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Adrian L Harris

Publications and source records attributed to Adrian L Harris.

At least 127 records · Page 7Linked to original sources
PubMed2002

Comprehensive proteomic analysis of breast cancer cell membranes reveals unique proteins with potential roles in clinical cancer.

Proteins associated with cancer cell plasma membranes are rich in known drug and antibody targets as well as other proteins known to play key roles in the abnormal signal transduction processes required for carcinogenesis. We describe here a proteomics process that comprehensively annotates the protein content of breast tumor cell membranes and defines the clinical relevance of such proteins. Tumor-derived cell lines were used to ensure an enrichment for cancer cell-specific plasma membrane proteins because it is difficult to purify cancer cells and then obtain good membrane preparations from clinical material. Multiple cell lines with different molecular pathologies were used to represent the clinical heterogeneity of breast cancer. Peptide tandem mass spectra were searched against a comprehensive data base containing known and conceptual proteins derived from many public data bases including the draft human genome sequences. This plasma membrane-enriched proteome analysis created a data base of more than 500 breast cancer cell line proteins, 27% of which were of unknown function. The value of our approach is demonstrated by further detailed analyses of three previously uncharacterized proteins whose clinical relevance has been defined by their unique cancer expression profiles and the identification of protein-binding partners that elucidate potential functionality in cancer.

Amino Acid Sequence↗
PubMed2002

A mycobacterial iron chelator, desferri-exochelin, induces hypoxia-inducible factors 1 and 2, NIP3, and vascular endothelial growth factor in cancer cell lines.

Hypoxia is a key phenomenon in tumor behavior, selecting for resistance to apoptosis, conferring resistance to radiotherapy and chemotherapy, and also inducing angiogenic factors such as vascular endothelial growth factor (VEGF). Exochelins are naturally evolved iron chelators produced by Mycobacterium tuberculosis. Because iron chelation has been reported to activate the hypoxia-inducible factor (HIF), we investigated the effects of an exochelin [desferri-exochelin (DFE) 772SM] on this hypoxia-inducible pathway and downstream target genes. DFE induced HIF-1alpha and HIF-2alpha transcription factors regulating the hypoxic response in the breast tumor cell line MDA468. DFE was 10 times more potent and more rapid in onset of effect than the clinically used iron chelator deferoxamine. The expression of downstream hypoxia-responsive target genes VEGF and the proapoptotic protein NIP3 was activated by transcription. MDA468 proliferation was inhibited via HIF-independent pathways, related to other effects of iron chelation. DFE inhibited effects of VEGF on endothelial cell proliferation. DFE potentially could be useful in cancer therapy by inducing apoptosis via NIP3 in conjunction with other non-HIF-related growth inhibitory pathways and blocking endothelial proliferation despite the presence of VEGF.

Adenocarcinoma↗
PubMed2002

The development of [(124)I]iodinated-VG76e: a novel tracer for imaging vascular endothelial growth factor in vivo using positron emission tomography.

