawy, Sonia L.; El-Aal, Wafaa E. Abd; Abbas, Naglaa F.

    2015-01-01

    AIM: This study aimed to clarify how macrophages affect prognosis in cancer colon and their association with tumor angiogenesis. MATERIAL AND METHODS: Forty four biopsies of colon carcinoma and 15 of benign adenomatous polyps were investigated for macrophages infiltration and microvessels density using immunohistochemistry and image morphometric analysis. Macrophages and blood vessels were stained immunohistochemically by CD68 and F-VIII markers respectively. The morphometric analysis was carried out on the immunohistochemically stained slides using the Leica Qwin 500 Image Analyzer. Both of macrophages infiltration and microvessels density were correlated with histological tumor grade, stage and lymph node metastases and were correlated with each others. RESULTS: Macrophage infiltration was significantly higher in malignant cases than in benign polyps. High macrophage infiltration and hypervascularity were significantly correlated with T-staging and lymph nodes metastasis. A significant correlation was found between macrophage infiltration and microvessels densitie in malignant tumors where hypervascularity was significantly correlated with high macrophages infiltration. CONCLUSION: The significant correlation between macrophage infiltration and tumor angiogenesis suggests an interaction between macrophages and cancer cells stimulating microvessels formation, tumor invasion and metastasis in colon cancer. We recommend that macrophages infiltration should be evaluated to investigate their clinical value in development of individualized therapeutic regimens for management of colon carcinoma.

  19. Short chain fatty acids and colon cancer.

    PubMed

    Augenlicht, Leonard H; Mariadason, John M; Wilson, Andrew; Arango, Diego; Yang, WanCai; Heerdt, Barbara G; Velcich, Anna

    2002-12-01

    The development of intestinal cancer involves complex genetic and epigenetic alterations in the intestinal mucosa. The principal signaling pathway responsible for the initiation of tumor formation, the APC-beta-catenin-TCF4 pathway, regulates both cell proliferation and colonic cell differentiation, but many other intrinsic and extrinsic signals also modulate these cell maturation pathways. The challenge is to understand how signaling and cell maturation are also modulated by nutritional agents. Through gene expression profiling, we have gained insight into the mechanisms by which short chain fatty acids regulate these pathways and the differences in response of gene programs, and of the specific regulation of the c-myc gene, to physiological regulators of intestinal cell maturation, such as butyrate, compared with pharmacological regulators such as the nonsteroidal antiinflammatory drug sulindac. Moreover, we used a combination of gene expression profiling of the response of cells in culture to sulindac and the response of the human mucosa in subjects treated with sulindac for 1 month, coupled with a mouse genetic model approach, to identify the cyclin dependent kinase inhibitor p21(WAF1/Cip1) as an important suppressor of Apc-initiated intestinal tumor formation and a necessary component for tumor inhibition by sulindac. Finally, the mucous barrier, secreted by intestinal goblet cells, is the interface between the luminal contents and the intestinal mucosa. We generated a mouse genetic model with a targeted inactivation of the Muc2 gene that encodes the major intestinal mucin. These mice have no recognizable goblet cells due to the failure of cells to synthesize and store mucin. This leads to perturbations in intestinal crypt architecture, increased cellular proliferation and rates of cell migration, decreased apoptosis and development of adenomas and adenocarcinomas in the small and large intestine and the rectum. PMID:12468628

  20. TPX2 is a novel prognostic marker for the growth and metastasis of colon cancer

    PubMed Central

    2013-01-01

    Background We have previously demonstrated an aberrant overexpression of the microtubule-associated protein TPX2 in colon cancer using a genome-wide gene expression profiling analysis. Here, we aim to investigate its expression pattern, clinical significance, and biological function in colon cancer. Methods TPX2 expression was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo. Results TPX2 was overexpressed in 129 of the 203 (60.8%) colon cancer metastatic lesions, with the expression being significantly higher than that in primary cancerous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with clinical staging, vessel invasion, and metastasis. In survival analyses, patients with TPX2 overexpression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistent with this, suppression of TPX2 expression inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT-mediated MMP2 activity. Conclusions These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer, and may represent a novel prognostic biomarker and therapeutic target for the disease. PMID:24341487

  1. 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

  2. Black Raspberry-Derived Anthocyanins Demethylate Tumor Suppressor Genes Through the Inhibition of DNMT1 and DNMT3B in Colon Cancer Cells

    PubMed Central

    Wang, Li-Shu; Kuo, Chieh-Ti; Cho, Seung-Ju; Seguin, Claire; Siddiqui, Jibran; Stoner, Kristen; Weng, Yu-I; Huang, Tim H.-M.; Tichelaar, Jay; Yearsley, Martha; Stoner, Gary D.; Huang, Yi-Wen

    2013-01-01

    We previously reported that oral administration of black raspberry powder decreased promoter methylation of tumor suppressor genes in tumors from patients with colorectal cancer. The anthocyanins (ACs) in black raspberries are responsible, at least in part, for their cancer-inhibitory effects. In the present study, we asked if ACs are responsible for the demethylation effects observed in colorectal cancers. Three days of treatment of ACs at 0.5, 5, and 25 μg/ml suppressed activity and protein expression of DNMT1 and DNMT3B in HCT116, Caco2 and SW480 cells. Promoters of CDKN2A, and SFRP2, SFRP5, and WIF1, upstream of Wnt pathway, were demethylated by ACs. mRNA expression of some of these genes was increased. mRNA expression of β-catenin and c-Myc, downstream of Wnt pathway, and cell proliferation were decreased; apoptosis was increased. ACs were taken up into HCT116 cells and were differentially localized with DNMT1 and DNMT3B in the same cells visualized using confocal laser scanning microscopy. Although it was reported that DNMT3B is regulated by c-Myc in mouse lymphoma, DNMT3B did not bind with c-Myc in HCT116 cells. In conclusion, our results suggest that ACs are responsible, at least in part, for the demethylation effects of whole black raspberries in colorectal cancers. PMID:23368921

  3. Metastatic male ductal breast cancer mimicking obstructing primary colon cancer.

    PubMed

    Koleilat, Issam; Syal, Anil; Hena, Muhammad

    2010-03-01

    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

  4. 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

  5. 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

  6. 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

  7. Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon.

    PubMed

    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

    2014-10-01

    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

  8. Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer

    PubMed Central

    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. PMID:26339368

  9. 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.

  10. 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

  11. Tolfenamic acid downregulates β-catenin in colon cancer.

    PubMed

    Ha, Taekyu; Lou, Zhiyuan; Baek, Seung Joon; Lee, Seong-Ho

    2016-06-01

    Tolfenamic acid is one of the fenamic acid-derived non-steroid anti-inflammatory drugs (NSAIDs) and has been shown to exhibit anti-cancer activities in several types of cancer. Both mutations and aberrant expression of β-catenin are highly associated with progression of cancer. Therefore, β-catenin is considered to be a promising molecular target for cancer prevention and treatment. The current study investigates the role of tolfenamic acid on β-catenin expression in colon cancer. Treatment with tolfenamic acid led to inhibition of cell growth and down-regulation of β-catenin expression in a dose- and time-dependent manner in human colon cancer cell lines. Reduction of β-catenin upon tolfenamic acid treatment was associated with ubiquitin-mediated proteasomal degradation, without affecting mRNA level and promoter activity of β-catenin. In addition, treatment with tolfenamic acid downregulated Smad2 and Smad3 expression, while overexpression of Smad2, but not Smad3, blocked tolfenamic acid-induced suppression of β-catenin expression. Tolfenamic acid also decreased expression of β-catenin target genes, including vascular endothelial growth factor (VEGF). Compared to adjacent normal tissue, intestinal tumor tissues of Apc(Min/+) mice exhibited increased expression of β-catenin, Smad2, Smad3, and VEGF, which were down-regulated with tolfenamic acid treatment at a dose of 50mg/kg body weight. In conclusion, our findings suggest that tolfenamic acid inhibits growth of colon cancer cells through downregulation of Smad2 and, subsequently, facilitating ubiquitin-proteasome-mediated β-catenin degradation in colon cancer. PMID:27089389

  12. 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

  13. 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

  14. A Little Excess Weight May Boost Colon Cancer Survival

    MedlinePlus

    ... 158930.html A Little Excess Weight May Boost Colon Cancer Survival Researchers saw an effect, but experts ... a surprise, a new study found that overweight colon cancer patients tended to have better survival than ...

