Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased expression and/or activity of c-Met, the receptor protein tyrosine kinase for hepatocyte growth factor/scatter factor, occurs commonly during colon tumor progression. To examine potential roles for c-Met in promoting metastasis, we compared the colon tumor cell line KM12C with low metastatic potential to the isogenic variants KM,12L4 and KM12SM with high metastatic potential. KM12C cells express c-Met with low levels of tyrosine phosphorylation in the absence of HGF. The high metastatic cells express a c-Met that is constitutively tyrosine phosphorylated, they have increased colony formation, and are minimally responsive to HGF relative to the parental cells. Tyrosine-phosphorylated beta-catenin was constitutively associated with c-Met in the more metastatic cells, but was inducible only after HGF addition in the less metastatic cells. Functions mediated by beta-catenin, including cell-cell adhesion and migration, and activation of the tcf (T-cell factor) family of transcription factors, were also elevated in the more metastatic KM12SM and L4 cells. Furthermore, analysis of the known tcf transcriptional target genes, cyclin D1, c-Myc, and uPAR, demonstrated increased expression in the high metastatic cells, correlating with the levels of tcf activity. Collectively, these results suggest that endogenous activation of c-Met in highly metastatic KM12SM CRC cells results in increased survival and growth under anchorage independent conditions, increased in vitro migration, and elevated levels of tcf target genes. Thus, beta-catenin association with activated c-Met may contribute to a more aggressive liver metastatic phenotype of these cells.
Clin Exp Metastasis 2003
PMID:Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated beta-catenin. 1285 16

The protein beta-catenin can not be degraded in CRC due to different reasons. This leads to an increased formation of beta-catenin/Tcf4 complex, which has a strong transcription factor activity. We investigated the mRNA expression of beta-catenin and Tcf4 in N, T and M in 12 cell lines and in tissues samples of 14 patients. We found a significant increase of beta-catenin mRNA expression in the primary tumors and in the metastases. These data show for the first time that apart from the known mechanisms the overexpression of beta-catenin mRNA can be an additional factor contributing to the increase of beta-catenin amount in cells of CRC. The resulting increased transcription of hitherto unknown target genes might be involved in the progression and the metastatic process of CRC.
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PMID:[beta-catenin overexpression in metastasized colorectal carcinoma--an important mechanism in progression of the disease?]. 1451 65

There is significant recent progress in the surgical and oncological treatment of colorectal liver metastases. In our review we try to explain the variability and the multidisciplinarity approach we use to treat our patients more successful after the year of 2000. Beside the old rule: "Resect if possible"--thanks to the improvement of chemotherapy and new surgical instruments- there are new trends: "Make it resectable" or "resect it as many times as possible" thanks to the loco-regional and systemic neoadjuvant chemotherapy and/or the repeated interventions in metastasis surgery. The most important prognostic factors influencing the overall survival rate are free surgical margins, synchronous or metachronous metastasis and the need for repeated interventions. The view about extra hepatic metastases of CRC is changed in the last decade as the resection of these metastases is also suggested. After the year 2000 colorectal liver metastases should be treated "a-la-carte", based on multidisciplinary planning and treatment in specialised centres providing the long survival rates.
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PMID:[Surgical treatment of colorectal liver metastasis in the year 2000]. 1527 May 18

