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Nicholas Coleman

Publications and source records attributed to Nicholas Coleman.

At least 37 records · Page 2Linked to original sources
PubMed2004

Minichromosome maintenance protein in myxofibrosarcoma.

Histopathological assessment of myxofibrosarcoma may be difficult, especially on the basis of a small core biopsy, which enables only a crude evaluation of grade and prognosis. We have tested the hypothesis that determination of cell cycle state may assist in the diagnostic assessment of myxofibrosarcoma. We have studied 51 cases of high-grade (n=20), intermediate-grade (n=21), and low-grade (n=10) myxofibrosarcomas, as well as nine cases of benign myxoma. Cell cycle state within tumors was determined by immunostaining for the recently described marker minichromosome maintenance protein 2 (MCM2), together with Ki67. Labelling indices for both markers were correlated with tumor grade, mitotic index, and time to first recurrence. The MCM2 labelling indices were significantly higher than the Ki-67 labelling indices. Both indices showed a significant correlation with the mitotic index and both showed significant increases with increasing grade of myxofibrosarcoma. The MCM2 labelling index (but not the Ki67 labelling index) showed a significant inverse exponential correlation with the time to first recurrence. Myxoid and cellular areas showed no difference in the MCM2 and Ki-67 labeling index, suggesting that clinically useful information could be obtained from any component of a myxofibrosarcoma sampled in a needle biopsy and/or cytological specimen. We therefore suggest that assessment of cell cycle state may be a useful diagnostic adjunct in the histopathological assessment of myxofibrosarcoma, by enabling more accurate determination of grade and prediction of outcome.

Adult↗
PubMed2004

In vitro acid exposure has a differential effect on apoptotic and proliferative pathways in a Barrett's adenocarcinoma cell line.

INTRODUCTION: Acid, a principal component of refluxate, may contribute to the neoplastic progression of Barrett's esophagus. Brief acid exposure in vivo and in vitro has been shown to increase cell proliferation. The mechanisms underlying the hyperproliferative response are not well elucidated but may include alterations in Na(+)-H+ exchanger activity and MAPK signaling pathways. OBJECTIVE: To ascertain the effects of pulsatile acid exposure on gene expression in a Barrett's adenocarcinoma cell line (SEG-1). METHODS: SEG-1 cells were exposed to either acidified DMEM at pH 3.5 (0.1 M hydrochloric acid) or pH 7.4 (control) for 20 min followed by neutralization of the medium. Total RNA was extracted before acid exposure and over a 10-h time course (0.5, 2, 4, 6, 8, and 10 hours) and hybridized to Affymetrix human U133A oligonucleotide arrays. Data were analyzed using the Affymetrix statistical expression algorithms. Only alterations in gene expression that were > or = 2 and < or = -2 fold were studied further and a subset was further investigated by reverse transcription polymerase chain reaction (RT-PCR) and densitometry. Apoptosis was assayed in SEG-1 cells by western blot for cleaved caspase 3 and an apoptosis ELISA assay. RESULTS: Changes in expression were identified for 138 genes. Analysis of gene function identified immediate downregulation of genes associated with apoptosis and early upregulation of genes associated with proliferation. The gene expression profiles suggest that MAPK pathways may be involved and suppression of apoptosis may occur via p53-dependent mechanisms. CONCLUSIONS: Microarray analysis of gene expression changes in a Barrett's adenocarcinoma cell line has identified cellular pathways that may be disrupted following acid exposure.

Adenocarcinoma↗
PubMed2003

Minichromosome maintenance protein 2 is a strong independent prognostic marker in breast cancer.

