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S B Fox

Publications and source records attributed to S B Fox.

At least 55 records · Page 3Linked to original sources
PubMed1995

Increased expression of CD44v6 and CD44v3 in ulcerative colitis but not colonic Crohn's disease.

Immune mechanisms, possibly involving cell-surface molecules such as CD44, have been invoked to explain the pathogenesis of inflammatory bowel disease. We used monoclonal antibodies against epitopes encoded within the variable region of CD44 to investigate CD44 isoform expression in colon, small intestine, and liver in patients with various intestinal disorders and in controls. Biopsy samples from patients with ulcerative colitis showed significantly increased epithelial expression of CD44 isoforms containing the v6 and v3 epitopes, detected with antibodies 2F10 and 3G5, respectively. CD44v6 was detected on colonic crypt epithelial cells in 23 of 25 ulcerative colitis samples compared with 3 of 18 colonic Crohn's disease samples (p = 3.0 x 10(-6); odds ratio 57.5 [95% CI 6.83-702]) and 3 of 52 controls (22 normal colon, 10 infective colitis, 2 radiation colitis, and 18 colonic Crohn's disease; p < 1 x 10(-8); odds ratio 199 [25.5-2294]). No significant expression of CD44v6, CD44v3, or CD44v8/9 was found in samples of normal proximal colon from 4 patients with distal ulcerative colitis, whereas samples from the affected area showed staining for CD44v6 and CD44v3. No expression of CD44 variants was found in 15 samples of normal small intestine, 11 small-bowel pouchitis, 8 coeliac disease, 3 small-bowel Crohn's disease, 6 normal liver, 6 primary biliary cirrhosis, or 9 primary sclerosing cholangitis. The high intensity of CD44v6 and v3 epitope expression on crypt epithelial cells in ulcerative colitis suggests that CD44 isoforms may have an important role in ulcerative colitis. Their detection could have diagnostic potential in differentiating ulcerative colitis from other forms of colonic inflammation including Crohn's disease.

Antibodies, Monoclonal↗
PubMed1995

Thymidine phosphorylase is angiogenic and promotes tumor growth.

Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). The effect of TP on [methyl-3H]thymidine uptake does not arise from de novo DNA synthesis and the molecule is not a growth factor. Despite this, TP is strongly angiogenic in a rat sponge and freeze-injured skin graft model. Neutralizing antibodies and site-directed mutagenesis confirmed that the enzyme activity of TP is a condition for its angiogenic activity. The level of TP was found to be elevated in human breast tumors compared to normal breast tissue (P < 0.001). Overexpression of TP in MCF-7 breast carcinoma cells had no effect on growth in vitro but markedly enhanced tumor growth in vivo. These data and the correlation of expression in tumors with malignancy identify TP as a target for antitumor strategies.

Animals↗
PubMed1995

Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in normal tissues: an immunohistochemical study.

Angiogenesis is the formation of new blood vessels from the existing vascular bed. It is a complex multi-step process controlled by a number of angiogenic factors. One such factor is platelet-derived endothelial cell growth factor (PD-ECGF), recently shown to be thymidine phosphorylase (TP), which is angiogenic in several in vivo assays and tumour systems. PD-ECGF/TP catalyses the reversible phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. Since PD-ECGF/TP has an important role in cellular metabolism and in angiogenesis and its expression has been only partially characterized, we raised a monoclonal antibody against recombinant PD-ECGF/TP and used an immunohistochemical approach to examine the expression of PD-ECGF/TP in a comprehensive range of normal human tissues. The clone P-GF44.C, which recognizes recombinant PD-ECGF/TP and cell lysates transfected with a plasmid expressing PD-ECGF/TP cDNA on Western blotting, was selected for its ability to stain routinely processed tissue. Staining was observed in both the cytoplasm and/or the nucleus. Immunoreactivity was strongly expressed by macrophages, stromal cells, glial cells, and some epithelia. Gastrointestinal epithelium, smooth muscle, adrenal, lung, and testis were negative. Although endothelial cell expression was observed, there was no correlation with sites of new vessel growth. This pattern of expression suggests tight PD-ECGF/TP regulation and that cellular thymidine pools may serve to control its different functions. Thus, in the nucleus it might modulate the pool for DNA synthesis, whilst in the cytoplasm it could control other effects through different enzyme systems. The high expression present in macrophages and skin might be important for total body thymidine homeostasis.

