共查询到20条相似文献,搜索用时 31 毫秒
1.
Ingunn M. Stefansson Maria Raeder Elisabeth Wik Monica Mannelqvist Kanthida Kusonmano G?ril Knutsvik Ingfrid Haldorsen Jone Trovik Anne M. ?yan Karl-H. Kalland Anne Cathrine Staff Helga B. Salvesen Lars A. Akslen 《Oncotarget》2015,6(12):10634-10645
Background
Angiogenesis is a hallmark of cancer. The aim of this study was to explore whether microvessel proliferation is associated with gene expression profiles or copy number alterations in endometrial cancer.Methods
A prospective series of endometrial carcinomas was studied for angiogenesis markers, gene expression profiles, and gene copy number data. For validation, an independent series of endometrial carcinomas as well as an external cohort of endometrial cancer patients were examined by gene expression microarrays.Results
Increased microvessel proliferation (MVP) was associated with aggressive tumor features and reduced survival, and a 32-gene expression signature was found to separate tumors with high versus low MVP. An increased 32-gene signature score was confirmed to associate with high-grade tumor features and reduced survival by independent cohorts. Copy number studies revealed that amplification of the 6p21 region was significantly associated with MVP, a high 32-gene score, as well as reduced survival.Conclusion
Increased MVP was significantly associated with aggressive endometrial cancer and reduced survival. Integrated analyses demonstrated significant associations between increased vascular proliferation, amplification of the 6p21 region, VEGF-A mRNA expression, and the 32-gene angiogenesis signature. Our findings indicate amplification of 6p21 as a possible driver of tumor vascular proliferation in endometrial cancer. 相似文献2.
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Background:
There is a need to develop robust and clinically applicable gene expression signatures. Hypoxia is a key factor promoting solid tumour progression and resistance to therapy; a hypoxia signature has the potential to be not only prognostic but also to predict benefit from particular interventions.Methods:
An approach for deriving signatures that combine knowledge of gene function and analysis of in vivo co-expression patterns was used to define a common hypoxia signature from three head and neck and five breast cancer studies. Previously validated hypoxia-regulated genes (seeds) were used to generate hypoxia co-expression cancer networks.Results:
A common hypoxia signature, or metagene, was derived by selecting genes that were consistently co-expressed with the hypoxia seeds in multiple cancers. This was highly enriched for hypoxia-regulated pathways, and prognostic in multivariate analyses. Genes with the highest connectivity were also the most prognostic, and a reduced metagene consisting of a small number of top-ranked genes, including VEGFA, SLC2A1 and PGAM1, outperformed both a larger signature and reported signatures in independent data sets of head and neck, breast and lung cancers.Conclusion:
Combined knowledge of multiple genes'' function from in vitro experiments together with meta-analysis of multiple cancers can deliver compact and robust signatures suitable for clinical application. 相似文献4.
Melissa Rotunno Xuezheng Sun Jonine Figueroa Mark E Sherman Montserrat Garcia-Closas Paul Meltzer Tyisha Williams Sallie Smith Schneider D Joseph Jerry Xiaohong R Yang Melissa A Troester 《Breast cancer research : BCR》2014,16(1):R74
Introduction
Relationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor–positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve understanding of the biological mechanisms underlying this complex pattern of risk.Methods
We developed a parity signature by analyzing microRNA microarray data from 130 reduction mammoplasty (RM) patients (54 nulliparous and 76 parous). This parity signature, together with published parity signatures, was evaluated in gene expression data from 150 paired tumors and adjacent benign breast tissues from the Polish Breast Cancer Study, both overall and by tumor estrogen receptor (ER) status.Results
We identified 251 genes significantly upregulated by parity status in RM patients (parous versus nulliparous; false discovery rate = 0.008), including genes in immune, inflammation and wound response pathways. This parity signature was significantly enriched in normal and tumor tissues of parous breast cancer patients, specifically in ER-positive tumors.Conclusions
Our data corroborate epidemiologic data, suggesting that the etiology and pathogenesis of breast cancers vary by ER status, which may have implications for developing prevention strategies for these tumors. 相似文献5.
