Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that addition of short chain fructo-oligosaccharides (indigestible carbohydrates) to food prevented colon tumors in C57BL/6-Apc(Min/+) mice, a model for human colon cancer. As gut-associated lymphoid tissue was concomitantly developed, we suggested that the immune response generated by this food may interfere with carcinogenesis due to involvement of mucosal cells in the regulation of tissue homeostasis. In the present experiment, we tested whether T cell status may influence colon tumor formation in Min mice fed a food supplement of short chain fructo-oligosaccharides. Min mice depleted of CD4(+) and CD8(+) lymphocytes developed twice as many tumors as immunocompetent mice (0.8 as compared with 0.4, the mean number in 7-week-old Min mice when food supplementation began; P = 0.02). It is concluded that food supplementation with a substrate (a known prebiotic) fermented in the colon may stimulate a mechanism of immunosurveillance that would otherwise remain inefficient.
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PMID:T cell status influences colon tumor occurrence in min mice fed short chain fructo-oligosaccharides as a diet supplement. 1050 10

The authors report that the nature of the T-cell-receptor--derived signal in normal CD4+ T cells can induce interleukin-2 (IL-2) secretion or perforin-mediated cytolytic activity. Normal human T cells were genetically modified to express the tumor antigen specific chimeric immune receptor, CC49-zeta. The CC49-zeta chimeric immune receptor is comprised of the intracellular signaling domains of the TCR CD3zeta protein fused to the single chain scFv of the humanized CC49 antibody, which binds the pan-adenocarcinoma tumor antigen TAG-72. Patient-specific T cells genetically modified to express the CC49-zeta receptor have been used in patients with colon cancer. The authors report that both CD4 and CD8 T cells expressing the CC49-zeta receptor mediated the major histocompatibility complex-unrestricted lysis of TAG-72--expressing tumor cells with comparable efficiency. However, although the CC49-zeta receptor mediated target cell lysis, it did not support the production of IL-2, even in the presence of CD28 stimulation. Robust IL-2 secretion and T-cell proliferation were observed when the same CD4 CC49-zeta T cells were stimulated through the CD28 receptor and endogenous T-cell receptor. These results indicate that CD4 T lymphocytes possess the capacity to act as both cytolytic and helper T cells and that this difference in effector function is controlled by the nature of the T-Cell receptor--derived signals.
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PMID:Anti-Tumor CC49-zeta CD4 T cells possess both cytolytic and helper functions. 1118 54

There is accumulating evidence that CD4(+) T cell responses are important in antitumor immunity. Accordingly, we generated CD4(+) T cells against the murine CT26 colon cancer. Three of three independent CT26-specific CD4(+) hybridomas were found to recognize the high m.w. precursor of the env gene product gp90. The CD4(+) response was completely tumor specific in that the same glycoprotein expressed by other tumors was not recognized by the CT26-specific hybridomas. The recognition of gp90 by the hybridomas was strictly dependent on the conformation of gp90. Different procedures that disrupted the conformation of the glycoprotein, such as disulfide bond reduction and thermal denaturation, completely abrogated recognition of gp90 by all three hybridomas. In CT26 cells, but not in other tumor cells tested, a large proportion of gp90 was retained in the endoplasmic reticulum, mostly bound to the endoplasmic reticulum chaperone, calreticulin. Although calreticulin was not essential for the stimulation of the gp90-specific hybridomas, most of the antigenic form of gp90 was bound to it. The antigenicity of gp90 correlated well with calreticulin binding, reflecting the fact that specificity of binding of calreticulin to its substrate required posttranslational modifications that were also necessary for the generation of this tumor-specific CD4(+) epitope.
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PMID:An immunodominant MHC class II-restricted tumor antigen is conformation dependent and binds to the endoplasmic reticulum chaperone, calreticulin. 1141 43

