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K C Gatter

Publications and source records attributed to K C Gatter.

At least 109 records · Page 6Linked to original sources
PubMed1996

The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium.

Tumour angiogenesis is a complex multistep process regulated by a number of angiogenic factors. One such factor, platelet-derived endothelial cell growth factor has recently been shown to be thymidine phosphorylase (TP). TP catalyses the reversible phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. Although known to be generally elevated in tumours, the expression of this enzyme in breast carcinomas is unknown. Therefore, we used ribonuclease protection assays and immunohistochemistry to examine the expression of TP in 240 primary breast carcinomas. Nuclear and/or cytoplasmic TP expression was observed in the neoplastic tumour epithelium in 53% of tumours. Immunoreactivity was also often present in the stromal, inflammatory and endothelial cell elements. Although endothelial cell staining was usually focal, immunoreactivity was observed in 61% of tumours and was prominent at the tumour periphery, an area where tumour angiogenesis is most active. Tumour cell TP expression was significantly inversely correlated with grade (P = 0.05) and size (P = 0.003) but no association was observed with other tumour variables. These findings suggest that TP is important for remodelling the existing vasculature early in tumour development, consistent with its chemotactic non-mitogenic properties, and that additional angiogenic factors are more important for other angiogenic processes like endothelial cell proliferation. Relapse-free survival was higher in node-positive patients with elevated TP (P = 0.05) but not in other patient groups. This might be due to the potentiation of chemotherapeutic agents like methotrexate by TP. Therefore, this enzyme might be a prediction marker for response to chemotherapy.

Adult↗
PubMed1996

Loss of interleukin 4 receptor-associated molecule gp200-MR6 in human breast cancer: prognostic significance.

Several in vitro studies stress a potentially important role of interleukin 4 (IL-4) and the related gp200-MR6 molecule in the immunological response to cancer and in tumour proliferation. In the present study, we assessed the expression of gp200-MR6 in primary breast cacrinomas using the MR6 monoclonal antibody. Results were correlated with tumour parameters (T-,N-stage, histology, grade, oestrogen and epidermal growth factor (EGF) receptors), and the impact on survival was assessed. Twenty-four out of 110 cases (22%) were positive for gp200-MR6, 62 out of 110 (56%) expressed weak staining and 24 out of 114 (22%) did not stain. The normal breast epithelia were invariably stained for gp200-MR6 showing that down-regulation or loss of this molecule occurred during the evolution of breast cancer. Gp200-MR6 loss was independent from differentiation, nodal positivity and oestrogen receptor levels as well as patients' age. Loss of the gp200-MR6 molecule was more frequent in lobular cases (P=0.03). The overall survival was better, although not reaching statistical significance, in patients with positive gp200-MR6 expression (92% alive at 5 years compared with 70% for those with weak or no expression, P=0.1). The local relapse-free survival was independent of gp200-MR6 status. It is concluded that loss of gp200-MR6 may be one of the mechanisms through which breast cancer cells escape immune surveillance, resulting in an increased metastatic potential and poorer outcome. Evidence of down-regulation of the gp200-MR6 molecule has implications for IL-4-linked toxin therapy and, as IL-4 is an inhibitor of breast epithelial growth, may represent loss of a tumour-suppression mechanism.

Analysis of Variance↗
PubMed1996

Bladder carcinomas and normal urothelium universally express gp200-MR6, a molecule functionally associated with the interleukin 4 receptor (CD 124).

Monoclonal antibody MR6 detects gp200-MR6, a molecule functionally associated with the interleukin 4 (IL- 4) receptor. Positive immunolabeling with MAb MR6 was obtained in 28/28 transitional cell carcinomas of the bladder, representing a range of different grades and stages of disease, as well as in all control non-neoplastic urothelia. The expression of mutant p53 protein and epidermal growth factor receptor was detected in 14/28 and 20/28 cases respectively. Proliferation indices, determined by Ki67 labeling, ranged from 5% to 95% among these tumours. The universal expression of gp200-MR6 in neoplastic and non-neoplastic urothelium has important implications for the possible use of IL-4 in tumour therapy and suggests that IL- 4 may play a role in differentiation and homeostasis of urothelium and other mucosal epithelia.