The development of anticancer therapies that target the angiogenic process is an area of major growth in oncology. A method of noninvasively measuring tumor vascular endothelial growth factor (VEGF) in vivo could provide important efficacy information for VEGF-dependent antiangiogenic agents and the role of VEGF in cancer biology. We have developed a novel radiotracer for use with positron emission tomography (PET) that enables noninvasive imaging of VEGF. This radiotracer comprises an IgG1 monoclonal antibody, known as VG76e, that binds to human VEGF, labeled with a positron-emitting radionuclide, iodine-124 ([(124)I]-SHPP-VG76e). Three radiolabeling strategies were evaluated to synthesize the radiotracer with optimal radiochemical yield, purity, and immunoreactivity. To evaluate the pharmacokinetics and VEGF-specific localization of [(124)I]-SHPP-VG76e, two subclones of the HT1080 human fibrosarcoma selected on the basis of differing VEGF production (26.6 and 1/3C, the former producing 2-4-fold more in vitro) were established in culture and grown as solid tumor xenografts in immune-deficient mice. A single i.v. injection of the radiotracer into tumor-bearing mice revealed a time dependent and specific localization of [(125)I]-SHPP-VG76e to the tumor tissue. Three validation studies established the VEGF specificity and potential for use of [(124)I]-SHPP-VG76e in vivo: (a) uptake of [(125)I]-SHPP-VG76e was 1.8-fold higher in HT1080-26.6 compared with HT1080-1/3C tumors (P < 0.05); (b) uptake of [(125)I]-SHPP-VG76e in HT1080-26.6 tumors was specifically blocked by prior administration of excess unlabeled VG76e (P < 0.05); and (c) tumor uptake of the IgG1, [(125)I]-SHPP-CIP5, which has a similar molecular weight as [(125)I]-SHPP-VG76e but does not recognize VEGF, was the same for both HT1080-26.6 and HT1080-1/3C (P > 0.05). Other than tumor localization, [(125)I]-SHPP-VG76e was present in urine and blood and to a lesser extent in heart, lungs, liver, kidney, and spleen. Whole-animal PET imaging studies revealed a high tumor-to-background contrast and also revealed [(124)I]-SHPP-VG76e distributions in the major organs. These studies support further development of [(124)I]-SHPP-VG76e as a radiotracer for measuring tumor levels of VEGF in humans.

Animals↗
PubMed2002

Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma.

BACKGROUND: Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha are essential regulatory proteins for the adaptation of tumor cells to hypoxia, and they stimulate angiogenesis through activation of the vascular endothelial growth factor (VEGF) gene. METHODS: HIF-1alpha and HIF-2alpha proteins were studied immunohistochemically in a group of 81 patients with Stage I endometrial adenocarcinoma of the endometrioid cell type. The results were correlated with intratumoral angiogenesis, the expression of the angiogenic factors VEGF and thymidine phosphorylase (TP), and the VEGF/receptor (VEGF/KDR) complex. Relations also were sought with estrogen receptor (ER) and progesterone receptor (PR), with the apoptosis-related proteins bcl-2 and p53, with several histopathologic parameters, and with patient prognosis. In addition, a sample of 25 normal endometria at various phases of the menstrual cycle was studied for the presence of HIF-1alpha and HIF-2alpha. RESULTS: HIF-1alpha expression was detected in 49% of endometrial carcinomas. The expression was cytoplasmic or mixed nuclear/cytoplasmic. HIF-1alpha expression was associated with up-regulation of the VEGF pathway and with increased standard microvessel density (sMVD) and activated VEGF/KDR microvessel density (aMVD). It also was associated with a poor prognosis in both univariate and multivariate analyses. HIF-2alpha protein showed a pattern of expression similar to the pattern seen in HIF-1alpha, but expression of HIF-2alpha protein occurred in only 17% of endometrial carcinomas, and it was associated with increased TP reactivity. There also was a relation of HIF-1alpha expression with well-differentiated endometrial neoplasms, and there was a marginal association of HIF-1alpha and HIF-2alpha with ER expression. With reference to normally cycling tissues, HIF-1alpha nuclear/cytoplasmic expression was particularly strong in the samples of early proliferative phase endometrium compared with HIF-2alpha protein expression, which showed a constant reaction throughout the menstrual cycle. CONCLUSIONS: The up-regulation of HIF-1alpha and, to a lesser extent, of HIF-2alpha is a common event in Stage I endometrial adenocarcinomas. In these tumors, HIF-1alpha expression is related to increased angiogenesis, through activation of the VEGF angiogenic pathway, and to an unfavorable prognosis. HIF-2alpha accumulation is associated with increased expression of the angiogenic factor TP.

Adenocarcinoma↗
PubMed2002

Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer.

