| 1. |
- Harbst, Katja, et al.
(författare)
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Molecular and genetic diversity in the metastatic process of melanoma.
- 2014
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 233:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk.
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| 2. |
- Augsten, Martin, et al.
(författare)
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Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties
- 2014
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Ingår i: Cancer Research. - 1538-7445. ; 74:11, s. 2999-3010
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Tidskriftsartikel (refereegranskat)abstract
- Cancer-associated fibroblasts (CAF) stimulate tumor growth and metastasis. Signals supporting CAF function are thus emerging as candidate therapeutic targets in the tumor microenvironment. The chemokine CXCL14 is a potent inducer of CAF protumorigenic functions. This study is aimed at learning how the protumoral functions of CXCL14-expressing CAF are maintained. We found that the nitric oxide synthase NOS1 is upregulated in CXCL14-expressing CAF and in fibroblasts stimulated with CXCL14. Induction of Nos1 was associated with oxidative stress and occurred together with activation of NRF2 and HIF1 alpha signaling in CXCL14-expressing CAF. Genetic or pharmacologic inhibition of NOS1 reduced the growth of CXCL14-expressing fibroblasts along with their ability to promote tumor formation following coinjection with prostate or breast cancer cells. Tumor analysis revealed reduced macrophage infiltration, with NOS1 downregulation in CXCL14-expressing CAF and lymphangiogenesis as a novel component of CXCL14-promoted tumor growth. Collectively, our findings defined key components of a signaling network that maintains the protumoral functions of CXCL14-stimulated CAF, and they identified NOS1 as intervention target for CAF-directed cancer therapy. (C) 2014 AACR.
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| 3. |
- Frings, Oliver, et al.
(författare)
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Prognostic Significance in Breast Cancer of a Gene Signature Capturing Stromal PDGF Signaling
- 2013
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 182:6, s. 2037-2047
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we describe a novel gene expression signature of platelet-derived growth factor (PDGF) activated fibroblasts, which is able to identify breast cancers with a PDGF-stimulated fibroblast stroma and displays an independent and strong prognostic significance. Global gene expression was compared between PDGF-stimulated human fibroblasts and cultured resting fibroblasts. The most differentially expressed genes were reduced to a gene expression signature of 113 genes. The biological significance and prognostic capacity of this signature were investigated using four independent clinical breast cancer data sets. Concomitant high expression of PDGF beta receptor and its cognate Ligands is associated with a high PDGF signature score. This supports the notion that the signature detects tumors with PDGF-activated stroma. Subsequent analyses indicated significant associations between high PDGF signature score and clinical characteristics, including human epidermal growth factor receptor 2 positivity, estrogen receptor negativity, high tumor grade, and large tumor size. A high PDGF signature score is associated with shorter survival in univariate analysis. Furthermore, the high PDGF signature score acts as a significant marker of poor prognosis in multivariate survival analyses, including classic prognostic markers, Ki-67 status, a proliferation gene signature, or other recently described stroma-derived gene expression signatures.
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| 4. |
- Olsson, Eleonor, et al.
(författare)
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CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers.
- 2011
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The CD44 cell adhesion molecule is aberrantly expressed in many breast tumors and has been implicated in the metastatic process as well as in the putative cancer stem cell (CSC) compartment. We aimed to investigate potential associations between alternatively spliced isoforms of CD44 and CSCs as well as to various breast cancer biomarkers and molecular subtypes. METHODS: We used q-RT-PCR and exon-exon spanning assays to analyze the expression of four alternatively spliced CD44 isoforms as well as the total expression of CD44 in 187 breast tumors and 13 cell lines. ALDH1 protein expression was determined by IHC on TMA. RESULTS: Breast cancer cell lines showed a heterogeneous expression pattern of the CD44 isoforms, which shifted considerably when cells were grown as mammospheres. Tumors characterized as positive for the CD44+/CD24- phenotype by immunohistochemistry were associated to all isoforms except the CD44 standard (CD44S) isoform, which lacks all variant exons. Conversely, tumors with strong expression of the CSC marker ALDH1 had elevated expression of CD44S. A high expression of the CD44v2-v10 isoform, which retain all variant exons, was correlated to positive steroid receptor status, low proliferation and luminal A subtype. The CD44v3-v10 isoform showed similar correlations, while high expression of CD44v8-v10 was correlated to positive EGFR, negative/low HER2 status and basal-like subtype. High expression of CD44S was associated with strong HER2 staining and also a subgroup of basal-like tumors. Unsupervised hierarchical cluster analysis of CD44 isoform expression data divided tumors into four main clusters, which showed significant correlations to molecular subtypes and differences in 10-year overall survival. CONCLUSIONS: We demonstrate that individual CD44 isoforms can be associated to different breast cancer subtypes and clinical markers such as HER2, ER and PgR, which suggests involvement of CD44 splice variants in specific oncogenic signaling pathways. Efforts to link CD44 to CSCs and tumor progression should consider the expression of various CD44 isoforms.
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| 5. |
- Pena, Cristina, et al.
(författare)
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STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer
- 2013
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 74:4, s. 1287-1297
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4); 1287-97.
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| 6. |
- Wikman, Agneta Taune, et al.
(författare)
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Noninvasive Single-Exon Fetal RHD Determination in a Routine Screening Program in Early Pregnancy.
- 2012
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Ingår i: Obstetrics and Gynecology. - 1873-233X. ; 120:2, s. 227-234
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop a simple and robust assay suitable for fetal RHD screening in first-trimester pregnancy and to estimate the sensitivity and specificity of the test after its implementation in an unselected pregnant population. METHODS: Pregnant women attending their first antenatal visit were included, and fetal RHD determination was performed for all women who typed RhD-negative by routine serology. DNA was extracted by an automated system and quantitative polymerase chain reaction was done by an assay based on exon 4. Reporting criteria were simple and strict. RESULTS: Four thousand one hundred eighteen pregnancies, with a median gestational age of 10 weeks, were included. After 211 (5.1%) reanalyses, fetal RHD was reported positive in 2,401 (58.3%), negative in 1,552 (37.7%), and inconclusive in 165 (4.0%) based on the first sample. After a second sample in 147 of 165, only 14 remained inconclusive, all resulting from a weak or silent maternal RHD gene. Using blood group serology of the newborns as the gold standard, the false-negative rate was 55 of 2,297 (2.4%) and the false-positive rate was 15 of 1,355 (1.1%). After exclusion of samples obtained before gestational week 8, the false-negative rate was 23 of 2,073 (1.1%) and the false-positive rate was 14 of 1,218 (1.1%). Both sensitivity and specificity were close to 99% provided samples were not collected before gestational week 8. From gestational week 22, sensitivity was 100%. CONCLUSION: : Fetal RHD detection in early pregnancy using a single-exon assay in a routine clinical setting is feasible and accurate. LEVEL OF EVIDENCE: : I.
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