Antibodies, Monoclonal↗
PubMed1996

EBV latent membrane protein (LMP-1) and bcl-2 protein expression in Reed-Sternberg-like cells in post-transplant lymphoproliferative disorders.

An inconsistent association exists between EBV-LMP-1 and bcl-2 protein expression in Reed-Sternberg cells seen in Hodgkin's disease. In fact, many studies have concluded that there is no correlation between EBV-LMP and bcl-2 expression in Hodgkin's disease. We undertook an analysis of post-transplant lymphoproliferative disorders to explore the relationship between EBV-LMP and bcl-2 in Reed-Sternberg-like cells found in this condition, given the strong association between this disorder and EBV. Reed-Sternberg-like cells were found histologically in 11 of 28 cases of renal, heart and heart-lung post-transplant lymphoproliferative disorders. Formalin-fixed, paraffinembedded sections were stained with monoclonal antibodies to EBV-LMP-1 and bcl-2 proteins. Reed-Sternberg-like cells in all 11 cases co-expressed EBV-LMP and bcl-2. A similar relationship was noted with large, mononuclear cells and occasional small lymphoid cells. The staining pattern seen with both antibodies was of similar intensity and both displayed cytoplasmic Golgi accentuation. In the setting of post-transplant lymphoproliferative disorders. Reed-Sternberg-like cells exhibit strong co-expression of EBV-LMP-1 and bcl-2 proteins, supporting a positive correlation between them. This is in contrast to the findings in Hodgkin's disease. The reason for this discrepancy may be due to the iatrogenic immunosuppression and resultant severe EBV infection, together with other cellular events.

Herpesvirus 4, Human↗
PubMed1996

The immunoexpression of bcl-2 and p53 in Kaposi's sarcoma.

The aim of this study was to examine the immunohistochemical expression of p53 and bcl-2 in Kaposi's sarcoma and relate this with proliferation index (as measured by MIB-1 staining) and clinicopathological subtypes. Twenty formalin-fixed, paraffin-embedded cases of Kaposi's sarcoma were stained with commercially available antibodies to p53, bcl-2 and MIB-1, after pressure cooking antigen retrieval. All cases were strongly positive for bcl-2 with the majority containing more than 75% positive cells. In comparison, p53 expression was less striking. Eleven cases contained less than 24% (+1) of cells staining positively. Only two cases showed greater than 75% of positive cells, and both of these latter two lesions had metastasized. The MIB-1 staining in all cases of Kaposi's sarcoma was strongly positive, irrespective of clinicopathological type, in keeping with the highly proliferative nature of this lesion. Thus, we have demonstrated uniformly increased expression of bcl-2 protein in Kaposi's sarcoma irrespective of clinicopathological subtype and MIB-1 staining, while p53 expression is relatively less common, except in those cases which have metastasized. This may help identify those cases that will behave in a more aggressive manner. However, more cases need to be evaluated to verify this.

Adolescent↗
PubMed1996

Thymidine phosphorylase expression in Kaposi sarcoma.

