| 1. |
- Jensen, Lasse Dahl, et al.
(författare)
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Clock controls angiogenesis
- 2013
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Ingår i: Cell Cycle. - : Landes Bioscience. - 1538-4101 .- 1551-4005. ; 12:3, s. 405-408
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Tidskriftsartikel (refereegranskat)abstract
- Circadian rhythms control multiple physiological and pathological processes, including embryonic development in mammals and development of various human diseases. We have recently, in a developing zebrafish embryonic model, discovered that the circadian oscillation controls developmental angiogenesis. Disruption of crucial circadian regulatory genes, including Bmal1 and Period2, results in marked impairment or enhancement of vascular development in zebrafish. At the molecular level, we show that the circadian regulator Bmal1 directly targets the promoter region of the vegf gene in zebrafish, leading to an elevated expression of VEGF. These findings can reasonably be extended to developmental angiogenesis in mammals and even pathological angiogenesis in humans. Thus, our findings, for the first time, shed new light on mechanisms that underlie circadian clock-regulated angiogenesis.
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| 2. |
- 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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| 3. |
- Mushtaq, Muhammad, et al.
(författare)
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The MRPS18-2 protein levels correlate with prostate tumor progression and it induces CXCR4-dependent migration of cancer cells
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- We have earlier found abnormal expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2, S18-2) in endometrial cancer, compared to the expression in hyperplasia and in normal endometrium. Here we report that expression of S18-2 was increased with disease progression in clinical specimens of prostate cancer (PCa). The level of induction of epithelial to mesenchymal cell transition (EMT) correlated with the expression level of S18-2 in PCa cell lines. Moreover, cells acquired increased ability of migration upon S18-2 overexpression, as was evaluated in zebrafish embryo model and in trans-well assay. We found that this is due to increased CXCR4 cell surface expression. Neutralizing CXCR4 protein or abrogating S18-2 expression in cells significantly reduced their migratory ability directed toward CXCL12. The mRNA expression of TWIST2, encoding one of transcription factors that induce EMT upon CXCR4 increase, positively correlated with the S18-2 protein level. Together, these data suggest that the S18-2 protein induces EMT through the TWIST2/E-cadherin signalling and, consequently, CXCR4-mediated migration of PCa cells.
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| 4. |
- Oliva, Delmy, 1967-
(författare)
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Prediction of side effects from anticancer treatment with the purpose of increasing quality of life
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer and its treatments can cause a variety of symptoms. Some of these symptoms are related to the disease and others are seen as a consequence of the treatment. Since patients experience side effects to different degrees despite undergoing the same treatment, it is hypothesized that there is a genetic factor. The individual variation that exists between different patients regarding nausea triggered by chemotherapy, radiotherapy induced skin reactions as well as sleep disorders associated with cancer could partly be explained by genetic differences. We have in these studies confirmed these individual differences. Previous nursing research has mainly focused on the symptoms themselves. The focus in this thesis are the following three main symptoms; nausea and vomiting related to chemotherapy, acute skin inflammation following radiotherapy and sleep problems associated with cancer diagnosis and -treatment.The aim of this thesis was to find biological markers that can identify the risk of and/or protective factors for nausea and/or vomiting (CINV) as well as understand its heterogeneity (Study 1 and 2). It also aimed to understand the individual factors behind acute radiation skin reactions (ARSR) (Study 3) and sleeping disturbances in patients treated for cancer (Study 4), permitting a more individualized care and optimized health-related quality of life (HRQoL).In Study 1 and 2 the patients themselves had to document in a diary their experience of nausea and vomiting and well-being. Well-being was considered as synonymous with quality of life. We found a variability and heterogeneity of those symptoms (Study 1). Three genetic markers, FAS/CD95, RB1/LPAR6 and CCL2 that could explain the individual differences and assess the risk of chemotherapy-induced nausea were found in Study 2.Acute radiation skin reactions (ARSR) along with itching and burning sensation associated with radiotherapy (RT) was assessed by the patients themselves (Study 3) with help of the VAS- and RTOG scales, scoring for visible redness. We found two possible genetic markers, XRCC2 and IFNG. Also, individual differences in symptoms behavior were found.Sleep disturbances were common and were reported with obvious individual differences [1]. For data collection were used a sleep questionnaire, the Medical Outcomes Study Sleep Scale (MOS), open ended questions and EORTC QLQ- C30 questionnaire of quality of life. Sleep, which is important for all primary body functions, is often affected in connection with cancer diagnosis and -treatment.Through collaboration between nursing staff and specialists in basic science, we have found that biological markers can help in creating individualized care. Knowledge of individual variations in the severity of chemo- or radiotherapy-induced side effects is important in order to better personalize the treatment and care, improve the treatment results and alleviate or prevent the side effects of oncological treatments. By linking symptoms to biological markers, it will hopefully be able to increase the patients’ total health-related quality of life, this being the main goal of this thesis.
