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1.
Turid Hellevik Ingvild Pettersen Vivian Berg Jack Bruun Kristian Bartnes Lill-Tove Busund Anthony Chalmers Roy Bremnes Iñigo Martinez-Zubiaurre 《Translational oncology》2013,6(1):66-74
In the context of radiotherapy, collateral effects of ablative doses of ionizing radiation (AIR) on stromal components of tumors remains understudied. In this work, cancer-associated fibroblasts (CAFs) isolated from freshly resected human lung tumors were exposed to AIR (1x 18 Gy) and analyzed for their release of paracrine factors. Inflammatory mediators and regulators of angiogenesis and tumor growth were analyzed by multiplex protein assays in conditioned medium (CM) from irradiated and non-irradiated CAFs. Additionally, the profile of secreted proteins was examined by proteomics. In functional assays, effects of CAF-CM on proliferative and migratory capacity of lung tumor cells (H-520/H-522) and human umbilical vein endothelial cells (HUVECs) and their tube-forming capacity were assessed. Our data show that exposure of CAFs to AIR results in 1) downregulated release of angiogenic molecules such as stromal cell-derived factor-1, angiopoietin, and thrombospondin-2 (TSP-2); 2) upregulated release of basic fibroblast growth factor from most donors; and 3) unaffected expression levels of hepatocyte growth factor, interleukin-6 (IL-6), IL-8, IL-1β, and tumor necrosis factor-α. CM from irradiated and control CAFs did not affect differently the proliferative or migratory capacity of tumor cells (H-520/H-522), whereas migratory capacity of HUVECs was partially reduced in the presence of irradiated CAF-CM. Overall, we conclude that AIR mediates a transformation on the secretory profile of CAFs that could influence the behavior of other cells in the tumor tissue and hence guide therapeutic outcomes. Downstream consequences of the changes observed in this study merits further investigations. 相似文献
2.
Thomas K. Kilvaer Erna-Elise Paulsen Sigurd M. Hald Tom Wilsgaard Roy M. Bremnes Lill-Tove Busund Tom Donnem 《PloS one》2015,10(8)
Background
In non-small cell lung cancer (NSCLC), nodal metastasis is an adverse prognostic factor. Several mediating factors have been implied in the development of nodal metastases and investigated for predictive and prognostic properties in NSCLC. However, study results differ. In this structured review and meta-analysis we explore the published literature on commonly recognized pathways for molecular regulation of lymphatic metastasis in NSCLC.Methods
A structured PubMed search was conducted for papers reporting on the expression of known markers of lymhangiogenesis in NSCLC patients. Papers of sufficient quality, presenting survival and/or correlation data were included.Results
High levels of vascular endothelial growth factor C (VEGF-C, HR 1.57 95% CI 1.34–1.84) and high lymphatic vascular density (LVD, HR 1.84 95% CI 1.18–2.87) were significant prognostic markers of poor survival and high expression of VEGF-C, vascular endothelial growth factor receptor 3 (VEGFR3) and LVD was associated with lymph node metastasis in NSCLC.Conclusion
Lymphangiogenic markers are prognosticators of survival and correlate with lymph node metastasis in NSCLC. Their exact role and clinical implications should be further elucidated. 相似文献3.
