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

Mononuclear phagocytes participate in host immunological defense against tumors. We have investigated the role of selected recombinant cytokines on human macrophage-mediated tumor cytotoxicity in vitro utilizing a human colon cancer cell line target, SW1116, and murine monoclonal antibody 17-1A. Blood monocytes were kept in continuous culture to allow differentiation into macrophages. Maximum antibody dependent cellular cytotoxicity (ADCC) as measured in a 3H-thymidine release assay occurred after culturing the monocytes for 5-7 days. Human recombinant macrophage colony stimulating factor (CSF) (1,000 U/ml) did not increase ADCC above control levels whereas recombinant human granulocyte-macrophage colony stimulating factor, interleukin 4, and interleukin 3 were all capable of increasing ADCC. Antibodies to the CD11/CD18 integrin receptors did not significantly inhibit ADCC. When the ADCC incubation occurred in the presence of antibodies to the human Fc receptors, ADCC was inhibited significantly only by anti-FcRIII (3G8). A role for tumor necrosis factor alpha or other soluble mediators of cytotoxicity was not demonstrable in this system. These studies suggest avenues for manipulation and augmentation of macrophage-mediated antitumor ADCC.
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PMID:Cytokine effects and role of adhesive proteins and Fc receptors in human macrophage-mediated antibody dependent cellular cytotoxicity. 167 19

Tumor-infiltrating lymphocytes (TIL) were isolated from 22 human primary and metastatic liver tumors, and expanded in vitro in the presence of either interleukin-2 (IL-2, 100 U/ml) plus tumor necrosis factor alpha (TNF alpha, 1000 U/ml), IL-2 (1000 U/ml) plus IL-4 (1000 U/ml) or IL-2 (1000 U/ml) alone. TIL proliferated in culture in 20/22 cases. Among different cytoline combination, TNF alpha and IL-2 were most effective in promoting the outgrowth of CD3+CD8+T lymphocytes (mean +/- SEM: 90% +/- 5) in the cultures of TIL from primary liver tumors. Cytotoxicity against autologous tumor cells was demonstrated in all early cultures of TIL from primary liver cancers in the presence of IL-2 plus TNF alpha. In contrast, cultures of TIL derived from colon cancer metastatic to liver had significantly lower levels of autotumor cytotoxicity and proportions of CD3+CD8+ cells (40% +/- 13) than those of TIL from primary liver tumors. The addition on day 0 of interferons (alpha or gamma) to TIL cultured in the presence of TNF alpha and IL-2, significantly augmented cytotoxicity against autologous tumor. In contrast, incubation of TIL in the presence of IL-4 and IL-2 did not result in increased autotumor responses in the cultures of TIL from primary liver tumors. The expansion (-fold) of TIL (day 30) cultured in the presence of IL-2 alone compared to that in the presence of TNF alpha and IL-2 was significantly greater for hepatocellular carcinoma (median, 280 vs 260) than for autologous peripheral blood lymphocytes (36 vs 27), cholangiocarcinoma (42 vs 51) or TIL from metastatic colon cancer (39 vs 30). Outgrowth of TIL in IL-2 plus TNF alpha offers an opportunity for in vitro enrichment in cells with autotumor cytotoxicity in primary liver tumors. However, this cytokine combination was unable to promote and sustain growth of autotumor effectors from TIL in metastatic liver cancer.
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PMID:Effects of cytokines on in vitro growth of tumor-infiltrating lymphocytes obtained from human primary and metastatic liver tumors. 184 44

The effect of recombinant human interleukin 4 (IL-4) on the expression of antitumor activity of human alveolar macrophages (AM) obtained by bronchoalveolar lavage from healthy donors was examined. AM were incubated for 16 h in medium with various macrophage activators [lipopolysaccharide, des-methyl muramyldipeptide, Nocardia rubra cell wall skeleton, and heptanoyl-gamma-D-Glu-(L)-meso-alpha,epsilon-A2pm(L)-D-Al aOH] in the presence or absence of IL-4, and then their tumoricidal activity was assayed by measuring 125I-UdR release from human melanoma (A375) cells. The spontaneous tumoricidal activity of AM was slightly suppressed by IL-4 in 3 of 7 donors. Addition of IL-4 to cultures of AM with the activators resulted in dose-dependent suppression of AM-mediated cytotoxicity against A375 cells. IL-4 also inhibited AM-mediated cytotoxicity against A375-R cells, which are resistant to interleukin 1 (IL-1) and tumor necrosis factor alpha, HT-29 colon cancer cells, and KB cells. IL-4 inhibited the early induction phase of AM activation. Pretreatment of AM with IL-4 also suppressed their expression of antitumor activity in response to lipopolysaccharide. IL-4 inhibited the production of monokines (IL-1 and tumor necrosis factor alpha) by AM at the protein and mRNA levels. These findings suggest that IL-4 may be important in vivo in the down-regulation of antitumor expression of AM in the lung by inhibiting the production of monokines and other killing mechanisms.
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PMID:Down-regulation by interleukin 4 of activation of human alveolar macrophages to the tumoricidal state. 191 71