  15. Six Ways to Reduce Your Risk of Colon Cancer

    MedlinePlus

    ... html Six Ways to Reduce Your Risk of Colon Cancer Diet, weight and physical activity play a significant ... March 8, 2016 (HealthDay News) -- Half of the colon cancer cases in the United States could be prevented ...

  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. 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

  18. 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

  19. 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.

  20. 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

  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. Prognostic and Predictive Significance of Stromal Fibroblasts and Macrophages in Colon Cancer

    PubMed Central

    Owusu, Benjamin Y.; Vaid, Mudit; Kaler, Pawan; Klampfer, Lidija

    2015-01-01

    Colon cancer development and malignant progression are driven by genetic and epigenetic alterations in tumor cells and by factors from the tumor microenvironment. Cancer cells become reliant on the activity of specific oncogenes and on prosurvival and proliferative signals they receive from the abnormal environment they create and reside in. Accordingly, the response to anticancer therapy is determined by genetic and epigenetic changes that are intrinsic to tumor cells and by the factors present in the tumor microenvironment. Recent advances in the understanding of the involvement of the tumor microenvironment in tumor progression and therapeutic response are optimizing the application of prognostic and predictive factors in colon cancer. Moreover, new targets in the tumor microenvironment that are amenable to therapeutic intervention have been identified. Because stromal cells are with rare exceptions genetically stable, the tumor microenvironment has emerged as a preferred target for therapeutic drugs. In this review, we discuss the role of stromal fibroblasts and macrophages in colon cancer progression and in the response of colon cancer patients to therapy. PMID:26568685

  3. Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1

    PubMed Central

    Guo, Yue; Shu, Limin; Zhang, Chengyue; Su, Zheng-Yuan; Kong, Ah-Ng Tony

    2015-01-01

    Colorectal cancer remains the most prevalent malignancy in humans. The impact of epigenetic alterations on the development of this complex disease is now being recognized. The dynamic and reversible nature of epigenetic modifications makes them a promising target in colorectal cancer chemoprevention and treatment. Curcumin (CUR), the major component in Curcuma longa, has been shown as a potent chemopreventive phytochemical that modulates various signaling pathways. Deleted in lung and esophageal cancer 1 (DLEC1) is a tumor suppressor gene with reduced transcriptional activity and promoter hypermethylation in various cancers, including colorectal cancer. In the present study, we aimed to investigate the inhibitory role of DLEC1 in anchorage-independent growth of the human colorectal adenocarcinoma HT29 cells and epigenetic regulation by CUR. Specifically, we found that CUR treatment inhibited colony formation of HT29 cells, whereas stable knockdown of DLEC1 using lentiviral short hairpin RNA vector increased cell proliferation and colony formation. Knockdown of DLEC1 in HT29 cells attenuated the ability of CUR to inhibit anchorage-independent growth. Methylation-specific polymerase chain reaction (MSP), bisulfite genomic sequencing, and methylated DNA immunoprecipitation revealed that CUR decreased CpG methylation of the DLEC1 promoter in HT29 cells after 5 days of treatment, corresponding to increased mRNA expression of DLEC1. Furthermore, CUR decreased the protein expression of DNA methyltransferases and subtypes of histone deacetylases (HDAC4, 5, 6, and 8). Taken together, our results suggest that the inhibitory effect of CUR on anchorage-independent growth of HT29 cells could, at least in part, involve the epigenetic demethylation and up-regulation of DLEC1. PMID:25640947

  4. Laparoscopic sigmoidectomy for colon cancer.

    PubMed

    Kanellos, D; Pramateftakis, M G; Vrakas, G; Mantzoros, I; Tsachalis, T; Hatzigianni, P; Kanellos, I

    2010-11-01

    The aim of this study is to report our experience with laparoscopic sigmoidectomy due to cancer. Between 2007 and 2009, laparoscopic sigmoidectomy for cancer was performed in 3 patients. The average operative time was 176 min. The average hospital stay was 10.2 days. There was one anastomotic leak. The patient was subjected to laparotomy and a Hartmann's procedure and drainage of the peritoneal cavity was performed. In conclusion, laparoscopic sigmoidectomy for cancer is a safe and efficient procedure. PMID:20694496

  5. 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

  6. A cancer-favoring oncolytic vaccinia virus shows enhanced suppression of stem-cell like colon cancer

    PubMed Central

    Yoo, So Young; Bang, Seo Young; Jeong, Su-Nam; Kang, Dae Hwan; Heo, Jeong

    2016-01-01

    Stem cell-like colon cancer cells (SCCs) pose a major challenge in colon cancer treatment because of their resistance to chemotherapy and radiotherapy. Oncolytic virus-based therapy has shown promising results in uncured cancer patients; however, its effects on SCCs are not well studied yet. Here, we engineered a cancer-favoring oncolytic vaccinia virus (CVV) as a potent biotherapeutic and investigated its therapeutic efficacy in terms of killing SCCs. CVV is an evolved Wyeth strain vaccinia virus (EVV) lacking the viral thymidine kinase. SCC models were established using human or mouse colon cancer spheres, which continuously expressed stemness markers. The cancer-favoring characteristics and different cytotoxic pathways for killing cancer cells successfully overrode general drug resistance, thereby killing colon cancer cells regardless of the presence of SCCs. Subcutaneously injected HT29 spheres showed lower growth in CVV-treated models than in 5-Fu-treated models. Intraperitoneally injected CT26 spheres induced tumor masses in the abdominal region. CVV-treated groups showed higher survival rates and smaller tumor mass formation, compared to 5-Fu-treated groups. Interestingly, the combined treatment of CVV with 5-Fu showed improved survival rates and complete suppression of tumor mass. The CVV developed in this study, thus, effectively suppresses SCCs, which can be synergistically enhanced by simultaneous treatment with the anticancer drug 5-Fu. Our novel CVV is highly advantageous as a next-generation therapeutic for treating colon cancer. PMID:26918725

