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Breast Cancer Research update, jul 3

Written by admin on Jul 6th, 2008 | Filed under: oncology UPDATE

Risk prediction models with incomplete data with application to prediction of estrogen receptor positive breast cancer: prospective data from the Nurses’ Health Study

from Breast Cancer Research by Bernard Rosner, Graham A. Colditz, J. Dirk Iglehart and Susan E. Hankinson
IntroductionA number of breast cancer risk prediction models have been developed to provide insight into a woman’s individual breast cancer risk. Although circulating levels of estradiol in postmenopausal women predict subsequent breast cancer risk, whether the addition of estradiol levels adds significantly to a model’s predictive power has not previously been evaluated. Methods: Using linear regression, the authors developed an imputed estradiol score using measured estradiol levels (the outcome) and both case status and risk factor data (e.g., body mass index) from a nested case-control study conducted within a large prospective cohort study and used multiple imputation methods to develop an overall risk model including both risk factor data from the main cohort and estradiol levels from the nested case-control study. Results: The authors evaluated the addition of imputed estradiol level to the previously published Rosner and Colditz log incidence model for breast cancer risk prediction within the larger Nurses’ Health Study cohort. Follow-up was from 1980-2000; during this time 1559 invasive estrogen receptor positive breast cancer cases were confirmed. The addition of imputed estradiol levels significantly improved risk prediction; the age-specific concordance statistic increased from 0.635+/-0.007 to 0.645+/-0.007 (p<0.001) after addition of imputed estradiol. Conclusions: Circulating estradiol levels in postmenopausal women appear to add to other lifestyle factors in predicting a woman’s individual risk of breast cancer.

SELDI-TOF proteomic profiling of breast carcinomas identifies clinicopathologically relevant groups of patients similar to previously defined clusters from cDNA expression

from Breast Cancer Research by Bashar A Zeidan and Paul A Townsend
Expression profiling and biomarker(s) discovery aim to provide means for tumour diagnosis, classification, therapy response and prognosis. The identification of novel markers could potentially lead to the building of robust early detection strategies and personalized, effective breast cancer therapies that would improve patient outcome. Recent evidence supports the hypothesis that genomic expression profiling using microarray analysis is a reliable method for breast cancer classification and prognostication. However, genes clearly do not act by themselves, or indeed they do not have catalytic or signalling capabilities. Hence, genetic biomarker information alone cannot perfectly predict cancer and its response to treatment. Genes clearly exert their effect after transcription through translation into active proteins. Consequently, postgenomic projects correlating protein expression profiles with tumour classification have led to some established biomarkers. In this regard, these biomarkers associate with disease prediction and can be associated with treatment response. Recently, Brozokova and colleagues demonstrated that surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) profiling of breast cancer tissue proteomes can potentially expand the biomarker repertoire and our knowledge of breast cancer behaviour.

PMC42, a breast progenitor cancer cell line, has normal-like mRNA and miRNA transcriptomes

from Breast Cancer Research by Anna Git, Inmaculada Spiteri, Cherie Blenkiron, Mark Dunning, Jessica CM Pole, Suet-Feung Chin, Yanzhong Wang, James Smith, Frederick J Livesey and Carlos Caldas
IntroductionThe use of cultured cell lines as model systems for normal tissue is limited by the molecular alterations accompanying the immortalisation process, including changes in the mRNA and miRNA repertoire. Therefore, identification of cell lines with normal-like expression profiles is of paramount importance in studies of normal gene regulation. Methods: The mRNA and miRNA expression profiles of several breast cell lines of cancerous or normal origin were measured using printed slide arrays, Luminex bead arrays and real-time RT-PCR. Results: We demonstrate that the mRNA expression profiles of two breast cell lines are similar to that of normal breast tissue: HB4a, immortalised normal breast epithelium, and PMC42, a breast cancer cell line that retains progenitor pluripotency allowing in culture differentiation to both secretory and myoepithelial fates. In contrast, only PMC42 exhibits a normal-like miRNA expression profile. We identified a group of miRNAs that are highly expressed in normal breast tissue and PMC42 but are lost in all other cancerous and normal-origin breast cell lines, and observed a similar loss in immortalised lymphoblastoid cell lines compared to healthy uncultured B cells. Moreover, like tumour suppressor genes, these miRNAs are lost in a variety of tumours. We show that the mechanism leading to the loss of these miRNAs in breast cancer cell lines has genomic, transcriptional and post-transcriptional components. Conclusion: We propose that despite its neoplastic origin, PMC42 is an excellent molecular model for normal breast epithelium, providing a unique tool to study breast differentiation and the function of key miRNAs which are typically lost in cancer.