A critical issue for cancer treatment is control of metastatic or disseminated tumors. Although immune gene therapy has been considered as a possible strategy for treatment of such tumors, successful results have not yet been obtained. To evoke antitumor immunity more efficiently, macrophage inflammatory protein-1beta (MIP-1beta) was used for gene therapy of colon cancer in mice. Injection of hemagglutinating virus of Japan (HVJ) cationic liposomes-MIP-1beta into subcutaneous tumor masses resulted in local expression of MIP-1beta and local accumulation of CD4(+) T lymphocytes. Few studies of cancer gene therapies have targeted peritoneal dissemination. In a mouse model of peritoneal dissemination of colon tumor, we used a luciferase-based assay to demonstrate that HVJ cationic liposomes had high tumor specificity and were effective vectors for transfer of genes in peritoneal dissemination. When mice were treated by intraperitoneal injection of HVJ cationic liposomes containing the MIP-1beta gene, the survival periods of the MIP-1beta-treated mice were significantly longer than those of control mice. Therefore, this HVJ cationic liposome strategy may serve as a powerful tool against peritoneal disseminated cancer.
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PMID:Novel immunotherapy for peritoneal dissemination of murine colon cancer with macrophage inflammatory protein-1beta mediated by a tumor-specific vector, HVJ cationic liposomes. 1177 75

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

Since the advent of HAART, the natural history of HIV disease has been changing, with decreased risk of life-threatening opportunistic infections and prolonged survival. Concurrently, a variety of non-AIDS-defining cancers have been reported with increased incidence in HIV-infected adults, including anal cancer, Hodgkin's disease, head and neck cancer, testicular cancer, lung cancer, colon cancer, basal cell cancer, squamous cell cancer of the skin, and melanoma. It appears that these tumors may have a more aggressive clinical course in HIV-infected people. Available data, however, suggest that antitumor response and survival in HIV-infected people with malignancy are improved in people with higher CD4 counts. The possible mechanisms for the increased incidence and altered clinical course of these malignancies in HIV-infected people remain unclear.
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PMID:Non-AIDS-defining cancer in HIV-infected people. 1285 61

Roles for host immune response in carcinogenesis are not well defined. Recent studies have shown that microbially driven inflammation can lead to colon cancer and that prior transfer of regulatory lymphocytes expressing CD4 and CD25 prevents the innate inflammatory events that lead to colon cancer in mice. To further examine the ability of regulatory lymphocytes to inhibit carcinogenesis, 129/SvEv Rag-2-deficient mice were inoculated by gastric gavage with Helicobacter hepaticus, an enteric bacterial pathogen of mice. Mice were then treated at 1, 3, or 12 months after infection with adoptive transfer of CD4(+)CD45RB(lo)CD25(+)-regulatory cells. Mice dosed with regulatory cells at 4 or 12 weeks after H. hepaticus infection had reduced severity of inflammatory bowel disease and significantly lower risk of colon cancer during the 8 month observation period, compared with infected mice that had not received cells. This suggested that regulatory cells were able to interrupt the ongoing innate immune events in the stepwise progression to cancer. Transfer of regulatory cells into chronically infected mice with established cancer reduced severity of colitis, epithelial dysplasia, and cancer, but did not eliminate all tumors. Regulatory cells lacking anti-inflammatory cytokine interleukin (IL)-10 were unable to inhibit inflammatory bowel disease, dysplasia, or cancer, showing that IL-10 was required for the protective effects of lymphocytes in this setting. Taken together, the data suggest that IL-10-mediated suppression of host innate inflammatory response was pivotal in interrupting carcinogenesis. Regulatory lymphocytes and cytokines may have implications for novel therapies for colon cancer in humans.
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PMID:CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. 1452 33