Human CD4+ T cells activated with staphylococcal enterotoxin A (SEA) were fractionated by Percoll discontinuous density gradient centrifugation to enrich SEA-reactive CD4+ T cells. The SEA-reactive CD4+ T cells showed significant cytotoxicity, so-called superantigen-dependent cell-mediated cytotoxicity, against SEA-coated class II-positive tumor cells. During lysis of SEA-coated tumor cells, SEA-reactive CD4+ T cells produced high levels of IL-2 and IFN-gamma but not IL-4 in an Ag-specific manner. The skewing of human CD4+ T cells to Th1-type helper/killer T cells was also demonstrated when SEA-reactive CD4+V beta 5.3+ clonal T cells were cultured with SEA, but not with PHA or OKT3 mAb. Interestingly, the generation of SEA-reactive helper/killer T cells was negatively regulated by IL-4, but up-regulated by IL-12. The SEA-reactive CD4+ helper/killer T cells were able to generate from PBMC of tumor patients and could be expanded to 10(9) levels in a 7-day culture. The SEA-reactive CD4+ helper/killer T cells were specifically targeted to c-erbB-2 positive human colon cancer cells using SEA-conjugated-anti-c-erbB-2 mAb. These results initially demonstrated that SEA-activated human CD4+ T cells are a Th1 type of Th cell that has both helper and killer functions which may be useful for adoptive tumor immunotherapy in combination with SEA-conjugated antitumor mAb.
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PMID:Superantigen-induced human CD4+ helper/killer T cell phenomenon. Selective induction of Th1 helper/killer T cells and application to tumor immunotherapy. 783 62

We examined the role of two T cell-growth factors, interleukin (IL)-2 and IL-4, in expansion of tumor-infiltrating lymphocytes (TILs) from human tumors. In sarcoma, IL-4 (1,000 U/ml) with IL-2 (10 or 1,000 U/ml) grew TILs better than did IL-2 alone in six of 10 cases during 6 weeks of culture. IL-4 decreased the relative number of CD56+ cells, which correlated with a decrease in cytolysis against Daudi in six of 10 cases. The addition of IL-4 with 1,000 U of IL-2 maintained or increased cytolysis against autologous sarcoma, while decreasing nonspecific cytolysis against Daudi or allogeneic sarcoma in three of eight cases. IL-4 decreased cytolysis against both autologous sarcoma and Daudi in four of 10 cases, suggesting nonspecific activity in these instances. In renal cell cancer (RCC), IL-4 with IL-2 (10 or 1,000 U/ml) augmented TIL growth in six of eight cases, especially during the first 2-3 weeks of culture. IL-4 with 10 U of IL-2 increased cytolysis against both autologous RCC and Daudi in six of eight cases, suggesting possible prior cell activation. In contrast, IL-4 addition with 1,000 U of IL-2 maintained or increased cytolysis against autologous RCC, while decreasing cytolysis against Daudi or allogeneic RCC in four of eight cases. In cases of bladder and of prostate cancer, IL-4 with 1,000 U of IL-2 grew TILs slightly better in five of seven cases for the first 2-3 weeks. Bladder TILs grown with IL-2 and/or IL-4 were CD+ T cell predominant (three of five) and rarely lytic for autologous tumor. In colon cancer and hepatoma, TILs grown with IL-2 and/or IL-4 were nonlytic for the autologous tumor. IL-4 in conjunction with IL-2 could therefore augment growth of some TILs especially for the first 2-3 weeks from various human tumors.
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PMID:Expansion of tumor-infiltrating lymphocytes from human tumors using the T-cell growth factors interleukin-2 and interleukin-4. 828 Jul 17

