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Aberrant Wnt signaling mediated by mutations affecting APC (adenomatous polyposis coli) or beta-catenin initiates the majority of human colorectal cancers (CRC) and drives tumorigenesis through the activation of specific genes such as MYC. We report here a novel association whereby another oncogenic transcription factor, MYB/c-Myb, is necessary for intestinal adenoma development directed by activated Wnt signaling. APC(Min/+) mice in which c-myb is haploinsufficient survive longer than wild-type APC(Min/+) animals due to a delay in adenoma formation. Intestinal adenomas from APC(Min/+) mice were assessed and found to have high levels of c-myc gene expression. We explored the relationship between activated Wnt signaling and MYB in regulating MYC and found activated beta-catenin in combination with MYB induces robust upregulation of MYC promoter activity, as well as endogenous MYC mRNA and protein expression, in human cells. This cooperation occurred through independent binding of MYB and beta-catenin to the MYC promoter. These data highlight a cooperative function for MYB in the context of activated Wnt signaling and provide a molecular basis for the expression of MYC in CRC.

Background and Purpose: This retrospective study was performed to examine the relationship between the size and metastasis of hepatic lymph node in patients with liver metastasis of colorectal cancer., Patients and Methods: We analyzed a total of 163 hepatic lymph nodes that were removed during surgery from 55 patients with synchronous liver metastasis of colorectal cancer, who underwent resection of primary tumor without any residual lesions except for liver metastasi (e) s. The relationship between the size and metastasis was examined on paraffin-embedded specimens., Results: The maximal and minimal diameters were significantly greater in positive lymph nodes (n=35) than in negative lymph nodes (n=128). The area under the curve of receiver operating curve for predicting metastasis by size was 0.69. The sensitivity, specificity, and accuracy were 62.9%, 60.9%, and 61.4%, respectively, when the cutoff value was set at 7 mm., Conclusion: These findings suggest that selecting patients with hepatic lymph node metastasis based on the size of lymph nodes would be difficult.

Background: COX-2 is involved in tumor angiogenesis and modulation of the production of angiogenetic factors by colorectal carcinoma cells. It has been shown that COX-2 inhibitors have inhibitory activities against various types of tumor, including colorectal carcinoma. In this study, we investigated the tumor vessels of small metastatic liver tumors in rats and the effect of meloxicam, a selective COX-2 inhibitor, on their growth and microvasculature., Methods: The metastatic liver tumors were produced by intraportal inoculation of RCN-H4 cells in male F344/DuCrj rats (n = 40). The microvasculature was examined by scanning electron microscopy and stereomicroscopy. Microvascular casts were produced by perfusion via the abdominal aorta 14 days after tumor inoculation. Four groups (control, groups 1-3) of rats were treated with meloxicam 0, 0.6, 1.0 and 3.0 mg/kg/day, respectively, by oral gavage 5 days/week for two weeks from the day of inoculation of RCN-H4 cells., Results: The mean number of tumors was significantly decreased in groups 1-3 (5.6+/-0.8 standard deviation, SD; 3.6+/-1.1; and 5.5+/-1.1, respectively) compared with control (11.2+/-2.7; P = 0.0002, each). Meloxicam also significantly reduced the mean diameter of the tumor: 730+/-254, 685+/-212 and 644+/-139 in groups 1-3, respectively, in comparison with 870+/-276 in control (P = 0.0025, 0.0011 and <0.0001, respectively)., Conclusions: Meloxicam's anti-angiogenic activity interferes with the growth of metastatic liver tumors. Meloxicam might have therapeutic potential for liver metastasis of colorectal carcinoma.

Little is known about the expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT) in diffusely infiltrating colorectal cancer. We semiquantified the mRNA levels of these enzymes in colorectal cancer specimens from 10 patients with diffusely infiltrating type and 20 patients with other types (control) matched by the maximal diameter and pathological stage, using the Dannenberg tumor profiling method. The relative expression of these enzymes did not significantly differ between diffusely infiltrating and other types of tumors. There were no significant relationships among the relative expression of the four enzymes in the diffusely infiltrating tumors, while the following three combinations were found to be correlated with each other in the control tumors: TS versus TP,TS versus DPD, and TP versus DPD. In 5 patients who received 5-fluorouracil-based chemotherapy for evaluable lesions, there were no specific relationships between the expression of these enzymes and therapeutic response. In conclusion, diffusely infiltrating colorectal cancer does not appear to have any characteristics in terms of the expression of these enzymes, which may not alter the effect of 5-fluorouracil-based chemotherapy.

Purpose: To clarify the clinical significance of determining plasma levels of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in colorectal cancer, changes in plasma levels of VEGF and sFIt 1 during hepatic arterial chemotherapy were investigated in patients with liver metastases of colorectal cancer., Patients and Methods: The relationship between plasma level of VEGF or sFlt-1 and serum level of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), or the efficacy of hepatic arterial chemotherapy was investigated in patients with liver metastases of colorectal cancer (n=19). Plasma levels of VEGF and sFlt-1 were determined by the enzyme linked immunosorbent assay., Results: There was a positive relationship between plasma level of sFlt-1 and serum level of CEA (p = 0.13). The other combinations did not show any statistical correlations. Also, in terms of the doubling time (DT), there was a positive relationship between the sFlt1-DT and the CEA-DT (p = 0.04). The levels of VEGF tended to change in accordance with the efficacy of chemotherapy. In contrast, plasma levels of sFlt-1 increased in patients with the progressive disease, whereas the levels did not decrease in patients with the partial response., Conclusions: These results suggested that (1) VEGF may be a useful tumor marker during the chemotherapy in patients, whose CEA and CA19-9 are below the cutoff, and (2) the shrinkage of liver metastases may not cause a decrease in sFlt-1 or the half-life of sFlt-1 may be considerably long.

