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author:("ezzell, F")
1.  p53 and bcl-2 expression in high-grade B-cell lymphomas: correlation with survival time. 
British Journal of Cancer  1994;69(2):337-341.
B-cell high-grade lymphomas are heterogeneous in terms of histology, clinical presentation, treatment response and prognosis. As bcl-2 and p53 gene deregulations are frequently involved in several types of lymphoid malignancies, we aimed our investigation at the study of the relation between bcl-2 and p53 expression and survival probability in a group of 119 patients with B-cell high-grade lymphoma. These were obtained from the Virgen de la Salud Hospital, Toledo, Spain (73 cases), John Radcliffe Hospital, Oxford, UK (31 cases), and the Istituto Nazionale dei Tumori, Milan, Italy (15 cases). The relation between bcl-2 protein expression and survival was small, depending on the primary localisation of the tumour (in lymph node of mucosae), and lacked a significant correlation with overall survival. In contrast with this, p53 expression was related to survival probability in our series, this relation being both significant and independent of histological diagnosis. p53-positive patients showed a sudden decrease in life expectancy in the first months after diagnosis. Multivariant regression analysis confirmed that the only parameters significantly related with survival were extranodal origin, which is associated with a better prognosis, and p53 expression, which indicates a poor prognosis. Simultaneous expression of bcl-2 and p53 was associated with a poorer prognosis than p53 alone. This is particularly significant for large B-cell lymphomas presenting in lymph nodes. The cumulative poor effect of both p53 and bcl-2 in large B-cell lymphomas, which is more significant in nodal tumours, could confirm the existence of a multistep genetic deregulation in non-Hodgkin's lymphoma. This indicates that the genetic mechanisms controlling apoptosis and their disregulation are critical steps in the progression of lymphomas.
PMCID: PMC1968699  PMID: 8297731
2.  Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases 
British Journal of Cancer  2011;104(12):1877-1881.
Background:
Anti-angiogenic therapy with bevacizumab (an anti-vascular endothelial growth factor (VEGF) antibody) predominantly targets immature blood vessels. Bevacizumab has shown a survival benefit in non-small cell lung carcinoma (NSCLC) and has recently been demonstrated to be safe in patients with brain metastases. However, it is not known whether bevacizumab is effective against brain metastases or whether metastases are representative of their primary in terms of VEGF expression, hypoxia, proliferation and vascular phenotype. The aim of this study was to evaluate these factors in a series of matched primary NSCLCs and brain metastases.
Methods and Results:
Immunohistochemistry showed strong correlation of carbonic anhydrase 9 expression (a marker of hypoxia) in primary and secondary cancers (P=0.0002). However, the proliferation index, VEGF expression, microvessel density and the proportion of mature vessels were discordant between primary and secondary cancers. The mean proportion of mature vessels was 63.2% higher in the brain metastases than the primary tumours (P=0.004). Moreover, the vascular pattern of the primary tumour was not representative of the metastasis.
Conclusions:
Brain metastases have a significantly higher proportion of mature vasculature, suggesting that they may be refractory to anti-VEGF therapy. These findings may have implications for clinical trials and biomarker studies evaluating anti-angiogenic agents in brain metastases.
doi:10.1038/bjc.2011.147
PMCID: PMC3111192  PMID: 21540863
vascular; angiogenesis; non-small cell lung carcinoma; brain; metastases
3.  Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer 
British Journal of Cancer  2009;101(10):1749-1757.
Background:
Delta-like ligand 4 (Dll4) is a Notch ligand that is upregulated by hypoxia and vascular endothelial growth factor-A (VEGF-A) and is reported to have a role in tumor angiogenesis. Evidence from xenograft studies suggests that inhibiting Dll4–Notch signalling may overcome resistance to anti-VEGF therapy. The aim of this study was to characterise the expression of Dll4 in colon cancer and to assess whether it is associated with markers of hypoxia and prognosis.
Method:
In all, 177 colon cancers were represented in tissue microarrays. Immunohistochemistry was performed using validated antibodies against Dll4, VEGF, hypoxia-inducible factor (HIF)-1α, HIF-2α, prolyl hydroxylase (PHD)1, PHD2, PHD3 and carbonic anhydrase 9 (CA9).
