Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We established a mouse rising dbl quote, left (low)primary tumor resection model" in which a transplanted tumor was resected after an orthotopic transplantation of colorectal cancer tissue to estimate the therapeutic effect of an angiogenesis inhibitor on metastasis. The angiogenesis inhibitor FR-118487 is a member of the fumagillin family. Here, 1 mg / kg / day of FR-118487 was subcutaneously administered to nude mice for 1 week, 2 weeks, or 4 weeks through an osmotic pump. Liver metastasis developed in 7 of 9 control mice, 2 of 6 mice that underwent the tumor resection 2 weeks after transplantation (early resection), and in all 7 of the mice that underwent the tumor resection 4 weeks after transplantation (late resection). In the short treatment trial, the FR-118487 administration immediately after the early resection completely inhibited both hepatic and peritoneal metastases, whereas its administration after the late resection had no effect on liver metastasis. In the prolonged treatment trial, inhibitory effects of prolonged treatment with FR-118487 on both hepatic and peritoneal metastases after the late resection were clearly demonstrated. The mice of the resection-alone group all died within 106 days after tumor inoculation, due to metastases of colon carcinoma. In contrast, half of the mice that underwent resection and then received antiangiogenic therapy were alive at the end of the observation period (160 days after transplantation). In conclusion, the combination of surgery and subsequent antiangiogenic therapy may be useful to prevent the distant metastasis of colorectal cancer and to improve the prognosis of patients with colorectal cancer.
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PMID:Prevention of hepatic and peritoneal metastases by the angiogenesis inhibitor fr-118487 after removal of growing tumor in mice. 1117 49

Mechanisms that regulate the transition of micrometastases from clinically undetectable and dormant to progressively growing are critically important but poorly understood in cancer biology. Here we examined the effect of a primary tumor on the growth of solitary tumor cells in the mouse liver, as well as on the development of tumor angiogenesis in a dorsal skin-fold chamber. s.c. placement of a CT-26 (BALB/c-derived mouse colon carcinoma) primary tumor markedly inhibited development of liver metastasis in BALB/c mice after subsequent intraportal injection of tumor cells. Dorsal skin-fold chamber experiments showed that this growth inhibition paralleled a strong antiangiogenic effect by the primary tumor. Furthermore, intravital microscopy of the liver after intraportal injection of green fluorescent protein-expressing tumor cells showed that primary tumors promoted dormancy of single tumor cells for up to 7 days. Immunohistological staining for Ki-67 confirmed that these solitary cells were indeed dormant. In contrast, in the absence of a primary tumor, GFP-expressing tumor cells quickly developed into micrometastases. Thus, primary CT-26 tumor implants nearly abrogated tumor metastasis by inhibition of angiogenesis and by promoting a state of single-cell dormancy. Knowledge of the mechanism underlying this dormancy state could result in the development of new therapeutic tools to fight cancer.
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PMID:A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. 1145 10

The spRAD17 gene is an essential component of the DNA damage and replication checkpoints in the fission yeast Schizosaccharomyces pombe. Cloning of the human homologue of spRAD17, hRAD17, indicated that it exhibits structural similarity with the replication accessory protein family, which include subunits of the Replication factor C complex. We have analyzed the phosphorylation status of hRad17 in response to DNA damaging agents. Our results showed that phosphorylation of hRad17 occurred immediately after UV and ionizing radiation treatment and reached peak level at approximately 3 h, suggesting that hRad17 may be a component of the DNA damage checkpoint. When primary tumor samples were analyzed, we observed that the majority (74%) of non-small cell lung carcinoma samples exhibited a significantly higher level of hRad17 expression compared with matched normal tissue controls. In contrast, hRad17 protein levels in a panel of primary colon carcinoma samples did not show an elevated level of expression compared with normal colon tissues. This observation suggests that the function of the hRAD17 gene may be involved in lung cancer development and may serve as a potential tumor marker.
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PMID:Human Rad17 is phosphorylated upon DNA damage and also overexpressed in primary non-small cell lung cancer tissues. 1160 73

To determine whether the tissue inhibitor of metalloproteinases 1 (TIMP-1) can modulate in vivo tumor growth and metastasis, we transfected TIMP-1 cDNA into KM12SM human colon carcinoma cells and determined the implanted tumor volume and incidence of liver metastasis in orthotopically implanted colon cancer in nude mice. We also treated the implanted tumors with repeated intraperitoneal injections of recombinant human TIMP-1 (rTIMP-1), and compared the inhibitory efficacy on liver metastasis with that achieved by the TIMP-1 transfectants. The TIMP-1 transfectants had a significantly greater inhibitory effect, in association with TIMP-1 expression, on the growth of the primary tumor and on liver metastasis as compared with the controls. However, the intraperitoneal administration of rTIMP-1 did not decrease the rate of liver metastasis. In situ hybridization demonstrated that TIMP-1 mRNA in the cecal tumors implanted with the highly produced KM12SMT-2 cells with TIMP-1 was mainly expressed by the tumor cells. These results suggest that the increased expression of TIMP-1 in KM12SM cells was responsible for their decreased metastatic potential, and that the endogenous increase in TIMP-1 production by the tumor cells might be more effective for counteracting the matrix metalloproteinases (MMPs) in tumor tissue and for inhibiting liver metastasis from colon cancer than the exogenous administration of TIMPs.
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PMID:Inhibition of liver metastasis from orthotopically implanted colon cancer in nude mice by transfection of the TIMP-1 gene into KM12SM cells. 1168 57