  7. A cancer-favoring oncolytic vaccinia virus shows enhanced suppression of stem-cell like colon cancer.

    PubMed

    Yoo, So Young; Bang, Seo Young; Jeong, Su-Nam; Kang, Dae Hwan; Heo, Jeong

    2016-03-29

    Stem cell-like colon cancer cells (SCCs) pose a major challenge in colon cancer treatment because of their resistance to chemotherapy and radiotherapy. Oncolytic virus-based therapy has shown promising results in uncured cancer patients; however, its effects on SCCs are not well studied yet. Here, we engineered a cancer-favoring oncolytic vaccinia virus (CVV) as a potent biotherapeutic and investigated its therapeutic efficacy in terms of killing SCCs. CVV is an evolved Wyeth strain vaccinia virus (EVV) lacking the viral thymidine kinase. SCC models were established using human or mouse colon cancer spheres, which continuously expressed stemness markers. The cancer-favoring characteristics and different cytotoxic pathways for killing cancer cells successfully overrode general drug resistance, thereby killing colon cancer cells regardless of the presence of SCCs. Subcutaneously injected HT29 spheres showed lower growth in CVV-treated models than in 5-Fu-treated models. Intraperitoneally injected CT26 spheres induced tumor masses in the abdominal region. CVV-treated groups showed higher survival rates and smaller tumor mass formation, compared to 5-Fu-treated groups. Interestingly, the combined treatment of CVV with 5-Fu showed improved survival rates and complete suppression of tumor mass. The CVV developed in this study, thus, effectively suppresses SCCs, which can be synergistically enhanced by simultaneous treatment with the anticancer drug 5-Fu. Our novel CVV is highly advantageous as a next-generation therapeutic for treating colon cancer. PMID:26918725

  8. Role of colonic stents in the management of colorectal cancers

    PubMed Central

    Sagar, Jayesh

    2016-01-01

    Colorectal cancer is one of the commonly encountered cancers across the Western World. In United Kingdom, this constitutes third most common ranked cancer and second most common ranked cause of cancer related deaths. Its acute presentation as a malignant colonic obstruction imposes challenges in its management. Colonic stent has been used for many years to alleviate acute obstruction in such cases allowing optimisation of patient’s physiological status and adequate staging of cancer. In this review, current literature evidence regarding use of colonic stent in acute malignant colonic obstruction is critically appraised and recommendations on the use of colonic stent are advocated. PMID:26962401

  9. 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

  10. 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.

  11. STAT3 in Epithelial Cells Regulates Inflammation and Tumor Progression to Malignant State in Colon1

    PubMed Central

    Nguyen, Andrew V; Wu, Yuan-Yuan; Liu, Qiang; Wang, Donghai; Nguyen, Stephanie; Loh, Ricky; Pang, Joey; Friedman, Kenneth; Orlofsky, Amos; Augenlicht, Leonard; Pollard, Jeffrey W; Lin, Elaine Y

    2013-01-01

    Chronic inflammation is an important risk factor for the development of colorectal cancer; however, the mechanism of tumorigenesis especially tumor progression to malignancy in the inflamed colon is still unclear. Our study shows that epithelial signal transducer and activator of transcription 3 (STAT3), persistently activated in inflamed colon, is not required for inflammation-induced epithelial overproliferation and the development of early-stage tumors; however, it is essential for tumor progression to advanced malignancy. We found that one of the mechanisms that epithelial STAT3 regulates in tumor progression might be to modify leukocytic infiltration in the large intestine. Activation of epithelial STAT3 promotes the infiltration of the CD8+ lymphocyte population but inhibits the recruitment of regulatory T (Treg) lymphocytes. The loss of Stat3 in epithelial cells promoted the expression of cytokines/chemokines including CCL19, CCL28, and RANTES, which are known to be able to recruit Treg lymphocytes. Linked to these changes was the pathway mediated by sphingosine 1-phosphate receptor 1 and sphingosine 1-phosphate kinases, which is activated in colonic epithelial cells in inflamed colon with functional STAT3 but not in epithelial cells deleted of STAT3. Our data suggest that epithelial STAT3 plays a critical role in inflammation-induced tumor progression through regulation of leukocytic recruitment especially the infiltration of Treg cells in the large intestine. PMID:24027425

  12. Antiangiogenic Therapy Impedes Infiltration by CD4+ and CD8+ Cells Into an Early Colon Tumor

    PubMed Central

    Yang, Yoon Jung; Choi, Joon-Seok; Choi, Jin Woo

    2015-01-01

    Background: While the majority of angiogenesis studies have focused on the late stages of cancer, the emergence of neovascularization in colon tumorigenesis has been observed an earlier stage than expected. Recent reports implied that early angiogenesis might be a defense mechanism to stimulate the natural clearance of microadenomas during colon tumorigenesis. However, little is known about how early angiogenesis affects the natural clearance of tumors. Methods: Spontaneous colon tumors were developed in adenomatous polyposis coli conditional knockout mice with Cre recombinase adenovirus administration. Vascular endothelial growth factor (VEGF) antagonist, DC101, was administrated to determine the effect of early angiogenesis and then infiltration of immune cells into tumor and concentration of cytokines were evaluated. Results: The continuous administration of the VEGF receptor 2 antagonist DC101 in the mouse models impeded the infiltration by CD4+ and CD8+ cells into the tumor region. Furthermore, the administration of the VEGF antagonist decreased the amounts of anti-tumoral cytokines such as interleukin (IL)-6 and IL-10. Conclusions: We revealed that newly formed vessels during tumorigenesis can be channels for particular anti-tumoral immune cells. Our results may confer insight for the clinical development of an efficient antiangiogenic therapeutic manual and a timely chemoprevention to suppress tumor growth. PMID:26151046

  13. Prognostic significance of preoperative fibrinogen in patients with colon cancer

    PubMed Central

    Sun, Zhen-Qiang; Han, Xiao-Na; Wang, Hai-Jiang; Tang, Yong; Zhao, Ze-Liang; Qu, Yan-Li; Xu, Rui-Wei; Liu, Yan-Yan; Yu, Xian-Bo

    2014-01-01

    AIM: To investigate the prognostic significance of preoperative fibrinogen levels in colon cancer patients. METHODS: A total of 255 colon cancer patients treated at the Affiliated Tumor Hospital of Xinjiang Medical University from June 1st 2005 to June 1st 2008 were enrolled in the study. All patients received radical surgery as their primary treatment method. Preoperative fibrinogen was detected by the Clauss method, and all patients were followed up after surgery. Preoperative fibrinogen measurements were correlated with a number of clinicopathological parameters using the Student t test and analysis of variance. Survival analyses were performed by the Kaplan-Meier method and Cox regression modeling to measure 5-year disease-free survival (DFS) and overall survival (OS). RESULTS: The mean preoperative fibrinogen concentration of all colon cancer patients was 3.17 ± 0.88 g/L. Statistically significant differences were found between preoperative fibrinogen levels and the clinicopathological parameters of age, smoking status, tumor size, tumor location, tumor-node-metastasis (TNM) stage, modified Glasgow prognostic scores (mGPS), white blood cell (WBC) count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA) levels. Univariate survival analysis showed that TNM stage, tumor cell differentiation grade, vascular invasion, mGPS score, preoperative fibrinogen, WBC, NLR, PLR and CEA all correlated with both OS and DFS. Alpha-fetoprotein (AFP) and body mass index correlated only with OS. Kaplan-Meier analysis revealed that both OS and DFS of the total cohort, as well as of the stage II and III patients, were higher in the hypofibrinogen group compared to the hyperfibrinogen group (all P < 0.05). In contrast, there was no significant difference between OS and DFS in stage I patients with low or high fibrinogen levels. Cox regression analysis indicated preoperative fibrinogen levels, TNM stage, mGPS score, CEA, and

  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. PMID:26018088

  15. [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

  16. Vaccine against MUC1 antigen expressed in inflammatory bowel disease and cancer lessens colonic inflammation and prevents progression to colitis associated colon cancer

    PubMed Central

    Beatty, Pamela L.; Narayanan, Sowmya; Gariépy, Jean; Ranganathan, Sarangarajan; Finn, Olivera J.