Only a limited number of target molecules have been shown to be recognized by colon tumor-reactive T cells, limiting the options for the development of immunotherapies for patients with colon cancer. The current studies were undertaken in an attempt to generate tumor-reactive T cells that could be used to identify and characterize novel colon tumor-associated antigens. Multiple CD4(+) T-cell clones isolated either from tumor-infiltrating lymphocytes or peripheral blood mononuclear cells that were sensitized in vitro with autologous tumor cells from a colon cancer patient, 1869, recognized autologous tumor cells in a class II HLA-DR-restricted manner. One of the peripheral blood mononuclear cell clones, clone C111, was used to screen pools of clones that were generated from an autologous colon tumor cell line cDNA library. A cDNA clone that was isolated encoded a protein that was termed colorectal tumor-associated antigen-1 (COA-1). This product was recognized in the context of the two autologous HLA-DRbeta1 alleles, HLA-DRbeta1*0402 and DRbeta1*1301. The nucleotide sequence of the COA-1 transcript was nearly identical to multiple expressed sequence tag sequences that encode variants of Socius, a protein that was found recently to bind to members of the Rnd family of GTPases. The COA-1 gene was expressed at relatively comparable levels in colorectal and melanoma tumor cells, EBV-infected B cells, normal B cells, and cultured fibroblast cell lines. However, the gene that was isolated from normal cell types contained a single nucleotide substitution, resulting in an amino acid change near the COOH terminus of the protein. Although the minimal epitope recognized by CD4(+) cells was encoded by sequences that were upstream from this substitution, C111 T cells did not appear to recognize the normal gene product. Therefore, this alteration may either affect the localization or the processing of this gene product, which may at least in part be responsible for the differential recognition of tumor and normal cells.
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PMID:Identification of a colorectal tumor-associated antigen (COA-1) recognized by CD4(+) T lymphocytes. 1458 68

CD25(+) regulatory T (T reg) cells suppress the activation/proliferation of other CD4(+) or CD8(+) T cells in vitro. Also, down-regulation of CD25(+) T reg cells enhance antitumor immune responses. In this study, we show that depletion of CD25(+) T reg cells allows the host to induce both CD4(+) and CD8(+) antitumoral responses following tumor challenge. Simultaneous depletion of CD25(+) and CD8(+) cells, as well as adoptive transfer experiments, revealed that tumor-specific CD4(+) T cells, which emerged in the absence of CD25(+) T reg cells, were able to reject CT26 colon cancer cells, a MHC class II-negative tumor. The antitumoral effect mediated by CD4(+) T cells was dependent on IFN-gamma production, which exerted a potent antiangiogenic activity. The capacity of the host to mount this antitumor response is lost once the number of CD25(+) T reg cells is restored over time. However, CD25(+) T reg cell depletion before immunization with AH1 (a cytotoxic T cell determinant from CT26 tumor cells) permits the induction of a long-lasting antitumoral immune response, not observed if immunization is conducted in the presence of regulatory cells. A study of the effect of different levels of depletion of CD25(+) T reg cells before immunization with the peptide AH1 alone, or in combination with a Th determinant, unraveled that Th cells play an important role in overcoming the suppressive effect of CD25(+) T reg on the induction of long-lasting cellular immune responses.
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PMID:CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. 1463 4

The carcinoembryonic antigen (CEA) is an attractive target for immunotherapeutic purposes because of its expression profile, its role in tumor progression, and its immunogenicity. However, CEA belongs to the CD66 immunoglobulin super-gene family that comprises highly homologous molecules expressed on leukocytes, making CEA a potential autoantigen expressed on hematopoietic cells. We used a MHC class II epitope prediction algorithm (TEPITOPE) to select 11 sequence segments of CEA that could form promiscuous CD4(+) T-cell epitopes and used synthetic peptides corresponding to the predicted sequences to propagate in vitro CD4(+) T cells from healthy donors and colon cancer patients. CD4(+) T cells from all subjects strongly recognized the sequence segment (LWWVNNQSLPVSP), repeated at residues 177-189 and 355-367. Importantly, we demonstrated that this highly immunodominant region contains a naturally processed epitope(s). Cross-recognition experiments with peptide analogues present on the CD66 homologous proteins showed that CEA(177-189/355-367)-specific CD4(+) T cells did not recognize the analogues, demonstrating that recognition of the immunodominant epitope is CEA specific. These data suggest that the repertoire of CEA(177-189/355-367)-specific CD4(+) T cells might have been shaped by a selective process to exclude CD4(+) T cells specific for CD66 homologues expressed on leukocyte, while preserving the CEA-specific repertoire. The features of strong immunogenicity and immunodominance in the absence of potential induction of autoimmunity make the identified CEA epitope of particular interest for the development of antitumor vaccines.
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PMID:CD4(+) T cells from healthy subjects and colon cancer patients recognize a carcinoembryonic antigen-specific immunodominant epitope. 1467 13


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