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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Surgical manipulation of a tumor may result in increased influx of tumor cells into the systemic and portal circulation and give rise to formation of metastases. In addition, major surgery has been reported to cause profound immunosuppression. In an attempt to increase the host-antitumor immune mechanisms following surgery we have studied the effect of preoperative administration of interferon-gamma, related to the antimetastatic effects of Kupffer cells (KC) and natural killer cells (NK-cells) in the early phase of liver metastasis formation. Colon carcinoma cells were injected into the superior mesenteric vein of syngeneic mice and after 17 days metastases were quantified by weight, number, and uptake of [125I]iododeoxyuridine. Unstimulated control mice developed 10.5 surface nodules per liver 17 days following injection of colon carcinoma cells into the superior mesenteric vein of syngeneic mice. This figure was only 2.6 in mice stimulated with a single dose of 1000 IU IFN-gamma 4 h prior to inoculation of tumor cells. Administration of GdCl3, which is reported to deplete and block the function of Kupffer cells, 24 h prior to tumor cell inoculation resulted in a 5-fold tumor mass increase relative to control. Injection of anti-asiolo-GM1 antiserum, which eliminates the hepatic NK-cells, induced a 10-fold increase in tumor mass. These results indicate an important early antimetastatic function of hepatic NK-cells and KC and that presurgical administration of IFN-gamma may be important for eliminating circulating tumor cells and inhibiting development of residual tumors.
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PMID:Early events of hepatic metastasis formation in mice: role of Kupffer and NK-cells in natural and interferon-gamma-stimulated defense. 1009 Aug 31

Cancer cells often resist Fas-mediated apoptosis even when the Fas receptor is expressed at the cell surface. We show here that human and rat colon cancer cells undergo massive apoptosis when they are exposed to soluble Fas ligand in the presence of sodium butyrate, an agent that induces by itself only a low rate of apoptosis. Sodium butyrate potentiates Fas-dependent apoptosis in seven out of eight colon cancer cell lines. Sodium butyrate does not increase Fas receptor cell surface expression and does not modify cell levels of Bcl-2, Bcl-xL, Bcl-xS and Bax. Sodium butyrate also induces tumor cell sensitization to the apoptotic effect of the combination of TNF-alpha and IFN-gamma, but it does not modify the level of the FADD/Mort1 adaptator molecule, at the connection between Fas- and TNF-dependent apoptosis pathways. Because the clinical toxicity of butyrate is low, its ability to enhance Fas-signal delivery in cancer cells could be of therapeutic interest.
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PMID:Cancer cell sensitization to fas-mediated apoptosis by sodium butyrate. 1020 Apr 99

To identify prostate cancer-associated Ags, tumor-reactive T lymphocytes were generated using iterative stimulations of PBMC from a prostate cancer patient with an autologous IFN-gamma-treated carcinoma cell line in the presence of IL-2. A CD8+ T cell line and TCR alphabeta+ T cell clone were isolated that secreted IFN-gamma and TNF-alpha in response to autologous prostate cancer cells but not to autologous fibroblasts or lymphoblastoid cells. However, these T cells recognized several normal and malignant prostate epithelial cell lines without evidence of shared classical HLA molecules. The T cell line and clone also recognized colon cancers, but not melanomas, sarcomas, or lymphomas, suggesting recognition of a shared epithelium-associated Ag presented by nonclassical MHC or MHC-like molecules. Although Ag recognition by T cells was inhibited by mAb against CD8 and the TCR complex (anti-TCR alphabeta, CD3, Vbeta12), it was not inhibited by mAb directed against MHC class Ia or MHC class II molecules. Neither target expression of CD1 molecules nor HLA-G correlated with T cell recognition, but beta2-microglobulin expression was essential. Ag expression was diminished by brefeldin A, lactacystin, and cycloheximide, but not by chloroquine, consistent with an endogenous/cytosolic Ag processed through the classical class I pathway. These results suggest that prostate cancer and colon cancer cells can process and present a shared peptidic Ag to TCR alphabeta+ T cells via a nonclassical MHC I-like molecule yet to be defined.
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PMID:Recognition of a shared human prostate cancer-associated antigen by nonclassical MHC-restricted CD8+ T cells. 1057 Mar 28

