| 21. |
- Nallapalli, Rajesh K, et al.
(författare)
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Targeting filamin A reduces K-RAS-induced lung adenocarcinomas and endothelial response to tumor growth in mice
- 2012
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Ingår i: Molecular Cancer. - : BioMed Central. - 1476-4598. ; 11:50
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. less thanbrgreater than less thanbrgreater thanMethods: First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. less thanbrgreater than less thanbrgreater thanResults: Knockout of Flna significantly reduced K-RAS-induced lung tumor formation and the proliferation of oncogenic K-RAS-expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. less thanbrgreater than less thanbrgreater thanConclusions: We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.
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| 22. |
- Tina, Elisabet, 1975-, et al.
(författare)
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The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors
- 2012
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Overexpression of the human epidermal growth factor receptor (HER) 2 is associated with poor prognosis and shortened survival in breast cancer patients. HER2 is a potent activator of several signaling pathways that support cell survival, proliferation and metabolism. In HER2-positive breast cancer there are most likely unexplored proteins that act directly or indirectly downstream of well established pathways and take part in tumor development and treatment response.Methods: In order to identify novel copy number variations (CNVs) in HER2-positive breast cancer whole-genome single nucleotide polymorphism (SNP) arrays were used. A PCR-based loss of heterozygosis (LOH) assay was conducted to verify presence of deletion in HER2-positive breast cancer cases but also in HER2 negative breast cancers, cervical cancers and lung cancers. Screening for mutations was performed using single-strand conformation polymorphism (SSCP) followed by PCR sequencing. Protein expression was evaluated with immunohistochemistry (IHC).Results: A common deletion at chromosome Xq24 was found in 80% of the cases. This locus harbors the gene solute carrier (SLC) family 25A member 43 (SLC25A43) encoding for a mitochondrial transport protein. The LOH assay revealed presence of SLC25A43 deletion in HER2-positive (48%), HER2-negative (9%), cervical (42%) and lung (67%) cancers. HER2-positive tumors with negative or low SLC25A43 protein expression had significantly lower S-phase fraction compared to tumors with medium or high expression (P = 0.024).Conclusions: We have found deletion in the SLC25A43 gene to be a common event in HER2-positive breast cancer as well as in other cancers. In addition, the SLC25A43 protein expression was shown to be related to S-phase fraction in HER2-positive breast cancer. Our results indicate a possible role of SLC25A43 in HER2-positive breast cancer and support the hypothesis of altered mitochondrial function in cancer.
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| 23. |
- Zhang, Hong, et al.
(författare)
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WRAP53 is an independent prognostic factor in rectal cancer- a study of Swedish clinical trial of preoperative radiotherapy in rectal cancer patients
- 2012
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 12:294
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Tidskriftsartikel (refereegranskat)abstract
- Background: Expression of WRAP53 protein has oncogenic properties and it is up regulated in several types of tumors. less thanbrgreater than less thanbrgreater thanMethods: We examined expression of WRAP53 protein in rectal cancers and analyzed its relationship to the response to preoperative radiotherapy and patient survival. The WRAP53 protein was examined by immunohistochemistry in normal mucosa, primary tumors and lymph node metastases from 143 rectal cancer patients participated in a Swedish clinical trial of preoperative radiotherapy. less thanbrgreater than less thanbrgreater thanResults: Frequency of WRAP53 protein expression was increased in primary rectal cancer compared to the normal mucosa (p andlt; 0.05). In non-radiotherapy group positive WRAP53 in primary tumors (p = 0.03, RR, 3.73, 95% CI, 1.13-11.89) or metastases (p = 0.01, RR, 4.11, 95% CI, 1.25-13.14), was associated with poor prognosis independently of stages and differentiations. In radiotherapy group, positive WRAP53 in the metastasis correlated with better survival (p = 0.04). An interaction analysis showed that the correlations of WRAP53 with the prognostic significance with and without radiotherapy in the metastasis differed (p = 0.01). In the radiotherapy group, expression of WRAP53 in metastases gave a better outcome (p = 0.02, RR, 0.32, 95% CI, 0.13-0.84), and an interaction analysis showed significance between the two groups (p = 0.01). less thanbrgreater than less thanbrgreater thanConclusion: WRAP53 may be a new biomarker used to predict prognosis and to select suitable patients for preoperative radiotherapy.