Aims
Transforming growth factor-β (TGF-β), fascin, nuclear factor-kappa B (NF-κB) p105, protein-kinase C-zeta (PKC-ζ), partioning-defective protein-6 (Par-6), E-cadherin and vimentin are tumor promoting molecules through mechanisms involved in cell dedifferentiation. In soft tissue sarcomas, their expression profile is poorly defined and their significance is uncertain. We aimed to investigate the prognostic impact of TGF-β1, NF-κB p105, PKC-ζ, Par-6α, E-cadherin and vimentin in non-gastrointestinal stromal tumor soft tissue sarcomas (non-GIST STSs).Patients and Methods
Tumor samples and clinical data from 249 patients with non-GIST STS were obtained, and tissue microarrays (TMAs) were constructed for each specimen. Immunohistochemistry (IHC) was used to evaluate marker expression in tumor cells.Results
In univariate analysis, the expression levels of TGF-β1 (P = 0.016), fascin (P = 0.006), NF-κB p105 (P = 0.022) and PKC-ζ, (P = 0.042) were significant indicators for disease specific survival (DSS). In the multivariate analysis, high TGF-β1 expression was an independent negative prognostic factor for DSS (HR = 1.6, 95% CI = 1.1–2.4, P = 0.019) in addition to tumor depth, malignancy grade, metastasis at diagnosis, surgery and positive resection margins.Conclusion
Expression of TGF-β1 was significantly associated with aggressive behavior and shorter DSS in non-GIST STSs. 相似文献4.
Elin Richardsen Rebecca Dale Uglehus Jan Due Christer Busch Lill-Tove Busund 《Cancer epidemiology》2010,34(3):316-322
Background: The immune modulating molecules cyclooxygenase-2 (COX-2), transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) have regulatory roles in cancer progression. There are conflicting data regarding the roles of these molecules in prostate cancer. To elucidate the prognostic impact of these proteins and provide information on prognosis and treatment, we compared the expression of COX-2, TGF-β, and IL-10 in prostate cancer specimens with or without metastases. Ki67 was included as a measure of growth fraction of tumor cells. Methods: Digital video analysis images from tumor cell areas and tumor stromal areas were analyzed on formalin fixed, paraffin-embedded and immunohistochemical stained cancer specimens from 59 patients: 32 patients with metastases and 27 patients without clinical, biochemical, or radiological evidence of metastases within 10 years after diagnosis. The expression of COX-2 was scored as negative, weak, moderate, or strong. The expressions of TGF-β and IL-10 were assessed as proportions of moderately or strongly stained cells. Ki67 was detected as strong nuclear staining in proliferating cells. Results: In primary cancers in the metastatic group, COX-2, TGF-β and Ki67 were stronger expressed in epithelial tumor cell and tumor stromal areas compared with non-metastatic cancers (for all markers, p < 0.0001). High intensity of COX-2 staining in tumor areas was strongly associated with death from prostate cancer in univariate analyses (hazard ratio [HR] 95% CI, 4.0 (1.1–14.5)). In multivariate analyses, the risk estimate was strengthened but did not reach significance. No associations to death were found for the other markers. Conclusion: High expression of COX-2, TGF-β and Ki67 were in metastatic primary prostate carcinoma compared to non-metastatic cancers. High expression of COX-2 was associated to death from prostate carcinoma. 相似文献
5.
Sveinung W. Sorbye Thomas K. Kilvaer Andrej Valkov Tom Donnem Eivind Smeland Khalid Al-Shibli Roy M. Bremnes Lill-Tove Busund 《PloS one》2012,7(10)
Purpose
The purpose of this study is to clarify the prognostic significance of expression of Jab1, p16, p21, p62, Ki67 and Skp2 in soft tissue sarcomas (STS). Optimised treatment of STS requires better identification of high risk patients who will benefit from adjuvant therapy. The prognostic significance of Jab1, p16, p21, p62, Ki67 and Skp2 in STS has not been sufficiently investigated.Experimental Design
Tissue microarrays from 193 STS patients were constructed from duplicate cores of viable and representative neoplastic tumor areas. Immunohistochemistry was used to evaluate the expression of Jab1, p16, p21, p62, Ki67 and Skp2.Results
In univariate analyses, high tumor expression of Ki67 (P = 0.007) and Skp2 (P = 0.050) correlated with shorter disease-specific survival (DSS). In subgroup analysis, a correlation between Skp2 and DSS was seen in patients with malignancy grade 1 or 2 (P = 0.027), tumor size >5 cm (P = 0.018), no radiotherapy given (P = 0.029) and no chemotherapy given (P = 0.017). No such relationship was apparent for Jab1, p16, p21 and p62; but p62 showed a positive correlation to malignancy grade (P = 0.019). Ki67 was strongly positively correlated to malignancy grade (P = 0.001). In multivariate analyses, Skp2 was an independent negative prognostic factor for DSS in women (P = 0.009) and in patients without administered chemotherapy or radiotherapy (P = 0.026).Conclusions
Increased expression of Skp2 in patients with soft tissue sarcomas is an independent negative prognostic factor for disease-specific survival in women and in patients not administered chemotherapy or radiotherapy. Besides, further studies are warranted to explore if adjuvant chemotherapy or radiotherapy improve the poor prognosis of STS with high Skp2 expression. 相似文献6.