    2009-01-01

    Association of chronic inflammation with an increased risk of cancer is well established but the contributions of innate versus adaptive immunity are not fully delineated. There has furthermore been little consideration of the role played by chronic inflammation-associated antigens, including cancer antigens, and the possibility to use them as vaccines to lower the cancer risk. We studied the human tumor antigen MUC1 that is abnormally expressed in colon cancers and also in inflammatory bowel disease (IBD) that gives rise to colitis associated colon cancer (CACC). Using our new mouse model of MUC1+ IBD that progresses to CACC, IL-10−/− mice crossed with MUC1 transgenic mice, we show that vaccination against MUC1 delays IBD and prevents progression to CAAC. One mechanism is the induction of MUC1-specific adaptive immunity (anti-MUC1 IgG, anti-MUC1 CTL) that appears to eliminate abnormal MUC1+ cells in IBD colons. The other mechanism is the change in the local and the systemic microenvironments. Compared to IBD in vaccinated mice, IBD in control mice is dominated by larger numbers of neutrophils in the colon and myeloid-derived suppressor cells (MDSC) in the spleen, which can compromise adaptive immunity and facilitate tumor growth. This suggests that the tumor-promoting microenvironment of chronic inflammation can be converted to a tumor-inhibiting environment by increasing adaptive immunity against a disease-associated antigen. PMID:20332301

  17. 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

  18. 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

  19. 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

  20. In-silico analysis of kallikrein gene expression in pancreatic and colon cancers.

    PubMed

    Yousef, George M; Borgoño, Carla A; Popalis, Cynthia; Yacoub, George M; Polymeris, Mary-Ellen; Soosaipillai, Antoninus; Diamandis, Eleftherios P

    2004-01-01

    Human kallikreins are a cluster of 15 serine protease genes located in the chromosomal band 19q13.4, a non-randomly rearranged region in many solid tumors, including pancreatic cancer. We utilized the SAGE and EST databases of the Cancer Genome Anatomy Project to perform in-silico analysis of kallikrein gene expression in normal and cancerous pancreatic and colon tissues and cell lines using virtual Northern blotting (VNB), digital differential display (DDD) and X-profiler. At least two kallikreins, KLK6 and KLK10, are significantly up-regulated in pancreatic cancer. We probed 2 normal and 6 pancreatic cancer SAGE libraries with gene-specific tags for each of these kallikreins. KLK6 was found to be expressed in 5/6 cancer libraries and showed the most marked (5-fold) increase in average expression levels in cancer vs. normal. These data were verified by screening the EST databases, where all mRNA clones isolated were from cancerous libraries, with no clones detected in normal pancreatic tissues or cell lines. X-profiler comparison of two pools of normal and cancerous pancreatic libraries further verified the significant increase of KLK6 expression levels in pancreatic cancer. DDD data showed a 13-fold increase in KLK10 expression in pancreatic cancer. Three kallikrein genes, KLK6, 8 and 10 are overexpressed in colon cancer compared to normal colon, while one kallikrein, KLK1, is down-regulated. While no expression of KLK6 was detected in normal colon, KLK6-specific tags were detectable in 2 cancer libraries. Similar results were obtained by EST screening; no KLK6 clones were detected in any of the 28 normal libraries examined, while 10 KLK6 EST clones were found in colon adenocarcinoma. KLK10 was not detectable in normal colon. Gene-specific tags were, however, detectable with high density in colon cancer and 7 EST clones were found to be expressed in colon Adenocarcinoma. PMID:15015574

  1. 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

  2. IEX-1 deficiency protects against colonic cancer.

    PubMed

    Ustyugova, Irina V; Zhi, Liang; Abramowitz, Joel; Birnbaumer, Lutz; Wu, Mei X

    2012-06-01

    The immediate early response gene X-1 (IEX-1) is involved in regulation of various cellular processes including proliferation, apoptosis in part by controlling homeostasis of reactive oxygen species (ROS) at mitochondria. The present study shows reduced inflammatory responses and colorectal cancer in IEX-1 knockout (KO) mice treated with azoxymethane/dextran sulfate sodium (DSS). However, DSS induced worse colitis in RAG(-/-)IEX-1(-/-) double KO mice than in RAG and IEX-1 single KO mice, underscoring an importance of T cells in IEX-1 deficiency-induced protection against colon inflammation. Lack of IEX-1 promoted the differentiation of interleukin (IL)-17-producing T cells, concomitant with upregulation of Gαi2 expression, a gene that is well-documented for its role in the control of inflammation in the colon. In accordance with this, T-helper 17 (T(H)17) cell differentiation was compromised in the absence of Gαi2, and deletion of Gαi2 in T cells alone aggravated colon inflammation and colorectal cancer development after azoxymethane/DSS treatment. Null mutation of IEX-1 also enhanced both proliferation and apoptosis of intestinal epithelial cells (IEC) after injury. A potential impact of this altered IEC turnover on colon inflammation and cancer development is discussed. These observations provide a linkage of IEX-1 and Gαi2 expression in the regulation of T(H)17 cell differentiation and suggest a previously unappreciated role for IEX-1 in the control of colon epithelial homeostasis. PMID:22550081

  3. 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

  4. A Case of Very Well-Differentiated Adenocarcinoma With Carcinoid Tumor in the Ascending Colon

    PubMed Central

    Yamauchi, Hayato; Sakurai, Shinji; Tsukagoshi, Ritsuko; Suzuki, Masaki; Tabe, Yuichi; Fukasawa, Takaharu; Kiriyama, Shinsuke; Fukuchi, Minoru; Naitoh, Hiroshi; Kuwano, Hiroyuki

    2014-01-01

    Malignant tumors with mixed glandular and neuroendocrine characteristics with at least 30% of each component are classified as mixed adenoneuroendocrine carcinoma (MANEC) by the World Health Organization 2010 classification. We report here a case of very well-differentiated adenocarcinoma accompanied by carcinoid tumor, categorized as MANEC. A 41-year-old Japanese man was clinically diagnosed with ascending colon cancer and underwent right hemicolectomy. Using an immunohistologic technique, the pathologic diagnosis was very well-differentiated adenocarcinoma accompanied by carcinoid tumor and marked eosinophil infiltration, which was categorized as MANEC. By immunohistochemical analysis, tumor cells of the carcinoid component exhibited very low proliferation activity. Our case was thought to be MANEC without high malignant potential. MANEC as per the World Health Organization 2010 classification seems to include tumors with diverse grades of malignancy, and it might need to have subclassifications according to the malignancy potential of the tumor cells. PMID:24670022

  5. A case of very well-differentiated adenocarcinoma with carcinoid tumor in the ascending colon.

    PubMed

    Yamauchi, Hayato; Sakurai, Shinji; Tsukagoshi, Ritsuko; Suzuki, Masaki; Tabe, Yuichi; Fukasawa, Takaharu; Kiriyama, Shinsuke; Fukuchi, Minoru; Naitoh, Hiroshi; Kuwano, Hiroyuki