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| 5. |
- Ali, Zaheer, et al.
(författare)
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Abstract 6124 : Translation of zebrafish tumor-derived xenograft-models for improved diagnosis and treatment planning in urinary bladder cancer patients
- 2020
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 80:6 Supplement, s. 6124-6124
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Tidskriftsartikel (refereegranskat)abstract
- Precision medicine in oncology aims to identify the most effective treatment for any given patient based on individualized analyses of patient material. Currently, precision medicine relies on sequencing of DNA or RNA to identify patient tumor-specific mutational profiles that may be coupled to drug response. These techniques, however, fail to reveal actionable mutations in approximately 85% of the cancer patients, and have not been established at all for many commonly used drugs including cisplatin-based treatments used in urinary bladder cancer. While mouse-PDX models can determine drug response rates with high accuracy in most patients and for most drugs, such techniques are too slow and expensive to be relevant for first line treatment planning. Urinary bladder cancer patients are often treated with cisplatin-containing combination therapy, with the hope of down-staging tumors before surgery. 60%, however, do not respond or even progress on this treatment, and these patients would benefit from immediate surgery upon diagnosis. To help identify non-responding patients, we show here that patient-derived tumor xenograft models can be established in zebrafish larvae (ZTX models) and that the resulting tumors exhibit differential responses to the two main cisplatin-containing treatments GC and MVAC.Preliminary results from the first 19 patients are presented. Two tumor biopsies were destroyed during transport and two did not allow isolation of sufficient viable cells for implantation. From the remaining 15 samples an average of 2,6 million cells with average viability of 53% were isolated and used to implant at least 60 2-days old larvae. All 15 samples implanted in the larvae and survived and/or grew exhibiting varying degrees of metastatic dissemination (average between 2 and 13 metastasized cells per embryo and model) within only three days from implantation. Four ZTX models exhibited different responses to GC and MVAC demonstrating that these treatments are not equally effective in all patients. Non-response in ZTX models was associated with tumors having re-appeared in the bladder upon radical cystectomy in all patients undergoing surgery prior to Dec. 5th 2019 (n=3). GC inhibited metastasis in all models (average 69% inhibition), whereas MVAC inhibited metastasis in 40% of the models (average 36% inhibition).In conclusion: The ZTX urinary bladder cancer platform presented here overcome limitations associated with long assay time and high cost of other functional models within precision medicine as well as the low hit-rate of actionable mutations associated with genomic techniques. ZTX models will therefore likely become a powerful method for functional precision medicine within oncology, in the near future.
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| 6. |
- Hosaka, Kayoko, et al.
(författare)
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Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis
- 2013
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Ingår i: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 4:2129
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Tidskriftsartikel (refereegranskat)abstract
- Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dose-dependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-beta signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-beta and inactivation of the PDGF-beta signalling decreases integrin alpha 1 beta 1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.