Blotting, Western↗
PubMed1995

Quantitation and prognostic value of breast cancer angiogenesis: comparison of microvessel density, Chalkley count, and computer image analysis.

In some studies of breast cancer, quantitation of immunohistochemically highlighted microvessel 'hot spots' has been shown to be a powerful prognostic tool. However, the antibody used, the number and size of the 'hot spots' assessed, and the stratification of patients into high and low vascular groups vary between studies. Furthermore, little is known about the relationship between microvessel density and other vascular parameters. These uncertainties and the laborious nature of the technique make it unsuitable for diagnostic practice. Both manual and computerized image analysis techniques were used in this study to examine the relationship between microvessel density and the vascular parameters in different sized microscopic fields in a pilot series of 30 invasive breast carcinomas. Automated pixel analysis of immunohistochemical staining, Chalkley point counting, and observer subjective vascular grading were also assessed as more rapid methods of measuring tumour vascularity. A Chalkley count was also performed on a further 211 invasive breast carcinomas. Significant correlations were observed between manual microvessel density and luminal perimeter (r = 0.6, P = 0.0004), luminal area (r = 0.56, P = 0.002), and microvessel number (r = 0.57, P = 0.0009) by computerized analysis. There were also significant correlations between the microscopic hot spots of 0.155 mm2 and 0.848 mm2 for microvessel number (r = 0.81, P < 0.00005), luminal perimeter (r = 0.78, P < 0.00005), and luminal area (r = 0.65, P = 0.0001). In addition, a significant correlation was observed between microvessel density and both subjective vascular grade (P = 0.002) and Chalkley count (P = 0.0001). A significant reduction in overall survival was observed between patients stratified by Chalkley count in both a univariate (P = 0.02) and a multivariate (P = 0.05) analysis in the 211 invasive breast carcinomas. These findings show that Chalkley counting is a rapid method of quantifying tumour angiogenesis and gives independent prognostic information which might be useful in diagnostic practice.

Adult↗
PubMed1995

The increased expression of adhesion molecules ICAM-3, E- and P-selectins on breast cancer endothelium.

Sequential interaction of neoplastic cells with the endothelium of tumour neovasculature is believed to be a significant step in tumour metastasis. Increasing evidence suggests that inducible endothelial adhesion molecules are intimately involved in this process. An immunohistochemical approach was used to examine the expression of adhesion molecules in 14 normal controls and a series of 64 invasive breast carcinomas. Endothelium in normal breast showed constitutive expression of PECAM (100 per cent), ICAM-2 (100 per cent), and P-selectin (64 per cent); variable and focal expression of ICAM-1 (71 per cent); and only weak staining for E-selectin (21 per cent). No ICAM-3 or VCAM-1 expression was observed. Similarly to normal breast endothelium, widespread and intense immunoreactivity on the endothelium of tumour-associated vessels was seen for PECAM (100 per cent), ICAM-1 (69 per cent), and ICAM-2 (95 per cent). In contrast to normal tissues, E- and P-selectins showed increased intensity of staining (52 and 67 per cent of cases, respectively) and expression of E- and P-selectins was more prominent at the tumour periphery. ICAM-3 expression was increased on tumour endothelium (15 per cent of cases), but in common with VCAM-1 (10 per cent) expression was focal. A previously unreported finding was the immunoreactivity of the neoplastic epithelial cells for the non-epithelial lineage markers ICAM-1 (34 per cent), ICAM-3 (10.9 per cent), PECAM (1.6 per cent), and E- and P-selectins (7 and 37 per cent of cases, respectively). These findings show that tumour endothelium displays significant heterogeneity and can assume a pro-inflammatory phenotype, probably as a result of cytokine stimulation. Upregulation of adhesion molecules might contribute to changes in invasive phenotype by promoting endothelial cell adhesion and angiogenesis, as well as forming a substratum for tumour cells to assemble and attract macrophages.

