| 61. |
- Kopsida, Maria, et al.
(författare)
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RhoB expression associated with chemotherapy response and prognosis in colorectal cancer
- 2024
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To examine the role of RhoB expression in relation to chemotherapy response, clinical outcomes and associated signaling pathways in colorectal cancer patients.Materials and methods: The study included 5 colon cancer cell lines, zebrafish embryos and 260 colorectal cancer patients treated with 5-fluorouracil (5-FU) and oxaliplatin (OXL). The methods consisted of CRISPR/Cas9, reactive oxygen species (ROS), caspase-3 activity, autophagy flux, in-silico RNA sequencing and immunohistochemistry. Gene expression analysis and pathway analysis were conducted using RNA-seq data.Results: All cancer lines tested, including SW480, SW480-KO13 (RhoB knockout), SW480-KO55 (RhoB knockout), HCT116 and HCT116-OE (RhoB overexpressed), exhibited cytotoxicity to 5-FU and OXL. RhoB knockout cell lines demonstrated significantly reduced migration compared to the control cell lines. Furthermore, RhoB played a role in caspase-3-dependent apoptosis, regulation of ROS production and autophagic flux. The mRNA sequencing data indicated lower expression levels of oncogenes in RhoB knockout cell lines. The zebrafish model bearing SW480-KO showed a light trend toward tumor regression. RhoB expression by immunohistochemistry in patients was increased from normal mucosa to tumor samples. In patients who received chemotherapy, high RhoB expression was related to worse survival compared to low RhoB expression. Furthermore, the molecular docking analysis revealed that OXL had a higher binding affinity for RhoB than 5-FU, with a binding affinity of -7.8 kcal/mol and HADDOCK predicted molecular interactions between RhoB and caspase 3 protein. Gene-set enrichment analysis supported these findings, showing that enrichment of DNA damage response pathway and p53 signaling in RhoB overexpression treatment group, while the RhoB knockout treatment group exhibited enrichment in the negative regulation pathway of cell migration.Conclusion: RhoB was negatively associated with chemotherapy response and survival in colorectal cancers. Therefore, RhoB inhibition may enhance chemotherapeutic responses and patient survival.
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| 62. |
- Kowald, Saskia, et al.
(författare)
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Novel zebrafish patient-derived tumor xenograft methodology for evaluating efficacy of immune-stimulating bcg therapy in urinary bladder cancer
- 2023
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bacillus Calmette-Guérin (BCG) immunotherapy is the standard-of-care adjuvant therapy for non-muscle-invasive bladder cancer in patients at considerable risk of disease recurrence. Although its exact mechanism of action is unknown, BCG significantly reduces this risk in responding patients but is mainly associated with toxic side-effects in those facing treatment resistance. Methods that allow the identification of BCG responders are, therefore, urgently needed.METHODS: Fluorescently labelled UM-UC-3 cells and dissociated patient tumor samples were used to establish zebrafish tumor xenograft (ZTX) models. Changes in the relative primary tumor size and cell dissemination to the tail were evaluated via fluorescence microscopy at three days post-implantation. The data were compared to the treatment outcomes of the corresponding patients. Toxicity was evaluated based on gross morphological evaluation of the treated zebrafish larvae.RESULTS: BCG-induced toxicity was avoided by removing the water-soluble fraction of the BCG formulation prior to use. BCG treatment via co-injection with the tumor cells resulted in significant and dose-dependent primary tumor size regression. Heat-inactivation of BCG decreased this effect, while intravenous BCG injections were ineffective. ZTX models were successfully established for six of six patients based on TUR-B biopsies. In two of these models, significant tumor regression was observed, which, in both cases, corresponded to the treatment response in the patients.CONCLUSIONS: The observed BCG-related anti-tumor effect indicates that ZTX models might predict the BCG response and thereby improve treatment planning. More experiments and clinical studies are needed, however, to elucidate the BCG mechanism and estimate the predictive value.
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| 63. |
- Krishnan, Harini, et al.