PURPOSE: To test the hypothesis that prognostic information in breast cancer may be derived from an accurate assessment of epithelial cell cycle entry, as indicated by expression of minichromosome maintenance (MCM) proteins. MATERIALS AND METHODS: We used immunohistochemistry to examine the distribution of Mcm-2 in breast tissue. Power calculations based on a pilot study of 67 whole tissue sections led to selection of an independent 347-core breast carcinoma tissue microarray validation set. We tested for associations between Mcm-2 (and Ki-67) labeling index (LI) and various clinicopathologic parameters. RESULTS: Mcm-2 was expressed more frequently than the standard proliferation marker Ki-67 in whole tissue sections of normal breast (P =.0003) and breast carcinoma (P <.0001). In 221 assessable cores of invasive carcinoma, the Mcm-2 LI showed a positive association with tumor size (P =.002), mitotic index (P <.0001), histologic grade (P <.0001), and the Nottingham Prognostic Index (NPI) score (P <.0001). Using a cutoff value of 50%, Mcm-2 LI was associated with overall survival (P =.0007), disease-free interval (P =.0002), and with the development of regional recurrence (P =.011) and distant metastases (P =.0016). Cox regression analysis suggested that the Mcm-2 LI is a strong prognostic factor in breast cancer that is independent and superior to histologic grade, lymph node stage, and Ki-67 LI, but not the NPI score. CONCLUSION: Mcm-2 may be of utility as a prognostic marker to refine the prediction of outcome in breast cancer, for example when combined with parameters currently used in the NPI.

Adult↗
PubMed2003

Vaccinia-expressed human papillomavirus 16 and 18 e6 and e7 as a therapeutic vaccination for vulval and vaginal intraepithelial neoplasia.

PURPOSE: Anogenital intraepithelial neoplasia is a chronic disorder associated with infection by high-risk human papillomavirus (HPV) types. It is frequently multifocal and recurrence after conventional treatment is high. Boosting HPV-specific cell-mediated immune responses may reduce progression to carcinoma and could lead to disease clearance. We have tested the safety, immunogenicity, and efficacy of a recombinant vaccinia candidate vaccine (TA-HPV) in women with anogenital intraepithelial neoplasia. EXPERIMENTAL DESIGN: Twelve women, aged 42-54 years with high-grade HPV-positive vulval or vaginal intraepithelial neoplasia of up to 15 years duration, completed a Phase II study of TA-HPV, a live recombinant vaccinia virus, expressing modified versions of the E6 and E7 open reading frames from HPV-16 and HPV-18. RESULTS: The vaccine was well tolerated. Five of 12 (42%) patients showed at least a 50% reduction in total lesion diameter over 24 weeks with 1 patient showing complete regression of her lesion. Overall, 83% of women showed some improvement with an average decrease in lesion size of 40%. All cases showed an increased IgG titer and T-cell response to the vaccinia virus. An IFN-gamma enzyme-linked immunospot assay using pooled 22-mer peptides spanning HPV-16 E6 and E7 showed an increased specific T-cell response after vaccination in 6 of the 10 cases available for testing. There was no increase in specific cytotoxic response to selected individual HLA class I-restricted HPV-16 E6/7 peptides. CONCLUSIONS: The results suggest that the vaccine may have an effect on HPV-positive vulval intraepithelial neoplasia/vaginal intraepithelial neoplasia and that additional studies are warranted to develop an effective therapeutic vaccine.

Adolescent↗
PubMed2003

FUS/ERG gene fusions in Ewing's tumors.

Ewing's tumors are rare pediatric neoplasms that are characterized by specific chromosomal translocations and gene rearrangements. All of the fusion genes reported to date in Ewing's tumors juxtapose the EWS gene at 22q12 to an ETS-related gene, the most common of which are FLI1 at 11q24 and ERG at 21q22. We present here four cases of Ewing's tumor, which showed no evidence of a EWS gene rearrangement, but instead contained translocations involving 16p11 and 21q22. A rearrangement involving the same chromosome bands, t(16;21)(p11;q22), is found in rare cases of acute myeloid leukemia and fuses the FUS gene at 16p11 to the ERG gene at 21q22. In two of our Ewing's tumor cases, we were able to show at the sequence level that the translocation between chromosomes 16 and 21 similarly results in a FUS/ERG fusion. In one case, exons 1-5 and most of exon 6 of FUS were fused in-frame to exon 9 of ERG; in the other case, FUS exons 1-7 were fused in-frame to ERG exons 8-9. The functional fusion transcript is expected to be expressed from the der(21)t(16;21) derivative. In the two other t(16;21)-positive Ewing's cases, we performed bacterial artificial chromosome fluorescence in situ hybridization analysis on metaphases and interphase nuclei to demonstrate colocalization of bacterial artificial chromosomes containing FUS and ERG genes, also highly suggestive of fusion gene formation. These represent the first four cases where FUS, rather than EWS, is rearranged with an ETS-family transcription factor in Ewing's tumors. Our data provide additional evidence that the transactivation domains of the TET family of RNA-binding proteins (such as EWS and FUS) are interchangeable, and suggests a novel mechanism of oncogenesis in Ewing's tumors.