Adult↗
PubMed1995

The prognostic value of quantitative angiogenesis in breast cancer and role of adhesion molecule expression in tumor endothelium.

Angiogenesis is the formation of new capillaries from the existing vascular network and is essential for tumor growth and metastases. Increased microvessel density in breast cancer is associated with lymph node metastasis and reduced survival. We have assessed tumor vascularity in 211 breast carcinomas using a more rapid technique based on a Chalkley point eyepiece graticule. We confirmed using this method a significant reduction in overall survival between patients stratified by Chalkley count in both a univariate (p = 0.02) and multivariate (p = 0.05) analysis. Since studies have suggested that cell adhesion molecules (CAMs) might be important in the angiogenic process, and interaction of neoplastic cells with this neovasculature is a significant step in tumor metastasis, we have also examined the expression of CAMs in a subset of these tumors (n = 64). Using immunohistochemistry we observed widespread and intense staining on the endothelium of tumor-associated vessels for PECAM (100%), ICAM 1 (69%), and E- and P-selectins (52% and 59% of cases respectively). Endothelial expression of the selectins was more prominent at the tumor periphery. Immunoreactivity of ICAM-1 (34%), PECAM (1.6%), and E- and P-selectins (7% and 37% of cases respectively) was also observed on the neoplastic element of the tumors.

Analysis of Variance↗
PubMed1995

An immunohistochemical and prognostic evaluation of cathepsin D expression in 105 bladder carcinomas.

Cathepsin D is a widely expressed aspartyl lysosomal protease. Clinical studies in several tumor types have shown a strong correlation between cathepsin D expression and tumor progression. In breast carcinoma, its expression is an independent prognostic factor associated with an increased risk of death. However, there have been no studies evaluating cathepsin D in bladder tumors. Therefore, the aim of this study was to determine the pattern of expression of cathepsin D in a large series of bladder carcinomas and assess its role as a prognostic factor against established variables. The tumors from 105 patients (median age 73) (median follow-up 26 months) with transitional cell carcinoma of bladder were examined. Forty-nine patients had superficial tumors (16 pTa; 33 pT1), 56 had invasive tumors (14 pT2; 42 pT3); there were 35 grade 1/2 tumors and 70 grade 3 tumors. These were stained by a standard immunohistochemical technique with an anti-cathepsin D monoclonal antibody. All 4 normal bladder specimens were positive for cathepsin D. Fifty-four tumors (51%) were positive for cathepsin D and 51 (49%) were negative. Chi square analysis showed a significant positive relationship between negative cathepsin D expression and stage (p < 0.0005), grade (p < 0.0001) and tumor morphology (p = 0.001). There was no relationship between cathepsin D expression and tumor ploidy (p > 0.1) or patient age (p = 0.09). Univariate analysis of disease-free and overall survival showed that negative cathepsin D expression (p = 0.01 and p = 0.0003 respectively), stage (p = 0.004 and p < 0.005 respectively) and grade (p = 0.02 and p = 0.0007 respectively) were associated with significantly worse prognosis. However, in a multivariate analysis of age, stage, grade and cathepsin D expression, only stage remained significant for overall survival (p < 0.005). The observed result for cathepsin D in the univariate analysis is probably due to its strong association with grade and stage. Nevertheless, cathepsin D status was able to provide additional prognostic information for overall survival in invasive tumors when stratifying for grade (p = 0.047), which suggests that it might provide additional prognostic data within particular tumor stages.

