Showing papers by "Adrian C Bateman published in 2004"

Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma.

Abstract: Purpose: The purpose of this study was to determine the role of functional interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) in the formation of the desmoplastic reaction (DR) in pancreatic cancer and to characterize the effect of type I collagen (the predominant component of the DR) on pancreatic cancer cell phenotype. Experimental Design: PSCs and type I collagen were identified in sections of pancreatic cancer using immunohistochemistry, and their anatomic relationship was studied. Interactions among pancreatic cancer cell lines (MIA PaCa-2, Panc-1, and AsPC-1), primary cultures of human PSCs, and type I collagen were investigated in a series of tissue culture models. Results: In vivo, the DR causes gross distortion of normal pancreas, bringing cancer cells into close contact with numerous PSCs and abundant type I collagen. In tissue culture models of pancreatic cancer, conditioned media from each cell line increased PSC [ 3 H]thymidine incorporation up to 6.3-fold that of controls, and AsPC-1 cells also increased PSC collagen synthesis 1.3-fold. Type I collagen was observed to increase long-term survival of pancreatic cancer cells treated with 5-fluorouracil, by up to 62% in clonogenic assays. This was because type I collagen increased the proliferation of cancer cells ([ 3 H]thymidine incorporation was up to 2.8-fold that of cells cultured on tissue culture plastic) and reduced apoptosis of AsPC-1 cells in response to 5-fluorouracil (by regulating mcl-1). Conclusions: These experiments elucidate a mechanism by which the DR in pancreatic cancer may form and, via the collagen within it, promote the malignant phenotype of pancreatic cancer cells, suggesting significant detriment to the host.

Cytokine gene polymorphisms and breast cancer susceptibility and prognosis.

Abstract: Summary Single nucleotide polymorphisms (SNPs) in the promoter regions of cytokine genes are associated with differential levels of cytokine expression. We hypothesized that these SNPs might influence breast tumour development and progression by affecting the efficiency of the antitumour immune response and/or pathways of angiogenesis. A total of 144 female breast cancer patients and 263 cancerfree population controls were genotyped for the interleukin (IL)-1β −511 (T/C), IL-6 −174 (G/C), tumour necrosis factor (TNF)-α −308 (A/G), IL-10 −1082 (A/G), IL-8 −251 (A/T) and vascular endothelial growth factor (VEGF) −1154 (A/G) SNPs, using amplification refractory mutation system polymerase chain reaction (ARMS-PCR) and TaqMan® (Applied Biosystems, Foster City, CA, USA) 5′ nuclease assays for allelic discrimination. No significant associations were seen. Patient‐control comparisons revealed a non-significant trend for association between the TNF-α −308 GG genotype and breast cancer compared to controls (79.7 vs. 68.2%, P = 0.03, P c = 0.54). Stratification of the patient group according to the Nottingham Prognostic Index and individual prognostic factors revealed trends for association between IL-6 −174 GC and IL-8 −251 AA genotypes and markers of poor prognosis (P = 0.04, P c = 0.72 and P = 0.02, P c = 0.36, respectively). There were also trends for associations between VEGF −1154 AG and IL-1β −511 TC genotypes and markers of good prognosis (P = 0.02, P c = 0.36 and P = 0.05, P c = 0.90, respectively). These results suggest that the role of cytokine promoter SNPs in both susceptibility to and prognosis in breast cancer requires further investigation in a larger study.

Up-regulation of collagen and tissue inhibitors of matrix metalloproteinase in colonic diverticular disease.