PURPOSE: Hypoxia-inducible factors HIF1alpha and HIF2alpha (HIFalphas) regulate the expression of a variety of genes encoding proteins related to angiogenesis and to anaerobic metabolism of cells exposed to hypoxic stress. Their putative role as markers of clinically relevant hypoxia and, therefore, as predictors of response to chemoradiotherapy is herein examined. PATIENTS AND METHODS: Using immunohistochemistry, we assessed the expression of HIFalphas in normal head-neck mucosa and in 75 cancer specimens from patients with locally advanced squamous cell head-and-neck cancer (SCHNC), treated with concurrent carboplatin chemoradiotherapy. RESULTS: Head-and-neck mucosa from normal individuals did not show any HIF1alpha or HIF2alpha reactivity. SCHNC showed a varying expression of HIFalphas ranging through negative reactivity, to weak or focally strong cytoplasmic reactivity, or to strong diffuse cytoplasmic/nuclear reactivity. Fifty-two percent and 33% of cancer samples showed the latter expression pattern for HIF1alpha and HIF2alpha, respectively, and were considered to bear "high" HIF reactivity. Bone/cartilage involvement was more frequent in tumors with high HIF1alpha expression (p = 0.05). HIF1alpha and HIF2alpha overexpression were significantly associated with high microvessel density (p = 0.002 and 0.02, respectively) and with VEGF expression (p = 0.01 and 0.005, respectively). HIF1alpha was related to high thymidine phosphorylase expression (p = 0.03), whereas VEGF/KDR-activated tumor vasculature was significantly more frequent in HIF2alpha-overexpressing tumors (p = 0.02). High HIF1alpha and HIF2alpha were associated with incomplete response to chemoradiation (p = 0.007 and p = 0.02, respectively). In univariate analysis, high HIF1alpha and HIF2alpha expression were significantly associated with poor local relapse-free survival (p = 0.003 and 0.003, respectively) and with poor overall survival (p = 0.05 and 0.001, respectively). In multivariate models, HIF2alpha expression was an independent prognostic factor. In biopsies performed after the delivery of 20 Gy of radiotherapy, upregulation of HIFalphas was noted in some cases. CONCLUSIONS: It is concluded that the overexpression of HIFalphas in SCHNC is related to locally aggressive behavior, to intensification of angiogenesis, and to an important resistance to carboplatin chemoradiotherapy.

Antineoplastic Agents↗
PubMed2002

Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation.

The von Hippel-Lindau tumor suppressor protein acts as the substrate recognition component of a ubiquitin E3 ligase that targets hypoxia-inducible factor (HIF)-alpha subunits for proteolysis. Stabilization of HIF-alpha subunits has been described in VHL-defective cell lines, leading to HIF activation and up-regulation of hypoxia-inducible mRNAs. Mutations of the von Hippel-Lindau tumor suppressor protein are found in most clear cell renal cell carcinomas (CC-RCCs) but not other renal tumors, raising a question about the importance of activation of the HIF pathway in CC-RCC development. To address this question, we have examined the expression of HIF-alpha subunits in 45 primary renal tumors and related this to tumor subtype, the presence of VHL mutations, and measures of angiogenesis. We show that HIF-alpha is up-regulated in the majority of CC-RCCs, and that the pattern of expression is biased toward the HIF-2alpha isoform. Expression of HIF-alpha proteins was associated significantly with up-regulation of VEGF mRNA and protein and increased microvessel density. Up-regulation of HIF-alpha in CC-RCC was found to involve increased mRNA as well as protein expression, suggesting that both VHL-dependent and VHL-independent mechanisms are involved. These results suggest that activation of the HIF pathway is functionally important in CC-RCC development and might provide a new therapeutic target.

Adenocarcinoma, Clear Cell↗
PubMed2002

Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients.