We have previously reported on the expression of interleukin-4 receptors (IL-4R) on many human epithelial cancer cells; however, the binding characteristics, structure, function, and signal transduction through the IL-4R in cancer cells is not known. IL-4 binding characteristics were determined in human colon carcinoma cell lines by a 125I-IL-4 binding assay, which demonstrated that the HT-29 and WiDr colon cancer cell lines expressed high affinity IL-4R (Kd = 200 pM). Cross-linking experiments revealed a major band of 140 kDa and a broad band at 70 kDa. While the common gamma chain of IL-2R is associated with IL-4R in immune cells and is similar in size to the 70-kDa protein, this chain was not expressed in these colon cancer cells. Interestingly, IL-13, which has many functions similar to IL-4, inhibited 125I-IL-4 binding to both the 140- and 70-kDa molecules. Next, we investigated the mechanism of IL-4-induced signal transduction in colon cancer cells. After stimulation with IL-4, a 170-kDa band was primarily phosphorylated within 1 min of exposure and was identified as insulin receptor substrate-1. In addition, by immunoprecipitation assay, three other phosphorylated bands were identified as JAK1, JAK2, and Tyk2 tyrosine kinases. The phosphorylation of JAK1 and JAK2 was induced by IL-4 stimulation; however, Tyk2 was constitutively phosphorylated, and IL-4 treatment further augmented this phosphorylation. The kinetics and in vitro kinase assays demonstrated that JAK1, JAK2, and Tyk2 were phosphorylated within minutes and that JAK1 and JAK2 were activated after IL-4 exposure. Contrary to observations in immune cells. JAK3 mRNA was neither detected in colon cancer cells nor did IL-4 treatment cause phosphorylation of JAK3. These data indicate that in colon carcinoma cells JAK1, JAK2, Tyk2, and insulin receptor substrate-1 are phosphorylated after IL-4 stimulation. In addition, as is the case in lymphoid cells, IL-4 activated and phosphorylated signal transducers and activators of transcription (IL-4-STAT or STAT-6) protein in both colon cancer cell lines. These results indicate that the IL-4R complex is composed of different subunits in different tissues and shares a component with the IL-13R complex. In addition, we demonstrate for the first time that like its family members (e.g. IL-3 and GM-CSF), IL-4 can phosphorylate and activate JAK-2 kinase.
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PMID:Receptors for interleukin (IL)-4 do not associate with the common gamma chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. 853 May 27

We have recently reported that IL-13R may share a component with IL-4R. Here we report that both IL-4 and IL-13 share signaling events in human colon carcinoma cell lines (HT-29 and WiDr). IL-13 caused rapid phosphorylation of the three out of four members of the known Janus family of kinases (JAKs). We show that JAK2 kinase is rapidly phosphorylated and activated in response to IL-13. Within 1 min of activation, JAK2 was phosphorylated, and peaked in 10 min. In addition, IL-13 phosphorylated insulin response substrate-1, IL-4R p140, JAK1, and Tyk2, but not JAK3 kinase. IL-4 also stimulated all three kinases and substrates, but unlike in immune cells, IL-4 did not involve JAK3 activation for its signaling in colon cancer cell lines. Furthermore, JAK2 associated with the IL-4R p140 before and after stimulation with IL-13. Both IL-13 and IL-4 induced phosphorylation of IL-4 STAT (STAT6) but not STAT1, STAT3, or STAT5. 125I-IL-13 did not bind to colon cancer cell lines, but unlabeled IL-13 competed for the binding of 125I-IL-4. Our data suggest that IL-13 utilizes IL-4R and its signaling pathway, and JAK2 may play an important role in the function of IL-4R and IL-13R in colon cancer cells.
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PMID:IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling. 860 18