(författare)
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Podoplanin: An emerging cancer biomarker and therapeutic target
- 2018
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Ingår i: Cancer Science. - : WILEY. - 1347-9032 .- 1349-7006. ; 109:5, s. 1292-1299
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Forskningsöversikt (refereegranskat)abstract
- Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition, migration, invasion, metastasis and inflammation. Antibodies, CAR-T cells, biologics and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer, including glioma, squamous cell carcinoma, mesothelioma and melanoma.
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| 64. |
- Kumarathunge, Dushan P., et al.
(författare)
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Acclimation and adaptation components of the temperature dependence of plant photosynthesis at the global scale
- 2019
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Ingår i: New Phytologist. - : John Wiley & Sons. - 0028-646X .- 1469-8137. ; 222:2, s. 768-784
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Tidskriftsartikel (refereegranskat)abstract
- The temperature response of photosynthesis is one of the key factors determining predicted responses to warming in global vegetation models (GVMs). The response may vary geographically, owing to genetic adaptation to climate, and temporally, as a result of acclimation to changes in ambient temperature. Our goal was to develop a robust quantitative global model representing acclimation and adaptation of photosynthetic temperature responses.We quantified and modelled key mechanisms responsible for photosynthetic temperature acclimation and adaptation using a global dataset of photosynthetic CO2 response curves, including data from 141 C3 species from tropical rainforest to Arctic tundra. We separated temperature acclimation and adaptation processes by considering seasonal and common-garden datasets, respectively.The observed global variation in the temperature optimum of photosynthesis was primarily explained by biochemical limitations to photosynthesis, rather than stomatal conductance or respiration. We found acclimation to growth temperature to be a stronger driver of this variation than adaptation to temperature at climate of origin.We developed a summary model to represent photosynthetic temperature responses and showed that it predicted the observed global variation in optimal temperatures with high accuracy. This novel algorithm should enable improved prediction of the function of global ecosystems in a warming climate.
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| 65. |
- Kumsars, Indulis, et al.
(författare)
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Randomised comparison of provisional side branch stenting versus a two-stent strategy for treatment of true coronary bifurcation lesions involving a large side branch : the Nordic-Baltic Bifurcation Study IV
- 2020
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Ingår i: Open heart. - : BMJ Publishing Group Ltd. - 2053-3624. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is still uncertain whether coronary bifurcations with lesions involving a large side branch (SB) should be treated by stenting the main vessel and provisional stenting of the SB (simple) or by routine two-stent techniques (complex). We aimed to compare clinical outcome after treatment of lesions in large bifurcations by simple or complex stent implantation.Methods: The study was a randomised, superiority trial. Enrolment required a SB >= 2.75 mm, >= 50% diameter stenosis in both vessels, and allowed SB lesion length up to 15 mm. The primary endpoint was a composite of cardiac death, non-procedural myocardial infarction and target lesion revascularisation at 6 months. Two-year clinical follow-up was included in this primary reporting due to lower than expected event rates.Results: A total of 450 patients were assigned to simple stenting (n = 221) or complex stenting (n=229) in 14 Nordic and Baltic centres. Two-year follow-up was available in 218 (98.6%) and 228 (99.5%) patients, respectively. The primary endpoint of major adverse cardiac events (MACE) at 6 months was 5.5% vs 2.2% (risk differences 3.2%, 95% CI -0.2 to 6.8, p=0.07) and at 2 years 12.9% vs 8.4% (HR 0.63, 95% CI 0.35 to 1.13, p = 0.12) after simple versus complex treatment. In the subgroup treated by newer generation drug-eluting stents, MACE was 12.0% vs 5.6% (HR 0.45, 95% CI 0.17 to 1.17, p = 0.10) after simple versus complex treatment.Conclusion: In the treatment of bifurcation lesions involving a large SB with ostial stenosis, routine two-stent techniques did not improve outcome significantly compared with treatment by the simpler main vessel stenting technique after 2 years.
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| 66. |
- Lee, Chunsik, et al.
(författare)
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VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway
- 2023
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Ingår i: SIGNAL TRANSDUCTION AND TARGETED THERAPY. - : SPRINGERNATURE. - 2095-9907 .- 2059-3635. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.
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| 67. |
- Lee, Samantha Lin Chiou, et al.