We have previously identified mutated ras peptides reflecting the glycine to valine substitution at position 12 as HLA-A2-restricted, CD8+ CTL neo-epitopes. CTL lines produced against these peptide epitopes lysed the HLA-A2+ Ag-bearing SW480 primary colon adenocarcinoma cell line, although IFN-gamma treatment of the targets was necessary to achieve efficient cytotoxicity. Here, we compared the lytic phenotype of the SW480 cell line to its metastatic derivative, SW620, as an in vitro paradigm to further characterize the nature of a HLA class I-restricted, Ag-specific CTL response against neoplastic cell lines of primary and metastatic origin. Although both colon carcinoma cell lines were lysed by these Ag-specific CTL following IFN-gamma pretreatment, the mechanisms of lysis were distinct, which reflected differential levels of sensitivity to the Fas pathway. Whereas IFN-gamma pretreatment rendered SW480 cells sensitive to both Fas-dependent and -independent (perforin) pathways, SW620 cells displayed lytic susceptibility to Fas-independent mechanisms only. Moreover, pretreatment of SW480 cells with the anti-colon cancer agent, 5-fluorouracil (5-FU), led to enhanced Fas and ICAM-1 expression and triggered Ag-specific CTL-mediated lysis via Fas- and perforin-based pathways. In contrast, these phenotypic and functional responses were not observed with SW620 cells. Overall, these data suggested that 1) IFN-gamma and 5-FU may enhance the lytic sensitivity of responsive colon carcinoma cells to immune effector mechanisms, including Fas-induced lysis; 2) the malignant phenotype may associate with resistance to Fas-mediated lysis in response to Ag-specific T cell attack; and 3) if Ag-specific CTL possess diverse lytic capabilities, this may overcome, to some extent, the potential "escape" of Fas-resistant carcinoma cells.
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PMID:Differential role of Fas/Fas ligand interactions in cytolysis of primary and metastatic colon carcinoma cell lines by human antigen-specific CD8+ CTL. 1077 5

Increased expression of prostaglandin endoperoxide H synthase-2 (PGHS-2) has been implicated in pathological conditions such as inflammatory bowel diseases and colon cancer. Recently, it has been demonstrated that inducible nitric oxide synthase (NOS II) expression and nitric oxide (NO) production are up-regulated in these diseases as well. However, the apparent link between PGHS-2 and NOS II has not been thoroughly investigated in nontransformed and nontumorigenic colonic epithelial cells. In the present study, we examined the concomitant expression of PGHS-2 and NOS II as well as the production of prostaglandin E2 (PGE2) and NO in conditionally immortalized mouse colonic epithelial cells, namely YAMC (Apc(+/+)). We found that the induction of PGHS-2 and generation of PGE2 in these cells by IFN-gamma and lipopolysaccharide (LPS) were greatly reduced by two selective NOS II inhibitors, L-NIL and SMT. To ascertain the effect of NO on PGHS-2 overexpression, we tested NO-releasing compounds, NOR-1 and SNAP, and found that they caused PGHS-2 expression and PGE2 production. This effect was abolished by hemoglobin, a NO scavenger. Using electrophoretic mobility shift assays, we found that both NOR-1 and SNAP caused beta-catenin/LEF-1 DNA complex formation. Super-shift by anti-beta-catenin antibody confirmed the presence of beta-catenin in the complex. Cell fractionation studies indicated that NO donors caused an increase in free soluble cytoplasmic beta-catenin. This is further corroborated by the immunocytochemistry data showing the redistribution of beta-catenin from the predominantly membrane localization into the cytoplasm and nucleus after treatment with NO donors. To further explore the possible connection between PGHS-2 expression and beta-catenin/LEF-1 DNA complex formation, we studied IMCE (Apc(Min/+)) cells, a sister cell line of YAMC with similar genetic background but differing in Apc genotype and, consequently, their beta-catenin levels. We found that IMCE cells, in comparison with YAMC cells, had markedly higher beta-catenin/LEF-1 DNA complex formation under both resting conditions as well as after induction with NO. In parallel fashion, IMCE cells expressed significantly higher levels of PGHS-2 mRNA and protein, and generated more PGE2. Overall, this study suggests that NO may be involved in PGHS-2 overexpression in conditionally immortalized mouse colonic epithelial cells. Although the molecular mechanism of the link is still under investigation, this effect of NO appears directly or indirectly to be a result of the increase in free soluble beta-catenin and the formation of nuclear beta-catenin/LEF-1 DNA complex.
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PMID:Expression of prostaglandin endoperoxide H synthase-2 induced by nitric oxide in conditionally immortalized murine colonic epithelial cells. 1083 41

