| 1. |
- All-Ericsson, Charlotta, et al.
(författare)
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c-Kit-dependent growth of uveal melanoma cells : a potential therapeutic target?
- 2004
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 45:7, s. 2075-82
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: This study was conducted to investigate the expression and functional impact of the proto-oncogene c-kit in uveal melanoma. METHODS: Based on immunohistochemical (IHC) study of paraffin-embedded specimens from 134 uveal melanomas and Western blot analysis on eight fresh-frozen samples the expression of c-kit in uveal melanoma was studied. Furthermore, the phosphorylation of c-kit and the impact of the tyrosine kinase inhibitor STI571 was examined in the three uveal melanoma cell lines OCM-1, OCM-3, and 92-1. RESULTS: Eighty-four of 134 paraffin-embedded samples and six of eight fresh-frozen samples expressed c-kit. c-Kit was strongly expressed and tyrosine phosphorylated in cultured uveal melanoma cells compared with cutaneous melanoma cells. Moreover, in contrast to cutaneous melanoma cell lines c-kit maintained a high phosphorylation level in serum-depleted uveal melanoma cells. No activation-related mutations in exon 11 of the KIT gene were found. On the contrary, expression of the stem cell growth factor (c-kit ligand) was detected in all three uveal melanoma cell lines, suggesting the presence of autocrine (paracrine) stimulation pathways. Treatment of uveal melanoma cell lines with STI571, which blocks c-kit autophosphorylation, resulted in cell death. The IC(50) of the inhibitory effects on c-kit phosphorylation and cell proliferation was of equal size and less than 2.5 microM. CONCLUSIONS: The results confirm that c-kit is vastly expressed in uveal melanoma, suggest that the c-kit molecular pathway may be important in uveal melanoma growth, and point to its use as a target for therapy with STI571.
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| 2. |
- All-Ericsson, Charlotta
(författare)
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Uveal melanoma : cytogenetics, molecular biology and tumor immunology
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Uveal melanoma is the most common primary intraocular malignancy. The metastatic spread is hematogenous and exclusively to the liver. Although eye-sparing treatments are used more frequently the tumor-related mortality in uveal melanoma is still 30-50%. Only 2% of the patients have detectable metastases at the time of diagnosis. The aim of this study was to test various prognostic markers and possibly new treatment modalities. Chromosomal aberrations were studied on 35 paraffin-embedded tumor specimens with comparative genomic hybridization (CGH) technique. 29 out of 35 tumors showed copy number changes. The most common losses were on chromosome 3, 6q, and 1p and the most common gains on chromosome 8q, 6p and 1q. The mean number of DNA copy number changes was significantly higher in the metastasizing tumors and metastases. The expression of human leukocyte antigen (HLA) class 1, beta-2-microglobulin and HLA class 11 were studied with inummohistochemistry (IHC) on 65 tumor samples. In all three groups high expression was correlated to an adverse clinical outcome. The insulin-like growth factor- I receptor (IGF-1R) has been implicated as an important factor for tumor progression in several different tumors. We could show by both IHC and Western blotting (WB) that IGF-1R is expressed in uveal melanoma. Furthermore we were able to induce cell growth arrest and cell death by using tunicamycin and lovastatin, which inhibit the N-linked glycosylation, and alphaIR-3 which blocks the binding domain of IGF-1R. Previous studies have indicated that the proto-oncogene c-kit is important in tumor progression. We found when using IHC that 84 out of 134 (64%) tumors expressed c-kit. This result could be confirmed by WB where 6 out of 8 samples expressed c-kit. To study the antiproliferative effects of the tyrosine kinase inhibitor ST1571 we treated four uveal melanoma and two skin melanoma cell lines. Cell proliferation was completely inhibited after 48h by 0. 1 - I muM ST1571 in the uveal melanoma cell lines but not in the skin melanoma cell lines. In conclusion, this study suggests that chromosomal aberrations on chromosome 1, 3, 6 and 8, and expression of HLA may be used as prognostic markers and that the IGF-1R and c-kit may in the future be used as therapeutic targets.