Adult↗
PubMed1994

Normal human tissues, in addition to some tumors, express multiple different CD44 isoforms.

At least 20 different isoforms of the human CD44 lymphocyte-homing receptor/hyaluronan receptor have been described to date that arise from the differential splicing of up to 10 alternative exons (termed v1-v10) encoding the membrane-proximal extracellular domain. Although numerous analyses at the mRNA level have indicated tissue-specific expression of CD44 variants, few analyses have been performed at the protein level because of limited availability of suitable monoclonal antibodies. Recently, however, exon-specific monoclonal antibodies have been generated using bacterial fusion proteins, and these have been reported to detect high levels of vCD44 containing the v6 exon on human tumors. Together with earlier evidence linking this particular exon with tumor metastasis in the rat, these latter experiments have led to the interpretation that v6 splice variants play a causative role in tumor dissemination. In this paper we describe the use of a new and comprehensive panel of CD44 exon-specific monoclonal antibodies generated against a recombinant CD44(v3-10)-immunoglobulin chimera to study vCD44 expression in a large number of normal and neoplastic tissues. We show that the expression of vCD44 varies greatly among different human tumors and that some express either very low levels of vCD44 or no CD44 at all. Furthermore, we demonstrate that expression is not limited to isoforms containing the v6 exon but includes variants carrying v3, v4/5, and v8/9. Additionally, normal epithelial tissues are shown to express considerable levels of these same vCD44 isoforms. Such results argue against a ubiquitous role for vCD44 isoforms in promoting tumor growth and metastasis.

Antibodies, Monoclonal↗
PubMed1994

The epidermal growth factor receptor as a prognostic marker: results of 370 patients and review of 3009 patients.

Epidermal growth factor receptor (EGFR) and estrogen receptor (ER) were assayed by ligand binding in tumors from 370 patients with primary breast carcinoma with a median follow up of 18 months. Forty seven percent (175/370) and 57% (210/370) of tumors had > 20 fmol/mg and > 10 fmol/mg of EGFR and ER respectively. There was a highly significant inverse relationship between EGFR and ER (p = 0.0032). There was also a significant association between EGFR and patient age (p = 0.0006) but not correlation between EGFR and lymph node status, tumor grade, or tumor size (p = 0.104, p = 0.198, and p = 0.085 respectively). In a univariate analysis of all patients, EGFR expression was not associated with a significant reduction in overall survival (OS). However, there was a significant decrease in relapse-free survival (RFS) and OS in node negative EGFR positive patients (p = 0.03 and p = 0.05 respectively). In a multivariate analysis (Cox proportional hazard model) of all patients, lymph node status was an independent prognostic indicator for OS and RFS (p < 0.00005) and p = 0.00005 respectively), ER status for RFS (p = 0.0006), and EGFR (in the node negative model) for RFS (p = 0.03). When all patients were stratified for EGFR and ER, there was a significant difference in RFS and OS such that EGFR positive and ER negative had the worst prognosis (p = 0.0034 and p = 0.005 respectively).

Adult↗
PubMed1994

Tumor angiogenesis in node-negative breast carcinomas--relationship with epidermal growth factor receptor, estrogen receptor, and survival.

Angiogenesis is essential for tumor growth and metastases. Studies in breast carcinomas suggest that microvessel quantitation as a measure of angiogenesis might be one of the most powerful prognostic tools available. Node negative breast cancer is a particular group for which better prognostic markers would be helpful. We therefore measured microvessel density in a series of well characterised node negative breast carcinomas to evaluate angiogenesis as a prognostic marker and assess its relationship to epidermal growth factor receptor (EGFR) and estrogen receptor (ER), which have previously been reported to be of value. 109 patients with a mean age of 55 years and a median follow-up of 25 months were examined. Vessels were immunohistochemically highlighted using an antibody to platelet endothelial cell adhesion molecule CD31, and microvessel density was quantified using a Chalkley point eyepiece graticule. No significant correlation was observed with patient age, tumor size, grade, ER, or EGFR expression. In a univariate analysis of survival, whereas ER expression was not a significant indicator of either relapse-free (RFS) or overall survival (OS), vascular count (VC) predicted both early RFS and OS (p = 0.01) and p = 0.028 respectively). Furthermore, in patients with ER positive tumors, a subgroup usually considered to have a good prognosis, there was a significant reduction in RFS and OS if tumors had high VCs (p = 0.05 and p = 0.002 respectively). A further statistically significant reduction in RFS (p = 0.05) was observed for EGFR positive highly vascular tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas.