Results:
The expression of Dll4 was observed preferentially in the endothelium of 71% (125 out of 175) of colon cancers, but not in the endothelium adjacent to normal mucosa (none out of 107, P<0.0001). The expression of VEGF was significantly associated with HIF-2α (P<0.0001) and Dll4 (P=0.010). Only HIF-2α had a significant multivariate prognostic effect (hazard ratio 1.61, 95% confidence interval 1.01–2.57). Delta-like ligand 4 was also expressed by neoplastic cells, particularly neoplastic goblet cells.
Conclusion:
Endothelial expression of Dll4 is not a prognostic factor, but is significantly associated with VEGF. Assessing endothelial Dll4 expression may be critical in predicting response to anti-VEGF therapies.
doi:10.1038/sj.bjc.6605368
PMCID: PMC2778546  PMID: 19844231
delta-like ligand 4; colon cancer; hypoxia; angiogenesis; survival
4.  The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy 
British Journal of Cancer  2009;100(2):405-411.
Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1α, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1α, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients.
doi:10.1038/sj.bjc.6604844
PMCID: PMC2634728  PMID: 19165203
breast; hypoxia; carbonic anhydrase; predictive; basal
5.  Prognostic significance of microvessel density and other variables in Japanese and British patients with primary invasive breast cancer 
British Journal of Cancer  2007;97(9):1277-1286.
The purpose of this study is to investigate the associations of microvessel density (MVD) and other pathological variables with survival, and whether they accounted for survival differences between Japanese and British patients. One hundred seventy-three Japanese and 184 British patients were included in the study. British patients were significantly older (56.3±11.4 years vs 52.5±12.9 years; P<0.01) and had smaller tumours (2.2±1.3 vs 2.7±1.8 cm; P<0.01), which were more frequently oestrogen receptor positive (78.8 vs 57.2%, P<0.01), had more grade III tumours (29.9 vs 21.4%, P=0.04) and more infiltrating lobular carcinomas (13.6 vs 4.0%, P<0.01) and a higher MVD compared with Japanese patients (57.9±19.8 vs 53.2±18.6; P=0.01). However, no difference in the prevalence of lymph-node metastasis was found between them (39.1 vs 37.5%, P=0.75). Younger British patients (age <50 years) had the highest MVD compared with Japanese and older British patients (P<0.01). Japanese patients were proportionately more likely to receive chemotherapy than endocrine therapy (P<0.01). British patients had a significantly worse relapse-free survival and overall survival compared with Japanese patients, after statistical adjustment for variables (hazard ratio=2.1, 2.4, P<0.01, P<0.01, respectively), especially, in T2 stage, low MVD and older subgroup (HR: 3.6, 5.0; 3.1, 3.3; 3.2, 3.9, respectively), but only in ER negative cases (P=0.04, P=0.01, respectively). The present study shows that MVD contributes to the Japanese–British disparity in breast cancer. However, the MVD variability did not explain the survival differences between Japanese and British patients.
doi:10.1038/sj.bjc.6604015
PMCID: PMC2360458  PMID: 17923874
angiogenesis; breast cancer; microvessel density; international differences
6.  CD70 (TNFSF7) is expressed at high prevalence in renal cell carcinomas and is rapidly internalised on antibody binding 
British Journal of Cancer  2006;95(3):298-306.
In order to identify potential markers of renal cancer, the plasma membrane protein content of renal cell carcinoma (RCC)-derived cell lines was annotated using a proteomics process. One unusual protein identified at high levels in A498 and 786-O cells was CD70 (TNFSF7), a type II transmembrane receptor normally expressed on a subset of B, T and NK cells, where it plays a costimulatory role in immune cell activation. Immunohistochemical analysis of CD70 expression in multiple carcinoma types demonstrated strong CD70 staining in RCC tissues. Metastatic tissues from eight of 11 patients with clear cell RCC were positive for CD70 expression. Immunocytochemical analysis demonstrated that binding of an anti-CD70 antibody to CD70 endogenously expressed on the surface of A498 and 786-O cell lines resulted in the rapid internalisation of the antibody–receptor complex. Coincubation of the internalising anti-CD70 antibody with a saporin-conjugated secondary antibody before addition to A498 cells resulted in 50% cell killing. These data indicate that CD70 represents a potential target antigen for toxin-conjugated therapeutic antibody treatment of RCC.
doi:10.1038/sj.bjc.6603222
PMCID: PMC2360640  PMID: 16892042
proteomics; renal cell carcinoma (RCC); CD70; antibody; internalisation
7.  Is nonangiogenesis a novel pathway for cancer progression? A study using 3-dimensional tumour reconstructions 
British Journal of Cancer  2006;94(8):1176-1179.