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| 24. |
- Olsson, Erik, 1960, et al.
(författare)
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Hippocampal volumes in patients exposed to low-dose radiation to the basal brain. A case--control study in long-term survivors from cancer in the head and neck region.
- 2012
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Ingår i: Radiation oncology (London, England). - 1748-717X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: An earlier study from our group of long time survivors of head and neck cancer who had received a low radiation dose to the hypothalamic-pituitary region, with no signs of recurrence or pituitary dysfunction, had their quality of life (QoL) compromised as compared with matched healthy controls. Hippocampal changes have been shown to accompany several psychiatric conditions and the aim of the present study was to test whether the patients' lowered QoL was coupled to a reduction in hippocampal volume. METHODS: Patients (11 men and 4 women, age 31--65) treated for head and neck cancer 4--10 years earlier and with no sign of recurrence or pituitary dysfunction, and 15 matched controls were included. The estimated radiation doses to the basal brain including the hippocampus (1.5 -- 9.3 Gy) had been calculated in the earlier study. The hippocampal volumetry was done on coronal sections from a 1.5 T MRI scanner. Measurements were done by two independent raters, blinded to patients and controls, using a custom method for computer assisted manual segmentation. The volumes were normalized for intracranial volume which was also measured manually. The paired t test and Wilcoxon's signed rank test were used for the main statistical analysis. RESULTS: There was no significant difference with respect to left, right or total hippocampal volume between patients and controls. All mean differences were close to zero, and the two-tailed 95% confidence interval for the difference in total, normalized volume does not include a larger than 8% deficit in the patients. CONCLUSION: The study gives solid evidence against the hypothesis that the patients' lowered quality of life was due to a major reduction of hippocampal volume.
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| 25. |
- Lundin, Catarina, et al.
(författare)
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High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - Malden : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:2, s. 196-206
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Tidskriftsartikel (refereegranskat)abstract
- Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as less than10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
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| 26. |
- Falck, Eva, 1975-, et al.
(författare)
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The impact of the genetic background on the genome make-up of tumor cells
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - Malden, USA : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:5, s. 438-446
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial adenocarcinoma (EAC) is the most common form of malignancy in the female genital tract, ranking as the fourth leading form of invasive tumors that affect women. The BDII inbred rat strain has been used as a powerful tumor model in studies of the genetic background of EAC. Females from the BDII strain are prone to develop tumors with an incidence of more than 90%. Development of EAC in BDII female rats has similarities in pathogenesis, histopathological, and molecular properties to that of human, and thus represents a unique model for analysis of EAC tumorigenesis and for comparative studies in human EACs. In a previous study, a set of rat EAC cell lines derived from tumors developed in female crossprogenies between BDII and nonsusceptible rat strains were analyzed by spectral karyotyping (SKY). Here we present an analysis with specific focus on the impact of different genetic backgrounds on the rate and occurrence of genetic aberrations in experimental tumors using data presented in the previous report. We could reveal that the ploidy state, and the abundance and type of structural as well as numerical change differed between the two genetic setups. We have also identified chromosomes harboring aberrations independent of genetic input from the nonsusceptible strains, which provide valuable information for the identification of the genes involved in the development of EAC in the BDII model as well as in human endometrial tumors. (C) 2012 Wiley Periodicals, Inc.
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| 27. |
- Isaksson-Mettävainio, Martin, et al.