The interaction between CD40 ligand (CD40L, CD154) and its receptor CD40 on antigen-presenting cells, is essential for the initiation of cell-mediated and humoral immune responses. In this study, we investigated the antitumor effect of in vivo gene transfer of CD40L to tumor cells using an adenoviral vector (AdCMVmCD40L) in a murine CT-26 colon cancer model. We found that injection of AdCMVmCD40L caused tumor regression in a dose-dependent manner. A complete regression of tumor was observed in 81% of mice treated with 10(9) p.f.u. of AdCMVmCD40L. The antitumor effect induced by CD40L was mediated by CD8+ T cells and was associated with the generation of tumor-specific cytolytic T lymphocytes (CTL). Animals that eradicated the tumor were protected against tumor cell rechallenge, and both CD4+ and CD8+ T cells were involved in specific protective immunity. Treatment with AdCMVmCD40L in one tumor nodule also caused complete regression of established tumors at distant sites. The antitumor effect elicited by AdCMVmCD40L was associated with the intratumoral production of IL-12 and IFN-gamma and with an increased intratumoral expression of chemokines such as MIP- 1alpha, MIP-1beta, MIP-2, RANTES, and eotaxin. These data demonstrate that intratumoral injection of AdCMVmCD40L induces a powerful cascade of chemokines and cytokines in the tumor mass and stimulates an efficient antitumor immunity leading to regression of established colon cancer and protection against tumor cell rechallenge.
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PMID:In vivo gene transfer of CD40 ligand into colon cancer cells induces local production of cytokines and chemokines, tumor eradication and protective antitumor immunity. 1100 66

Tributyrin has been shown to be cytostatic to tumor cells by inducing differentiation and apoptosis. On the other hand, immunological NK cells can kill tumor cells, particularly when stimulated with interleukin-2 (IL-2) and/or interleukin-12(IL-12). However, little is known about whether and how both antitumor mechanisms act together, although in vivo such an interaction must exist. Here we demonstrate in vitro, that pretreatment of human LS 174T colon cancer cells with nontoxic concentrations of tributyrin augments the sensitivity to spontaneous NK cell activity two-fold. However, when NK cells have been activated with an optimized combination of IL-2 and IL-12, the immunocytotoxicity increases up to five-fold (from 14% to 70%), versus a 3.8-fold increase against untreated cancer cells. These effects are accompanied by increased IFN-gamma secretion and decreased TGF-beta1 secretion. Tributyrin is found to be a potent inducer of ICAM-1, LFA-3 and Fas on target cells corresponding to an increase of the FasL expression by IL-2/IL-12 on the effector cells. Our data suggest a synergistic link between induction of tumor cell differentiation and immunological defense mechanisms that may provide a rational basis for the improvement of clinical protocols, especially for colon cancer.
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PMID:Tributyrin enhances the cytotoxic activity of interleukin-2/interleukin-12 stimulated human natural killer cells against LS 174T colon cancer cells in vitro. 1140 Oct 27