Evren Yilmaz Meral Koyuncuoglu ?lknur Bilkay G?rken Emre Okyay Bahadir Saatli Emine Cagnur Ulukus Ugur Saygili 《Journal Of Gynecologic Oncology》2011,22(2):89-96
Objective
To determine matrix metalloproteinase-2 and survivin expressions in endometrial cancers, their relation to clinical and histologic parameters and to investigate any difference in the expression of these markers between endometrioid and nonendometrioid cancers.Methods
Ninety-five patients with endometrial cancer, were included. Matrix metalloproteinase-2 and survivin expressions were analyzed immunohistochemically from paraffin-embedded tissues by using specific monoclonal antibodies.Results
Survivin nuclear expression was higher in endometrioid cancer as compared to nonendometrioid cancer (p=0.040), but there was no difference for cytoplasmic survivin and matrix metalloproteinase-2 expressions between type I and type II carcinomas. Survivin cytoplasmic staining was significantly lower in patients with deep myometrial invasion (p=0.038). Nuclear expression of survivin is decreased in histologic grade 3 tumors compared to grade 1 and 2 tumors (p=0.013), but there is no difference between grade 1 and 2. We did not find any statistically significant difference between survivin or matrix metalloproteinase-2 expressions and survival.Conclusion
Survivin and matrix metalloproteinase-2 are present in endometrioid and nonendometrioid cancers. Grade 1 and 2 tumors and carcinomas having myometrial invasion less than 50% have higher survivin expression. These results supports that, survivin may play an important role in early stage tumors and early phases of tumor development. We did not find any association between matrix metalloproteinase-2 expression and classical prognostic factors in endometrial cancer and both proteins were not associated with survival. 相似文献6.
Sofia Winslow Karin Leandersson Anders Edsj? Christer Larsson 《Breast cancer research : BCR》2015,17(1)
Introduction
Global gene expression analysis of tumor samples has been a valuable tool to subgroup tumors and has the potential to be of prognostic and predictive value. However, tumors are heterogeneous, and homogenates will consist of several different cell types. This study was designed to obtain more refined expression data representing different compartments of the tumor.Methods
Formalin-fixed paraffin-embedded stroma-rich triple-negative breast cancer tumors were laser-microdissected, and RNA was extracted and processed to enable microarray hybridization. Genes enriched in stroma were identified and used to generate signatures by identifying correlating genes in publicly available data sets. The prognostic implications of the signature were analyzed.Results
Comparison of the expression pattern from stromal and cancer cell compartments from three tumors revealed a number of genes that were essentially specifically expressed in the respective compartments. The stroma-specific genes indicated contribution from fibroblasts, endothelial cells, and immune/inflammatory cells. The gene set was expanded by identifying correlating mRNAs using breast cancer mRNA expression data from The Cancer Genome Atlas. By iterative analyses, 16 gene signatures of highly correlating genes were characterized. Based on the gene composition, they seem to represent different cell types. In multivariate Cox proportional hazard models, two immune/inflammatory signatures had opposing hazard ratios for breast cancer recurrence also after adjusting for clinicopathological variables and molecular subgroup. The signature associated with poor prognosis consisted mainly of C1Q genes and the one associated with good prognosis contained HLA genes. This association with prognosis was seen for other cancers as well as in other breast cancer data sets.Conclusions
Our data indicate that the molecular composition of the immune response in a tumor may be a powerful predictor of cancer prognosis.Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0530-2) contains supplementary material, which is available to authorized users. 相似文献7.
William M Merritt Aparna A Kamat Jee-Young Hwang Justin Bottsford-Miller Chunhua Lu Yvonne G Lin Donna Coffey Whitney Spannuth Elizabeth Nugent Liz Y Han Charles N Landen Alpa M Nick Rebecca L Stone Karen T Coffman Elizabeth Bruckheimer Russell Broaddus David M Gershenson Robert L Coleman Anil K Sood 《Cancer biology & therapy》2010,10(12):1306-1314
Objective
EphA2 overexpression predicts poor prognosis in endometrial cancer. To explore mechanisms for this association and assess its potential as therapeutic target, the relationship of EphA2 expression to markers of angiogenesis was examined using patient samples and an orthotopic mouse model of uterine cancer.Results
Of 85 EE C samples, EphA2 was overexpressed in 47% of tumors and was significantly associated with high VEGF expression (p = 0.001) and high MVD counts (p = 0.02). High EphA2 expression, high VEGF expression and high MVD counts were significantly associated with shorter disease-specific survival. EA5 led to decrease in EphA2 expression and phosphorylation in vitro. In the murine model, while EA5 (33–88%) and docetaxel (23–55%) individually led to tumor inhibition over controls, combination therapy had the greatest efficacy (78–92%, p < 0.001). In treated tumors, combination therapy resulted in significant reduction in MVD counts, percent proliferation and apoptosis over controls.Experimental Design
Expression of EphA2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, vascular endothelial growth factor (VEGF) and microvessel density (MVD) was evaluated using immunohistochemistry in 85 endometrioid endometrial adenocarcinomas (EEC) by two independent investigators. Results were correlated with clinicopathological characteristics. The effect of EphA2-agonist monoclonal antibody EA5, alone or in combination with docetaxel was studied in vitro and in vivo. Samples were analyzed for markers of angiogenesis, proliferation and apoptosis.Conclusions
EphA2 overexpression is associated with markers of angiogenesis and is predictive of poor clinical outcome. EphA2 targeted therapy reduces angiogenesis and tumor growth in orthotopic uterine cancer models and should be considered for future clinical trials.Key words: endometrial cancer, EphA2, VEGF, microvessel density, angiogenesis 相似文献8.