The nonangiogenic lung tumour is characterized by neoplastic cells co-opting the pre-existent vasculature and filling the alveoli space. 3-Dimensional reconstruction of the tumour reveals that this particular tumour progresses without neovascularization and there is no major destruction of the lung's architectural integrity.
doi:10.1038/sj.bjc.6603039
PMCID: PMC2361259  PMID: 16622442
lung cancer; angiogenesis; 3D reconstruction
8.  A quantitative analysis of lymphatic vessels in human breast cancer, based on LYVE-1 immunoreactivity 
British Journal of Cancer  2005;93(10):1168-1174.
This study was undertaken to determine the highly sensitive method for detecting tumour lymphatic vessels in all the fields of each slide (LV), lymphatic microvessel density (LMVD) and lymphatic vessel invasion (LVI) and to compare them with other prognostic parameters using immunohistochemical staining with polyclonal (PCAB) and monoclonal antibodies (MCAB) to the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), and the pan-endothelial marker factorVIII in a series of 67 human breast cancers. In all LYVE-1-stained sections, LV (some of which contained red blood cells) were frequently found localised in extralobular stroma, dermis, connective tissue stroma and adjacent to artery and vein, but were rare within the intralobular stroma or the tumour body (3/67 cases) or areas of widespread invasion. In contrast small blood vessels were observed in intra- and extralobular stroma in the factor VIII-stained sections. Quantitation of vessel numbers revealed that LYVE-1/PCAB detected a significantly larger number of LV than either H&E or LYVE-1/MCAB (P<0.0001). LYVE-1/PCAB detected LVI in 25/67 cases (37.3%) and their presence was significantly associated with both lymph node metastasis (χ2=4.698, P=0.0248) and unfavourable overall survival (OS) (P=0.0453), while not relapse- free survival (RFS) (P=0.2948). LMVD had no influence for RFS and OS (P=0.4879, P=0.1463, respectively). Our study demonstrates that immunohistochemistry with LYVE-1/PCAB is a highly sensitive method for detecting tumour LV/LVI in breast cancer and LVI is a useful prognostic indicator for lymphatic tumour dissemination.
doi:10.1038/sj.bjc.6602844
PMCID: PMC2361506  PMID: 16251871
breast cancer; lymphangiogenesis; lymphatic microvessel density; lymphatic vessel invasion; lymphatic tumour dissemination; LYVE-1
9.  Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression 
British Journal of Cancer  2004;92(1):94-101.
Tumour-associated angiogenesis is partly regulated by the hypoxia-inducible factor (HIF) pathway. Endocrine tumours are highly vascularised and the molecular mechanisms of their angiogenesis are not fully delineated. The aim of this study is to evaluate angiogenesis and expression of HIF-related molecules in a series of patients with pancreatic endocrine tumours (PETs). The expression of vascular endothelial growth factor (VEGF), HIF-1α, HIF-2α and carbonic anhydrase 9 (CA9) was examined by immunohistochemistry in 45 patients with PETs and compared to microvascular density (MVD), endothelial proliferation, tumour stage and survival. Microvascular density was very high in PETs and associated with a low endothelial index of proliferation. Microvascular density was significantly higher in benign PETs than in PETs of uncertain prognosis, well-differentiated and poorly differentiated carcinomas (mean values: 535, 436, 252 and 45 vessels mm−2, respectively, P<0.0001). Well-differentiated tumours had high cytoplasmic VEGF and HIF-1α expression. Poorly differentiated carcinomas were associated with nuclear HIF-1α and membranous CA9 expression. Low MVD (P=0.0001) and membranous CA9 expression (P=0.0004) were associated with a poorer survival. Contrary to other types of cancer, PETs are highly vascularised, but poorly angiogenic tumours. As they progress, VEGF expression is lost and MVD significantly decreases. The regulation of HIF signalling appears to be specific in pancreatic endocrine tumours.