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| 3. |
- Bartuma, Katarina, et al.
(författare)
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A 10-year experience of outcome in chemotherapy-treated hereditary retinoblastoma
- 2014
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 92:5, s. 404-411
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The aim is to report the 10-year retrospective experience of systemic chemotherapy for a population-based group of patients with hereditary retinoblastoma at a national referral centre. The outcomes include control rates, treatment side-effects, adjuvant therapy, failure rate, survival, secondary cancers and visual acuity. Methods: All patients (n = 24, 46 eyes) diagnosed with retinoblastoma and treated with systemic chemotherapy at a national referral centre during 2001-2011 were included. Data were extracted from medical records. Results: The patients were followed for a mean of 60 months (range 13-144). Four-six cycles of VEC was administered to all newly diagnosed group B/C/D/E eyes with bilateral disease and 83% (38 of 46) responded to the treatment. None of the patients discontinued chemotherapy because of adverse reactions. Altogether 26% (12 of 46) of the eyes received second-line therapy (other than thermotherapy, cryotherapy and chemotherapy). The failure rate was 35% (16 of 46) and mortality rate 0%. None of the patients developed CNS manifestations (metastases or trilateral retinoblastoma). One of the patients developed a second primary tumour (osteosarcoma) 4 years following retinoblastoma diagnosis. Altogether 17% (4 of 24) patients received radiation therapy, 28% (13 of 46) of the eyes had to be enucleated, and one patient underwent bilateral enucleation. The age-correlated visual acuity was mean of 73% of expected visual acuity. Conclusion: Group A/B retinoblastomas have a distinct chemotherapy response, while group C/D/E tumours do not respond as well. The success rate was 65%; while patients have a good prognosis for life, approximately one-third of all hereditary cases received radiation therapy or underwent enucleation.
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| 4. |
- Fard, Shahrzad Shirazi, et al.
(författare)
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The heterogenic final cell cycle of chicken retinal Lim1 horizontal cells is not regulated by the DNA damage response pathway
- 2014
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Ingår i: Cell Cycle. - : Informa UK Limited. - 1538-4101 .- 1551-4005. ; 13:3, s. 408-417
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Tidskriftsartikel (refereegranskat)abstract
- Cells with aberrations in chromosomal ploidy are normally removed by apoptosis. However, aneuploid neurons have been shown to remain functional and active both in the cortex and in the retina. Lim1 horizontal progenitor cells in the chicken retina have a heterogenic final cell cycle, producing some cells that enter S-phase without proceeding into M-phase. The cells become heteroploid but do not undergo developmental cell death. This prompted us to investigate if the final cell cycle of these cells is under the regulation of an active DNA damage response. Our results show that the DNA damage response pathway, including gamma-H2AX and Rad51 foci, is not triggered during any phase of the different final cell cycles of horizontal progenitor cells. However, chemically inducing DNA adducts or double-strand breaks in Lim1 horizontal progenitor cells activated the DNA damage response pathway, showing that the cells are capable of a functional response to DNA damage. Moreover, manipulation of the DNA damage response pathway during the final cell cycle using inhibitors of ATM/ATR, Chk1/2, and p38MAPK, neither induced apoptosis nor mitosis in the Lim1 horizontal progenitor cells. We conclude that the DNA damage response pathway is functional in the Lim1 horizontal progenitor cells, but that it is not directly involved in the regulation of the final cell cycle that gives rise to the heteroploid horizontal cell population.
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| 5. |
- Höiom, Veronica, et al.
(författare)
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Hereditary uveal melanoma : A report of a germline mutation in BAP1
- 2013
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 52:4, s. 378-384
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma of the eye is a rare and distinct subtype of melanoma, which only rarely are familial. However, cases of uveal melanoma (UM) have been found in families with mixed cancer syndromes. Here, we describe a comprehensive search for inherited genetic variation in a family with multiple cases of UM but no aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM at 16 years who within 6 months developed liver metastases. We also identified two older paternal relatives of the proband who had died from UM. We performed exome sequencing of germline DNA from members of the affected family. Exome-wide analysis identified a novel loss-of-function mutation in the BAP1 gene, previously suggested as a tumor suppressor. The mutation segregated with the UM phenotype in this family, and we detected a loss of the wild-type allele in the UM tumor of the proband, strongly supporting a causative association with UM. Screening of BAP1 germline mutations in families predisposed for UM may be used to identify individuals at increased risk of disease. Such individuals may then be enrolled in preventive programs and regular screenings to facilitate early detection and thereby improve prognosis.