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| 7. |
- 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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| 8. |
- 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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| 9. |
- Mukwaya, Anthony
(författare)
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Regulation of inflammation and angiogenesis in the cornea
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammation and angiogenesis, the growth of new blood vessels from pre-existing ones, are involved in tumor growth, ocular diseases and wound healing. In ocular angiogenesis, new pathological vessels grow into a specific eye tissue, leak fluid, and disrupt vision. The development of safe and effective therapies for ocular angiogenesis is of great importance for preventing blindness, given that current treatments have limited efficacy or are associated with undesirable side effects. The search for alternative treatment targets requires a deeper understanding of inflammation and how it can lead to angiogenesis in the eye in pathologic situations. This thesis provides new insights into the regulation of inflammation and angiogenesis, particularly at the gene expression and phenotypic levels, in different situations characterized by angiogenesis of the cornea, often called corneal neovascularization. For instance, specific genes and pathways are either endogenously activated or suppressed during active inflammation, wound healing, and during resolution of inflammation and angiogenesis, serving as potential targets to modulate the inflammatory and angiogenic response. In addition, as part of the healing response to restore corneal transparency, inflammation and angiogenesis subside with time in the cornea. In this context, LXR/RXR signaling was found to be activated in a time-dependent manner, to potentially regulate resolution of inflammation and angiogenesis. During regression of new angiogenic capillaries, ghost vessels and empty basement membrane sleeves are formed, which can persist in the cornea for a long time. Here, ghost vessels were found to facilitate subsequent revascularization of the cornea, while empty basement membrane sleeves did not revascularize. The revascularization response observed here was characterised by vasodilation, increased inflammatory cell infiltration and by sprouting at the front of the reperfused vessels. Importantly, reactive oxygen species and nitrous oxide signaling among other pro-inflammatory pathways were activated, and at the same time anti-inflammatory LXR/RXR signaling was inhibited. The interplay between activation and inhibition of these pathways highlights potential mechanisms that regulate corneal revascularization. When treating corneal neovascularization clinically, corticosteroids are in widespread use due to their effectiveness. To minimize the many undesirable side effects associated with corticosteroid use, however, identifying new and more selective agents is of great importance. Here, it was observed that corticosteroids not only suppressed pro-inflammatory chemokines and cytokines, but also activated the classical complement pathway. Classical complement may represent a candidate for further selective therapeutic manipulation to investigate its effect on treatment of corneal neovascularization.In summary, this thesis identifies genes, pathways, and phenotypic responses involved in sprouting and remodeling of corneal capillaries, highlights novel pathways and factors that may regulate inflammation and angiogenesis in the cornea, and provides insights into regulation of capillary regression and reactivation. Further investigation of these regulatory mechanisms may offer alternative and effective treatment targets for the treatment of corneal inflammation and angiogenesis.
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| 10. |
- Oliva, Delmy, et al.
(författare)
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Opposing inflammatory biomarker responses to sleep disruption in cancer patients before and during oncological therapy
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSleep disruption is known to be highly prevalent in cancer patients, aggravated during oncological treatment and closely associated with reduced quality of life, therapeutic outcome and survival. Inflammatory factors are associated with sleep disruption in healthy individuals and cancer patients, but heterogeneity and robustness of inflammatory factors associated with sleep disruption and how these are affected by oncological therapy remain poorly understood. Furthermore, due to the complex crosstalk between sleep-, and therapy-associated factors, including inflammatory factors, there are currently no established biomarkers for predicting sleep disruption in patients undergoing oncological therapy. MethodsWe performed a broad screen of circulating biomarkers with immune-modulating or endocrine functions and coupled these to self-reported sleep quality using the Medical Outcomes Study (MOS) sleep scale. Ninety cancer patients with gastrointestinal, urothelial, breast, brain and tonsillar cancers, aged between 32 and 86 years, and scheduled for adjuvant or palliative oncological therapy were included. Of these, 71 patients were evaluable. Data was collected immediately before and again 3 months after onset of oncological therapy. ResultsSeventeen among a total of 45 investigated plasma proteins were found to be suppressed in cancer patients exhibiting sleep disruption prior to treatment onset, but this association was lost following the first treatment cycle. Patients whose sleep quality was reduced during the treatment period exhibited significantly increased plasma levels of six pro-inflammatory biomarkers (IL-2, IL-6, IL-12, TNF-a, IFN-g, and GM-CSF) 3 months after the start of treatment, whereas biomarkers with anti-inflammatory, growth factor, immune-modulatory, or chemokine functions were unchanged. ConclusionOur work suggests that biomarkers of sleep quality are not valid for cancer patients undergoing oncological therapy if analyzed only at a single timepoint. On the other hand, therapy-associated increases in circulating inflammatory biomarkers are closely coupled to reduced sleep quality in cancer patients. These findings indicate a need for testing of inflammatory and other biomarkers as well as sleep quality at multiple times during the patient treatment and care process.
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