Hypoxia within head and neck squamous cell carcinoma (HNSCC) predicts a poor response to radiotherapy and poor prognosis. Hypoxia-inducible factor (HIF)-1 and HIF-2 are nuclear transcription factors that regulate the cellular response to hypoxia and are important for solid tumor growth and survival. Overexpression of HIF-1alpha and HIF-2alpha was demonstrated in three HNSCC cell lines under hypoxia and tumor tissue versus normal tissue (n = 20, HIF-1alpha, P = 0.023; HIF-2alpha, P = 0.013). On immunostaining, HIF-1alpha and HIF-2alpha expression were localized to tumor nuclei; HIF-2alpha expression was also seen in tumor-associated macrophages. Expression of HIF-1alpha in surgically treated patients with HNSCC (n = 79) was associated with improved disease-free survival (P = 0.016) and overall survival (P = 0.027).

Adolescent↗
PubMed2002

Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer.

How tumors access and spread via the lymphatics is not understood. Although it is clear that dissemination via the blood system involves hemangiogenesis, it is uncertain whether tumors also induce lymphangiogenesis or simply invade existing peritumoral vessels. To address the issue we quantitated tumor lymph vessels in archival specimens of head and neck cancer by immunostaining for the recently described lymphatic endothelial marker LYVE-1, the vascular endothelial marker CD34, and the pKi67 proliferation marker, correlating lymph vessel density and proliferation index with clinical and pathological variables. Discrete "hotspots" of intratumoral small proliferating lymphatics were observed in all carcinomas, and a high intratumoral lymph vessel density was associated with neck node metastases (n = 23; P = 0.027) and an infiltrating margin of tumor invasion (P = 0.046) in the oropharyngeal subgroup. Quantitation of the lymphangiogenic growth factor vascular endothelial growth factor C by real-time PCR and immunohistochemistry revealed higher levels of mRNA in tumor tissue than in normal samples (n = 8; P = 0.017), but no obvious correlation with intratumoral lymphatics. Our results provide new evidence that proliferating lymphatics can occur in human cancers and may in some cases contribute to lymph node metastasis.

Adolescent↗
PubMed2002

Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer.

Tumor-associated macrophages (TAMs) produce angiogenic factors and in breast cancer are associated with high vascular grade and poor survival. TAMs preferentially migrate to hypoxic areas within tumors and strongly express hypoxia-inducible factor (HIF)-2 alpha. This study examined whether HIF-2 alpha was involved in TAM angiogenic activation by correlating its expression with tumor microvessel density as a marker of angiogenesis, and other tumor variables, in a series of human primary invasive breast carcinomas. A correlation was found between high TAM HIF-2 alpha and high tumor vascularity (P < 0.0001), as well as high tumor grade (P = 0.007). The relation of HIF-2 alpha expression to a recently described oxygen-dependent pathway of angiogenesis was also studied, and an inverse relationship was found between TAM HIF-2 alpha and tumor thymidine phosphorylase expression (P = 0.02). These results suggest that TAM HIF-2 signaling may be a useful target for future antiangiogenic strategies but show that tumors use both oxygen-dependent and oxygen deficiency-regulated pathways for angiogenesis. Thus, combined blockade of pathways and careful assessment of these pathways in trials are necessary.

Adult↗
PubMed2002

Metabolic changes detected by in vivo magnetic resonance studies of HEPA-1 wild-type tumors and tumors deficient in hypoxia-inducible factor-1beta (HIF-1beta): evidence of an anabolic role for the HIF-1 pathway.