Mammographic density. Measurement of mammographic density

from Breast Cancer Research by Martin J Yaffe
Mammographic density has been strongly associated with increased risk of breast cancer. Furthermore, density is inversely correlated with the accuracy of mammography and, therefore, a measurement of density conveys information about the difficulty of detecting cancer in a mammogram. Initial methods for assessing mammographic density were entirely subjective and qualitative; however, in the past few years methods have been developed to provide more objective and quantitative density measurements. Research is now underway to create and validate techniques for volumetric measurement of density. It is also possible to measure breast density with other imaging modalities, such as ultrasound and MRI, which do not require the use of ionizing radiation and may, therefore, be more suitable for use in young women or where it is desirable to perform measurements more frequently. In this article, the techniques for measurement of density are reviewed and some consideration is given to their strengths and limitations.

The CD44+/CD24- phenotype is enriched in basal-like breast tumors

from Breast Cancer Research by Gabriella Honeth, Pär-Ola Bendahl, Markus Ringnér, Lao H Saal, Sofia K Gruvberger-Saal, Kristina Lövgren, Dorthe Grabau, Mårten Fernö, Åke Borg and Cecilia Hegardt
IntroductionHuman breast tumors are heterogeneous and consist of phenotypically diverse cells. Breast cancer cells with a CD44+/CD24- phenotype have been suggested to have tumor-initiating properties with stem cell-like and invasive features, although it is unclear whether their presence within a tumor has clinical implications. There is also a large heterogeneity between tumors, illustrated by reproducible stratification into various subtypes based on gene expression profiles or histopathological features. We have explored the prevalence of cells with different CD44/CD24 phenotypes within breast cancer subtypes. Methods: Double-staining immunohistochemistry was used to quantify CD44 and CD24 expression in 240 human breast tumors for which information on other tumor markers and clinical characteristics was available. Gene expression data was also accessible for a cohort of the material. Results: A considerable heterogeneity in CD44 and CD24 expression was seen both between and within tumors. A complete lack of both proteins was evident in 35% of the tumors, while 13% contained cells of more than one of the CD44+/CD24-, CD44-/CD24+ and CD44+/CD24+ phenotypes. CD44+/CD24- cells were detected in 31% of the tumors, ranging in proportion from only a few to close to 100% of tumor cells. The CD44+/CD24- phenotype was most common in the basal-like subgroup characterized as negative for the estrogen and progesterone receptors as well as for HER2 and positive for cytokeratin 5/14 and/or EGFR, and particularly common in BRCA1 hereditary tumors of which 94% contained CD44+/CD24- cells. The CD44+/CD24- phenotype was surprisingly scarce in HER2+ tumors, which had a predominantly CD24+ status. A CD44+/CD24- gene expression signature was generated, which included CD44 and alpha-6 integrin (CD49f) among the top-ranked overexpressed genes. Conclusions: We demonstrate an association between basal-like and particularly BRCA1 hereditary breast cancer and presence of CD44+/CD24- cells. However, not all basal-like and very few HER2+ tumors contain CD44+/CD24- cells, which emphasizes that a putative tumorigenic ability may not be confined to cells of this phenotype and that other breast cancer stem cell markers remain to be identified.

