Molecular events including p53 and k-ras alterations in the in vitro progression of a human colorectal adenoma cell line to an adenocarcinoma

The aim of the current study was to identify genetic abnormalities in human colorectal adenoma and carcinoma derived cell lines, and to determine whether the genetic changes which occur in vitro are relevant to the in vivo situation. Loss of 1p(33-35) region was shown to be the most common chromosome 1 abnormality and loss of heterozygosity (LOH) of the DCC gene and/or adjacent sequences was detected in all adenoma derived cells as well as the carcinoma cell lines. The level of p53 protein was also investigated as increased cellular p53 protein had previously been associated with mutation of the p53 gene. A further aim was to investigate genetic changes in our in vitro model of tumour progression, where the adenoma derived PC/AA cell line has previously been converted in vitro to two distinct tumorigenic phenotypes, producing either an adenocarcinoma or a mucinous carcinoma in athymic nude mice. Progression to the adenocarcinoma phenotype was shown to involve a specific chromosome 1 rearrangement, loss of both normal copies of chromosome 18 (although DCC gene sequences were retained), loss of the remaining wild type allele of k-ras resulting in homozygosity for the k-ras codon 12 mutation and increased cellular p53 protein as detected by SDS-PAGE Western blotting. The increase in p53 protein was shown not to be due to the acquisition of a mutation in the p53 gene. Interestingly, progression of the adenoma derived PC/AA cell line to the mucinous malignant phenotype did not involve any of these molecular rearrangements, suggesting that different genetically distinct pathways are involved in colorectal carcinogenesis. These studies show that the genetic changes in our in vitro model of human colorectal tumour progression are similar to those observed in in vivo studies.     

Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells

Inadequate presentation of tumor antigens by host professional antigen-presenting cells (APCs), including dendritic cells (DCs), is one potential mechanism for the escape of tumors from the host immune system. Here, we show that human cancer cell lines release a soluble factor or factors that dramatically affect DC maturation from precursors without affecting the function of relatively mature DCs. One factor responsible for these effects was identified as vascular endothelial growth factor (VEGF). Thus, VEGF may play a broader role in the pathogenesis of cancer than was previously thought, and therapeutic blockade of VEGF action may improve prospects for immunotherapy as well as inhibit tumor neovasculature.     

Confirmation that Thiobacillus halophilus and Thiobacillus hydrothermalis are distinct species within the gamma-subclass of the Proteobacteria

BACKGROUND: There is controversy regarding the most appropriate investigation for suspected colorectal carcinoma. We offered these patients same-day flexible sigmoidoscopy (FS) and double-contrast barium enema (DCBE). METHODS: We reviewed the results of 117 consecutive adult patients. All patients underwent FS followed by DCBE on the same day. The radiographs were reviewed by two of the authors who were blinded to the clinical information, flexible sigmoidoscopy reports, and the original DCBE report. RESULTS: One hundred seventeen patients made up the study population. Thirty-four of the 117 patients had polyps and/or carcinoma. Three malignant tumours were detected by DCBE; one of these was also seen on FS, and the other two cancers were out of FS range. Fifty-three polyps were found by FS; nine were removed by biopsy prior to the enema examination. Of the 44 remaining polyps, DCBE failed to detect 87% of the 0-9-mm group and 67% of the >9-mm group. Ten polyps were seen only on DCBE; seven of these 10 were beyond the range of the sigmoidoscope, and the three remaining polyps were less than 5 mm. CONCLUSION: DCBE is insensitive in the detection of rectosigmoid polyps. FS should continue to be used as a complementary examination to DCBE in the investigation of suspected colorectal carcinoma.