doi:10.1038/sj.bjc.6602245
PMCID: PMC2361752  PMID: 15558070
pancreas; endocrine tumours; angiogenesis; Hypoxia; HIF
10.  Prognostic value of nonangiogenic and angiogenic growth patterns in non-small-cell lung cancer 
British Journal of Cancer  2004;91(7):1293-1300.
doi:10.1038/sj.bjc.6602134
PMCID: PMC2409915  PMID: 15328525
non-small-cell lung cancer; growth pattern; prognosis; angiogenesis; nonangiogenic growth; survival analysis
11.  Prevalence of headache in an elderly population: attack frequency, disability, and use of medication 
OBJECTIVES—To assess the 1 year prevalence of tension-type headache (TTH), migraine headache (MH), and chronic daily headache (CDH), as well as of headache in general in a rural elderly population.
METHODS—A door to door two phase survey was carried out on all elderly (⩾65 years) residents in three villages in central Italy. Participants completed a standardised headache questionnaire and underwent a clinical evaluation by a neurologist. Headache diagnosis was made according to the classification of the International Headache Society, with minor modifications for the classification of patients with MH with⩾15 attacks/month.
RESULTS—Eight hundred and thirty three (72.6%) of the 1147 eligible persons completed the study protocol. One year prevalence rates were respectively 44.5% for TTH, 11.0% for MH, 2.2% for symptomatic headaches, and 0.7% for the remaining types of headache. The prevalence of headache in general was 51.0% because 62 residents had both TTH and MH attacks. Prevalence rates of patients with headache were higher in women than men (62.1% and 36.6% respectively) and decreased steadily with age for the 65-74, 75-84, and 85-96 age groups (56.7%, 45.2% and 26.1% respectively). Prevalence rates were 20.4% for patients with moderate to severe attacks, 18.0% for those with ⩾1 attacks a month, and 4.4% for those with CDH. Of the 425 with headache 52 (12.2%) had not taken any drugs for their attacks in the previous year, 195 (45.9%) had taken them regularly, and 178 (41.9%) had taken them only when the headache pain interfered with activities that could not be postponed. Medication overuse was reported by 37.8% of patients with CDH with higher proportions for transformed migraine than for patients with chronic TTH (69.2% and 23.8% respectively, p=0.009)
CONCLUSIONS—A consistent proportion of elderly people have primary headaches and consultation with a specialist is particularly recommended for patients with moderate or severe attacks, or with CDH.


doi:10.1136/jnnp.70.3.377
PMCID: PMC1737286  PMID: 11181862
12.  Vascular patterns in reactive lymphoid tissue and in non-Hodgkin's lymphoma 
British Journal of Cancer  2003;88(4):553-559.
doi:10.1038/sj.bjc.6600742
PMCID: PMC2377172  PMID: 12592369
lymphoma; lymph node; angiogenesis; vascular regression; vascular phenotype
13.  Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer 
British Journal of Cancer  2003;88(4):537-547.
doi:10.1038/sj.bjc.6600731
PMCID: PMC2377175  PMID: 12592367
fascin; nonsmall cell lung cancer; immunocytochemistry; prognosis; metastasis; angiogenesis
14.  Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas 
British Journal of Cancer  2002;86(2):244-249.
We have previously described a group of non-small cell lung carcinomas without morphological evidence of neo-angiogenesis. In these tumours neoplastic cells fill up the alveoli and the only vessels present appear to belong to the trapped alveolar septa. In the present study we have characterised the phenotype of the vessels present in these non-angiogenic tumours, in normal lung and in angiogenic non-small cell lung carcinomas. The vessels, identified by the expression of CD31, were scored as mature when expressing the epitope LH39 in the basal membrane and as newly formed when expressing αVβ3 on the endothelial cells and/or lacking LH39 expression. In the nine putative non-angiogenic cases examined, the vascular phenotype of all the vessels was the same as that of alveolar vessels in normal lung: LH39 positive and αVβ3 variable or negative. Instead in 104 angiogenic tumours examined, only a minority of vessels (mean 13.1%; range 0–60%) expressed LH39, while αVβ3 (in 45 cases) was strongly expressed on many vessels (mean 55.5%; range 5–90%). We conclude that in putative non-angiogenic tumours the vascular phenotype is that of normal vessels and there is no neo-angiogenesis. This type of cancer may be resistant to some anti-angiogenic therapy and different strategies need to be developed.