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Akslen LA Straume O Geisler S Sørlie T Chi JT Aas T Børresen-Dale AL Lønning PE 《British journal of cancer》2011,105(1):9-12
Background:
Glomeruloid microvascular proliferation (GMP), a novel histology-based angiogenesis marker, has been associated with decreased survival in several human cancers.Methods:
In this study, we evaluated the ability of GMP to predict clinical response to neoadjuvant chemotherapy in a series of locally advanced breast cancers (n=112).Results:
Presence of GMP (21% of the cases) was significantly associated with high-grade tumours and TP53 mutations in addition to the basal-like and HER2 subtypes of breast cancer as defined by gene expression data. GMP was correlated to a gene expression signature for tumour hypoxia response. The GMP pattern was also significantly associated with lack of treatment response and progressive disease (P=0.004).Interpretation:
The findings suggest that GMP might be able to predict the lack of response to neoadjuvant chemotherapy in locally advanced breast cancer. Whether GMP may be an independent predictor compared with other factors including TP53 mutation status and tumour grade needs confirmation in larger studies. 相似文献11.
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Balazs Jóri Rick Kamps Sofia Xanthoulea Bert Delvoux Marinus J. Blok Koen K. Van de Vijver Bart de Koning Felicia Trups Oei Carli M. Tops Ernst J. M. Speel Roy F. Kruitwagen Encarna B. Gomez-Garcia Andrea Romano 《Oncotarget》2015,6(38):41108-41122
Background
The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer.Methods
A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis.Results
A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype.Conclusion
A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling. 相似文献13.
Haiyu Zhang Adam L Cohen Sujatha Krishnakumar Irene L Wapnir Selvaraju Veeriah Glenn Deng Marc A Coram Caroline M Piskun Teri A Longacre Michael Herrler Daniel O Frimannsson Melinda L Telli Frederick M Dirbas AC Matin Shanaz H Dairkee Banafshe Larijani Gennadi V Glinsky Andrea H Bild Stefanie S Jeffrey 《Breast cancer research : BCR》2014,16(2):R36
Introduction
Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779).Methods
We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1,401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts.Results
Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and five of six primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated.Conclusions
A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations. 相似文献14.
Jang Hyun Lee Jae-Kyung Pyon Dong Wook Kim Sang Han Lee Hae Seon Nam Chul Han Kim Sang Gue Kang Yoon Jin Lee Mi Youn Park Dong Jun Jeong Moon Kyun Cho 《Journal of experimental & clinical cancer research : CR》2010,29(1):116
Abstracts
Background
Src family kinases (SFKs) play an important role in cancer proliferation, survival, motility, invasiveness, metastasis, and angiogenesis. Among the SFKs, c-Src and c-Yes are particularly over-expressed or hyper-activated in many human epithelial cancers. However, only a few studies have attempted to define the expression and role of c-Src and c-Yes in cutaneous carcinomas.Objectives
To investigate the expression of c-Src and c-Yes in cutaneous carcinomas to include malignant melanoma (MM), squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).Methods
We examined 6 normal skin tissues and 18 malignant skin tumor tissues using western blotting for the expression of c-Src and c-Yes. In another set, 16 specimens of MM, 16 SCCs and 16 BCCs were analyzed for the expression of c-Src and c-Yes using immunohistochemical staining.Results
Western blotting showed that c-Src was expressed in all malignant skin tumors, but not in normal skin, while c-Yes was expressed in MM and SCC, but not in BCC and normal skin. Immunohistochemical staining results of c-Src and c-Yes in MM, SCC, and BCC mirrored those of the western blot analysis.Conclusions
c-Src, rather than c-Yes, plays a key role in the proliferation and progression of malignant skin cancers. 相似文献15.
A M Jubb H Turley H C Moeller G Steers C Han J-L Li R Leek E Y Tan B Singh N J Mortensen I Noguera-Troise F Pezzella K C Gatter G Thurston S B Fox A L Harris 《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. 相似文献16.
Jacqueline Lehmann-Che Anne-Sophie Hamy Rapha?l Porcher Marc Barritault Fatiha Bouhidel Hanadi Habuellelah Solenne Leman-Detours Anne de Roquancourt Laurence Cahen-Doidy Edwige Bourstyn Patricia de Cremoux Cedric de Bazelaire Marcela Albiter Sylvie Giacchetti Caroline Cuvier Anne Janin Marc Espié Hugues de Thé Philippe Bertheau 《Breast cancer research : BCR》2013,15(3):R37
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Xiangqian Guo Shirley X Zhu Alayne L Brunner Matt van de Rijn Robert B West 《Breast cancer research : BCR》2013,15(6):R117