    2014-01-01

    Malignant tumors with mixed glandular and neuroendocrine characteristics with at least 30% of each component are classified as mixed adenoneuroendocrine carcinoma (MANEC) by the World Health Organization 2010 classification. We report here a case of very well-differentiated adenocarcinoma accompanied by carcinoid tumor, categorized as MANEC. A 41-year-old Japanese man was clinically diagnosed with ascending colon cancer and underwent right hemicolectomy. Using an immunohistologic technique, the pathologic diagnosis was very well-differentiated adenocarcinoma accompanied by carcinoid tumor and marked eosinophil infiltration, which was categorized as MANEC. By immunohistochemical analysis, tumor cells of the carcinoid component exhibited very low proliferation activity. Our case was thought to be MANEC without high malignant potential. MANEC as per the World Health Organization 2010 classification seems to include tumors with diverse grades of malignancy, and it might need to have subclassifications according to the malignancy potential of the tumor cells. PMID:24670022

  6. Expression of Nucleophosmin/NPM1 correlates with migration and invasiveness of colon cancer cells

    PubMed Central

    2012-01-01

    Background We aimed to examine the expression level of Nucleophosmin (NPM1) protein in colon cancer tissues and to investigate the potential role of NPM1 in the regulation of cell migration and invasiveness. Methods Immunohistochemical assay was performed to examine the expression pattern of NPM1 in 31 groups of colonic carcinoma samples, including colon tumors, adjacent normal tissues, and matched metastatic lymph nodes from the same patients. Small interfering RNA technique and exogenous expression of wild type NPM1 methods were used to further verify the function of NPM1. Results High-expression of NPM1 correlates with lymph node metastasis (P = 0.0003) and poor survival rate of human colon cancer patients (P = 0.017). SiRNA-mediated reduction of NPM1 was also shown to inhibit the migration and invasiveness of metastatic colon cancer HCT116 cell line. In addition, the exogenous expression of NPM1 in HT29 cells, a NPM1 low expression and low invasive colon cancer cell line, enhanced cell migration and invasiveness along with increased cell proliferation. Conclusions The current study uncovered the critical role of NPM1 in the regulation of colon cancer cells migration and invasion, and NPM1 may serve as a potential marker for the prognosis of colon cancer patients. PMID:22631075

  7. Understanding your colon cancer risk

    MedlinePlus

    ... the chance that you could get cancer. Some risk factors you can control, such as drinking alcohol. Others, such as family ... cannot be changed. But just because you have risk factors you cannot control does not mean you cannot take steps to ...

  8. Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations.

    PubMed

    Grady, William M; Willis, Joseph E; Trobridge, Patty; Romero-Gallo, Judith; Munoz, Nina; Olechnowicz, Joseph; Ferguson, Kelly; Gautam, Shiva; Markowitz, Sanford D

    2006-02-01

    Approximately 15% of human colon cancers have microsatellite instability (MSI) and carry frameshift mutations in a polyadenine tract (BAT-RII) in the type II transforming growth factor beta (TGF-beta) receptor (TGFBR2), a required component of the TGF-beta receptor. The BAT-RII mutations in MSI colon cancers make the tumors resistant to the effects of TGF-beta. In cultured epithelial cells, TGF-beta can inhibit cell proliferation and induce apoptosis, and in vitro it can regulate the expression of a variety of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. These effects are context- and tissue type-dependent, raising questions about which of these in vitro effects of TGF-beta signaling inactivation contribute to the formation of primary colon cancer. Thus, this study sought to determine the pathogenetically relevant effects of TGFBR2 inactivation in primary MSI colon cancers with mutant BAT-RII. Colon cancers with mutant BAT-RII were found to have increased proliferation compared to cancers with wild-type BAT-RII. Assessment of cdk4, cyclin D1 and p27(kip1) expression revealed that only cdk4 expression was increased in the cancers with mutant BAT-RII. In order to determine if TGFBR2 inactivation was the cause of these changes, TGFBR2 was reconstituted in an MSI colon cancer cell line, resulting in decreased proliferation and decreased cdk4 expression and kinase activity. These results suggest that TGFBR2 mutations in primary colon cancers may be responsible for the increased proliferation and cdk4 expression in these tumors and provide evidence that deregulation of cdk4 is a pathogenic in vivo consequence of TGFBR2 inactivation in primary colon cancer. PMID:16108056

  9. Hereditary Colon Cancer: Lynch Syndrome

    PubMed Central

    Jang, Eunjeong

    2010-01-01

    Lynch syndrome is the most common familial colorectal cancer syndrome. It is linked to germline mutations in one of four DNA mismatch repair (MMR) genes. A comprehensive family history is one important way to identify at-risk individuals. The elucidation of the molecular genetics of this syndrome has made it possible to screen for the disorder with molecular tests. Microsatellite instability and/or immunohistochemistry followed by germline testing for mutations in MMR genes is now a standard approach for clinically suspected cases. Correctly recognizing Lynch syndrome is essential for the application of appropriate screening and surveillance measures. Close surveillance and risk-reducing operations can decrease cancer-related mortality. In addition, counseling is an important component of the management of any family with Lynch syndrome. PMID:20559516

  10. The multihit model of carcinogenesis: etiologic implications for colon cancer

    SciTech Connect

    Sutherland, J.V.; Bailar, J.C.

    1984-01-01

    A new multihit model of carcinogenesis is developed for use in evaluating age-specific cancer incidence rates in human populations. The model allows for some heterogeneity in both risk (perhaps genetic) and pathway (number of hits). Fitting the model yields estimates of (1) levels of effect of background exposure to environmental agents, (2) tumor growth times after initiation of a malignant cell, and (3) relative sizes of high-risk groups in a human population. Maximum likelihood procedures are used to fit the model to the polyposis coli data of Veale and the colon cancer incidence data from the Third National Cancer Survey. Model estimates may be verified in some cases by review of independent data in the literature and results have both theoretical and practical implications. Findings are generally consistent with the adenoma-carcinoma etiologic sequence postulated by Hill, Morson and Bussey with one exception. A large proportion of the population may be at risk of four-hit colon tumors following a non-adenoma etiologic sequence.

  11. Butyrate-rich colonic microenvironment is a relevant selection factor for metabolically adapted tumor cells.

    PubMed

    Serpa, Jacinta; Caiado, Francisco; Carvalho, Tânia; Torre, Cheila; Gonçalves, Luís G; Casalou, Cristina; Lamosa, Pedro; Rodrigues, Margarida; Zhu, Zhenping; Lam, Eric W F; Dias, Sérgio

    2010-12-10

    The short chain fatty acid (SCFA) butyrate is a product of colonic fermentation of dietary fibers. It is the main source of energy for normal colonocytes, but cannot be metabolized by most tumor cells. Butyrate also functions as a histone deacetylase (HDAC) inhibitor to control cell proliferation and apoptosis. In consequence, butyrate and its derived drugs are used in cancer therapy. Here we show that aggressive tumor cells that retain the capacity of metabolizing butyrate are positively selected in their microenvironment. In the mouse xenograft model, butyrate-preselected human colon cancer cells gave rise to subcutaneous tumors that grew faster and were more angiogenic than those derived from untreated cells. Similarly, butyrate-preselected cells demonstrated a significant increase in rates of homing to the lung after intravenous injection. Our data showed that butyrate regulates the expression of VEGF and its receptor KDR at the transcriptional level potentially through FoxM1, resulting in the generation of a functional VEGF:KDR autocrine growth loop. Cells selected by chronic exposure to butyrate express higher levels of MMP2, MMP9, α2 and α3 integrins, and lower levels of E-cadherin, a marker for epithelial to mesenchymal transition. The orthotopic model of colon cancer showed that cells preselected by butyrate are able to colonize the animals locally and at distant organs, whereas control cells can only generate a local tumor in the cecum. Together our data shows that a butyrate-rich microenvironment may select for tumor cells that are able to metabolize butyrate, which are also phenotypically more aggressive. PMID:20926374