Adolescent↗
PubMed2003

A novel immunohistochemical method to estimate cell-cycle phase distribution in archival tissue: implications for the prediction of outcome in colorectal cancer.

An immunohistochemical method for assessing cell-cycle phase distribution in colorectal resection specimens would enable phase data to be incorporated into diagnostic algorithms for the estimation of prognosis and response to adjuvant chemotherapy in colorectal cancer. In contrast to flow cytometry, an immunohistochemical method would also allow the phase distribution to be examined within morphologically heterogeneous regions of neoplasms. Paraffin sections of normal colon (n = 25), colonic adenoma (n = 15), and colonic adenocarcinoma (n = 30) were analysed by immunohistochemistry using antibodies against markers of cell-cycle entry, Mcm-2 and Ki67, and putative markers of the cell-cycle phase, cyclins D1 and E (putative markers of G1 phase), cyclin A (S phase), cytoplasmic cyclin B1 (G2 phase), and phosphohistone H3 (M phase). The phase specificity of each marker was assessed by examining the degree of co-expression of adjacent phase markers using double-antibody fluorescence confocal microscopy and by comparison with flow cytometric analysis performed on adjacent tissue sections. The S-phase specificity of detectable cyclin A was also assessed in combination with in situ DNA replication using fluorescence confocal microscopy. All cells expressing phase markers co-expressed Mcm-2. Adjacent phase markers were not significantly co-expressed, confirming the relative specificity of these markers in tissue sections of colon. Cell-cycle phase distribution, calculated by immunohistochemistry, compared well with phase analyses obtained by flow cytometry. No cells expressed cyclin A in the absence of active DNA replication. The S-phase labelling index, as defined by detectable cyclin A expression, showed a positive correlation with the Mcm-2 labelling index and increased in the progression from normal colon to adenocarcinoma. In conclusion, a combination of these cell-cycle phase markers can be used to calculate the distribution of cells throughout each phase of the cell cycle in colorectal tissue sections. Detectable cyclin A can be used as a surrogate marker of S phase and may be of value in predicting prognosis and response to adjuvant therapy.

Adenocarcinoma↗
PubMed2003

Transplacental transmission of HIV: a potential role for HIV binding lectins.

Although the majority of vertical transmission of HIV occurs around the time of birth, 1.5-2% of pregnancies in HIV-positive women appear to result in the vertical transmission of HIV across the placenta. HIV infection of a number of placental cell types has been demonstrated, but the exact mechanisms of intrauterine vertical transmission remain obscure. The recent discovery of the HIV binding lectins dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN) and DC-SIGN-related molecule (DC-SIGNR) provides one possible explanation. Cells expressing these lectins are able to adsorb the virus and mediate high efficiency HIV infection of other cell types. Both lectins are expressed by the placenta, with DC-SIGN expression also being present on maternal cells intimately associated with the placenta. This review focuses on possible mechanisms by which these lectins may potentiate the intrauterine vertical transmission of HIV.

Animals↗
PubMed2003

Translational approaches to improving cervical screening.

Screening programmes for cervical cancer using the current test--the Pap smear--have markedly reduced the incidence of the disease. However, an individual Pap test is of limited sensitivity and is difficult and expensive to perform. Increased understanding of the molecular pathogenesis of cervical cancer indicates that new approaches to screening might offer increased accuracy, affordability and the potential for automation. Such approaches exemplify how improved understanding of the biology of neoplasia might be translated into clinical benefit.

Acetic Acid↗
PubMed2003

Structural genomic abnormalities of chromosomes 9 and 18 in myxopapillary ependymomas.