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| 6. |
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| 7. |
- Olofsson, Roger, 1978, et al.
(författare)
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Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial) : study protocol for a randomized controlled trial
- 2014
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Ingår i: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 15, s. 317-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). Methods/Design: This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. Discussion: Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint.
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| 8. |
- Shirazi Fard, Shahrzad, et al.
(författare)
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The terminal basal mitosis of chicken retinal Lim1 horizontal cells is not sensitive to cisplatin-induced cell cycle arrest
- 2014
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Ingår i: Cell Cycle. - : Informa UK Limited. - 1538-4101 .- 1551-4005. ; 13:23, s. 3698-3706
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Tidskriftsartikel (refereegranskat)abstract
- For proper development, cells need to coordinate proliferation and cell cycle-exit. This is mediated by a cascade of proteins making sure that each phase of the cell cycle is controlled before the initiation of the next. Retinal progenitor cells divide during the process of interkinetic nuclear migration, where they undergo S-phase on the basal side, followed by mitoses on the apical side of the neuroepithelium. The final cell cycle of chicken retinal horizontal cells (HCs) is an exception to this general cell cycle behavior. Lim1 expressing (+) horizontal progenitor cells (HPCs) have a heterogenic final cell cycle, with some cells undergoing a terminal mitosis on the basal side of the retina. The results in this study show that this terminal basal mitosis of Lim1+ HPCs is not dependent on Chk1/2 for its regulation compared to retinal cells undergoing interkinetic nuclear migration. Neither activating nor blocking Chk1 had an effect on the basal mitosis of Lim1+ HPCs. Furthermore, the Lim1+ HPCs were not sensitive to cisplatin-induced DNA damage and were able to continue into mitosis in the presence of γ-H2AX without activation of caspase-3. However, Nutlin3a-induced expression of p21 did reduce the mitoses, suggesting the presence of a functional p53/p21 response in HPCs. In contrast, the apical mitoses were blocked upon activation of either Chk1/2 or p21, indicating the importance of these proteins during the process of interkinetic nuclear migration. Inhibiting Cdk1 blocked M-phase transition both for apical and basal mitoses. This confirmed that the cyclin B1-Cdk1 complex was active and functional during the basal mitosis of Lim1+ HPCs. The regulation of the final cell cycle of Lim1+ HPCs is of particular interest since it has been shown that the HCs are able to sustain persistent DNA damage, remain in the cell cycle for an extended period of time and, consequently, survive for months.
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| 9. |
- Stenfelt, Sonya, et al.
(författare)
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Heterogeneity in retinoblastoma : a tale of molecules and models
- 2017
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Ingår i: CLINICAL AND TRANSLATIONAL MEDICINE. - : BIOMED CENTRAL LTD. - 2001-1326. ; 6
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Forskningsöversikt (refereegranskat)abstract
- Retinoblastoma, an intraocular pediatric cancer, develops in the embryonic retina following biallelic loss of RB1. However, there is a wide range of genetic and epigenetic changes that can affect RB1 resulting in different clinical outcomes. In addition, other transformations, such as MYCN amplification, generate particularly aggressive tumors, which may or may not be RB1 independent. Recognizing the cellular characteristics required for tumor development, by identifying the elusive cell-of-origin for retinoblastoma, would help us understand the development of these tumors. In this review we summarize the heterogeneity reported in retinoblastoma on a molecular, cellular and tissue level. We also discuss the challenging heterogeneity in current retinoblastoma models and suggest future platforms that could contribute to improved understanding of tumor initiation, progression and metastasis in retinoblastoma, which may ultimately lead to more patient-specific treatments.
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