  12. Active chinese mistletoe lectin-55 enhances colon cancer surveillance through regulating innate and adaptive immune responses

    PubMed Central

    Ma, Yan-Hui; Cheng, Wei-Zhi; Gong, Fang; Ma, An-Lun; Yu, Qi-Wen; Zhang, Ji-Ying; Hu, Chao-Ying; Chen, Xue-Hua; Zhang, Dong-Qing

    2008-01-01

    AIM: To investigate the potential role of Active Chinese mistletoe lectin-55 (ACML-55) in tumor immune surveillance. METHODS: In this study, an experimental model was established by hypodermic inoculating the colon cancer cell line CT26 (5 × 105 cells) into BALB/c mice. The experimental treatment was orally administered with ACML-55 or PBS, followed by the inoculation of colon cancer cell line CT26. Intracellular cytokine staining was used to detect IFN-γ production by tumor antigen specific CD8+ T cells. FACS analysis was employed to profile composition and activation of CD4+, CD8+, γδ T and NK cells. RESULTS: Our results showed, compared to PBS treated mice, ACML-55 treatment significantly delayed colon cancer development in colon cancer -bearing Balb/c mice in vivo. Treatment with ACML-55 enhanced both Ag specific activation and proliferation of CD4+ and CD8+ T cells, and increased the number of tumor Ag specific CD8+ T cells. It was more important to increase the frequency of tumor Ag specific IFN-γ producing-CD8+ T cells. Interestingly, ACML-55 treatment also showed increased cell number of NK, and γδT cells, indicating the role of ACML-55 in activation of innate lymphocytes. CONCLUSION: Our results demonstrate that ACML-55 therapy can enhance function in immune surveillance in colon cancer-bearing mice through regulating both innate and adaptive immune responses. PMID:18785279

  13. 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

  14. 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

  15. 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

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

    PubMed

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

    2014-06-01

    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

  17. 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

  18. The utility of Apc-mutant rats in modeling human colon cancer

    PubMed Central

    Irving, Amy A.; Yoshimi, Kazuto; Hart, Marcia L.; Parker, Taybor; Clipson, Linda; Ford, Madeline R.; Kuramoto, Takashi; Dove, William F.; Amos-Landgraf, James M.

    2014-01-01

    Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer. PMID:25288683

  19. 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

  20. 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.

  1. Differential expression of miRNAs in colon cancer between African and Caucasian Americans: Implications for cancer racial health disparities

    PubMed Central

    LI, ELLEN; JI, PING; OUYANG, NENGTAI; ZHANG, YUANHAO; WANG, XIN YU; RUBIN, DEBORAH C.; DAVIDSON, NICHOLAS O.; BERGAMASCHI, ROBERTO; SHROYER, KENNETH R.; BURKE, STEPHANIE; ZHU, WEI; WILLIAMS, JENNIE L.

    2014-01-01

    Colorectal cancer (CRC) incidence and mortality are higher in African Americans (AAs) than in Caucasian Americans (CAs) and microRNAs (miRNAs) have been found to be dysregulated in colonic and other neoplasias. The aim of this exploratory study was to identify candidate miRNAs that could contribute to potential biological differences between AA and CA colon cancers. Total RNA was isolated from tumor and paired adjacent normal colon tissue from 30 AA and 31 CA colon cancer patients archived at Stony Brook University (SBU) and Washington University (WU)-St. Louis Medical Center. miRNA profiles were determined by probing human genome-wide miRNA arrays with RNA isolated from each sample. Using repeated measures analysis of variance (RANOVA), miRNAs were selected that exhibited significant (p<0.05) interactions between race and tumor or significant (fold change >1.5, p<0.05) main effects of race and/or tumor. Quantitative polymerase chain reaction (q-PCR) was used to confirm miRNAs identified by microarray analysis. Candidate miRNA targets were analyzed using immunohistochemistry. RANOVA results indicated that miR-182, miR152, miR-204, miR-222 and miR-202 exhibited significant race and tumor main effects. Of these miRNAs, q-PCR analysis confirmed that miR-182 was upregulated in AA vs. CA tumors and exhibited significant race:tumor interaction. Immunohistochemical analysis revealed that the levels of FOXO1 and FOXO3A, two potential miR-182 targets, are reduced in AA tumors. miRNAs may play a role in the differences between AA and CA colon cancer. Specifically, differences in miRNA expression levels of miR-182 may contribute to decreased survival in AA colon cancer patients. PMID:24865442

  2. Potential Therapy for Refractory Colon Cancer.

    PubMed

    2016-04-01

    The drug MM-1151 may overcome resistance to cetuximab and panitumumab caused by some mutations in the extracellular domain of EGFR. The drug slowed disease progression in a colorectal cancer cell line that carried some of the mutations and curbed growth of cells derived from a cetuximab-resistant patient tumor. In a phase I trial, tumors shrank or stabilized in patients who carried the mutations and received the drug. PMID:26928314

  3. 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

  4. Quercetin induces human colon cancer cells apoptosis by inhibiting the nuclear factor-kappa B Pathway

    PubMed Central

    Zhang, Xiang-An; Zhang, Shuangxi; Yin, Qing; Zhang, Jing

    2015-01-01

    Quercetin can inhibit the growth of cancer cells with the ability to act as chemopreventers. Its cancer-preventive effect has been attributed to various mechanisms, including the induction of cell-cycle arrest and/or apoptosis as well as the antioxidant functions. Nuclear factor kappa-B (NF-κB) is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of cancer. Inhibitors of NF-κB pathway have shown potential anti-tumor activities. However, it is not fully elucidated in colon cancer. In this study, we demonstrate that quercetin induces apoptosis in human colon cancer CACO-2 and SW-620 cells through inhibiting NF-κB pathway, as well as down-regulation of B-cell lymphoma 2 and up-regulation of Bax, thus providing basis for clinical application of quercetin in colon cancer cases. PMID:25829782

  5. The Role of the CpG Island Methylator Phenotype on Survival Outcome in Colon Cancer

    PubMed Central

    Kang, Ki Joo; Min, Byung-Hoon; Ryu, Kyung Ju; Kim, Kyoung-Mee; Chang, Dong Kyung; Kim, Jae J.; Rhee, Jong Chul; Kim, Young-Ho

    2015-01-01

    Background/Aims CpG island methylator phenotype (CIMP)- high colorectal cancers (CRCs) have distinct clinicopathological features from their CIMP-low/negative CRC counterparts. However, controversy exists regarding the prognosis of CRC according to the CIMP status. Therefore, this study examined the prognosis of Korean patients with colon cancer according to the CIMP status. Methods Among a previous cohort population with CRC, a total of 154 patients with colon cancer who had available tissue for DNA extraction were included in the study. CIMP-high was defined as 3/5 methylated markers using the five-marker panel (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1). Results CIMP-high and CIMP-low/negative cancers were observed in 27 patients (17.5%) and 127 patients (82.5%), respectively. Multivariate analysis adjusting for age, gender, tumor location, tumor stage and CIMP and microsatellite instability (MSI) statuses indicated that CIMP-high colon cancers were associated with a significant increase in colon cancer-specific mortality (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.20 to 8.69; p=0.02). In microsatellite stable cancers, CIMP-high cancer had a poor survival outcome compared to CIMP-low/negative cancer (HR, 2.91; 95% CI, 1.02 to 8.27; p=0.04). Conclusions Regardless of the MSI status, CIMP-high cancers had poor survival outcomes in Korean patients. PMID:25167802