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Breast Cancer Research update - june 9

Written by admin on Jun 14th, 2008 | Filed under: oncology UPDATE

Mammosphere culture of metastatic breast cancer cells enriches for tumourigenic breast cancer cells.

from Breast Cancer Research by Matthew J Grimshaw, Lucienne Cooper, Konstantinos Papazisis, Julia A Coleman, Hermann R Bohnenkamp, Laura Chiapero-Stanke, Joyce M Taylor-Papadimitriou and Joy M Burchell
Background: The identification of potential breast cancer stem cells is of importance as the characteristics of stem cells suggest that they are resistant to conventional forms of therapy. Several techniques have been proposed to isolate or enrich for tumorigenic breast cancer stem cells including i) culture of cells in non-adherent, non-differentiating conditions to form mammospheres, and ii) sorting of the cells by their surface phenotype (expression of CD24 and CD44). Methods: We have cultured metastatic cells found in pleural effusions from breast cancer patients in non-adherent conditions without serum to form mammospheres. Dissociated cells from these mammospheres were used to determine the tumorigenicity of these cultures. Expression of CD24 and CD44 on uncultured cells and mammospheres derived from the pleural effusions was documented. Results: We found that the majority (20/27) of the pleural effusions tested contained cells capable of forming mammospheres of varying sizes that could be passaged. After dissociation and plating with serum onto adherent dishes the cells can differentiate, as determined by the increased expression of cytokeratins and MUC1. Analysis of surface expression of CD24 and CD44 on uncultured cells from 21 of the samples showed that the cells from some samples separated into two populations, but some did not. The proportion of cells that could be considered CD44+/CD24low/- was highly variable and did not appear to correlate with the ability to form the larger mammospheres. Of 8 pleural effusion mammospheres tested in SCID mice, 4 were found to induce tumours when only 5000 or fewer cells were injected, while the same number of uncultured cells did not form tumours. The ability to induce tumours appeared to correlate with the ability to produce the larger mammospheres. Uncultured cells from a highly tumorigenic sample (PE14) were uniformly negative for surface expression of both CD24 and CD44. Conclusions: This paper shows, for the first time, that mammosphere culture of pleural effusions enriches for cells capable of inducing tumours in SCID mice. The data suggest that mammosphere culture of these metastatic cells could provide a highly appropriate model for studying the sensitivity of the tumorigenic “stem” cells to therapeutic agents, and for further characterisation of the tumour inducing subpopulation of breast cancer cells.

Jab1 is a target of EGFR signaling in ER-alpha negative breast cancer

from Breast Cancer Research by Jiaxu Wang, Rebecca O Barnes, Nathan R West, Melanie Olson, Jenny E Chu and Peter H Watson
Introductionc-Jun activation domain binding protein-1 (Jab1) is a multifunctional signaling protein that has previously been shown to be a master regulator of a poor prognostic gene signature in invasive breast cancer and to mediate the action of S100A7. Since epidermal growth factor receptor (EGFR), like S100A7, is often expressed in ER-alpha negative breast cancer, we set out to investigate the role of Jab1 in mediating EGFR signaling, another facet of the ER-alpha negative phenotype. Methods: MDA-MB-231 and MDA-MB-468 ER-alpha negative/EGFR positive cell lines were assessed for localization of Jab1 and levels of downstream genes by immunofluorescence and nuclear protein extract assay following treatment with epidermal growth factor (EGF) and extracellular signal-regulated kinase (ERK) pathway inhibitor. A cohort of 424 human breast tumors was also assessed by immunohistochemistry. Results: EGF treatment of cell lines resulted in increased Jab1 nuclear expression. This effect was inhibited by the ERK pathway inhibitor, PD98059. EGF treatment was also associated with co-localization of pERK and Jab1, as well as regulation of the Jab1 downstream target gene, p27. When Jab1 activity was knocked down, p27 levels were restored to pre-EGF treatment level. Analysis of EGFR and Jab1 expression in a cohort of invasive breast tumors by tissue microarray and immunohistochemistry confirmed a relationship between EGFR and increased nuclear Jab1 within the ER-alpha negative subset (n=154, p=0.019). The same association was also confirmed for S100A7 and Jab1 (p=0.036), and high Jab1 nuclear expression was most frequent in tumors that were positive for both EGFR and S100A7 (p=0.004). Conclusions: Jab1 is a target of EGFR signaling in ER-alpha negative cell lines and breast tumors and therefore may be a common, central factor and potential therapeutic target for important cell signaling pathways in ER-alpha negative breast cancer.

Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?

from Breast Cancer Research by Graham B Byrnes, Melissa C Southey and John L Hopper
A woman typically presents for genetic counselling because she has a strong family history and is interested in knowing the probability she will develop disease in the future; that is, her absolute risk. Relative risk for a given factor refers to risk compared with either population average risk (sense a), or risk when not having the factor, with all other factors held constant (sense b). Not understanding that these are three distinct concepts can result in failure to correctly appreciate the consequences of studies on clinical genetic testing. Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls. To account for the selected case sampling (ascertainment), a statistical model that assumes that the effect of any measured variant multiplies the effect of unmeasured variants was applied. This multiplicative polygenic model in effect estimated the relative risk in the sense b, not sense a, and found it was in the range of 1.7 to 2.4. The authors concluded that the variants are “low penetrance”. They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers. This is because the relative risk multiplies polygenic risk, and the latter is predicted by family history. Therefore, mutation testing of these genes for women with a strong family history, especially if it is of early onset, may be as clinically relevant as it is for BRCA1 and BRCA2.

Mammary carcinoma behavior is programmed in the precancer stem cell

from Breast Cancer Research by Patrizia Damonte, J GRAEME Hodgson, Jane Q Chen, Lawrence JT Young, Robert D Cardiff and Alexander D Borowsky
IntroductionThe “MINO” mouse model of ductal carcinoma in situ (DCIS) consists of six lines with distinct morphologic phenotypes and behavior each meeting experimentally defined criteria for “pre-cancer”. Specifically, these lines grow orthotopically in cleared mammary fat pads and consistently progress to an invasive phenotype capable of ectopic growth. Transition to carcinoma has a consistent latency for each line and three of the lines also show pulmonary metastatic potential. Methods: Gland cleared orthotopic transplanted precancer MINO tissues were analyzed by BAC and oligo array CGH, microsatellite PCR, and telomerase repeat amplification assay. MINO cells were dissociated and cultured in three dimensional (3D) culture and transplanted in syngeneic gland cleared mammary fat pads. Results: Comparative genomic hybridization shows that the pre-cancer and invasive tumors are genetically stable with low level changes including whole chromosome gains in some lines. No changes are associated with progression, although spontaneous focal amplifications and deletions were detected occasionally. Microsatellite analysis shows a low frequency of alterations which are predominantly permanent within a MINO line. Telomerase activity is increased in both the MINO and the derived tumors when compared to normal mouse mammary gland. Dissociation of the precancer lesion cells and three dimensional “spheroid” culture of single cells reveals a bipotential for myoepithelial and luminal differentiation and the formation of unique 3D “MINOspheres.” These “MINOspheres” show features that are intermediate between spheroids that are derived from normal and carcinoma cells. Transplantation of a single cell derived MINOsphere recapitulates the outgrowth of the precancer morphology and progression to carcinoma. Conclusion: These data establish a pre-cancer stem cell capable of self renewal and multilineage differentiation as the origin of invasive cancer. In the context of this model, these cells have programmed potential for latency and metastasis that does not appear to require sequential genetic hits for transformation.

EGFR and phosphorylated EGFR (pEGFR) expression in invasive breast carcinomas; pEGFR relation to invasiveness and angiogenesis and the impact of EGFR/pEGFR phenotype on overall survival

