| 1. |
- Arildsen, Nicolai Skovbjerg, et al.
(författare)
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Simvastatin is a potential candidate drug in ovarian clear cell carcinomas
- 2020
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Ingår i: Oncotarget. - 1949-2553. ; 11:40, s. 3660-3674
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian clear cell carcinomas (OCCC) constitute a rare subtype of epithelial ovarian cancer, lacking efficient treatment options. Based on previous studies, we assessed the anti-proliferative effect of simvastatin, a Rho GTPase interfering drug, in three OCCC cell lines: JHOC-5, OVMANA and TOV-21G, and one high-grade serous ovarian cancer (HGSOC) cell line, Caov3. We used the Rho GTPase interfering drug CID-1067700 as a control. All OCCC cell lines were more sensitive to single-agent simvastatin than the HGSOC cells, while all cell lines were less sensitive to CID-1067700 than to simvastatin. Combinations of carboplatin and simvastatin were generally antagonistic. Most treatments inhibited migration, while only simvastatin and CID-1067700 also disrupted actin organization in the OCCC cell lines. All treatments induced a G1 arrest in JHOC-5 and TOV-21G cells. Treatments with simvastatin consistently reduced c-Myc protein expression in all OCCC cell lines and displayed evidence of causing both caspase-mediated apoptotic cell death and autophagic response in a cell line dependent manner. Differences between cell lines in response to the treatments were observed and such differences, including e. g. prior treatment, should be investigated further. Conclusively, simvastatin efficiently controlled OCCC proliferation and migration, thus showing potential as a candidate drug for the treatment of OCCC.
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| 2. |
- Bayani, Jane, et al.
(författare)
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Evaluation of multiple transcriptomic gene risk signatures in male breast cancer
- 2021
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Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these tests in male BCa. Here we present the gene expression results of 381 M0, ER+ve, HER2-ve male BCa patients enrolled in the Part 1 (retrospective analysis) of the International Male Breast Cancer Program. Using a custom NanoString™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDX®, and MammaPrint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by us previously. We also examined the prognostic value of other risk scores such as the Genomic Grade Index (GGI), IHC4-mRNA and our prognostic 95-gene signature. In this sample set of male BCa, we demonstrated prognostic utility on univariate analysis. Across all signatures, patients whose samples were identified as low-risk experienced better outcomes than intermediate-risk, with those classed as high risk experiencing the poorest outcomes. As seen with female BCa, the concordance between tests was poor, with C-index values ranging from 40.3% to 78.2% and Kappa values ranging from 0.17 to 0.58. To our knowledge, this is the largest study of male breast cancers assayed to generate risk scores of the current commercial and academic risk tests demonstrating comparable clinical utility to female BCa.
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| 3. |
- Briem, Oscar, et al.
(författare)
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CD169+ Macrophages in Primary Breast Tumors Associate with Tertiary Lymphoid Structures, Tregs and a Worse Prognosis for Patients with Advanced Breast Cancer
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- The presence of CD169+ macrophages in the draining lymph nodes of cancer patients is, for unknown reasons, associated with a beneficial prognosis. We here investigated the prognostic impact of tumor-infiltrating CD169+ macrophages in primary tumors (PTs) and their spatial relation to tumor-infiltrating B and T cells. Using two breast cancer patient cohorts, we show that CD169+ macrophages were spatially associated with the presence of B and T cell tertiary lymphoid-like structures (TLLSs) in both PTs and lymph node metastases (LNMs). While co-infiltration of CD169+/TLLS in PTs correlated with a worse prognosis, the opposite was found when present in LNMs. RNA sequencing of breast tumors further confirmed that SIGLEC1 (CD169) expression was associated with mature tertiary lymphoid structure (TLS), and Treg and Breg signatures. We propose that the negative prognostic value related to CD169+ macrophages in PTs is a consequence of an immunosuppressive tumor environment rich in TLSs, Tregs and Bregs.
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| 4. |
- Bååth, Maria, et al.
(författare)
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MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer
- 2021
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.
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| 5. |
- Bååth, Maria, et al.