(författare)
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High SMAD4 levels appear in MSI and hypermethylated colon cancers, and indicate a better prognosis
- 2012
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Ingår i: International Journal of Cancer. - Geneve : International union against cancer. - 0020-7136 .- 1097-0215. ; 131, s. 779-788
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is one of the most common causes of cancer related deaths in western countries. CRC are commonly divided in cancers showing microsatellite stability (MSS) or microsatellite instability (MSI). A more novel classification is dependent on promoter hypermethylation of CpG islands (the CpG island methylator phenotype, CIMP), where cancers show high, low or negative methylation status. SMAD4, located on chromosome 18q, has been thoroughly investigated during the last years. Loss of SMAD4 expression has been reported to correlate with poor CRC patient prognosis. In this study we analyze the impact of SMAD4 expression on prognosis in relation to MSI screening status and CIMP status. 479 paraffin-embedded specimens of CRC were examined for nuclear SMAD4 expression using immunohistochemistry. The tumors were scored loss (-), moderate (+) and high (++) expressing tumors. Loss of SMAD4 correlated significantly with decreased survival in all colon cancer patients. High SMAD4 expression, on the other hand, was significantly associated with increased survival, especially in colon cancer patients which has undergone potential curative surgery. In addition, in MSI tumors and CIMP-high tumors, high SMAD4 expression was significantly related to increase in survival, while loss of SMAD4 resulted in a significantly poorer prognosis. SMAD4 expression was not correlated to prognosis in rectal cancer cases. We conclude, loss of SMAD4 indicates a poor prognosis in colon cancer patients. The novel findings that high SMAD4 expression predicts a better prognosis suggests that SMAD4 immunohistochemistry could constitute a prognostic marker in combination with CIMP and MSI screening status.
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| 28. |
- Sorbe, Bengt, et al.
(författare)
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A phase II study of docetaxel weekly in combination with carboplatin every three weeks as first line chemotherapy in stage IIB-IV epithelial ovarian cancer: Neurological toxicity and quality-of-life evaluation
- 2012
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Ingår i: International Journal of Oncology. - Athens : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 40:3, s. 773-781
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to assess the response rate, toxicity, progression-free survival (PFS) and overall survival (OS) in a series of advanced stage ovarian carcinoma patients treated with a first-line weekly docetaxel and three weekly carboplatin regimens. All eligible patients were treated with intravenous docetaxel (30 mg/m(2)) on Days 1, 8 and 15, and carboplatin (area under the curve, 5) on Day 1; Q21 days for at least 6 cycles. Neurological tests, questionnaires, and the EORTC QLQ-C30 and OV28 were used for quality-of-life assessments. One hundred and six patients received at least one cycle of primary chemotherapy (median 6.0; range, 1-9) and they were evaluable for toxicity assessment. Eighty-five patients had evaluable disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% CI 70.1-87.5%) and the biochemical response was 92.8% (95% CI 87.2-98.4%). The median PFS was 12.0 months and the median OS was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3-4 sensory neuropathy. Epiphora, nail changes and fatigue were frequently recorded non-hematological side effects. The tolerable hematological toxicity (no need for colony-stimulating factors) and the low rate of severe neurotoxicity (only grade 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.