(författare)
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Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:46, s. 19485-19490
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms underlying pathological angiogenesis in relation to hypoxia in tumor invasion and metastasis remain elusive. Here, we have developed a zebrafish tumor model that allows us to study the role of pathological angiogenesis under normoxia and hypoxia in arbitrating early events of the metastatic cascade at the single cell level. Under normoxia, implantation of a murine T241 fibrosarcoma into the perivitelline cavity of developing embryos of transgenic fli1:EGFP zebrafish did not result in significant dissemination, invasion, and metastasis. In marked contrast, under hypoxia substantial tumor cells disseminated from primary sites, invaded into neighboring tissues, and metastasized to distal parts of the fish body. Similarly, expression of the hypoxia-regulated angiogenic factor, vascular endothelial growth factor (VEGF) to a high level resulted in tumor cell dissemination and metastasis, which correlated with increased tumor neovascularization. Inhibition of VEGF receptor signaling pathways by sunitinib or VEGFR2 morpholinos virtually completely ablated VEGF-induced tumor cell dissemination and metastasis. To the best of our knowledge, hypoxia- and VEGF-induced pathological angiogenesis in promoting tumor dissemination, invasion, and metastasis has not been described perviously at the single cell level. Our findings also shed light on molecular mechanisms of beneficial effects of clinically available anti-VEGF drugs for cancer therapy.
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| 68. |
- Lennikov, Anton, et al.
(författare)
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Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis
- 2018
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Ingår i: Angiogenesis. - : Springer Netherlands. - 0969-6970 .- 1573-7209. ; 21:2, s. 267-285
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Tidskriftsartikel (refereegranskat)abstract
- Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-kappa B signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-kappa B activation through selective blockade of the IKK complex I kappa B kinase beta (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNF alpha-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-alpha expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-kappa B by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-kappa B signaling in the development of pathologic corneal neovascularization.
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| 69. |
- Lindahl, Gabriel, et al.
(författare)
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Zebrafish tumour xenograft models: a prognostic approach to epithelial ovarian cancer
- 2024
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Ingår i: npj Precision Oncology. - : NATURE PORTFOLIO. - 2397-768X. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Epithelial ovarian cancer (EOC) is the gynaecological malignancy with highest mortality. Although adjuvant treatment with carboplatin and paclitaxel leads to an objective response in similar to 80% of these patients, a majority will relapse within two years. Better methods for assessing long-term treatment outcomes are needed. To address this, we established safe and efficacious doses of carboplatin and paclitaxel using IGROV-1 zebrafish-CDX models. Then fluorescently-labelled cell suspensions from 83 tumour biopsies collected at exploratory laparotomy of women with suspected EOC were generated and 37 (45%) were successfully implanted in zebrafish larvae. Among these 19 of 27 pathology-confirmed EOC samples (70%) engrafted. These zebrafish patient-derived tumour xenograft (ZTX) models were treated with carboplatin or paclitaxel and tumour growth/regression and metastatic dissemination were recorded. In a subgroup of nine patients, four ZTX models regressed during carboplatin treatment. All four corresponding patients had > 24 months PFS. Furthermore, both ZTX models established from two patients having < 24 months PFS failed to regress during carboplatin treatment. Seven of eight models seeding < 6 metastatic cells were established from patients having > 24 months PFS. In eleven of fourteen patients, FIGO stage I + II or III tumours gave rise to ZTX models seeding < 4 or > 4 metastatic cells, respectively. In conclusion, ZTX models predicted patients having > 24 or < 24 months PFS, based on response/no response to carboplatin. Furthermore, high metastatic dissemination in ZTX models correlated to shorter PFS and more advanced disease at diagnosis. These preliminary results suggest that ZTX models could become a useful prognostic tool in EOC treatment planning.
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| 70. |
- Liu, Caifeng, et al.
(författare)
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A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis
- 2017
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 23:16, s. 4769-4779
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor is at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAF) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes. Experimental Design: Multicolor-coded cancer cells and CAFs were coimplanted into the transparent zebrafish body and metastasis at a single-cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis. Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor was at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained in tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity. Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development. (C) 2017 AACR.
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