Hypoxia-induced up-regulation of angiopoietin-2 in colorectal cancer.

Angiogenesis is a compensatory mechanism that enables malignant tumors to survive in an oxygen-deficient environment. To test our hypothesis that hypoxia stimulates the production of angiopoietin-2 (Ang-2) in colorectal cancer (CRC), we investigated the expression of Ang-2 in three cultured CRC cell lines, and in specimens from 11 CRC metastatic liver tumors. Hypoxia-induced Ang-2 mRNA expression was clearly evident in HCT116 cells that did not express Ang-2 under normoxic conditions. Ang-2 mRNA was detected only after 48 h in hypoxic serum-deprived cultures in a LoVo cell line, and under both normoxic and hypoxic conditions without any noticeable difference in the HT29 cells. There was a stepwise increase in Ang-2 expression from the periphery to the central part of the liver metastatic foci, whereas an inverse result was noted in tumor blood vessels, with a gradual decrease in CD31-positive ECs from the edge to the central region of the metastatic lesion. An expression pattern similar to Ang-2 was found in glucose transporter 1 (Glut-1), a known hypoxia-induced factor. These findings suggest that hypoxia plays an important role in inducing the expression of Ang-2 in CRC.

Esophageal Endoscopic Submucosal Dissection Assisted by an Overtube with a Traction Forceps: An Animal Study.

Esophageal endoscopic submucosal dissection (ESD) is technically difficult. To make it safer, we developed a novel method using overtube with a traction forceps (OTF) for countertraction during submucosal dissection. We conducted an ex vivo animal study and compared the clinical outcomes between OTF-ESD and conventional method (C-ESD). A total of 32 esophageal ESD procedures were performed by four beginner and expert endoscopists. After circumferential mucosal incision for the target lesion, structured as the isolated pig esophagus 3 cm long, either C-ESD or OTF-ESD was randomly selected for submucosal dissection. All the ESD procedures were completed as en bloc resections, while perforation only occurred in a beginner's C-ESD procedure. The dissection time for OTF-ESD was significantly shorter than that for C-ESD for both the beginner and expert endoscopists (22.8 ± 8.3 min versus 7.8 ± 4.5 min, P < 0.001, and 11.3 ± 4.4 min versus 5.9 ± 2.5 min, P = 0.01, resp.). The frequency and volume of the submucosal injections were significantly smaller for OTF-ESD than for C-ESD (1.3 ± 0.6 times versus 2.9 ± 1.5 times, P < 0.001, and 5.3 ± 2.8 mL versus 15.6 ± 7.3 mL, P < 0.001, resp.). Histologically, muscular injury was more common among the C-ESD procedures (80% versus 13%, P = 0.009). Our results indicated that the OTF-ESD technique is useful for the safe and easy completion of esophageal ESD.

Minute liver metastases from a rectal carcinoid: A case report and review.

We here report a 43-year-old male patient with minute liver metastases from a rectal carcinoid. Hepatic nodules were diagnosed during surgery, although they were not diagnosed by preoperative computed tomography or ultrasound examination. The rectal carcinoid was resected together with liver metastases and the patient has had no disease recurrence for 5 years following postoperative treatment of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) and oral administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU). In 2003, a health check examination indicated presence of occult blood in his stool. Barium enema study revealed a rectal tumor in the lower rectum and colonoscopy showed a yellowish lesion with a size of 30 mm in diameter. Pathological examination of the biopsy specimen indicated that the rectal tumor was carcinoid. Although preoperative imaging examinations failed to detect liver metastases, 2 min nodules were found on the surface of liver during surgery. A rapid pathological examination revealed that they were metastatic tumors from the rectal carcinoid. Low anterior resection was performed for the rectal tumor and the pathological report indicated that there were 4 metastatic lymph nodes in the rectal mesentery. The patient received treatment by HAIC using 5-FU plus oral administration of HCFU and survived for 5 years.We also review world-wide current treatments and their efficacy for hepatic metastases of carcinoid tumors.

Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer: in vivo identification from hypoxic tumor cells.

PURPOSE: This study aimed to identify novel hypoxia-inducible and prognostic markers in vivo from hypoxic tumor cells. EXPERIMENTAL DESIGN: Using carbonic anhydrase 9 and CD34 as a guide for hypoxic tumor cells, laser capture microdissection was used to isolate colorectal cancer (CRC) liver metastases. The samples were analyzed by microarray analysis, in parallel with five CRC cell lines cultured under hypoxic conditions. To evaluate the prognostic impact of the expression of certain genes, samples from a total of 356 CRC patients were analyzed by microarray or quantitative reverse transcription-PCR. In vitro mechanistic studies and in vivo therapeutic experiments were also done about a histone H3 Lys(9) demethylase, Jumonji domain containing 1A (JMJD1A). RESULTS: Several candidate genes were identified by microarray analysis of liver metastases and culturing of CRC cells under hypoxic conditions. Among them, we found that JMJD1A was a novel independent prognostic factor for CRC (P = 0.013). In vitro assays revealed that loss of JMJD1A by small interfering RNA treatment was associated with a reduction of proliferative activity and decrease in invasion of CRC cell lines. Furthermore, treatment with an adenovirus system for antisense JMJD1A construct displayed prominent therapeutic effects when injected into established tumor xenografts of the CRC cell lines HCT116 and DLD1. CONCLUSIONS: JMJD1A is a useful biomarker for hypoxic tumor cells and a prognostic marker that could be a promising therapeutic target against CRC.

A multivariate analysis of adhesion molecules expression in assessment of colorectal cancer.

BACKGROUND AND OBJECTIVES: Adhesion molecules are implicated in the progression of colorectal cancer (CRC). Despite the evidence of association between their expression and patients' prognosis, the data have not been examined simultaneously in a same study; thus, the relative clinical value remained largely unknown. The aim of this study was to identify the adhesion factors that display the most significant prognostic value for CRC patients to guide clinical decision-making regarding appropriate treatment. PATIENTS AND METHODS: We examined by immunohistochemistry, the expression of E-cadherin and its associated catenins, alpha(alpha)-catenin and beta(beta)-catenin, DCC, and CD44 and its partner, MT1-MMP in a series of 140 CRC tissues at intermediate Stage II and Stage III to determine their prognostic significance. RESULTS: Clinicopathological survey indicated an inverse relationship between E-cadherin expression and tumor differentiation, and an association between CD44 expression and venous invasion. Univariate and multivariate analyses showed that loss of expression of E-cadherin and CD44 significantly correlated to poor survival, especially in Stage II. Combination studies indicated that loss of E-cadherin and loss of CD44 had the worst impact on patient prognosis, particularly in colon cancer. CONCLUSION: Immunohistochemical staining of E-cadherin and CD44 may help to identify a subgroup of high-risk patients with Stage II CRC, especially in colon cancer, who may need intensive follow-up and appropriate therapeutic strategy.