Gelatinase A (MMP-2) and gelatinase B (MMP-9) play a key role in the proteolytic cascade leading to ECM degradation during invasion and metastasis. The enzyme activity is regulated both at the intra- and extra-cellular level. Extracellular regulation is achieved mainly through the balance between proenzyme activation and inhibition, which appears to be altered in cancer patients. One of the mechanisms of MMP inhibition is the binding of the enzymes to appropriate tissue inhibitors (TIMP). In the recent literature, it has been suggested that MMP-2 and/or MMP-9 are indeed over-produced in many carcinomas, while the identity of the various enzymatic forms (latent, activated and enzyme/inhibitor complexes) remains to be elucidated. In this study we have analyzed the circulating forms of MMP-9 and MMP-2 in serum samples of patients with colon carcinoma, as well as the enzymatic activities present in tissue extracts from surgical fragments (primary tumor and its paired healthy tissue). Proteins were separated by means of mono-dimensional or bidimensional electrophoresis, and the enzymes detected by gelatin zymography and immunological assays. The results of densitometric analyses demonstrate that proMMP-9, but not proMMP-2, is significantly higher in the oncologic sera vs. the normal sera. In addition, several oligomeric circulating and tissue forms of MMP-9 are preferentially found in the oncologic samples, both in mono- and second-dimension zymograms. The activated forms of MMP-2 and MMP-9 are uniquely present in the primary tumor extracts, thus confirming the involvement of the tissue microenvironment in gelatinase activation and function.
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PMID:Zymographic analysis of circulating and tissue forms of colon carcinoma gelatinase A (MMP-2) and B (MMP-9) separated by mono- and two-dimensional electrophoresis. 1222 1

The majority of tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) exhibit a mutator phenotype characterized by widespread microsatellite instability (MSI) and somatic mutations in repeated sequences in several cancer-associated genes. An inverse relationship between MSI and chromosomal instability (CIN) has been demonstrated and HNPCC-associated tumors are generally characterized by diploid or near-diploid cells with few or no chromosomal rearrangements. We have studied MSI, somatic mutations in repeat-containing genes, DNA-ploidy, and cytogenetic aberrations in a colon carcinoma from a patient with a germline MLH1 mutation. Mutations in coding repeats were assessed in 10 macroscopically separate areas of the primary tumor and in two lymph nodes. Some of the genes studied (E2F4, MSH3, MSH6, TCF4, and TGFBRII) showed a consistent lack of mutations, whereas others (BAX, Caspase-5 and IGFIIR) displayed alterations in some tumor regions but not in others. The tumor had DNA-index 1.1-1.2 and a stable, aberrant karyotype with extra copies of chromosomes 7 and 12 and the structural aberrations i(1q), der(20)t(8;20), and der(22)t(1;22). The finding of CIN, MSI, and somatic mutations in coding repeats in this tumor suggests that these phenomena may act together in HNPCC tumorigenesis. Furthermore, the observed intratumoral heterogeneity of mutations in coding repeats implies these changes occur late in tumorigenesis and, thus, probably play a role in tumor progression rather than initiation.
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PMID:Cytogenetic aberrations and heterogeneity of mutations in repeat-containing genes in a colon carcinoma from a patient with hereditary nonpolyposis colorectal cancer. 1199 96

A major obstacle to obtaining more detailed insights into the diversity of phenotypic and molecular changes occurring in colon cancer cells is the lack of low-passage colon cancer cell lines, which would still closely reflect the phenotype of the colon cancer cells in vivo. Here, we characterize eight novel, low passage number human colon carcinoma cell lines, originating from colorectal cancers extensively characterized in the clinics. All cell lines closely resemble the original tumors with respect to phenotype, markers and detectable genetic changes. Cell morphology and marker expression is highly variable, ranging from fully polarized cells correctly expressing all basolateral epithelial markers, to cells with mesenchymal characteristics and a complete loss of polarity due to delocalization or loss of junction complex proteins. The alterations in phenotype and epithelial marker expression correspond to changes already detectable in the primary tumor in vivo. Seven of the cell lines show chromosomal instability, while one cell line is characterized by microsatellite instability. p53 associated with K-ras mutations were detected in three cell lines. Hitherto non-described E-cadherin mutations were found at both alleles in one cell line whereas in another cell line the E-cadherin protein was down-regulated. A stabilizing beta-catenin mutation (S45F) appears in the same cell line that carried the mutated E-cadherin gene. Six cell lines carried APC mutations, which in five of the lines led to an activated beta-catenin/Tcf/LEF signaling pathway. In accordance with beta-catenin/Tcf/LEF activation, the cell lines show increased migration and invasiveness. Our results show that the characterized, low-passage cell lines mirror the diversity of the individual tumors from which they were derived. Through molecular analyses of these cell lines we demonstrate that tumorgenicity events are much more diverse in human colon cancer than expected, despite the common origin of the tumors from a small patient group with similar tumor grading and clinical prognosis.
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PMID:Novel colon cancer cell lines leading to better understanding of the diversity of respective primary cancers. 1209 41