Marte Eilertsen Sigve Andersen Samer Al-Saad Yury Kiselev Tom Donnem Helge Stenvold Ingvild Pettersen Khalid Al-Shibli Elin Richardsen Lill-Tove Busund Roy M. Bremnes 《PloS one》2014,9(9)
Introduction
Monocarboxylate transporters (MCTs) 1–4 are lactate transporters crucial for cancers cells adaption to upregulated glycolysis. Herein, we aimed to explore their prognostic impact on disease-specific survival (DSS) in both cancer and tumor stromal cells in NSCLC.Methods
Tissue micro arrays (TMAs) were constructed, representing both cancer and stromal tumor tissue from 335 unselected patients diagnosed with stage I–IIIA NSCLC. Immunohistochemistry was used to evaluate the expression of MCT1-4.Results
In univariate analyses; ↓MCT1 (P = 0.021) and ↑MCT4 (P = 0.027) expression in cancer cells, and ↑MCT1 (P = 0.003), ↓MCT2 (P = 0.006), ↓MCT3 (P = 0.020) expression in stromal cells correlated significantly with a poor DSS. In multivariate analyses; ↓MCT1 expression in cancer cells (HR: 1.9, CI 95%: 1.3–2.8, P = 0.001), ↓MCT2 (HR: 2.4, CI 95%: 1.5–3.9, P<0.001), ↓MCT3 (HR: 1.9, CI 95%: 1.1–3.5, P = 0.031) and ↑MCT1 expression in stromal cells (HR: 1.7, CI 95%: 1.1–2.7, P = 0.016) were significant independent poor prognostic markers for DSS.Conclusions
We provide novel information of MCT1 as a candidate marker for prognostic stratification in NSCLC. Interestingly, MCT1 shows diverging, independent prognostic impact in the cancer cell and stromal cell compartments. 相似文献7.
Andersen S Donnem T Stenvold H Al-Saad S Al-Shibli K Busund LT Bremnes RM 《PloS one》2011,6(8):e23847
Introduction
Hypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival. HIFs are regulated by four hydroxylases; Prolyl hydroxylase (PHD)-1,-2,-3 and factor inhibiting HIF (FIH). We aimed to investigate the prognostic impact of these oxygen sensors in NSCLC.Methods
Tumor tissue samples from 335 resected stages I to IIIA NSCLC patients was obtained and tissue microarrays (TMAs) were constructed. Hydroxylase expression was evaluated by immunohistochemistry.Principal Findings
There was scorable expression for all HIF hydroxylases in tumor cells, but not in stroma. In univariate analyses, high tumor cell expression of all the HIF hydroxylases were unfavorable prognosticators for disease-specific survival (DSS); PHD1 (P = 0.023), PHD2 (P = 0.013), PHD3 (P = 0.018) and FIH (P = 0.033). In the multivariate analyses we found high tumor cell expression of PHD2 (HR = 2.03, CI 95% 1.20–3.42, P = 0.008) and PHD1 (HR = 1.45, CI 95% 1.01–2.10, P = 0.047) to be significant independent prognosticators for DSS. Besides, there was an additive prognostic effect by the increasing number of highly expressed HIF hydroxylases. Provided none high expression HIF hydroxylases, the 5-year survival was 80% vs. 23% if all four were highly expressed (HR = 6.48, CI 95% 2.23–18.8, P = 0.001).Conclusions
HIF hydroxylases are, in general, poor prognosticators for NSCLC survival. PHD1 and PHD2 are independent negative prognostic factors in NSCLC. Moreover, there is an additive poor prognostic impact by an increasing number of highly expressed HIF hydroxylases. 相似文献8.