(författare)
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SOX2 is a promising predictor of relapse and death in advanced stage high-grade serous ovarian cancer patients with residual disease after debulking surgery
- 2020
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Ingår i: Molecular and Cellular Oncology. - : Informa UK Limited. - 2372-3556. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor SOX2 is a well-established and important stem cell marker. Its role in cancer biology remains unclear, but it has been proposed to also be a marker of cancer stem cells. We investigated the role of SOX2 protein expression in women with high-grade serous ovarian cancer (HGSOC) to determine its potential prognostic and treatment predictive value. We constructed a tissue microarray of 130 advanced stage HGSOC tumors with an average of 6 cores each, stained for SOX2 protein expression and evaluated survival outcomes. We also treated two HGSOC cell lines with carboplatin and paclitaxel and measured SOX2 expression by RT-PCR and immunoblotting at different doses and time-points. Among patients with non-radical debulking surgery overall and progression-free survival were shorter for patients with SOX2 positive tumors (mean 26 vs. 39 months, log-rank test: p = .0076, and mean 14 vs. 19 months, p = .055, respectively). Knockdown of SOX2 in cell lines did not affect growth inhibition following chemotherapy treatment. Our results show that SOX2 has a strong prognostic potential among HGSOC patients with residual tumor tissue after debulking surgery and suggest that SOX2 expressing cells remaining after non-radical debulking surgery may constitute a subpopulation of cancer stem cells with greater tumor-initiating potential.
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| 6. |
- Ciesla, Maciej, et al.
(författare)
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Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer
- 2021
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765. ; 81:7
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Tidskriftsartikel (refereegranskat)abstract
- Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Here we unravel the core splice factor SF3A3 at the nexus of a translation-based program that rewires splicing during malignant transformation. Upon MYC hyperactivation, SF3A3 levels are modulated translationally through an RNA stem-loop in an eIF3D-dependent manner. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Our analysis reveals that SF3A3 protein levels predict molecular and phenotypic features of aggressive human breast cancers. These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis.
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| 7. |
- Corvigno, Sara, et al.
(författare)
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High density of stroma-localized CD11c-positive macrophages is associated with longer overall survival in high-grade serous ovarian cancer.
- 2020
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 159:3, s. 860-868
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Pre-clinical studies have identified marker- and tumor compartment-defined functionally distinct macrophage subsets. Our study analyzes marker-defined macrophage subsets in different tumor compartments of high-grade serous ovarian cancer (HGSC).METHODS: A discovery cohort (N = 113) was subjected to immunohistochemistry (IHC) analyses. CD68-positivity was confirmed for CD11c-, CD80- and CD163-positive cells. Subset-marker-positive cells were scored in the total tumor and in four tumor compartments. Correlation analyses investigated co-expression of subsets, relationship to CD8+ cells and survival associations. A validation cohort (N = 121) was used to confirm selected findings from the discovery cohort.RESULTS: CD163-positve cells was the most abundant subtype in all compartments. CD11c and CD163 subsets were strongly correlated with each other in stroma and epithelial areas, whereas CD80 and CD163 were correlated in epithelial areas. CD80 and CD11c in perivascular areas showed low correlations. Strong associations were detected between CD8 and CD80 in the tumor epithelium-dominated areas, and between CD8 and CD11c in stroma areas. High stromal CD11c density was associated with a longer median overall survival in the discovery cohort (HR 0.39; CI 95%, 0.23-0.68; p = 0.001) and in the validation cohort (HR 0.46; CI 95%, 0.22-0.93; p = 0.03).CONCLUSIONS: Our study supports the existence of clinically relevant marker- and localization defined macrophage subsets in HGSC, which are independently regulated. Moreover, it suggests stromal CD11c as a novel prognostic marker in HGSC.
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| 8. |
- Fleischer, Thomas, et al.
(författare)
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An integrated omics approach highlights how epigenetic events can explain and predict response to neoadjuvant chemotherapy and bevacizumab in breast cancer
- 2024
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Ingår i: Molecular Oncology. - 1574-7891 .- 1878-0261.