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| 29. |
- Çağlayan, Demet
(författare)
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Molecular and Cellular Complexity of Glioma : Highlights on the Double-Edged-Sword of Infiltration Versus Proliferation and the Involvement of T Cells
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma multiforme (GBM), the most common and malignant brain tumor, is characterized by high molecular and cellular heterogeneity within and among tumors. Parameters such as invasive growth, infiltration of immune cells and endothelial proliferation contribute in a systemic manner to maintain the malignancy.Studies in this thesis show that the expression of Sox2 is correlated with Sox21 in human gliomas. We demonstrate that an upregulation of Sox21 induces loss of proliferation, apoptosis and differentiation in glioma cells in vitro and in vivo and seems to correlate with decreased Sox2 expression. Induced expression of Sox21 in vivo significantly reduces the tumor size and increase the survival extensively, suggesting that Sox21 can act as a tumor suppressor Our studies indicate that the balance of Sox21-Sox2 in glioma cells is decisive of either a proliferative or a non-proliferative state.Several TGFß family members have an important role in glioma development. TGFß promotes proliferation and tumorigenicity whereas BMPs mostly inhibit proliferation. We demonstrate that BMP7 can induce the transcription factor Snail in glioma cells and that this reduces the tumorigenicity with a concomitant increase in invasiveness. Thus, we have identified a mechanism to the double-edged sword of proliferation versus invasiveness in GBM, the latter contributing to relapse in patients.Experimental gliomas were induced with the Sleeping Beauty (SB) model in mice with different immunological status of their T cells. The tumors that developed were either GBMs or highly diffuse in their growth, reminiscent of gliomatosis cerebri (GC). GC is a highly uncommon form of glioma characterized by extensive infiltrative growth in large parts of the brain. It is an orphan disease and today there is practically a total lack of relevant experimental models. The SB system would constitute a novel experimental model to study the mechanisms behind the development of diffusely growing tumors like GC. The presence or absence of T cells did not affect tumor development.The work in this thesis demonstrates that the proliferative and the invasive capacities of glioma cells can be dissociated and that the SB model constitutes an excellent model to study the highly proliferative cells in GBMs versus the highly invasive cells in diffuse tumors like .GC.
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| 30. |
- Crnalic, Sead, 1960-
(författare)
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Metastatic spinal cord compression in prostate cancer : clinical and morphological studies
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Bone metastases occur in most patients with advanced hormone-refractory prostate cancer causing pain, pathologic fractures, and spinal cord compression. Few studies specifically address surgical treatment of metastatic spinal cord compression (MSCC) in prostate cancer. Criteria for identifying patients who may benefit from surgery are poorly defined. Most of the current knowledge regarding tumor biology in prostate cancer is based on studies of primary tumors or soft tissue metastases. The mechanisms regulating growth of bone metastases are not fully established. Aims: a) to evaluate outcome after surgery for MSCC in prostate cancer and to identify prognostic factors for survival and functional recovery; b) to evaluate current practice for referral of prostate cancer patients with MSCC; c) to analyze expression of androgen receptor (AR), cell proliferation, apoptosis, and prostate-specific antigen (PSA) in bone metastases with regard to survival after surgery for complications of bone metastases. Patients and Methods: We retrospectively evaluated the hospital records of 68 consecutive patients operated for metastatic spinal cord compression. Tumor tissue from bone metastases was obtained on spinal surgery (54 patients), fracture surgery (4 patients) and biopsy (2 patients), and analyzed by immunohistochemistry. Results: Study I: Mortality and complication rate after surgery was high. Patients with hormone-naïve disease and those with hormone-refractory disease with good performance status and without visceral metastases had more favorable survival. The ability to walk after surgery was related to better survival. Study II: A new score for prognosis of survival after surgery for spinal cord compression includes: hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum PSA. The score is simple, tumor specific, and easy to apply in clinical practice. Study III: Our results suggest that delays in diagnosis and treatment may have negative impact on functional outcome. Pretreatment ability to walk, hormone status of prostate cancer, and time from loss of ambulation influenced neurological recovery after surgery for spinal cord compression. Study IV: High nuclear AR immunostaining in bone metastases and high preoperative serum PSA were associated with a poor outcome after metastasis surgery in patients with hormone-refractory prostate cancer. Short-term effect of castration therapy disclosed that nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected. Conclusion: Prostate cancer patients with metastatic spinal cord compression represent a heterogeneous group. We identified prognostic factors for survival and functional outcome, which may help clinicians in making decisions about treatment. Our results also implicate the need for development of local and regional guidelines for treatment of patients with spinal cord compression, as well as the importance of information to patients at risk.
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