加藤 高晴

BACKGROUND: ADAMTS19 encodes a member of the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) protein family with emerging roles in carcinogenesis and metastasis. ADAMTS shares several distinct protein modules including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. In a previous work, we found ADAMTS19 frequently hypermethylated in colorectal cancer (CRC). We explored the association of methylation with tumor genotype and phenotype. RESULTS: The methylation status of the CpG island in the promoter of ADAMTS19 was determined in 252 colorectal, 65 pancreatic, 33 breast and 169 ovarian primary tumors, 70 CRC metastases, and 10 CRC cell lines. Tumor-specific methylation of ADAMTS19 was significantly more frequent in gastrointestinal than in gynecological cancers (odds ratio (OR) = 2.9, confidence interval (CI) = (1.9-4.7), p = 5.2 × 10(-7)) and was independent of the methylation of adjacent loci in CRC. Hypermethylation associated with CRC with mutated BRAF oncogene (OR = 10.1, CI = (3.1-42.9), p = 6.3 × 10(-6)) and with the mucinous phenotype in CRC (OR = 2.1, CI = (1.1-4.1), p = 0.023) and ovarian cancer (OR = 60, CI = (16-346), p = 4 × 10(-16)). Methylation was significantly more frequent in CRC metastases homing to the ovary and omentum than in those homing to the liver and lung (OR = 6.1, CI = (1.8-22.2), p = 0.001). Differentiating local from distant metastatic spread, methylation negatively associated with tumor progression (p = 0.031) but positively with depth of invasion (p = 0.030). Hypermethylation associated with transcriptional repression in CRC cell lines, and treatment with 5'-AZA-2'-deoxycytidine led to reactivation of mRNA expression. shRNA-mediated silencing of ADAMTS19 had no effect on the in vitro proliferation rate of CRC cells but significantly diminished their collective migration speed (56 %, p = 3.3 × 10(-4)) and potential to migrate in collagen I (64 %, p = 4.3 × 10(-10)). CONCLUSIONS: Our results highlight the frequent involvement of ADAMTS19 epigenetic silencing in CRC and mucinous ovarian cancer. The mechanistic preferences for the target organ of metastatic spread may lead to the development of diagnostic CRC biomarkers. The association with the mucinous phenotype also may have diagnostic applications for ovarian cancer.

The aim of the present study was to present a retrospective review of 42 metastatic colorectal cancer (mCRC) patients treated using the XELIRI regimen as second-line chemotherapy during the period between 2010 and 2012. Patients were treated with capecitabine, 1,600 (≥65 years) or 2,000 mg/m2 (<65 years), on days 1-15, 200 mg/m2 irinotecan (CPT-11) on day 1, with or without 7.5 mg/kg bevacizumab on day 1 and every 21 days. A total of 21 patients underwent XELIRI and 21 underwent XELIRI plus bevacizumab treatment. Fifteen patients received continuous administration of bevacizumab in the first- and second-line settings [bevacizumab beyond progression (BBP)+], whereas 27 patients did not receive the treatment (BBP-). Forty patients (95.2%), including all the patients in the BBP+ group, received sequentially administered XELOX and XELIRI regimens from the first- to the second-line setting. The disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events were compared between the BBP- and BBP+ groups. The median relative dose intensity was similar (93.9% for capecitabine and 96.3% for CPT-11 in the BBP- group vs. 94.8% for capecitabine and 91.5% for CPT-11 in the BBP+ group). The DCR was 25.9% in the BBP- and 66.6% in the BBP+ groups (P=0.020). The median PFS was 3.5 months in the BBP- and 7.2 months in the BBP+ groups (P=0.028). The BBP+ group exhibited a higher median OS time compared to the BBP- group (12.5 months in the BBP- group vs. not reached in the BBP+ group; P=0.0267). The most common grade 3/4 adverse event (n≥20) was hypertension observed in the BBP+ group [three patients (20%)]: these three patients were well-controlled with a single antihypertensive drug. Treatment with sequentially administered XELOX and XELIRI regimens did not aggravate adverse events in the 40 patients. The results showed that the XELIRI regimen, involving continuous treatment with bevacizumab, was well-tolerated and effective as a second-line chemotherapy and sequentially administering XELOX and XELIRI was feasible and manageable for patients with mCRC.