OBJECTIVE: To evaluate angiogenesis as a prognostic marker of transitional cell carcinoma of the bladder and to assess its relationship to established variables for survival. MATERIALS AND METHODS: Forty-five tumours (two G2T2, seven G3T2 and 36 G3T3) from 36 men and nine women with a mean age of 73 years (range 50-91), who had been followed-up for a median of 37 months (range 1-50), were examined. Vessels were immunohistochemically highlighted using an antibody to the platelet endothelial cell adhesion molecule, CD31. Microvessel density was quantified using a Chalkley point eyepiece graticule. RESULTS: Univariate analysis of survival showed stage, grade and vascular count were significant indicators of prognosis (P = 0.002, P = 0.007, P = 0.019 respectively). No relationship was observed between stage and grade and vascular count. In a Cox proportional hazard model, adjusted for age and stage, microvessel density not only remained a significant prognostic indicator (P = 0.026) but was as informative as stage in predicting overall survival. A high vascular count conferred a 2.5 increased risk of mortality. CONCLUSIONS: These findings suggest that assessment of angiogenesis by microvessel quantification is an independent predictor of survival in patients with invasive bladder carcinoma and might be useful in selecting those who would benefit from adjuvant therapy.

Aged↗
PubMed1994

Prognostic value of c-erbB-2 and epidermal growth factor receptor in stage A1 (T1a) prostatic adenocarcinoma.

OBJECTIVE: To determine whether the presence or absence of the oncoproteins epidermal growth factor receptor (EGFR) and c-erbB-2 could predict tumour behaviour. PATIENTS AND METHODS: Tissue from 45 stage A1 (T1a) prostatic adenocarcinomas from patients with a mean age of 65 years were immunostained for EGFR (12E) and c-erbB-2 (NCL-CB11). Their expression in the tumour and surrounding benign hyperplastic epithelium was correlated with each other and with survival. RESULTS: Forty percent (18 of 45) and 36% (16 of 45) of patients respectively were EGFR and c-erbB-2 positive in the tumour. Expression of these tyrosine kinase oncogenes was not confined to the tumour and the surrounding hyperplastic prostate was also positive for EGFR in 76% (34/45) of patients and for c-erbB-2 in 16% (11 of 45). EGFR and c-erbB-2 expression was weakly associated in both benign and malignant epithelium. Statistical analysis of survival showed that tumour c-erbB-2 expression was associated with a significantly worse prognosis (exact two tailed P = 0.0316), whereas no significant association was observed between EGFR expression and survival (P = 0.737). CONCLUSION: As c-erbB-2 expression increases the rate of dying by 4.2 times, recording its expression by these tumours may be useful in selecting patients who would benefit from treatment in stage A1 (T1a) disease.

Adenocarcinoma↗
PubMed1993

Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer.