The aim of the work was to study the effects of changes in the location of E-cadherin from membrane to cytoplasm and the appearance of metastases and recurrence in patients with colon cancer of pT1 grade. The study group consisted of 34 patients with colon cancer. The material was fixed in 10% buffered, directly following surgery, fixed in fonnaldehyde and embedded in paraffin blocks by a standard method. Immunohistochemical reactions were performed, using monoclonal E-cadherin antibodies (Novocastra, NCL-E-Cad). Statistical analysis did not show any relation between the change in the location of E-cadherin expression, the patients' sex, and the location of changes. Simultaneously, we observed a strong relationship between the presence of exudate in the vessels from cancer cells, the histological grade and the loss of E-cadherin expression in the main tumour mass (p<0.01). We also noted a statistically significant correlation between the presence of lymph node invasion and distant metastases and the E-cadherin cytoplasmic reaction (p=0.0001, p=0.000001, respectively). A borderline significance of p=0.06 was noted in the association between the appearance of recurrence at the postoperative site and the change in location of E-cadherin expression in the main tumour mass from cytoplasm to membrane. On the basis of our results, we can conclude that a change in the location of E-cadherin expression (from membrane cytoplasm) is strongly associated with an increased aggressiveness of CRC, which is related to the appearance of proximal and distant metastases and to recurrence at the postoperative scar.
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PMID:Effects of changes at the site of E-cadherin expression as an indicator of colon cancer aggressiveness. 1563 79

The liver is the most frequent metastatic site from colorectal cancer, and the control of liver metastasis is an important issue in the treatment of progressive colorectal cancer. Hepatic arterial infusion (HAI) therapy can achieve a high drug concentration in the liver and relatively low level in the systemic circulation because of the first pass effect of the drug metabolism. With the high response rate, several reports have failed to show a significant survival benefit of HAI monotherapy, partially due to its inability to control extrahepatic metastasis. In this report, we used oral tegafur/uracil (UFT) and Leucovorin (LV) combined with HAI of 5-FU for four patients with liver metastasis of colorectal carcinoma. One of two patients with unresectable multiple hepatic metastases could undergo resectional surgery after 5 courses of this therapy. Two other cases in an adjuvant setting have been surviving free of tumors. In this series, adverse effects of this therapy were acceptable, including one case of grade 3 thrombocytopenia. The benefit of this combined therapy for survival in a case of liver metastasis from CRC remains to be evaluated. We are planning phase I and II clinical studies to evaluate the efficiency and feasibility of this combination therapy.
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PMID:[Combined chemotherapy with oral leucovorin (LV) + tegafur/uracil (UFT) and hepatic arterial infusion (HAI) therapy for liver metastasis of colorectal cancer]. 1604 71

Our aim was to evaluate the role of C-69T in GSTA1, Ile105Val in GSTP1, null allele in GSTT1 and GSTM1 in the prediction of toxicity in patients treated with 5-Fu/CPT-11/Lv regimens in metastatic CRC patients. Fifty-one patients with CRC metastatic disease were analysed. All patients had bidimensionally measurable disease according to WHO criteria. The gender distribution was 37 (74%) males and 13 (26%) females; age ranged from 41 to 71 years; performance status was in all patients > or = 80 (Karnofsky index). The analysis of gene polymorphism was performed in lymphocytes by using PCR-RFLP (GSTA1, GSTP1), PCR (GSTT1, GSTM1) and sequencing analysis (UGT1A1 *28). An appreciable significant association was observed between the GSTT1-null and toxicity: 57% developed gastrointestinal toxicity grade III versus 23% of patients with GSTT1-present genotype (p = 0.053). The other polymorphisms analysed did not show any significant relation with toxicity. Our data suggest that GSTT1-null is associated with a greater probability of developing toxicity to 5-Fu/CPT-11/Lv treatments, indicating a potential application of this genetic analysis in predicting adverse effects of this regimen.
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PMID:Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients. 1686 49

The management of patients who have hepatic metastases from CRC has become increasingly complex as the number of modalities that is available to treat these tumors has increased. Surgical resection remains the mainstay of treatment, when possible, and may become an option in an increasing proportion of patients that has advanced disease and previously were considered unresectable when treated with a combination of neoadjuvant systemic or hepatic arterial chemotherapy. The role of microwave coagulation and RFA can be considered only complementary to surgical resection at this point, but they may represent the best option in highly selected patients, such as those who are at high risk for extrahepatic recurrence or who are poor surgical candidates.
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PMID:Evolving techniques in the treatment of liver colorectal metastases: role of laparoscopy, radiofrequency ablation, microwave coagulation, hepatic arterial chemotherapy, indications and contraindications for resection, role of transplantation, and timing of chemotherapy. 1690 21