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with the anti-angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic data in breast cancer patients to predict response to therapy and pinpoint response-related epigenetic events. Fresh-frozen tumor biopsies taken before, during, and after treatment from human epidermal growth factor receptor 2 negative non-metastatic patients receiving neoadjuvant chemotherapy with or without bevacizumab were subjected to molecular profiling. Here, we report that DNA methylation at enhancer CpGs related to cell cycle regulation can predict response to chemotherapy and bevacizumab for the estrogen receptor positive subset of patients (AUC = 0.874), and we validated this observation in an independent patient cohort with a similar treatment regimen (AUC = 0.762). Combining the DNA methylation scores with the scores from a previously published protein signature resulted in a slight increase in the prediction performance (AUC = 0.784). We also show that tumors receiving the combination treatment underwent more extensive epigenetic alterations. Finally, we performed an integrative expression–methylation quantitative trait loci analysis on alterations in DNA methylation and gene expression levels, showing that the epigenetic alterations that occur during treatment are different between responders and non-responders and that these differences may be explained by the proliferation–epithelial-to-mesenchymal transition axis through the activity of grainyhead like transcription factor 2. Using tumor purity computed from copy number data, we developed a method for estimating cancer cell-specific methylation to confirm that the association to response reflects DNA methylation in cancer cells. Taken together, these results support the potential for clinical benefit of the addition of bevacizumab to chemotherapy when administered to the correct patients.
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| 9. |
- Gunnarsdottir, Frida Björk, et al.
(författare)
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Breast cancer associated CD169(+) macrophages possess broad immunosuppressive functions but enhance antibody secretion by activated B cells
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- CD169(+) resident macrophages in lymph nodes of breast cancer patients are for unknown reasons associated with a beneficial prognosis. This contrasts CD169(+) macrophages present in primary breast tumors (CD169(+) TAMs), that correlate with a worse prognosis. We recently showed that these CD169(+) TAMs were associated with tertiary lymphoid structures (TLSs) and T-regs in breast cancer. Here, we show that CD169(+) TAMs can be monocyte-derived and express a unique mediator profile characterized by type I IFNs, CXCL10, PGE(2) and inhibitory co-receptor expression pattern. The CD169(+) monocyte-derived macrophages (CD169(+) Mo-M) possessed an immunosuppressive function in vitro inhibiting NK, T and B cell proliferation, but enhanced antibody and IL6 secretion in activated B cells. Our findings indicate that CD169(+) Mo-M in the primary breast tumor microenvironment are linked to both immunosuppression and TLS functions, with implications for future targeted Mo-M therapy.
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| 10. |
- Haugen, Mads H., et al.
(författare)
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Protein signature predicts response to neoadjuvant treatment with chemotherapy and bevacizumab in HER2-negative breast cancers
- 2021
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Ingår i: JCO Precision Oncology. - 2473-4284. ; 5, s. 286-306
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Antiangiogenic therapy using bevacizumab has proven effective for a number of cancers; however, in breast cancer (BC), there is an unmet need to identify patients who benefit from such treatment. PATIENTS AND METHODS In the NeoAva phase II clinical trial, patients (N = 132) with large (= 25 mm) human epidermal growth factor receptor 2 (HER2)-negative primary tumors were randomly assigned 1:1 to treatment with neoadjuvant chemotherapy (CTx) alone or in combination with bevacizumab (Bev plus CTx). The ratio of the tumor size after relative to before treatment was calculated into a continuous response scale. Tumor biopsies taken prior to neoadjuvant treatment were analyzed by reverse-phase protein arrays (RPPA) for expression levels of 210 BC-relevant (phospho-) proteins. Lasso regression was used to derive a predictor of tumor shrinkage from the expression of selected proteins prior to treatment. RESULTS We identified a nine-protein signature score named vascular endothelial growth factor inhibition response predictor (ViRP) for use in the Bev plus CTx treatment arm able to predict with accuracy pathologic complete response (pCR) (area under the curve [AUC] = 0.85; 95% CI, 0.74 to 0.97) and low residual cancer burden (RCB 0/I) (AUC = 0.80; 95% CI, 0.68 to 0.93). The ViRP score was significantly lower in patients with pCR (P< .001) and in patients with low RCB (P<.001). The ViRP score was internally validated on mRNA data and the resultant surrogate mRNA ViRP score significantly separated the pCR patients (P = .016). Similarly, the mRNA ViRP score was validated (P < .001) in an independent phase II clinical trial (PROMIX). CONCLUSION Our ViRP score, integrating the expression of nine proteins and validated on mRNA data both internally and in an independent clinical trial, may be used to increase the likelihood of benefit from treatment with bevacizumab combined with chemotherapy in patients with HER2-negative BC.
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