Current studies of tumor angiogenesis rely on the concept that endothelium proliferates 30-40 times faster in tumors than in normal tissues. This evidence is based on histological autoradiographic data largely from animal studies. To assess endothelial cell proliferation in human cancer we used the more sensitive and specific technique of immunohistochemistry. We measured the frequency and distribution of endothelial cell proliferation and examined their relationship to tumor cell proliferation. For the first time, we also correlated endothelial and tumor cell proliferation with tumor vascularity. Twenty breast carcinomas from patients exposed to bromodeoxyuridine 3-8 h prior to surgery were double immunostained using antibodies to CD31 (as a marker of endothelium) and bromodeoxyuridine (as a marker of proliferation). The labeling index (LI) for both tumor and endothelial cells was determined and tumor vascularity was assessed by counting the number of CD31 positive vessels. Endothelial cell proliferation was predominantly at the tumor periphery while tumor cell proliferation occurred throughout the lesion. The mean LIs for endothelium and tumor were 2.2% (range, 0.8-5.3) and 7.3% (range, 1.3-17.1), respectively. There was no correlation between tumor and endothelial cell LI (P = 0.414) or between the tumor LI or endothelial cell LI and tumor vascularity (P = 0.08 and P = 0.39, respectively). These findings suggest that previous studies in animal tumors have significantly overestimated endothelial cell proliferation and that its importance in tumor angiogenesis may be related more to continual remodeling and migration of vessels than to proliferation alone.

Adult↗
PubMed1993

Expression of cathepsin D and estrogen receptor in male breast carcinoma.

Male breast cancer is probably hormone dependent, but studies are few due to the rarity of this tumor. We have studied 21 cases of male breast cancer immunohistologically for estrogen receptor (ER) and cathepsin D (CD) expression. In carcinoma of the female breast ER expression is associated with longer patient survival and responsiveness to hormonal manipulation. Cathepsin D is an estrogen-regulated lysosomal protease with proteolytic and mitogenic properties whose presence denotes a functioning ER. In our series of male breast carcinomas 86% were ER positive and 62% were CD positive; this compares with typical figures of 50% and 66%, respectively, for female breast cancer. We observed no trends between expression of ER and CD and patient survival; immunostaining for ER and CD is unlikely to be clinically useful in carcinoma of the male breast. The high rate of ER positivity in males suggests that male and female breast carcinomas are biologically different tumors.

Aged↗
PubMed1993

p53 and c-myc expression in stage A1 prostatic adenocarcinoma: useful prognostic determinants?

Forty-five stage A1 prostatic adenocarcinomas from patients with a mean age of 65 years were examined for p53 and c-myc expression to determine whether the presence or absence of these proteins could predict tumor behavior. Thirteen (6 of 45) and seventy-three percent (33 of 45) of cases were respectively p53 and c-myc positive. p53 expression was confirmed to the tumor cells, whereas c-myc immunoreactivity was present in both malignant and surrounding hyperplastic prostate. Statistical analysis showed that although p53 and c-myc expression were positively correlated, expression of neither nuclear protein was associated with a significantly worse survival (p53: p = 0.0791 exact two-tailed; c-myc: p = 0.738 exact two-tailed). These results suggest that while both p53 and c-myc may play a role in prostatic carcinogenesis, neither appears to identify patients who may benefit from treatment in stage A disease.

Adenocarcinoma↗
PubMed1992

Oestrogen receptor and epidermal growth factor receptor expression in male breast carcinoma.

Male breast carcinomas are probably hormone-dependent, but receptor studies are few because this is a relatively rare tumour. We have studied 21 cases of male breast carcinoma immunohistochemically for oestrogen receptor (ER) and epidermal growth factor receptor (EGFR) expression employing the antibodies ER-ICA and 12E on formalin-fixed, paraffin-embedded material. In our series, 86 per cent of male breast cancers were ER-positive and 76 per cent were EGFR-positive. Male breast carcinomas do not exhibit the inverse correlation between ER and EGFR expression that characterizes female breast carcinomas. Owing to the limitations of a small series, we were unable to comment on the relationship between ER and EGFR expression and patient survival. However, the relatively high incidence of ER expression may provide a growth advantage for this tumour in a male environment characterized by low levels of oestrogen. In addition, high EGFR expression may also contribute to a poor prognosis independent of ER status.

Aged↗