Hypoxia-inducible factor-1 (HIF-1) regulates many pathways potentially important for tumor growth, including angiogenesis and glycolysis. Most attention has focused on its role in the response to hypoxia, but HIF-1 is also constitutively expressed in many tumors. To analyze the role of this pathway in vivo, we used magnetic resonance (MR) methods and complementary techniques to monitor metabolic changes in tumors derived from HEPA-1 mouse hepatoma lines that were either wild type (WT) or deficient in hypoxia-inducible transcription factor HIF-1beta (c4). The c4 tumors grew significantly more slowly than the WT tumors (P < 0.05), but were examined at a similar size (0.4-0.6 g). At the tumor size used in these studies, no differences in vascularity were observed, and MR parameters measured that related to tumor blood flow, vascularity, and oxygenation demonstrated no significant differences between the two tumor types. Unexpectedly, the ATP content of the c4 tumor was approximately 5 times less than in the WT tumor [measured in tumor extracts (P < 0.001) and by metabolic imaging (P < 0.05)]. Noninvasive (31)P MR spectroscopy showed that the nucleoside triphosphate/P(i) ratio of the two tumor types was similar, so the low ATP content of the c4 tumors was not caused by (or a cause of) impaired cellular bioenergetics. Rather, glycine, an essential precursor for de novo purine formation, was significantly lower in the c4 tumors (P < 0.05), suggesting that ATP synthesis was impaired in the mutant tumor cells. Supporting evidence for this hypothesis came from the significantly lower concentrations of betaine, phosphocholine, and choline in the c4 tumors (P < 0.05); these are intermediates in an alternative pathway for glycine synthesis. No significant differences were seen in lactate or glucose content. MR resonances from phosphodiesters, which relate to the metabolic turnover of phospholipid membranes, were significantly lower in the WT tumors than in the c4 tumors, both in vivo (P < 0.05) and in extracts (P < 0.01). We propose that loss of up-regulation of expression of the genes for glucose transporters and glycolytic enzymes in the c4 tumors decreased formation of glycine, an essential precursor of ATP synthesis, and thus caused the low ATP content of the c4 tumors. In summary, these data suggest that disruption of the HIF-1 pathway in these tumor cells impairs the supply of anabolic precursors required for cell synthesis. They suggest potential biochemical targets that may be modified by therapy blocking HIF-1 function.

Animals↗
PubMed2002

A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis.

We have investigated the role of HIF-1 in the cellular response to redox modulation via the inhibition of oxidative phosphorylation. We demonstrate that manipulation of redox in air, achieved by inhibiting cytochrome oxidase with cyanide, induces HIF-1 mediated transcription in wild-type CHO and HT1080 human tumour cells but not in CHO cells deficient in the oxygen responsive, HIF-1alpha sub-unit of HIF-1. Hypoglycaemia attenuates cyanide-mediated transcription in non-transformed HIF-1 wild-type CHO cells but not the human tumour derived cell line. Cells lacking either HIF-1alpha, or the second composite sub-unit of HIF-1, HIF-1beta, were markedly more sensitive to the combined stress of perturbed redox and hypoglycaemia than wild-type cells. As such conditions together with hypoxia are prevalent in tumours, these data suggest that HIF-1 may have a protective role in adaptation to the tumour micro-environment. In support of this we demonstrate that HIF-1alpha deficient cells are less tumorigenic than wild-type cells. They showed a reduced growth rate when grown as xenografts in nude mice. This was not related to vascular parameters that were identical to those found in HIF-1 wild-type tumours. The HIF-1 deficient tumours lacked focal expression of Glut-1 in hypoxic tumour regions. Compromised glucose uptake and metabolic adaptation to the tumour micro-environment may form the basis of the reduced tumorigenicity associated with these cells.

Animals↗
PubMed2002

Angiogenic co-operation of VEGF and stromal cell TP in endometrial carcinomas.

Vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) are important angiogenic enzymes, inducing new blood vessel formation in many human malignancies. In this study, the immunohistochemical expression of the two molecules was analysed in a series of 121 endometrial carcinomas. VEGF was expressed exclusively in cancer cells, while TP expression was shown in cancer cells (TPcc) and in stromal cells (TPsc) of both fibroblastic and myometrial origin. In all cases, enzymatic detection was particularly evident at the invading tumour front. At this site, TPsc, but not VEGF, expression was associated with non-endometrioid-type carcinomas, high tumour grade, deep myometrial invasion, and advanced stage. VEGF, but not TP, expression was related to increased angiogenesis (p=0.01). Double stratification of the two factors, however, marked VEGF/TPsc co-expression as the most potent angiogenic phenotype (p=0.008), suggesting a synergistic function. Survival analysis revealed that VEGF and TPsc, whether expressed alone or in combination, define poor prognosis. In multivariate analysis, however, stage of disease (p<0.0001, t-ratio 4.4) and VEGF expression (p=0.01, t-ratio 2.4) were the most important prognostic variables. Furthermore, VEGF expression emerged as the only independent prognostic variable in stage I endometrial carcinomas (p=0.04, t-ratio 1.9). This was not shown for TP, probably because of its close association with histopathological parameters. In conclusion, VEGF is a major angiogenic factor in endometrial carcinomas and an independent prognostic factor in stage I endometrial disease. TP is not an effective contributor to the angiogenic process, but is associated with aggressive histological features. The two factors, when co-expressed, play a co-operative role in the induction of angiogenesis.