from Breast Cancer Research by Christina Magkou, Lydia Nakopoulou, Christina Zoubouli, Kanelina Karali, Irene Theohari, Panagiotis Bacarakos and Ioanna Giannopoulou
IntroductionEpidermal growth factor receptor (EGFR) is involved in regulating cell growth in breast carcinomas. Its activated form (pEGFR) is correlated with poor prognosis in lung cancer, whereas it has not yet been fully investigated in breast cancer. The aim of this study was to investigate the expression of EGFR and pEGFR and their correlation with overall and disease free, survival, clinicopathological parameters and biological markers of invasion and angiogenesis (pAkt, uPAR, MMP-14, VEGFR-1/Flt-1). Methods: A three-step immunohistochemical method (ABC/HPR) was applied on paraffin-embedded sections from 154 patients with invasive breast carcinoma to detect the expression of the proteins EGFR, pEGFR, ER, PR, c-erbB-2, pAkt, VEGFR-1/Flt-1, MMP-14 and uPAR. The results were statistically processed using chi-square test. Overall and disease-free survival distribution curves were assessed by Kaplan-Meier test and log-rank statistics followed by Cox’s proportional hazards regression model. Results: EGFR and pEGFR proteins were immunodetected in the membrane of the malignant cells (11.9% and 35.7% respectively). EGFR expression was positively correlated with nuclear grade (p=0.004) and negatively correlated with hormonal receptors ER (p=0.005). pEGFR was positively related to the Akt pathway (p=0.008) and appeared to participate in invasion and metastasis (uPAR: p=0.049, MMP-14: p=0.025 and VEGFR-1/Flt-1: p=0.016). Univariate analysis showed that EGFR/pEGFR phenotype was associated with poor overall survival (p=0.019), a finding further supported by multivariate analysis (p=0.013). Conclusions: These data provide the evidence that pEGFR expression is related to angiogenesis (via VEGFR-1/Flt-1, MMP-14 and pAkt pathways) and invasiveness (via uPAR, MMP-14 and pAkt pathways) and EGFR/pEGFR phenotype is associated with poor patient survival in invasive breast cancer.

Alternative splicing and the progesterone receptor in breast cancer

from Breast Cancer Research by David MW Cork, Thomas WJ Lennard and Alison J Tyson-Capper
Progesterone receptor status is a marker for hormone responsiveness and disease prognosis in breast cancer. Progesterone receptor negative tumours have generally been shown to have a poorer prognosis than progesterone receptor positive tumours. The observed loss of progesterone receptor could be through a range of mechanisms, including the generation of alternatively spliced progesterone receptor variants that are not detectable by current screening methods. Many progesterone receptor mRNA variants have been described with deletions of various whole, multiple or partial exons that encode differing protein functional domains. These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer. Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies. A comprehensive investigation into the expression profile and activity of progesterone receptor spliced variants in breast cancer is required to advance our understanding of tumour hormone receptor status. This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions.

Surface-enhanced laser desorption/ionization time-of-flight proteomic profiling of breast carcinomas identifies clinicopathologically relevant groups of patients similar to previously defined clusters from cDNA expression

from Breast Cancer Research by Kristyna Brozkova, Eva Budinska, Pavel Bouchal, Lenka Hernychova, Dana Knoflickova, Dalibor Valik, Rostislav Vyzula, Borivoj Vojtesek and Rudolf Nenutil
IntroductionMicroarray-based gene expression profiling represents a major breakthrough for understanding the molecular complexity of breast cancer. cDNA expression profiles cannot detect changes in activities that arise from post-translational modifications, however, and therefore do not provide a complete picture of all biologically important changes that occur in tumors. Additional opportunities to identify and/or validate molecular signatures of breast carcinomas are provided by proteomic approaches. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) offers high-throughput protein profiling, leading to extraction of protein array data, calling for effective and appropriate use of bioinformatics and statistical tools. Methods: Whole tissue lysates of 105 breast carcinomas were analyzed on IMAC 30 ProteinChip Arrays (Bio-Rad, Hercules, CA, USA) using the ProteinChip Reader Model PBS IIc (Bio-Rad) and Ciphergen ProteinChip software (Bio-Rad, Hercules, CA, USA). Cluster analysis of protein spectra was performed to identify protein patterns potentially related to established clinicopathological variables and/or tumor markers. Results: Unsupervised hierarchical clustering of 130 peaks detected in spectra from breast cancer tissue lysates provided six clusters of peaks and five groups of patients differing significantly in tumor type, nuclear grade, presence of hormonal receptors, mucin 1 and cytokeratin 5/6 or cytokeratin 14. These tumor groups resembled closely luminal types A and B, basal and HER2-like carcinomas. Conclusion: Our results show similar clustering of tumors to those provided by cDNA expression profiles of breast carcinomas. This fact testifies the validity of the SELDI-TOF MS proteomic approach in such a type of study. As SELDI-TOF MS provides different information from cDNA expression profiles, the results suggest the technique’s potential to supplement and expand our knowledge of breast cancer, to identify novel biomarkers and to produce clinically useful classifications of breast carcinomas.