Myxopapillary ependymomas (MPEs) are low-grade neuroepithelial tumors typically occurring in the conus-cauda equina-filum terminale region. Limited molecular and cytogenetic analysis of MPEs has not demonstrated consistent abnormalities. In an attempt to clarify the chromosomal status of these tumors and identify commonly aberrant regions in the genome we have combined 3 molecular/cyto/genetic methods to study 17 MPEs. Comparative genomic hybridization of 7/17 tumors identified concurrent gain on chromosomes 9 and 18 as the most frequent finding. The majority of the 17 tumors were also studied using microsatellite analysis with marker spanning the whole chromosomes 9 and 18 and interphase-FISH with centromeric probes for both chromosomes. Our combined results were consistent with concurrent gain in both chromosomes 9 and 18 in 11/17 cases, gain of either chromosome 9 or 18 and imbalance in the other chromosome in 3/17 tumors and allelic imbalances of chromosomes 9 or 18 in 3/17 and 1/17 tumors, respectively. Other abnormalities observed included gain of chromosomes 3, 4, 7, 8, 11, 13, 17q, 20, and X and loss of chromosomes 10 and 22. Our findings represent some steps towards understanding the molecular mechanisms involved in the development of MPE.

Adolescent↗
PubMed2003

Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers.

The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.

Biomarkers↗
PubMed2003

Myxofibrosarcomas contain large numbers of infiltrating immature dendritic cells.

Myxofibrosarcoma is a malignant tumor with distinctive histologic features and is believed to be derived from fibroblasts. The function of infiltrating myeloid cells in myxofibrosarcoma is poorly understood. It previously has been shown that a combination of dendritic morphologic features and expression of the C-type lectin, dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN), is useful for identifying DC populations in tissue sections. In the present study, we found that 3% to 61% (median, 22%) of cells in myxofibrosarcomas express DC-SIGN and have dendritic morphologic features. These DC-SIGN--positive cells are not in cell cycle and are consistent with infiltrating DCs. The percentage of DCs in myxofibrosarcomas is independent of tumor grade. It previously has been shown that DC-SIGN--positive cells are either immature DCs or DCs that predominantly activate TH2 cells, both subsets likely to give rise to ineffective antitumor responses. The DC-SIGN--positive DCs that we have identified in myxofibrosarcoma may, therefore, be involved in the induction of ineffective immune responses or even tolerance to tumor antigens.

Biomarkers, Tumor↗
PubMed2003

Surface expression of minichromosome maintenance proteins provides a novel method for detecting patients at risk for developing adenocarcinoma in Barrett's esophagus.

PURPOSE: The purpose is to determine whether a novel cell cycle marker, minichromosome maintenance protein 2 (Mcm2), predicted esophageal adenocarcinoma (AC) risk in Barrett's esophagus (BE) and whether this could be used in combination with a surface sampling method. EXPERIMENTAL DESIGN: Archival specimens [30 normal squamous esophagus (NE), 20 gastric antrum (GA), 13 duodenum (D2), 62 BE +/- dysplasia, and 16 (AC)] were stained for Mcm2. Sequential biopsies from nine patients who developed AC during surveillance were compared with 18 matched controls who did not progress. Prospective endoscopic cytological brushings (61 NE, 90 BE +/- dysplasia, and 11 AC) were scored as Mcm2 positive or negative. RESULTS: Mcm2 was not expressed on the luminal surface of NE, GA, and D2. In BE, the percentage of surface cells expressing Mcm2 correlated highly with the degree of dysplasia (P < 0.0001). In patients who developed AC, biopsies before dysplasia had higher Mcm2 expression than the matched control patients (mean, 28.4 and 3.4% positive cells, respectively, P < 0.0001). In the prospective cohort, the histopathological diagnosis of dysplasia or AC and the Mcm2-positive brushings were concordant in 91% of the patients (P < 0.005), and the results correlated with the frequency of cases with surface expression of Mcm2 in the retrospective study (P < 0.0001). CONCLUSIONS: Surface expression of Mcm2 can be used to detect dysplasia and AC, as well as patients with BE at risk for subsequent development of dysplasia and AC. A brushing technique combined with Mcm2 staining has the potential to be exploited in surveillance and screening protocols.

Adenocarcinoma↗
PubMed2002

Changes in cervical keratinocyte gene expression associated with integration of human papillomavirus 16.