British Journal of Cancer (2002) 86, 244–249. DOI: 10.1038/sj/bjc/6600015 www.bjcancer.com
© 2002 The Cancer Research Campaign
doi:10.1038/sj.bjc.6600015
PMCID: PMC2375177  PMID: 11870514
lung cancer; angiogenesis; vascular phenotype
15.  Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival 
British Journal of Cancer  2001;85(6):881-890.
Hypoxia inducible factors HIF1α and HIF2α are important proteins involved in the regulation of the transcription of a variety of genes related to erythropoiesis, glycolysis and angiogenesis. Hypoxic stimulation results in rapid increase of the HIF1α and 2α protein levels, as a consequence of a redox-sensitive stabilization. The HIFαs enter the nucleus, heterodimerize with the HIF1β protein, and bind to DNA at the hypoxia response elements (HREs) of target genes. In this study we evaluated the immunohistochemical expression of these proteins in 108 tissue samples from non-small-cell lung cancer (NSCLC) and in normal lung tissues. Both proteins showed a mixed cytoplasmic/nuclear pattern of expression in cancer cells, tumoural vessels and tumour-infiltrating macrophages, as well as in areas of metaplasia, while normal lung components showed negative or very weak cytoplasmic staining. Positive HIF1α and HIF2α expression was noted in 68/108 (62%) and in 54/108 (50%) of cases respectively. Correlation analysis of HIF2α expression with HIF1α expression showed a significant association (P < 0.0001, r = 0.44). A strong association of the expression of both proteins with the angiogenic factors VEGF (P < 0.004), PD-ECGF (P < 0.003) and bFGF (P < 0.04) was noted. HIF1α correlated with the expression of bek-bFGF receptor expression (P = 0.01), while HIF2α was associated with intense VEGF/KDR-activated vascularization (P = 0.002). HIF2α protein was less frequently expressed in cases with a medium microvessel density (MVD); a high rate of expression was noted in cases with both low and high MVD (P = 0.006). Analysis of overall survival showed that HIF2α expression was related to poor outcome (P = 0.008), even in the group of patients with low MVD (P = 0.009). HIF1α expression was marginally associated with poor prognosis (P = 0.08). In multivariate analysis HIF2α expression was an independent prognostic indicator (P = 0.006, t-ratio 2.7). We conclude that HIF1α and HIF2α overexpression is a common event in NSCLC, which is related to the up-regulation of various angiogenic factors and with poor prognosis. Targeting the HIF pathway may prove of importance in the treatment of NSCLC. © 2001 Cancer Research Campaignhttp://www.bjcancer.com
doi:10.1054/bjoc.2001.2018
PMCID: PMC2375073  PMID: 11556841
non-small-cell lung cancer; hypoxia inducible factors; angiogenesis; prognosis
17.  Relationship of the K-ras/c-mos expression patterns with angiogenesis in non-small cell lung carcinomas. 
Molecular Medicine  2001;7(9):590-597.