Binding of colon cancer to extracellular matrix (ECM) proteins and mesenchymal cells that comprise the basement membrane is important in migration and metastasis. This study defines the conditions and surface structures necessary for adhesion of HT-29 cells to ECM proteins and cell monolayers. Binding began within minutes and peaked by 1 hr, with 80-95% of HT-29 cells binding to the ECM proteins, collagen IV, laminin, fibronectin, and vitronectin and 40-75% binding to monolayers of fibroblasts, smooth muscle cells, and HT-29 cells. Treating mesenchymal cells with the fibrogenic cytokines, IL-1, IL-4, or TNF-alpha, which increase production of ECM proteins, did not alter binding of HT-29 cells to these monolayers. Attachment of HT-29 cells to cell monolayers was inhibited by cytochalasin D and sodium azide, but not cycloheximide or neuraminidase. Attachment to ECM proteins, in contrast, was unaffected by any of these metabolic inhibitors but required certain divalent cations (Mg2+ and Mn2+ but not Ca2+). Antibody to the integrin beta 1, chain (CD29) eliminated binding to collagen and laminin but not to fibronectin, fibroblasts, and HT-29 monolayers. Antibody to the vitronectin receptor inhibited binding to fibronectin. Antibodies to integrin alpha 1-alpha 6 chains had no effect on any adhesion event. Three colon cancer cell lines were tested for expression of VLA antigens: alpha 2 and alpha 3 were detected on all three, alpha 1 and alpha 6 were variably expressed, while alpha 4 and alpha 5 were absent. This study demonstrates that several mechanisms account for tumor cell attachment to substratum and cells.
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PMID:Mechanisms of colon cancer binding to substratum and cells. 876 78

We examined the possibility of the use of the IL-4 gene in cancer immuno-gene therapy protocols. Colon carcinoma cell (colon 26) clones engineered to express IL-4 were established. Expression of IL-4 significantly reduced tumorigenicity of colon 26 cells. Administration of anti-IL-4 antibody reversed the non-tumorigenic phenotype of the cells. Mice immunized with MMC-treated IL-4 positive cells rejected challenging IL-4 negative colon 26 cells. Strong CTL responses against colon 26 cells were observed in immunized mice. The lytic activity was tumor specific, and was blocked by the antibody against CD8. Histological examination showed that extensive infiltration of eosinophils occurred on day 5 after inoculation, while lymphocytes became the majority of the infiltrating cells on day 8. These results indicate that the expression of IL-4 in colon 26 cells can induce both eosinophil mediated local tumor killing and T-cell mediated systemic immunity in vivo. The dual mode of action of IL-4 may provide a basis for the advantage of IL-4 secrating tumor cells to apply in the cancer immuno-gene therapy.
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PMID:Expression of interleukin-4 in colon 26 cells induces both eosinophil mediated local tumor killing and T-cell mediated systemic immunity in vivo. 881 May 56

The story of tumor immunology includes periods of hope followed by ones of disenchantment as far as clinical applications are concerned. In antiquity, cancer was considered "contrary to Nature", a concept which was confirmed by Ehrlich at the beginning of our century when the layed down the foundations of immunology. The latter was defined as the defence against all "non-self" intruders, including cancer, as opposed to the protection of "self". This concept was further accentuated by the theory immune surveillance proposed by Burnet in 1969 which implicated a destruction of nascent neoplastic cells by T lymphocytes. To increase host defence was the basis of tumor immunotherapy with BCG, levamisol and other adjuvants. The appearance of the nude mouse, athymic, and yet free of spontaneous tumors, led to a new paradigm, the network theory proposed by Jerne. This was based on immunological homeostasis implicating that both "self" and "non-self" can be rejected and tolerated. Cancer gradually ceased to be considered as "contrary to Nature". As for the proposed viral etiology of cancer which was the basis of the National Cancer Act signed by Nixon in 1971, this led to various breakthroughs and Nobel Prizes (Table 1), to discoveries such as reverse transcriptase, cellular oncogenes, tumor suppressor genes, which gave a new explanation for neoplastic transformation. The latter can now be considered as the consequence of a cascade of molecular events which include oncogene expression, anti-oncogene deletion, etc... converting, step by step, for instance, a polyp into a colon cancer and its metastases. The availability of monoclonal antibodies capable of attacking tumor cells did not lead to the expected success because of the complexity of the immune system. Attempts at a better understanding of the latter have led to a subdivision of the T lymphocyte CD4 population into Th1 and Th2. Th1 favor rejection (tumoral, fetal or of transplants) through the elaboration of IL-2, IFN and TNF while Th2 led to tolerance or acceptation through the production of IL-4, IL-5 and IL-10: both functions neutralize each other establishing a "normal" equilibrium Th1 vs Th2. This could explain the state of "tumor dormancy" or tumors in situ which are apparently quite frequent. That any immunological stimulation would cause these dormant tumors to proliferate is the basis of the immunostimulation theory proposed by Prehn and supported by the clinical observations of Stewart. This new concept has led some authors to propose that instead of destroying the tumor cells an attempt be made to maintain them in a state of dormancy in congenial company with normal cells.
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PMID:[A retrospective view of tumor immunology]. 922 70


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