Episomal integration is a critical event in human papillomavirus (HPV)-related oncogenesis, although little information is currently available concerning the effect of integration on the host transcriptome. We have used expression microarrays to investigate the effect of integration of HPV16 on gene expression in cervical keratinocytes, using the unique cell line model W12. W12 was generated from a cervical low-grade squamous intraepithelial lesion "naturally" infected with HPV16 and at low passage contains approximately 100 HPV16 episomes/cell. With passage in vitro, integration of viral episomes is associated with the development of phenotypic and genomic abnormalities resembling those seen in cervical neoplastic progression in vivo. We have used the Affymetrix U95A oligonucleotide array that contains probes for 12,600 human transcripts and have identified 85 genes from a range of host cell pathways that show changes in expression levels after integration of HPV16. Whereas some of the genes have previously been implicated in HPV-related oncogenesis in vivo, we have also identified a range of genes not previously described as being involved in cervical neoplastic progression. Interestingly, integration is associated with up-regulation of numerous IFN-responsive genes, in comparison with a baseline of episomally infected cells. These genes include p48, a component of the primary regulator of the IFN response pathway, IFN-stimulated gene factor 3. The physical state of high-risk HPV may substantially influence the response to IFN in infected keratinocytes.

Blotting, Southern↗
PubMed2002

Analysis of minichromosome maintenance proteins as a novel method for detection of colorectal cancer in stool.

Colorectal cancer is a common disease, and more reliable screening methods are needed for early detection. We aim to develop a non-invasive, stool-based assay that can identify colorectal cancer by detection of minichromosome maintenance protein 2 (MCM2) expression in colonocytes retrieved from the faecal surface. We devised a cell line model to investigate methods and conditions for optimum colonocyte retrieval. In our clinical evaluation study, MCM2-positive cells were retrieved from 37 of 40 patients with symptomatic colorectal cancer, but from none of 25 healthy control individuals. These results suggest that immunocytochemical analysis of retrieved colonocytes might enable accurate detection of colorectal cancer in stool.

Adenocarcinoma↗
PubMed2002

Expression of human immunodeficiency virus (HIV)-binding lectin DC-SIGNR: Consequences for HIV infection and immunity.

DC-SIGNR is a human immunodeficiency virus (HIV)-binding C-type lectin that is expressed on endothelium in the hepatic sinusoids, lymph node sinuses and placenta. Like closely related DC-SIGN, DC-SIGNR can bind both ICAM-3 and HIV and can potentiate HIV infection of T lymphocytes in trans. In the present study we have investigated reasons underlying the restricted distribution of DC-SIGNR and have examined DC-SIGNR expression in relation to HIV entry receptors. We show that DC-SIGNR expression does not depend on endothelial cell specialization or on activation state. DC-SIGNR-positive endothelium continues to express DC-SIGNR in conditions of hyperplasia, whereas the molecule is lost after neoplastic transformation, most likely as a result of changes in the microenvironment of the endothelial cells. We have further shown that CCR5, but not CD4, is coexpressed with DC-SIGNR on hepatic sinusoidal and placental capillary endothelial cells. However, CD4-positive CCR5-positive cells, such as hepatic Kupffer cells, placental Hofbauer cells, and CD4-positive T lymphocytes in lymph nodes, can be found adjacent to DC-SIGNR-positive endothelium. Therefore, DC-SIGNR may be able to mediate HIV infection of these cells in trans. Finally, we demonstrate that DC-SIGN and DC-SIGNR can be coexpressed on lymph node sinus endothelial cells, which may lead to modulation of the function of both molecules.

Animals↗
PubMed2002

Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro.