The present study investigated the influence of dietary omega-3 fatty acid supplementation on the growth of human colon carcinoma xenograft in athymic nude mice. Four diets were fed to evaluate the effect of levels and types of fat on colon tumor growth. Animals were maintained on a standard diet modified by addition of fats containing omega-3 and omega-6 fatty acids to represent high and low fat intakes for 53 days. The final mean estimated tumor weight for the high fat corn oil (24%) fed group was 2,302 mg, whereas the low fat (8% corn oil) group was 1,681 mg. The final mean tumor weight of the high fat menhaden oil fed group was 782 mg representing a 66% decrease in growth compared to the high fat corn oil group and a decrease of 54% compared to the low corn oil fed group. The high fat golden algae oil fed group resulted in a mean final tumor weight of 223 mg representing a 90% inhibition of tumor growth relative to the high fat corn oil fed group and 87% inhibition of growth compared to the low fat corn oil fed group. These findings indicate that dietary omega-3 fatty acids possess significant tumor suppressing properties and that the primary tumor suppressing fatty acid is docosahexaenoic acid. Histopathologic examination of control and treated tumors and expression array analyses (human cytokine and apoptosis arrays) support the tumor growth inhibition data and provide evidence for discussion of possible mechanisms for the observed growth inhibition.
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PMID:Influence of omega-3 fatty acids on the growth of human colon carcinoma in nude mice. 1235 65

Colorectal cancer is one of the most common fatal malignancies in the United States, with an incidence second only to lung cancer. The liver is the most common site of colorectal metastases and frequently the only affected organ once the primary tumor has been surgically removed. The only potentially curative treatment for metastatic colorectal cancer in the liver is surgery, although most patients are not eligible for resection. We have therefore, evaluated the therapeutic efficacy of dendritic cells (DCs) engineered to express IL-12 in a liver metastasis model. Direct administration of DCs into the portal vein significantly inhibited the growth of established MC38 colon carcinoma in the liver in C57BL/6 mice. This effect was accompanied by an intratumoral accumulation of CD4+, CD8+, and NLDC-145+ immune effector cells, and also resulted in a systemic immune response as determined by enhanced production of IFN-gamma by T lymphocytes isolated from both spleen and draining lymph nodes. Evaluation of homing of Cy3-labeled DCs following the portal vein injection confirmed their distribution in the liver and lymphoid tissue. Thus, a local delivery of DCs transduced with the IL-12 gene can not only inhibit colorectal tumor growth in vivo but also mount systemic antitumor immune responses. This approach is likely to improve the outcome of immunotherapy for metastatic colorectal cancer since high numbers of tumor-associated DCs positively correlate with a more favorable prognosis. Simultaneous local gene therapy with IL-12 will further improve clinical efficacy without placing the patient at risk for systemic toxicity.
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PMID:Local administration of IL-12-transfected dendritic cells induces antitumor immune responses to colon adenocarcinoma in the liver in mice. 1244 Feb 25

Stage II colorectal carcinoma is characterized by negative lymph node pathology as determined by conventional microscopic examination. These patients generally do not receive adjuvant therapy although 20%-30% will die from metastatic disease. To determine whether K-ras mutations at codon 12 could be used as a sensitive indicator of occult lymph node metastasis in stage II colon carcinoma, a retrospective study was performed using restriction endonuclease-mediated selective polymerase chain reaction (REMS-PCR) amplification. Of 106 colonic tumors analyzed, 46 were identified as positive for a K12-ras mutation in the primary tumor. Multiple lymph node samples from 38 of these 46 patients were examined by a sensitive nested PCR protocol for the presence of a K12-ras mutation. Of these 38 patients, 14 had 1 or more positive lymph nodes by PCR (37%) and 24 were negative for the mutation (63%). Of the 14 patients with a K12-ras mutation detected in lymph nodes, 8 died of the disease within 5 years (57%) compared to only 4 of the 24 patients with ras-negative lymph nodes (17%). The difference in time to death from disease, stratified using K12-ras status of lymph nodes, was statistically significant (P = 0.036; log-rank test). These results suggest K-ras mutation status of lymph nodes in patients with stage II colon cancer might identify a subgroup of patients who are more likely to develop recurrent and/or metastatic disease and benefit from adjuvant therapy. Larger studies are indicated to determine whether detection of K-ras mutation positivity in histologically negative lymph nodes portends a poor prognosis and to determine whether more aggressive use of adjuvant therapy is warranted.
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PMID:Detection of mutated K12-ras in histologically negative lymph nodes as an indicator of poor prognosis in stage II colorectal cancer. 1244 69


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