The future of mammary stem cell biology: the power of in vivo transplants – authors’ response

from Breast Cancer Research by Gilbert H Smith and Daniel Medina
The letter from Drs. Lindeman, Visvader, Smalley and Eaves conveys their concern regarding the future of the prospective isolation and characterization of individual cells that may be characterized as mammary stem cells upon in vivo transplantation. As they have pointed out, the difficulties encountered in identifying specific mammary epithelial subtypes by different levels of fluorescence (particularly for membrane components that decorate most if not all mammary epithelial cells) leads to differential reporting and “resultant confusion” and “underscores the need for improved standardization”.

Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort

from Breast Cancer Research by Elizabeth M Azzato, Kristy E Driver, Fabienne Lesueur, Mitul Shah, David Greenberg, Douglas F Easton, Andrew E Teschendorff, Carlos Caldas, Neil E Caporaso and Paul DP Pharoah
IntroductionSomatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division. Methods: We examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis. Results: The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding. Conclusion: It is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.


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Cancer Cell International update, may 23

Written by admin on May 25th, 2008 | Filed under: oncology UPDATE

A novel and generalizable organotypic slice platform to evaluate stem cell potential for targeting pediatric brain tumors

from Cancer Cell International by Shengwen CALVIN Li and William GUNTER Loudon
Brain tumors are now the leading cause of cancer-related deaths in children under age 15. Malignant gliomas are, for all practical purposes, incurable and new therapeutic approaches are desperately needed. One emerging strategy is to use the tumor tracking capacity inherent in many stem cell populations to deliver therapeutic agents to the brain cancer cells. Current limitations of the stem cell therapy strategy include that stem cells are treated as a single entity and lack of uniform technology is adopted for selection of clinically relevant sub-populations of stem cells. Specifically, therapeutic success relies on the selection of a clinically competent stem cell population based on their capacity of targeting brain tumors. A novel and generalizable organotypic slice platform to evaluate stem cell potential for targeting pediatric brain tumors is proposed to fill the gap in the current work flow of stem cell-based therapy. The organotypic slice platform has advantages of being mimic in vivo model, easier to manipulate to optimize parameters than in vivo models such as rodents and primates. This model serves as a framework to address the discrepancy between anticipated in vivo results and actual in vivo results, a critical barrier to timely progress in the field of the use of stem cells for the treatment of neurological disorders.

Reduced paxillin expression contributes to the antimetastatic effect of 4-hydroxycoumarin on B16-F10 melanoma cells

from Cancer Cell International by Marco A Velasco-Velazquez, Nohemi Salinas-Jazmin, Nicandro Mendoza-Patino and Juan J Mandoki
Background: 4-Hydroxycoumarin (4-HC) is a coumarin that lacks anticoagulant activity. 4-HC affects the cytoskeletal stability and decreases cell adhesion and motility of the melanoma cell line B16-F10. Together with integrins and other cytoskeletal proteins, paxillin participates in the regulation of cell adhesion and motility, acting as an adapter protein at focal adhesions. The present study determined the participation of paxillin in the reported effects of 4-HC and analyzed the role of paxillin in the formation of melanoma metastases. Results: 4-HC decreased protein and mRNA levels of alpha- and beta-paxillin isoforms in B16-F10 cells. Paxillin downregulation correlated with an inadequate translocation of paxillin to focal adhesions and a reduced phosphotyr118-paxillin pool. Consequently, 4-HC altered paxillin-mediated signaling, decreasing the phosphorylation of FAK and the level of GTP-bound Rac-1. These results partially explain the mechanism of the previously reported effects of 4-HC. Additionally, we studied the effect of 4-HC on metastatic potential of B16-F10 cells through experimental metastasis assays. In vitro treatment of cells with 4-HC inhibited their capability to originate pulmonary metastases. 4-HC did not affect cell growth or survival, demonstrating that its antimetastatic effect is unrelated to changes on cell viability. We also studied the importance of paxillin in metastasis by transfecting melanoma cells with paxillin-siRNA. Transfection produced a modest reduction on metastatic potential, indicating that: i) paxillin plays a role as inducer of melanoma metastasis; and ii) paxillin downregulation is not sufficient to explain the antimetastatic effect of 4-HC. Therefore, we evaluated other changes in gene expression by differential display RT-PCR analysis. Treatment with 4-HC produced a downregulation of Adhesion Regulating Molecule-1 (ARM-1), which correlated with a decreased adhesion of melanoma cells to lung slides. Conclusions: This study shows that reduced paxillin expression is associated with the impaired cell adhesion and motility seen in 4-HC-treated cells and partially contributes to the antimetastatic effect of 4-HC. In contrast, the role of ARM-1 reduced expression in the effects of 4-HC is still to be clarified. The antimetastatic effect of 4-HC suggests that this compound, or others with similar mode of action, might be useful for the development of adjuvant therapies for melanoma.