Biomarkers, Tumor↗
PubMed2002

Expression of carbonic anhydrase IX in breast is associated with malignant tissues and is related to overexpression of c-erbB2.

CA IX is a tumour-associated carbonic anhydrase with proposed roles in pH modulation and intercellular communication. Its distribution was examined in normal, benign and malignant breast tissues and compared with expression of breast tumour markers including oestrogen receptor, c-erbB2, c-erbB3 and CD44. Tissue specimens were analysed using immunohistochemistry and/or reverse transcriptase-polymerase chain reaction (RT-PCR). CA IX was detected by IHC in 12/26 (46%) malignant tissues, 4/36 (11%) benign lesions, but not in 10 normal breasts. Staining was mostly confined to plasma membranes of abnormal epithelial cells, but in five cases was found in adjacent stroma. Semi-quantitative RT-PCR detected CA9 mRNA in 25/39 (64%) malignant tumours, 11/33 (33%) benign lesions, but in none of three normal breasts. Comparative RT-PCR analysis of malignant tissues revealed a relationship between CA9 positivity and c-erbB2 overexpression (p=0.05). Moreover, CA9-positive specimens displayed a significantly higher median level of c-erbB2 than CA9-negative ones (p=0.02). No significant association was found with the other markers. The results of this study support the possible importance of CA IX for breast carcinogenesis and suggest its potential use as a breast tumour marker.

Adult↗
PubMed2002

Expression of the angiopoietins and their receptor Tie2 in human renal clear cell carcinomas; regulation by the von Hippel-Lindau gene and hypoxia.

Angiogenesis is essential for tumour growth and metastasis, and is co-ordinated by several classes of angiogenic factors. To determine the significance and regulation of the angiopoietin (Ang) pathway in highly vascular human renal cell carcinomas (RCCs), this study has investigated the expression of the Ang-1, Ang-2, Ang-4, and Tie2 genes in a series of normal (n = 26) and neoplastic (n = 45; clear cell n = 35, papillary n = 10) human kidney tissues, examined the pattern of Ang-2 and Tie2 protein expression, and correlated expression with clinicopathological variables. The effect of the von Hippel-Lindau (VHL) gene and hypoxia in the renal cell lines RCC786-0 and RCC4 has also been investigated. Ang-1, Ang-2 and Tie2, but not Ang-4 mRNA, were detected in normal and tumour samples. A significant increase in Ang-2 (p < 0.001) and a decrease in Tie2 receptor mRNA (p = 0.001) were observed, but no significant difference was observed in Ang-1 mRNA abundance between normal kidney and RCC (p = 0.37). Immunohistochemistry for Ang-2 showed strong expression in vascular endothelium and weak expression in tumour cells, whereas Tie2 was expressed exclusively on endothelium. Tie2 gene expression was positively correlated with Ang-2 expression in cancers (p = 0.001) and showed a borderline significant association with Ang-1 (p = 0.06), but there was no significant relationship between Ang-1 and Ang-2 (p = 0.69). No significant relationships were observed in clear cell carcinomas between Ang-1, Ang-2 and Tie2 mRNA abundance and patient sex, patient age, or tumour size (p > 0.05). However, there was significantly greater Ang-1 (p = 0.02), Ang-2 (p = 0.03), and Tie2 (p = 0.04) mRNA abundance in clear cell than in chromophil RCCs. Ang-2 gene expression was down-regulated by hypoxia in VHL wild-type RCC786-0 and RCC4 transfectants (p = 0.0002 and p = 0.04, respectively), mirroring the low expression in human tumour cells. These data suggest that it is endothelial induction of Ang-2 in tumours that regulates vessel stability and supports targeting Tie2 as an effective novel anti-angiogenic therapy in clear cell RCCs.