AIMS: To examine the immunohistochemical distribution of thymidine phosphorylase (TP) in all clinicopathological subtypes of Kaposi sarcoma. METHODS: Thirty two biopsy specimens of Kaposi sarcoma (29 patients) were studied. Six of these patients represented classic, six endemic, eight HIV associated, seven post-immunosuppression/transplant related, and two unclassified variants of Kaposi sarcoma. The average age was 49 years (range 22-83 years) and the male: female ratio 24:5. Four samples of angiosarcoma and one of spindle cell haemangio-endothelioma were stained in parallel. All specimens were fixed in formalin, embedded in paraffin wax and processed routinely. Immunohistochemistry was carried out using an antibody directed against CD31 (JC70) and the monoclonal antibody P-GF.44C against TP. RESULTS: All biopsy specimens showed immunoexpression for TP. The spindle cell component stained more strongly than newly formed endothelium lined vessels and normal, resident vessels at a distance from the lesions. CONCLUSIONS: The strong immunoexpression of TP suggests up-regulation of TP and a role for TP in angiogensis in Kaposi sarcoma. The mechanism for the up-regulation of TP remains unknown, but viral infections may trigger it. The differential staining of the various cell components of Kaposi sarcoma also suggest that TP either plays a role in the differentiation and maturation of Kaposi sarcoma or is a reflection of such changes.

Adult↗
PubMed1995

The distribution of the deleted in colon cancer (DCC) protein in human tissues.

A gene called deleted in colon cancer (DCC) has been identified on a region of chromosome 18, which is deleted in 70% of colorectal cancers. The DCC gene encodes a protein belonging to the immunoglobulin superfamily with similarity to the N-CAM transmembrane proteins and is a putative tumor-suppressor gene. Alternative splicing of transcripts of transmembrane proteins, including N-CAM, is known to occur, resulting in different isoforms of the protein. Using five antibodies against the DCC gene product (three monoclonal antibodies raised in our laboratory, one commercially available antibody, and a rabbit polyclonal antibody), we have demonstrated by immunostaining a DCC protein isoform in reticuloendothelial cells in human thymus, tonsil, and lymph node. This can be distinguished from another isoform described in normal colonic epithelium, because this latter is not demonstrable with the antibodies we have used. It could not be detected in normal colonic epithelium, polyps or colorectal carcinomas. This restrictive distribution suggests that not all DCC gene products are important in colonic cancer.

3T3 Cells↗
PubMed1995

Loss of transporter in antigen processing 1 transport protein and major histocompatibility complex class I molecules in metastatic versus primary breast cancer.

We studied by immunohistochemistry the HLA-allelic, beta 2-microglobulin, and TAP-1 expression in primary breast carcinomas and related lymph node metastases. Thirty-three of the primary tumors and 44% of the lymph node metastases had a complete HLA class I loss. The higher incidence of antigenic loss in metastatic tumors suggests that recognition of HLA class I antigens by the host immunity could have an important role in the metastatic evolution of breast cancer. We observed a simultaneous defective expression of all three components involved in HLA class I expression. Since the controlling genes of heavy chain and TAP-1 are located in different chromosome than beta 2-microglobulin, it could be that a common factor exists regulating HLA class I antigenic expression. Five of 25 (20%) primary and metastatic tumors from HLA-A2-positive individuals also had a selective loss. The high incidence of HLA class I loss in breast cancer patients shows that adjuvant immunotherapy to induce HLA class I expression could be of value in a subgroup of patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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

Primary Hodgkin's disease of the lung.

Three cases of Hodgkin's disease presenting primarily in the lung are described. All 3 patients presented with respiratory symptoms and chest X-rays revealed discrete masses within the lung parenchyma. CT examination of the mediastinum did not reveal regional or generalized lymphadenopathy at the time of diagnosis in 2 of the cases. A diagnosis of Hodgkin's disease was made on open lung biopsies and despite aggressive chemotherapy, 2 patients died within 2 yrs. The histological and immunocytochemical features of these cases were typical of that expected in Hodgkin's disease. However, the stated indolent course of primary pulmonary Hodgkin's disease is not invariable. Those patients with bilateral interstitial disease and systemic symptoms have a poor prognosis. Furthermore, it is difficult to exclude definitely lymph node involvement (although not enlarged) at the time of diagnosis. Since several cases described in the literature have concurrent and/or subsequent nodal involvement, the entity of primary pulmonary Hodgkin's disease without lymph node involvement is exceedingly rare.

Adult↗