Thomas K. Kilvaer Mehrdad Rakaee Khanehkenari Turid Hellevik Samer Al-Saad Erna-Elise Paulsen Roy M. Bremnes Lill-Tove Busund Tom Donnem Inigo Z. Martinez 《PloS one》2015,10(8)
Background
Cancer Associated Fibroblasts (CAFs) are thought to regulate tumor growth and metastasis. Fibroblast Activating Protein 1 (FAP-1) is a marker for fibroblast activation and by many recognized as the main marker of CAFs. Alpha Smooth Muscle Actin (α-SMA) is a general myofibroblast marker, and can be used to identify CAFs. This study investigates the prognostic impact of FAP-1 and α-SMA in non-small cell lung cancer (NSCLC) patients and correlates their expression to 105 proteins investigated in the same cohort.Methods
Tumor specimens from 536 NSCLC patients were obtained and tissue micro-arrays were constructed. Immunohistochemistry was used to evaluate the expression of FAP-1 and α-SMA and explore their impact on survival and association with other tumor molecular markers in NSCLC patients.Results
High expression of FAP-1, but not α-SMA, in squamous cell carcinoma (SCC, P = 0.043, HR = 0.63 95% CI 0.40–0.99) was significantly associated with increased disease-specific survival. FAP-1 and α-SMA were not significantly correlated to each other. Analyses of FAP-1 and α-SMA associated with other tumor-related proteins revealed histotype-specific correlation patterns.Conclusion
The presence of FAP-1 expressing CAFs is an indicator of positive outcome for NSCLC-SCC patients. In addition, correlation analyses suggest FAP-1 and α-SMA to label different subsets of fibroblasts and their associations with other tumor-related proteins diverge according to histological subtype. 相似文献9.
Background
In non-gastrointestinal stromal tumor soft tissue sarcoma (non-GIST STS) optimal treatment is surgery with wide resection margins. Vascular endothelial growth factors (VEGFs) and receptors (VEGFRs) are known to be key players in the initiation of angiogenesis and lymphangiogenesis. This study investigates the prognostic impact of VEGFs and VEGFRs in non-GIST STS with wide and non-wide resection margins.Methods
Tumor samples from 249 patients with non-GIST STS were obtained and tissue microarrays were constructed for each specimen. Immunohistochemistry was used to evaluate the expressions of VEGF-A, -C and -D and VEGFR-1, -2 and -3.Results
In the univariate analyses, VEGF-A (P = 0.040) in the total material, and VEGF-A (P = 0.018), VEGF-C (P = 0.025) and VEGFR-3 (P = 0.027) in the subgroup with wide resection margins, were significant negative prognostic indicators of disease-specific survival (DSS). In the multivariate analysis, high expression of VEGFR-3 (P = 0.042, HR = 1.907, 95% CI 1.024-3.549) was an independent significant negative prognostic marker for DSS among patients with wide resection margins.Conclusion
VEGFR-3 is a strong and independent negative prognostic marker for non-GIST STSs with wide resection margins. 相似文献10.
Christian Melb?-J?rgensen Nora Ness Sigve Andersen Andrej Valkov Tom D?nnem Samer Al-Saad Yury Kiselev Thomas Berg Yngve Nordby Roy M. Bremnes Lill-Tove Busund Elin Richardsen 《PloS one》2014,9(11)