Inter-cellular adhesion disruption and the RAS/RAF and beta-catenin signalling in lung cancer progression

from Cancer Cell International by Rudolf Gotz
Cadherin cell adhesion molecules play an essential role in creating tight intercellular association and their loss has been correlated with poor prognosis in human cancer. Mutational activation of protein kinases and loss of cell adhesion occur together in human lung adenocarcinoma but how these two pathways interconnect is only poorly understood. Mouse models of human lung adenocarcinoma with oncogene expression targeted to subtypes of lung epithelial cells led to formation of adenomas or adenocarcinomas that lacked metastatic potential. Conditional genetic abrogation of epithelial tumour cell adhesion in mice with benign lung tumours induced by oncogenic RAF kinase has been demonstrated to induce intratumourous vascularization (angiogenic switch), progression to invasive adenocarcinoma and micrometastasis. Importantly, breaking cell adhesion in benign oncogene-driven lung tumour cells activated beta-catenin signalling and induced the expression of several genes that are normally expressed in intestine rather than the lung. I will discuss potential routes to nuclear beta-catenin signalling in cancer and how nuclear beta-catenin may epigenetically alter the plasticity of tumour cells during malignant progression.

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World Journal of Surgical Oncology update, may 21

Written by admin on May 23rd, 2008 | Filed under: oncology UPDATE, surgery UPDATE

An unusual case of low-grade tubulopapillary adenocarcinoma of the sinonasal tract

from World Journal of Surgical Oncology by Ashish Bansal, Keloth E Pradeep and Krishna P Gumparthy
Background: Low-grade papillary adenocarcinomas of the sinonasal tract are rare neoplasms. Over recent years, little doubt remains that this tumour represents a separate entity based on morphology, ultrastructural features and behaviour. We outline a case of this rare entity displaying a not hitherto described immunophenotype. Case presentationA 32 year old man presented recurrent epistaxis was evaluated with endoscopy which revealed a well circumscribed pedunculated mass lesion in left nares. The mass was arising from the nasal septum which was excised along with the mass. The biopsy revealed low-grade, non-intestinal type sinonasal tubulopapillary adenocarcinoma. Conclusions: TTF-1 immunoreactivity in absence of thyroid or pulmonary primary in the present case remains an enigma. However, this raises the possibility of the utility of this antibody to predict a better clinical outcome in the subset of low grade non-intestinal sinonasal adenocarcinoma. More cases of similar morphological appearance may need to be examined for TTF-1 immunoreactivity and clinically followed up to establish this theory.

Lymhatic mapping and sentinel node biopsy in gynecological cancer: a critical review of the literature