DC-SIGN is a C-type lectin, highly expressed on the surface of immature dendritic cells (DCs), that mediates efficient infection of T cells in trans by its ability to bind HIV-1, HIV-2, and SIV. In addition, the ability of DC-SIGN to bind adhesion molecules on surfaces of naïve T cells and endothelium also suggests its involvement in T-cell activation and DC trafficking. To gain further insights into the range of expression and potential functions of DC-SIGN, we performed a detailed analysis of DC-SIGN expression in adult and fetal tissues and also analyzed its regulated expression on cultured DCs and macrophages. First, we show that DC-SIGN expression is restricted to subsets of immature DCs in tissues and on specialized macrophages in the placenta and lung. There were no overt differences between DC-SIGN expression in adult and fetal tissues except that DC-SIGN expression in alveolar macrophages was only present after birth. Similarly, in tissues, DC-SIGN was observed primarily on immature (CD83-negative) DCs. Secondly, in the peripheral blood, we found expression of DC-SIGN on a small subset of BDCA-2+ plasmacytoid DC precursors (pDC2), concordant with our finding of large numbers of DC-SIGN-positive cells in allergic nasal polyps (previously shown to be infiltrated by DC2). Triple-label confocal microscopy indicated that DC-SIGN was colocalized with BDCA-2 and CD123 on DCs in nasal polyp tissue. Consistent with this finding is our observation that DC-SIGN can be up-regulated on monocyte-derived macrophages upon exposure to the Th2 cytokine, IL-13. In summary, our data demonstrate the relevant populations of DC and macrophages that express DC-SIGN in vivo where it may impact the efficiency of virus infection and indicate that DC-SIGN expression may be involved in the Th2 axis of immunity.

Adult↗
PubMed2002

Minichromosome maintenance protein 2 expression in normal kidney and renal cell carcinomas: relationship to tumor dormancy and potential clinical utility.

PURPOSE: A major problem in the management of patients with renal cell carcinoma is predicting tumor behavior. In the search for more accurate markers of prognosis, tumor cell proliferation has been investigated. These studies have mostly used antibodies directed against Ki-67 or proliferating cell nuclear antigen and have given conflicting results, findings that are likely because of a combination of specificity and methodological differences. Minichromosome maintenance (Mcm) proteins are a series of closely related proteins that are components of the prereplicative complex. The Mcm proteins are essential for initiating eukaryotic DNA replication and serve as useful markers of proliferating cells. EXPERIMENTAL DESIGN: The aims of this study were to determine the frequency and pattern of Mcm2 expression by immunohistochemistry in normal kidney (n = 10) and renal tumors [n = 56; clear cell n = 36; chromophil (papillary) n = 7; oncocytoma n = 5; and transitional cell carcinoma n = 8], compare its sensitivity to the established proliferation marker Ki-67, examine for differences in tumors derived from stable and labile epithelial cell populations in the kidney, and assess the relationship of Mcm2 proliferation to clinicopathological characteristics of kidney tumors. In addition, to additionally investigate the issue of tumor dormancy we wished to assess the relationship between Mcm2 labeling index (LI) and the angiogenic factors angiopoietin-1 (Ang) and Ang-2. RESULTS: In normal tissues, Mcm2 nuclear labeling was identified in both glomeruli (LI median 0.35%; range 0-1.7) and renal tubules (LI median 0.3%; range 0.1-2.9%). In tumors Mcm2 labeling was predominantly at the periphery with LIs ranging from 0.2-91.5%, which was significantly greater than Ki-67 LI (0.2-40.5%; P < 0.001). Mcm2 LI was also significantly higher in tumors derived from a labile epithelium (transitional cell carcinomas) than a stable epithelium (renal cell carcinomas; P = 0.013). A significant association was also demonstrated between Mcm2 LI and tumor grade (P = 0.0006), and angiogenic phenotype (defined by Ang expression; P = 0.03) but not with patient age (P = 0.84), patient sex (P = 0.25), tumor size (P = 0.74), or stage (P = 0.33). Furthermore, although not significant, a survival analysis demonstrated that 100% of patients with a low Mcm2 LI survived compared with 84% of those with a high Mcm2 LI over the follow-up period (up to 53.2 months; P = 0.14). CONCLUSIONS: This is the first study examining Mcm2 protein in normal and tumor kidney samples, and the first to perform histological subgroup analysis. It shows that Mcm2 is a superior marker to Ki-67 in the assessment of cell cycle entry in histological archival material and that normal kidney has a subset of cells within the glomerular and tubular compartments that are in cycle. It demonstrates that the frequency of cells in cycle in tumors formed from stable or labile epithelial populations mirrors that in the nonneoplastic epithelium. This study additionally demonstrates that the number of cells in cycle in tumors is limited by the angiogenic phenotype and supports animal models that show angiogenesis determines the likelihood of tumor dormancy. Additional study to confirm the clinical utility of Mcm2 as a prognostic marker is now indicated.

Adult↗