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. Primary colon cancer with a high serum PIVKA-II level

    PubMed Central

    Kato, Kazuya; Iwasaki, Yoshiaki; Taniguchi, Masahiko; Onodera, Kazuhiko; Matsuda, Minoru; Kawakami, Takako; Higuchi, Mineko; Kato, Kimitaka; Kato, Yurina; Furukawa, Hiroyuki

    2014-01-01

    Introduction Protein induced by vitamin K absence/antagonist-II (PIVKA-II) is an abnormal protein, and several reports have demonstrated the efficacy of PIVKA-II in the diagnosis of hepatocellular carcinoma (HCC). We report an extremely rare case of adenocarcinoma of the colon with a high serum PIVKA-II level. Presentation of Case A 95-year-old woman presented with right lower quadrant pain and appetite loss. An abdominal computed tomography scan and ultrasonography showed an ascending colon tumor and multiple metastatic tumors in the liver. The serum level of PIVKA-II was extremely high, 11,900 ng/mL. Colonoscopic examination revealed a tumor accompanied by an ulcer in the ascending colon, which was highly suspicious for malignancy. Multiple biopsies showed well-differentiated adenocarcinoma of the colon, which was evaluated as colon cancer, stage IV. PIVKA-II-productive colon cancer was confirmed. Chemotherapy with TS-1 was administered. The patient died 3 months after initial admission. Discussion The expression of PIVKA-II was detected in non-cancer areas, with non-specific expression observed in plasma cells in our case. There might be some possibility that hepatoid differentiation exists in other regions of the colon tumor or in the liver tumor, parenchymal cells or lung metastases, which were composed of PIVKA-II-positive and AFP-negative cells. Conclusion To the best of our knowledge, high serum levels of PIVKA-II resulting from colon adenocarcinoma have not been reported previously. We report this rare case together with a review of the literature. PMID:25528035

  12. Proteomic and Functional Investigation of the Colon Cancer Relapse-Associated Genes NOX4 and ITGA3

    PubMed Central

    2015-01-01

    Colon cancer is a major cause of cancer-related deaths worldwide. Adjuvant chemotherapy significantly reduces mortality in stage III colon cancer; however, it is only marginally effective in stage II patients. There is also increasing evidence that right-side colon cancer is different from left-side colon cancer. We have observed that the genes altered in expression between the poor and good prognosis tumors vary significantly depending on whether the malignancy originates on the right or left side of the colon. We have identified NADPH oxidase 4 (NOX4) to be highly predictive of relapse in stage II left-side colon cancer, whereas integrin alpha 3 beta 1 (ITGA3) is predictive of relapse in stage II right-side colon cancer. To investigate the underlying molecular mechanisms, we are analyzing the effect of ITGA3 and NOX4 silencing via RNA interference and pharmacological inhibition on global protein expression patterns via iTRAQ labeling and mass spectrometry in colon cancer cells. On the basis of bioinformatic analysis, the functions of these genes were assessed through phenotypic assays, revealing roles in cell migration and reactive oxygen species generation. These biomarkers for relapse risk are of clinical interest and lead to insight into how a tumor progresses to metastasis. PMID:25096929

  13. Biliary Ascariasis Mimicking Colonic Tumor Infiltration of the Biliary System.

    PubMed

    Sundriyal, Deepak; Mittal, Gyanendra; Kumar, Sushil; Manjunath, Suraj; Sharma, Navneet; Gupta, Mahesh

    2015-09-01

    Ascariasis is a common problem in developing countries with poor hygiene and sanitation. It is endemic in India and usually seen in the northern states. Biliary ascariasis is an uncommon cause of obstructive jaundice. We present a case of carcinoma of hepatic flexure of colon in which the patient developed biliary ascariasis and posed a diagnostic challenge as it mimicked tumor infiltration of the biliary system. PMID:27217679

  14. [A Case of Primary Cancer of the Pancreas and Colon Treated with the Combination of Gemcitabine and TS-1].

    PubMed

    Koyama, Muneyuki; Kinoshita, Akiyoshi; Tanaka, Ken; Koike, Kazuhiko; Nishino, Hirokazu

    2016-03-01

    The patient was a 74-year-old man. A medical examination for diabetes revealed a hypovascular tumor in the pancreatic head. A heterogeneously enhanced tumor in the ascending colon with wall thickening was observed on enhanced CT of the abdomen. He was diagnosed with multiple primary cancers of the pancreas and colon. He received 12 courses of chemotherapy with gemcitabine (1,000 mg/m 2) and TS-1 (60 mg/m2). After 12 courses of chemotherapy, the size of the pancreatic tumor was slightly decreased and the size of the tumor in the colon was significantly decreased. The tumor marker level was also significantly decreased. The combination of gemcitabine and TS-1 is a promising treatment regimen for patients with primary cancer of the pancreas and colon. PMID:27067858

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

    PubMed Central

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

    2015-01-01

    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. PMID:26053394

  16. 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. PMID:24129759

  17. 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

  18. 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

  19. HIF-1α and HIF-2α have divergent roles in colon cancer

    PubMed Central

    Imamura, Takaaki; Kikuchi, Hirotoshi; Herraiz, Maria-Teresa; Park, Do-Youn; Mizukami, Yusuke; Mino-Kenduson, Mari; Lynch, Maureen P.; Rueda, Bo R.; Benita, Yair; Xavier, Ramnik J.; Chung, Daniel C.

    2009-01-01

    Hypoxia-inducible factor (HIF)-1 and HIF-2 are heterodimeric transcription factors that mediate the cellular response to hypoxia. Their key regulatory subunits, HIF-1α and HIF-2α, are induced similarly by hypoxia, but their functional roles in cancer may be distinct and isoform-specific. SW480 colon cancer cells with stable expression of siRNA to HIF-1α or HIF-2α or both were established. HIF-1α-deficient cells displayed lower rates of proliferation and migration, but HIF-2α-deficient cells exhibited enhanced anchorage independent growth in a soft agar assay. Xenograft studies revealed that HIF-1α deficiency inhibited overall tumor growth, whereas deficiency of HIF-2α stimulated tumor growth. In human colon cancer tissues, expression of HIF-1α and to a lesser extent, HIF-2α, was linked to upregulation of VEGF and tumor angiogenesis. However, loss of expression of HIF-2α but not HIF-1α was strongly correlated with advanced tumor stage. DNA microarray analysis identified distinct sets of HIF-1α and HIF-2α target genes that may explain these phenotypic differences. Collectively, these findings suggest that HIF isoforms may have differing cellular functions in colon cancer. In particular, HIF-1α promoted the growth of SW480 colon cancer cells but HIF-2α appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform-specific properties. PMID:19030186

  20. Folate-Modified Lipoplexes Delivering the Interleukin-12 Gene for Targeting Colon Cancer Immunogene Therapy.

    PubMed

    Luo, Min; Liang, Xiao; Luo, Shun-Tao; Wei, Xia-Wei; Liu, Ting; Ren, Jun; Ma, Cui-Cui; Yang, Yu-Han; Wang, Bi-Lan; Liu, Li; Song, Xiang-Rong; He, Zhi-Yao; Wei, Yu-Quan