Background and Purpose: Hepatic arterial infusion chemotherapy for unresectable liver metastases of colorectal cancer is generally indicated to patients without extra hepatic lesions. This study was performed to examine the status of hepatic lymph node metastasis as an extra hepatic lesion in patients with synchronous multiple liver metastases of colorectal cancer., Patients and Methods: A total of 111 hepatic lymph nodes were removed from 33 patients with synchronous liver metastases of colorectal cancer during resection of the primary tumor at the D2- or D3- level. The frequency of hepatic lymph node metastases and factors predictive for hepatic lymph node metastasis were examined., Results: Hepatic lymph node metastasis was detected in nine patients (27%): The sites were classified into three categories: (1) along the hepatic arteries in three, (2) in the hepato-duodenal ligament except the peri-hepatic arterial region in three, and (3) both in three. The serum level of CEA (p = 0.02), CA19-9 (p = 0.05), and the rate of lymph node metastasis of the primary lesion (p = 0.08) were higher or tended to be higher in patients with hepatic lymph node metastases than in those without. There was no significant relationship between the involvement of hepatic lymph nodes and the other clinicopathologic factors examined., Conclusion: We should note the frequency of hepatic lymph node metastasis in the treatment of unresectable liver metastases of colorectal cancer.

The lung is a frequent site of metastasis from colorectal cancer, but angiogenesis of lung metastases has not been clarified. Some COX-2 inhibitors prevent tumor growth, although the inhibitory mechanism at the metastatic site is obscure. We investigated the microvascular structure of small lung metastases and the effect of JTE-522, a selective COX-2 inhibitor, on the angiogenesis of pulmonary metastases from colorectal cancer in rats. The tail veins of 25 male F344/DuCrj rats, aged 5 weeks, were injected with a tumor suspension containing 5 x 10(6) RCN-9, a rat colon cancer cell line. Three weeks later, pulmonary vascular resin corrosion casts were taken and the vascularity of metastases was studied using stereo and scanning electron microscopes. We investigated the effect of 0, 10 and 30 mg/kg/day of JTE-522 on the angiogenesis of pulmonary metastases in 3 groups of 5 male rats out of 25. JTE-522 reduced the diameter of tumor vessels as well as the number and size of metastatic tumors. The diameter of tumor vessels and the size of lung metastases significantly and positively correlated with neovascularization in the control group, but not in the JTE-522-treated groups. JTE-522 also affected type of vasculature of metastases, which differed depending on their size. JTE-522 interfered with the growth of hematogenous metastatic tumors by disrupting neovascularization. However, JTE-522 may have some important mechanisms other than inhibition of neovascularization. JTE-522 may be one of the therapeutic agents for the treatment of hematogenous metastasis of colorectal cancer., ((c) 2004 Wiley-Liss, Inc.)

We set out to determine whether carcinoembryonic antigen (CEA) levels in gallbladder bile and serum can predict metachronous liver metastasis of colorectal cancer. At the time of surgery, gallbladder bile and serum were sampled for enzyme immunoassays of CEA. Upper limit (mean +/- 2SD) of the normal range for CEA in bile was established from samples at surgery for nonneoplastic gallbladder disease. In 11 patients with synchronous liver metastases, biliary CEA levels correlated with the size of hepatic lesions. In 49 patients without evident liver metastases at the time of surgery, elevated biliary CEA levels predicted subsequent emergence of metachronous liver metastases with 75% sensitivity, 85% specificity, and 84% accuracy; serum CEA levels were not a reliable predictor. In conclusion, determination of biliary CEA level at the time of colorectal resection shows promise as a way to identify patients at high risk for hepatic recurrence.

A preliminary study was conducted to determine whether the measurement of CEA levels in gallbladder bile would be of value for diagnosis of occult liver metastases aiming at prophylactic regional hepatic chemotherapy in patients with colorectal cancer. Forty-fold dilution by normal human sera was necessary to measure CEA levels of gallbladder bile by the enzyme immunoassay (EIA). Bile CEA levels were 27.2 +/- 30.4 (M +/- SD) ng/ml in patients with benign biliary diseases (control), 248.5 +/- 426.3 ng/ml (p < 0.05, vs. control) in Dukes B, C patients, and 3,331.5 +/- 4,473.3 ng/ml (p < 0.01 vs. control, p < 0.05 vs. Dukes B, C) in patients with hepatic metastases from colorectal cancer, respectively. Bile CEA tended to demonstrate the existence of hepatic metastases more accurately than serum CEA. Our results obtained from a small number of patients suggest that patients with either elevation of bile CEA level or with a high ratio of bile CEA/serum CEA may be candidates for hepatic recurrence that requires prophylactic hepatic chemotherapy. However, it may be difficult to determine the bile CEA level at which occult liver metastases are demonstrated.