from World Journal of Surgical Oncology by Ali Ayhan, Husnu Celik and Polat Dursun
Although it does not have a long history of sentinel node evaluation (SLN) in female genital system cancers, there is a growing number of promising study results, despite the presence of some aspects that need to be considered and developed. It has been most commonly used in vulvar and uterine cervivcal cancer in gynecological oncology. According to these studies, almost all of which are prospective, particularly in cases where Technetium-labeled nanocolloid is used, sentinel node detection rate sensitivity and specificity has been reported to be 100%, except for a few cases. In the studies on cervical cancer, sentinel node detection rates have been reported around 80-86%, a little lower than those in vuvla cancer, and negative predictive value has been reported about 99%. It is relatively new in endometrial cancer, where its detection rate varies between 50 and 80%. Studies about vulvar melanoma and vaginal cancers are generally case reports.Although it has not been supported with multicenter randomized and controlled studies including larger case series, study results reported by various centers around the world are harmonious and mutually supportive particularly in vulva cancer, and cervix cancer. Even though it does not seem possible to replace the traditional approaches in these two cancers, it is still a serious alternative for the future. We believe that it is important to increase and support the studies that will strengthen the weaknesses of the method, among which there are detection of micro metastases and increasing detection rates, and render it usable in routine clinical practice.

Primary lymphoma of the breast involving both axillae with bilateral breast carcinoma

from World Journal of Surgical Oncology by Neeraj K Garg, Nitin B Bagul, Gary Rubin and Elizabeth F Shah
Background: Primary Non-Hodgkin’s Lymphoma (PHNL) of the breast is a rare entity, while secondary involvement of the breast with diffuse disease of Non-Hodgkin’s lymphoma (NHL) is more common. However, PNHL is the most frequent haematopoietic tumour of the breast. Diagnostic criteria for PNHL of the breast are presence of technically adequate pathologic specimens, close association of mammary tissue and lymphomatous infiltrate, no prior diagnosis of an extarammamary lymphoma, and no evidence of concurrent widespread disease, except for ipsilateral axillary lymph nodes if concomitant with the primary lesion.Case presentationA 57-year-old woman was recalled because her screening mammograms revealed three separate lesions in her right breast and one in the left. Histology of the lesions confirmed lymphoma in one breast with ductal carcinoma in the other. Conclusions: Most of reported cases in literature have been involving the right breast, and almost all the patients were females. NHLs of the breast typically present as unilateral mass; the frequency of bilateral disease at first presentation ranges from 5-25%. Our objective is to report a case of primary lymphoma of the breast involving both axillae with concomitant bilateral primary breast cancer which has not been reported yet to our best of knowledge in literature.

Vacuum-assisted breast biopsy: A comparison of 11-gauge and 8-gauge needles

from World Journal of Surgical Oncology by Markus Hahn, Stella Okamgba, Peter Scheler, Klaus Freidel, Gerald Hoffmann, Bernhard Kraemer, Diethelm Wallwiener and Ute Krainick-Strobel
Background: Minimal invasive breast biopsy is standard care for the diagnosis of suspicious breast lesions. There are different vacuum biopsy (VB) systems in use. The aim of the study was to determine the differences between the 8-gauge and the 11-gauge needle with respect to a) diagnostic reliability, b) complication rate and c) subjective perception of pain when used for vacuum-assisted breast biopsy. Methods: Between 01/2000 and 09/2004, 923 patients at St. Josefs-Hospital Wiesbaden underwent VB using the Mammotome(R) (Ethicon Endosurgery, Hamburg). Depending on preoperative detection, the procedure was performed under sonographic or mammographic guidance under local anaesthesia. All patients included in the study were followed up both clinically and using imaging techniques one week after the VB and a second time after a median of 41 months. Excisional biopsy on the ipsilateral breast was an exclusion criteria. Subjective pain scores were recorded on a scale of 0 - 10 (0 = no pain, 10 = unbearable pain). The mean age of the patients was 53 years (30 - 88). Results: 123 patients were included in the study in total. 48 patients were biopsied with the 8-gauge needle and 75 with the 11-gauge needle. The use of the 8-gauge needle did not show any significant differences to the 11-gauge needle with regard to diagnostic reliability, complication rate and subjective perception of pain. Conclusions: Our data show that there are no relevant differences between the 8-gauge and 11-gauge needle when used for VB. Under sonographic guidance, the use of the 8-gauge needle is recommended for firm breast tissue due to its sharp scalpel point and especially for complete removal of benign lesions. We did not find any advantages in the use of the larger 8-gauge needle compared to the 11-gauge needle in the mammography setting. The utilisation costs of the 8-gauge needle are somewhat higher.

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