    2015-11-01

    The incidence and mortality rate of colorectal cancer increase every year, making it a serious threat to human health. Targeted immunogene therapy is a novel method of treating this type of cancer. Colon cancer overexpresses folate receptor α (FRα) and folate-modified liposomes for colon cancer immunogene therapy may suppress tumor growth effectively. In this study, F-PLP/pIL12, an FRα-targeted lipoplex loading plasmid interleukin-12 (pIL12) was prepared and its physicochemical properties were characterized. Then the antitumor effect of F-PLP/pIL12 was studied in an in vivo model of CT-26 colon cancer. F-PLP/pIL12 was associated with about 56.6% tumor growth inhibition compared with the saline control. The production of malignant ascites was significantly less pronounced than in controls, and there were fewer tumor nodules and less overall tumor mass (P < 0.01). There was more IL12 expression and IFN-γ secretion in F-PLP/pIL12-treated tumor tissues, but there was less FRα expression. The antitumor mechanisms involved inducing tumor cell apoptosis, reducing microvessel density, and stimulating TNF-α secretion. In addition, there were fewer M2 macrophages in the tumor microenvironment of tissues stimulated with F-PLP/pIL12, which also activated the natural killer cells. H&E staining of vital organs suggested that F-PLP/pIL12 is safe for use in intraperitoneally administered cancer therapy. It was here concluded that F-PLP/plL12 may be a suitable targeting formulation for colon cancer immunogene therapy. PMID:26554159

  1. Pharmacological inhibition of polycomb repressive complex-2 activity induces apoptosis in human colon cancer stem cells

    PubMed Central

    Benoit, Yannick D.; Witherspoon, Mavee S.; Laursen, Kristian B.; Guezguez, Amel; Beauséjour, Marco; Beaulieu, Jean-Francois; Lipkin, Steven M.; Gudas, Lorraine J.

    2013-01-01

    Colorectal cancer is among the leading causes of cancer death in the USA. The polycomb repressive complex 2 (PRC2), including core components SUZ12 and EZH2, represents a key epigenetic regulator of digestive epithelial cell physiology and was previously shown to promote deleterious effects in a number of human cancers, including colon. Using colon cancer stem cells (CCSC) isolated from human primary colorectal tumors, we demonstrate that SUZ12 knockdown and treatment with DZNep, one of the most potent EZH2 inhibitors, increase apoptosis levels, marked by decreased Akt phosphorylation, in CCSCs, while embryonic stem (ES) cell survival is not affected. Moreover, DZNep treatments lead to increased PTEN expression in these highly tumorigenic cells. Taken together, our findings suggest that pharmacological inhibition of PRC2 histone methyltransferase activity may constitute a new, epigenetic therapeutic strategy to target highly tumorigenic and metastatic colon cancer stem cells. PMID:23588203

  2. Shogaol overcomes TRAIL resistance in colon cancer cells via inhibiting of survivin.

    PubMed

    Hwang, Jung Soon; Lee, Hai-Chon; Oh, Sang Cheul; Lee, Dae-Hee; Kwon, Ki Han

    2015-11-01

    In this study, we showed the ability of representative shogaol, which as a major component of ginger, to overcome TRAIL resistance by increasing apoptosis in colon cancer cells. Shogaol increased death receptor 5 (DR5) levels. Furthermore, shogaol decreased the expression level of antiapoptotic proteins (survivin and Bcl-2) and increased pro-apoptotic protein, Bax. Shogaol treatment induced apoptosis and a robust reduction in the levels of the antiapoptotic protein survivin but did not affect the levels of many other apoptosis regulators. Moreover, knockdown of survivin sensitized colon cancer cells to resistant of TRAIL-induced apoptosis. Therefore, we showed the functions of shogaol as a sensitizing agent to induce cell death of TRAIL-resistant colon cancer cells. This study gives rise to the possibility of applying shogaol as an antitumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant colon tumor therapy. PMID:26063410

  3. Sigmoid volvulus after laparoscopic surgery for sigmoid colon cancer.

    PubMed

    Sadatomo, Ai; Miyakura, Yasuyuki; Zuiki, Toru; Koinuma, Koji; Horie, Hisanaga; Lefor, Alan T; Yasuda, Yoshikazu

    2013-08-01

    We report the first case of sigmoid volvulus after laparoscopic surgery for sigmoid colon cancer. The patient is a 75-year-old man who presented with the sudden onset of severe abdominal pain. He had undergone laparoscopic sigmoidectomy for cancer 2 years before presentation. CT scan showed a distended sigmoid colon with a mesenteric twist, or "whirl sign." Colonoscopy showed a mucosal spiral and luminal stenosis with dilated sigmoid colon distally and ischemic mucosa. The diagnosis of ischemic colonic necrosis due to sigmoid volvulus was established. Resection of the necrotic sigmoid colon was performed and a descending colon stoma was created. A long remnant sigmoid colon and chronic constipation may contribute to the development of sigmoid volvulus after laparoscopic sigmoidectomy. Prompt diagnosis is essential for adequate treatment, and colonoscopy aids in the diagnosis of ischemic changes in patients without definitive findings of a gangrenous colon. PMID:23879414

  4. 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. PMID:27026680

  5. Prospective Multicenter Study of the Impact of Oncotype DX Colon Cancer Assay Results on Treatment Recommendations in Stage II Colon Cancer Patients

    PubMed Central

    Srivastava, Geetika; Renfro, Lindsay A.; Behrens, Robert J.; Lopatin, Margarita; Chao, Calvin; Soori, Gamini S.; Dakhil, Shaker R.; Mowat, Rex B.; Kuebler, J. Philip; Kim, George; Mazurczak, Miroslaw; Lee, Mark

    2014-01-01

    Purpose. The Oncotype DX colon cancer assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Patients and Methods. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician’s recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Results. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%–53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). Conclusion. Compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients. PMID:24710310

  6. Therapeutic effect of a TM4SF5-specific monoclonal antibody against colon cancer in a mouse model

    PubMed Central

    Kim, Dongbum; Park, Byoung Kwon; Park, Jeong-A; Choi, Kyung-Chan; Kim, Doo-Sik; Kwon, Hyung-Joo; Lee, Younghee

    2014-01-01

    Transmembrane 4 superfamily member 5 protein (TM4SF5) is presumed to serve as a molecular target to prevent or treat hepatocellular carcinoma (HCC) and colon cancer in a mouse model. Previously, we reported the efficacy of anti-cancer peptide vaccine targeting TM4SF5. In addition, we reported an anti-proliferative effect of anti-TM4SF5 monoclonal antibody in HCC. Here, we investigated expression of TM4SF5 in 45 primary colon cancer tissues. Almost all of the colon cancer tissues expressed TM4SF5 based on immunohistochemistry using anti-TM4SF5 monoclonal antibody. The treatment of human colon cancer cells with anti-TM4SF5 antibody reduced growth of TM4SF5 expressing cells and enhanced expression of E-cadherin and β-catenin. Using mouse colon cancer models, we then evaluated the in vivo anti-cancer effect of anti-TM4SF5 antibody. Injection of the antibody significantly reduced growth of tumors priorly established by subcutaneous injection of human colon cancer cells HT-29 in a xenograft setting. We obtained similar results with mouse colon cancer cell line CT-26 in an allograft setting. Therefore, we suggest that the TM4SF5-specific monoclonal antibody has a therapeutic effect against colon cancer. PMID:25268742

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

    PubMed

    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

    2016-02-01

    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

  8. 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

  9. Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K.

    PubMed

    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

  10. 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