The beneficial effect of yoghurt consumption on health and on the improvement of the mucosal immune system is well established, as is the diet-associated risk of colon cancer. In an experimental model in BALB/c mice we demonstrated that yoghurt added to the diet for 10 consecutive days, with the procedure repeated each 10 days for 6 months, inhibited the development of a colorectal carcinoma induced by 1,2 dimethylhydrazine (DMH). The immunoregulatory mechanisms involved in the inhibition of tumour growth by yoghurt were also examined in these studies. We determined B lymphocytes IgA(+) and IgG(+), as well as CD4(+) and CD8(+) T cells in the large intestine. We measured cellular apoptosis and the cytokines TNF-alpha, IFN-gamma and IL-10. An increase in the number of IgA(+) (P<0.01) was observed, but not in IgG(+) (P<0.01), or in the CD4(+) population (P<0.01) in the mice treated with DMH and yoghurt. While in the group with the carcinogen there was an enhancement in the IgG(+) B cells (P<0.01) and CD8(+) T cells (P<0.01). Yoghurt increased the number of apoptotic cells and induced IFN-gamma and TNF-alpha cytokine release, their production being regulated by an increase in IL-10 (P<0.001). We demonstrated that yoghurt may exert antitumour activity by a decrease in the inflammatory immune response mediated by IgA(+) increase, apoptosis induction and IL-10 release.
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PMID:Role of yoghurt in the prevention of colon cancer. 1214 67

Proper antigen presentation is paramount to the induction of effective and persistent antitumor immune responses. In a murine model of hepatic metastasis of colon cancer, we found that the numbers of in situ mature dendritic cells (DCs) and macrophages in tumor-infiltrating leukocytes (TILs) were significantly increased in mice treated with the combination therapy of herpes simplex virus thymidine kinase, interleukin 2, and GM-CSF genes when compared with control groups without GM-CSF treatment. Significantly higher levels of IFN-gamma, MIP-1 alpha, mIL-12, and GM-CSF were detected in the tumor after the combination therapy. T cells isolated from the combination therapy-treated mice exhibited higher ex vivo direct CTL activity than those from other treatment groups. Antigen-presenting cells (APCs) enriched from the TILs and liver of the combination therapy-treated mice induced higher levels of proliferation by the splenocytes from long-term surviving mice that had been cured of tumors at early time points (days 4 and 7) whereas significant APC activity was only observed in the spleen at the latter time point (day 7, 14) after the combination therapy. In contrast, APCs isolated from tk or tk + IL-2-treated mice did not induce any significant proliferation. Subcutaneous injection of fluorescence-labeled latex microspheres followed by the combination therapy showed a similar sequential trafficking of microspheres, day 4 after the combination therapy to tumor and day 14 to spleen. The results suggest that APCs recruited by intratumoral gene delivery of GM-CSF can capture antigens, mature to a stage suitable for antigen presentation, and subsequently migrate to the spleen where they can efficiently stimulate antigen-specific T cells.
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PMID:In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery. 1295 80

Cell-mediated immune responses are an essential aspect of tumour-host interactions in colorectal cancers. The progression from precancerous (adenomatous) colon polyps to malignant colorectal cancer depends on a complex pathway involving the activities of activated T lymphocytes. The immune response is initiated when either cytotoxic T lymphocyte (CTL) CD8+ cells or CD4+ T-helper cells recognize the antigen from a human cancer cell. The cell-mediated response is largely initiated and controlled by the actions of various cytokines, which exert profound effects on T cell proliferation, cell-cell adhesion, apoptosis, and host immunity. The existence of an immune response to colon cancer is supported by studies of immunological treatments in humans and transplantable murine cancer models in animals. IL-2, IL-12, IFN-gamma, TNF-alpha, and TRAIL are implicated in enhancing cytotoxic and apoptotic effects in response to colon adenomas. In addition, growth factors, oncogenic cytokines and immunosuppressive factors may play a crucial role in the growth and survival of premaligant colonic tissue. This review aims to increase knowledge of the immunological mechanisms underlying colon tumour progression in the hopes that a greater understanding of the molecular pathways will lead to improved methods of prognosis and treatment.
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PMID:Colon polyps and cytokines: emerging immunological mechanisms. 1450 22


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