Despite recent advances in the medical treatment of metastatic colorectal cancer (mCRC), which include irinotecan- and oxaliplatin-based first-line regimens, the concept of planned sequential therapy involving three active agents during the course of a patient's treatment and the increasing use of targeted monoclonal antibodies, 5-year survival rates for patients with advanced CRC remain unacceptably low. For patients with CRC liver metastases, liver resection remains the only chance of cure, with 5-year survival rates ranging from 25% to 40%. However, 80% to 85% of patients with stage IV CRC have liver disease which is considered unresectable at presentation. The rapid expansion in the use of improved combination chemotherapy regimens plus or minus biologics, to render initially unresectable metastases resectable has increased the percentage of patients eligible for potentially curative surgery. However, the current staging criteria for CRC patients with metastatic disease do not reflect these recent changes or the fact that there is also a large variation in the survival of patients with stage IV CRC. For example the survival for a patient with a solitary, resectable liver metastasis is better than that for a patient with stage III disease. A new staging system is therefore needed that acknowledges both the improvements that have been made in surgical techniques for resectable metastases and the impact of modern chemotherapy on rendering initially unresectable CRC liver metastases resectable, while at the same time distinguishing between patients with a chance of cure at presentation and those for whom only palliative treatment is possible.
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PMID:Urgent need for a new staging system in advanced colorectal cancer. 1871 Nov 70

Angiogenesis plays an important role in growth, progression, and metastasis of tumors. The most important regulator of angiogenesis is vascular endothelial growth factor (VEGF). VEGF expression has been associated with advance stage and poor survival of several cancers. In the present study we evaluated the association of functional polymorphisms in the VEGF gene with colorectal cancer development, prognosis, and survival. Three hundred twelve consecutive patients with surgically treated colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue and five VEGF (-2578C>A, -1154G>A, -634G>C, -460T>C, and +936C>T) gene polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism assay. VEGF -2578C>A, -1154G>A, -634G>C, -460T>C, and +936C>T genotype and allele frequencies were similar among patients and controls. There was a trend showing carriers of the -2578A and +936T alleles more frequent among patients with CRC, but these differences did not reach statistical significance. Furthermore, no correlation was found between all these variants and tumor characteristics like size, histological grading, positive regional lymph node metastases or tumor stage. However, the -2578AA, -634CC, and +936TT genotypes found to be related with a significantly lower overall survival in our study. In conclusion, VEGF gene polymorphisms were found to be an independent prognostic marker for Greek CRC patients.
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PMID:Common polymorphisms in the vascular endothelial growth factor gene and colorectal cancer development, prognosis, and survival. 1900 60

Recent insights into the molecular pathogenesis of colorectal cancer have given rise to specific target-directed therapies, including monoclonal antibodies against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). These drugs have been approved as second and third line therapies for metastatic colorectal cancer (mCRC). Activating mutations of the K-Ras family of genes are the most common genetic events in tumorigenesis and have been implicated as a predictive factor in determining response to anti-EGFR drugs in pivotal studies. Phase II and III trials, conducted for investigating the role of K-Ras status on anti-EGFR treatment, revealed that patients with wild-type K-Ras had better clinical response in terms of prolonged median progression-free survival and overall response rates when compared to mutant K-Ras. In contrast, patients with mCRC benefit from anti-VEGF treatment irrespective of K-Ras status. Interestingly, a combination of anti-EGFR and anti-VEGF demonstrates no added value in these patients. The studies concluded that pretreatment testing of K-Ras in patients with mCRC offers valuable information in deciding treatment options. There are several molecular methods for mutation detection that seem practical enough to apply in clinical practice. Further confirmatory prospective studies are needed to evaluate the role of K-Ras mutation detections in tumor metastases, early stage CRC, and method of sampling specimens.
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PMID:K-ras mutations in colorectal cancer: a practice changing discovery. 1927 41


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