BACKGROUND: Neo-angiogenesis is an acquired capability vital for a tumor to grow and metastasize. Evidence has shown that the mitogen-activated protein (MAP) kinase pathway is involved in this process. Alterations of K-ras and c-mos, two pivotal components of this pathway, have been implicated in non-small cell lung carcinogenesis. In the present report, we examine, in a series of non-small cell lung carcinomas (NSCLCs), the status of K-ras and c-mos oncoproteins in correlation with the tumor neo-angiogenesis state and the major angiogenic factor, vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: c-mos and p-ERK1/2 status was evaluated immunohistochemically in a total of 65 NSCLCs, whereas the presence of K-ras mutations was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) restriction fragment length polymorphism (RFLP) in available matched normal tumor material from 56 cases. Microvessel density (MVD) was estimated by immunodetection of CD3, endothelial marker, and VEGF expression was assessed by immunohistochemistry. All possible associations were examined by a series of statistical methods. RESULTS: Expression of oncogenic activated K-ras and c-mos overexpression was observed in 12 of 49 (25%) and in 16 of 61 (26%) informative cases, respectively. Only 1 of the 25 deregulated for K-ras or c-mos cases exhibited both alterations, suggesting a mutually exclusive relationship between activated K-ras and c-mos overexpression (p = 0.074) in a subset of NSCLCs. In these cases, the MAPK kinase kinase/MEK/ERK pathway was found to be activated. MVD and VEGF expression were 36.9 +/- 10.6 mv/mm2 and 73.1 +/- 20.0%, respectively. The most intriguing finding was that the [K-ras(No)/c-mos(P)] profile was significantly associated with low MVD levels compared to normal cases (p = 0.004); by contrast, no correlation was found between the other K-ras/c-mos patterns and MVD. Furthermore, the former group exhibited the lowest VEGF levels. CONCLUSIONS: The mutually exclusive relationship between mutated K-ras and c-mos overexpression in a subset of NSCLCs implies a common signal transduction pathway in lung carcinogenesis. The effect of this pathway on NSCLC neo-angiogenesis seems to depend upon the status of c-mos, which acts as a molecular "switch," possibly exerting a negative selective pressure on tumor progression.
PMCID: PMC1950074  PMID: 11778648
18.  Angiogenesis in myelodysplastic syndromes 
British Journal of Cancer  1999;81(8):1398-1401.
It is now well established that solid tumour growth depends on angiogenesis. However, less is known about the generation of new vessels in haematological malignancies and, in particular, in preleukaemic-myelodysplastic syndromes (MDS). In this study, bone marrow microvessel density (MVD) was assessed by immunohistochemistry and compared in trephine biopsies from 14 controls, five infectious disease (ID), 82 MDS, 15 acute myeloid leukaemia (AML) and 14 myeloproliferative disorder (MPD) patients. Statistical analysis (P < 0.001) demonstrated that MDS MVD was higher than in controls and ID (21 ± 9 vs 6 ± 2 and 10 ± 8 respectively) but lower than AML (30 ± 12) and MPD (40 ± 12). Among MDS-FAB subtypes, MVD was significantly higher in RAEB-t, CMML and fibrosis subsets compared to RA, RARS and RAEB subsets (P = 0.008). To further investigate angiogenesis machinery, the expression of vascular endothelial growth factor (VEGF) was evaluated by means of immunohistochemistry in control, MDS, AML and MPD biopsies. Even though VEGF mRNA expression was reported in the past in AML cell cultures and cell lines, in our samples VEGF expression was found to be particularly strong in most of the megakaryocytes but significantly less prominent in other cell populations including blasts. Since our findings suggest a correlation between angiogenesis and progression to leukaemia, additional work is now warranted to determine what regulates the generation of new vessels in MDS and leukaemia. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6693515
PMCID: PMC2362976  PMID: 10604739
myelodysplasia; angiogenesis; leukaemia; VEGF
19.  Antibody for detecting p53 protein by immunohistochemistry in normal tissues. 
Journal of Clinical Pathology  1994;47(7):592-596.
AIMS--To establish whether PAb248 recognises human p53 as well as murine p53 and if so, to determine its distribution in normal tissues. METHODS--The ability of PAb248 to recognise human p53 was established by analysis of the human osteosarcoma derived Saos-2 cell line, which lacks the p53 gene, before and after transfection with p53 cDNA, using western blotting and immunoprecipitation. Immunostaining on normal tissues and cell lines was carried out using an immunoperoxidase technique. The two anti-p53 antibodies PAb 240 and DO-7 were used as controls. RESULTS--The anti-p53 PAb248 monoclonal antibody stained the Saos-2 cell line after, but not before, transfection with p53 cDNA. Both western blots and immunoprecipitations performed with this antibody revealed a 53,000 molecular weight band. With immunostaining, this antibody detects p53 protein in most lymphoid and human epithelial cells in a cytoplasmic-perinuclear localisation that has not been described before. In the same tissues nuclear staining could be seen in a few scattered cells using the PAb240 antibody. The topographical distribution of wild type p53 was not related to proliferating areas but, rather, to short-lived populations of cells. CONCLUSIONS--Immunostaining of wild type p53 is demonstrable not only in its nuclear form using antibody PAb240 but also in it common cytoplasmic-perinuclear localisation in normal tissues using the PAb248 monoclonal antibody. This opens up new possibilities for its study in both physiological and pathological conditions.