Abstract: Thickening of the muscularis propria is a key pathologic feature of colonic diverticulosis but its cause is unknown This study was designed to investigate the role of collagens, matrix metalloproteinases, and tissue inhibitor of metalloproteinases in colonic diverticulosis Collagen content was determined by Sircol Collagen Assay and standard van Gieson staining Messenger-RNA expression for matrix metalloproteinases and tissue inhibitor of metalloproteinase was analyzed by quantitative competitive reverse transcription polymerase chain reaction Immunohistochemical staining was performed to localize tissue inhibitor of metalloproteinases in sections In mucosa and submucosal layer, complicated diverticular disease samples had a higher collagen content than uncomplicated disease, which in turn had higher levels than controls There was an 18-fold increase in tissue inhibitor of metalloproteinase-1 mRNA, and a threefold increase in tissue inhibitor of metalloproteinase-2 mRNA in complicated diverticulosis compared with controls In the muscularis propria, the amount of total soluble collagen also was higher in both uncomplicated and complicated diverticulosis samples than in the controls Tissue inhibitor of metalloproteinase-1 and metalloproteinase-2 mRNA was significantly increased in diverticulosis compared with controls Macrophage-like and fibroblast-like cells stained strongly positive for tissue inhibitor of metalloproteinases in the submucosa, serosa, and muscularis propria and in areas around the blood vessels Colonic diverticulosis is associated with altered collagen content and tissue inhibitor of metalloproteinases expression These factors may play a role in remodeling the gut wall in this condition

Economic and Practical Factors in Diagnosing HNPCC Using Clinical Criteria, Immunohistochemistry and Microsatellite Instability Analysis

Abstract: To determine a cost-efficient strategy for HNPCC molecular diagnostic testing. 138 families referred to a Regional Genetics Service had hMLH1 and hMSH2 mutation analysis. The sensitivity and specificity of clinical selection criteria with or without immunohistochemistry (IHC) and microsatellite instability (MSI) analysis to further refine case selection and the effect of these approaches on the cost of mutation analysis were examined. Clearly deleterious mutations were identified in 49/138 (35.5%) of all families tested. The most sensitive criteria for identifying families with MMR mutations were the full Bethesda guidelines but these have poor specificity. IHC and MSI were useful pre-screening tools. A cost-efficient approach in laboratories where IHC and/or MSI analysis are available, is to use inclusive (non-specific) criteria to select cases, followed by IHC and then MSI. Where one or both results are abnormal, proceed to further mutation analysis. Where MSI or IHC or tumour blocks are not available, more restrictive clinical criteria may be more appropriate for cost-efficient case selection.

Pathology of the breast

Abstract: Cellular pathology, comprising cytopathology and histopathology, is an essential component of the management of breast disease. The range of benign and malignant conditions encountered by the breast pathologist is diverse. Benign changes are common and may present as localized masses (e.g. fibroadenoma), diffuse textural alterations (e.g. fibrocystic change), nipple discharge (e.g. intraduct papilloma) or as microcalcifications on mammographic examination (e.g. sclerosing adenosis). Carcinoma is by far the most common breast malignancy and differentiation of in situ from invasive disease is crucial. Pure ductal carcinoma in situ has no propensity to metastasize and is curable by complete excision. Lobular carcinoma in situ is now viewed as a risk factor for the development of ductal carcinoma in situ and invasive carcinoma. Invasive carcinomas may invade local structures and metastasize to local lymph nodes as well as via the bloodstream. Invasive ductal carcinoma is the most common histological subtype of invasive carcinoma. Cytopathology is quick, minimally invasive and inexpensive and may confirm a malignant diagnosis in the outpatient setting although cannot differentiate ductal carcinoma in situ from invasive carcinoma. Histopathology (e.g. core biopsy, open biopsy) can distinguish invasive from in situ disease and determines prognostic/management factors such as tumour size, grade, hormone receptor, HER-2 receptor, lymph node and surgical margin status. Triple assessment (i.e. clinical examination, radiological studies and cytopathology or core biopsy) is important for accurate pre-operative diagnosis in breast disease, with case discussions at regular multidisciplinary team meetings, for NHS breast screening programmes and symptomatically detected lesions.

Genetic polymorphism, the immune response and chronic pancreatitis

Abstract: Chronic pancreatitis is characterised clinically by severe abdominal pain together with malabsorption and, in advanced disease, diabetes mellitus. The triggering event cannot be determined in every case. However, chronic excess alcohol consumption is the most common aetiological factor with other cases occurring due to chronic pancreatic duct occlusion, an inherited genetic predisposition (hereditary pancreatitis) or autoimmune pancreatitis.