Adult↗
PubMed2002

Differential gene expression patterns in HER2/neu-positive and -negative breast cancer cell lines and tissues.

Overexpression of the oncogene HER2/neu (c-erbB-2) occurs in up to 30% of breast cancers and is correlated with reduced survival, especially in node-positive disease. The aim of this study was to identify genes associated with the aggressive phenotype of HER2/neu-positive breast cancer cells using cDNA microarrays. RNA was extracted from three HER2/neu-positive and three HER2/neu-negative breast cancer cell lines. Pooled RNA was hybridized in duplicate to the breast specific microarray filters from Research Genetics containing 5184 unique cDNAs. Subsequently, a similar comparison was performed for pooled RNAs from 10 node-positive, ER-positive invasive ductal carcinomas, half of which were HER2/neu overexpressers. In HER2/neu overexpressing breast cancer cell lines, 90 (1.7%) genes were up-regulated and 46 (0.9%) were down-regulated, compared to cell lines with low HER2/neu protein levels. In contrast, in HER2/neu overexpressing primary breast cancers, more genes were down-regulated (N = 132, 2.5%) than up-regulated (N = 19, 0.4%). Many of the differentially expressed genes have previously not been known to play a role in human neoplasia, and some of them may represent novel tumor suppressor or oncogenes. No genes were up-regulated, and only a small number of genes were down-regulated both in cell lines and in carcinomas with high HER2/neu protein levels. These included transforming acidic coiled-coil containing protein 1, glycogen phosphorylase BB, complement 1q and one EST. The differential expression of select genes was confirmed by Northern blotting (trefoil factor 3) or by immunocytochemistry (glycogen phosphorylase BB, vimentin, KAI1). In an extended validation study, 18 of 41 ER-negative, but none of 46 ER-positive, breast carcinomas were found to express vimentin, and all but one of the vimentin-positive tumors were confined to the HER2/neu-negative subgroup (P = 0.0019). Our findings support an important role of the mammary stroma in determining the clinical breast cancer phenotype.

Base Sequence↗
PubMed2002

Angiogenesis in bladder cancer--prognostic marker and target for future therapy.

Angiogenesis is the process by which tumours induce a blood supply, crucial for growth and metastasis. Evidence for its role in bladder carcinogenesis, its usefulness as a marker of patient prognosis, and potential anti-angiogenic therapies for future development are discussed in this chapter.

Angiogenesis Inducing Agents↗
PubMed2002

Drug inhibition of angiogenesis.

Cancer is one of the leading causes of death in the Western world. Though advances in cancer therapy and diagnosis have considerably improved life expectancy, the overall survival rate of patients still remains poor - disseminated cancer at presentation and acquisition of tumour resistance are two reasons for this. Angiogenesis is one of the crucial steps in the pathogenesis of tumours. Drug inhibition of angiogenesis is an area of intense research and at least 10000 cancer patients worldwide have received some form of experimental antiangiogenic therapy. More than 300 angiogenesis inhibitors have been discovered to date; 80 antiangiogenic drugs are currently in clinical trials, 12 of which target the key angiogenic factor vascular endothelial growth factor. A convincing regression of tumours has been reported for drugs against this target. Antiangiogenic therapy has raised the hopes both of cancer sufferers and of the physicians looking after them. A concerted international effort by cancer researchers and the pharmaceutical industry will help to further develop this novel treatment strategy for cancer.

Angiogenesis Inhibitors↗