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PMCID: PMC502069  PMID: 8089212
20.  Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer. 
British Journal of Cancer  1996;73(2):148-153.
Presentation of endogenous antigenic peptides to cytotoxic T lymphocytes is mediated by the major histocompatibility complex (MHC) class I molecules. For the stable assembly of MHC class I complex it is necessary that the antigenic peptide is transported by the MHC-encoded transporters TAP-1 and TAP-2 into a pre-Golgi region. T-cell-mediated host-vs-tumour response might therefore depend on the presence of these molecules on tumour cells. The presence of MHC class I antigens and TAP-1 was studied in a series of 93 resection specimens of non-small-cell lung carcinomas (NSCLCs) by immunohistochemical methods using antibodies against the assembled class I molecule, beta 2-microglobulin (beta 2-m), heavy-chain A locus, A2 allele and TAP-1 protein. Eighty-six patients were included in the survival analysis. Total loss of class I molecule was observed in 38% of the cases and was usually accompanied by loss of beta 2-m and of heavy chain A locus. Selective loss of A locus was seen in 8.3% and of A2 allele in 27% of the cases. TAP-1 loss was always combined with beta 2-m and/or heavy chain A locus loss. No correlation was found between the expressional status of any of the above molecules, including the selective A2 allelic loss and histological type, degree of differentiation, tumoral stage, nodal stage and survival. Our findings suggest that loss of antigen-presenting molecules (including both MHC class I alleles and TAP-1) is a frequent event in lung cancer. However, the immunophenotypic profile of MHC class I and TAP-1 seems to be unrelated in vivo to the phenotype, growth or survival of NSCLC.
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PMCID: PMC2074307  PMID: 8546899
21.  bcl-2 in normal human breast and carcinoma, association with oestrogen receptor-positive, epidermal growth factor receptor-negative tumours and in situ cancer. 
British Journal of Cancer  1994;69(1):135-139.
The role of bcl-2 expression in solid tumours is as yet undefined. It was, therefore, the purpose of this study to investigate expression of bcl-2 protein in 111 human breast carcinomas using immunohistochemistry and the monoclonal antibody bcl-2 124. Expression was then compared with the established indicators of prognosis and biological behaviour in malignant breast disease. No relationship could be observed between bcl-2 and node status, tumour size, differentiation, type or age at excision. However, a strong positive relationship was seen between bcl-2 and oestrogen receptor (ER), with 70 of 88 (80%) bcl-2-positive tumours being ER positive also, compared with seven of 23 (30%) bcl-2-negative tumours being ER positive (P < 0.0001). The converse was found when bcl-2 was compared with epidermal growth factor receptor (EGFR). A strong negative relationship was observed, with 26 of 88 (30%) bcl-2-positive tumours being EGFR positive, compared with 16 of 23 (70%) bcl-2-negative tumours being EGFR positive (P = 0.001), raising the possibility that bcl-2 is an ER-regulated gene. An inverse relationship was also found between bcl-2 and the oncogenes c-erbB-2 and p53. Thus, loss of bcl-2 expression in breast cancer is associated with a range of molecular markers of poor prognosis and may define part of an ER-negative, EGFR-positive phenotype.
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PMCID: PMC1968762  PMID: 8286195
22.  Evaluation of bcl-2 protein expression and 14;18 translocation as prognostic markers in follicular lymphoma. 
British Journal of Cancer  1992;65(1):87-89.
Conflicting results have been published on the prognostic significance of t(14;18) in follicular lymphoma: Yunis et al. (1989) reported that its presence indicated poor response to therapy and short survival, whereas Levine et al. (1988) showed no difference in prognosis between cases with and without the translocation. However these results were based on small series of cases and on follow-up periods (no longer than 7 years) which are relatively short for a disease with such a slow clinical evolution. Here we report an investigation of 70 cases of follicular lymphoma with long term follow-up data (up to 17 years). This series has been studied for the presence of the 14;18 translocation and for the expression of bcl-2 protein. Our results show that there are no grounds for considering either the 14;18 translocation or the expression of the bcl-2 protein to be useful prognostic markers in clinical practice.
PMCID: PMC1977367  PMID: 1733447

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