| 1. |
- Andreasen, S., et al.
(författare)
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Genomic profiling of a combined large cell neuroendocrine carcinoma of the submandibular gland
- 2016
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 35:4, s. 2177-2182
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Tidskriftsartikel (refereegranskat)abstract
- A 69-year-old female with no previous medical history presented with a rapidly growing submandibular mass. Fine needle aspiration cytology suggested a small-cell carcinoma and PET-CT showed increased 18-FDG uptake in the submandibular mass as well as in a lung mass. Submandibular resection and selective neck dissection was performed and histopathologic examination revealed a combined large-cell neuroendocrine carcinoma (LCNEC) with a squamous component and without lymph node metastases. Resection of the lung tumor revealed a papillary adenocarcinoma that was morphologically distinctly different from the LCNEC. The patient died of her lung cancer after 19 months without evidence of recurrence of the LCNEC. Genomic profiling of the salivary gland LCNEC revealed a hypodiploid genome predominated by losses of whole chromosomes or chromosome arms involving chromosomes 3p, 4, 7q, 10, 11, 13, 16q and gains of 3q and 16p. In addition, there was a segmental gain of 9p23-p22.3 including the NFIB oncogene. Continued studies of salivary gland LCNEC may provide new knowledge concerning potential diagnostic biomarkers and may ultimately also lead to the identification of new treatment targets for patients with these aggressive carcinomas.
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| 2. |
- Dalmo, Johanna, et al.
(författare)
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Biodistribution of 177Lu-octreotate and 111In-minigastrin in female nude mice transplanted with human medullary thyroid carcinoma GOT2.
- 2012
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Ingår i: Oncology reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 27:1, s. 174-181
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Tidskriftsartikel (refereegranskat)abstract
- To be able to evaluate new radiopharmaceuticals and optimize diagnostic and therapeutic procedures, relevant animal models are required. The aim of this study was to evaluate the medullary thyroid carcinoma GOT2 animal model by analyzing the biodistribution of 177Lu-octreotate and 111In-minigastrin (MG0). BALB/c nude mice, subcutaneously transplanted with GOT2, were intravenously injected with either 177Lu-octreotate or 111In-MG0, with or without excess of unlabeled human minigastrin simultaneously with 111In-MG0. Animals were sacrificed 1-7 days after injection in the 177Lu-octreotate study and 1h after injection of 111In-MG0. The activity concentrations in organs and tissues were determined and mean absorbed doses from 177Lu were calculated. There was a specific tumor uptake of either 177Lu-octreotate or 111In-MG0. 177Lu-octreotate samples showed high activity concentrations in tissues expressing somatostatin receptors (SSTR). For both radiopharmaceuticals the highest activity concentrations were found in the kidneys. Compared to results from similar studies in mice with another MTC cell line (TT) the biodistribution was favorable (higher tumor uptake) for the GOT2 model, while compared to other animal models expressing SSTR, the tumor uptake of 177Lu-octreotate was modest. In conclusion, the GOT2 animal model is a valuable model for evaluation and optimization of diagnostic and therapeutic procedures using radiolabeled somatostatin, CCK2 and gastrin analogues prior to clinical studies.
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| 3. |
- Graflund, M., et al.
(författare)
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Relation between HPV-DNA and expression of p53, bcl-2, p21WAF-1, MIB-1, HER-2/neu and DNA ploidy in early cervical carcinoma : correlation with clinical outcome
- 2004
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Ingår i: Oncology Reports. - Athens, Greece : Spandidos Publications. - 1021-335X .- 1791-2431. ; 12:1, s. 169-176
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to analyze the relation between the expression of p53, bcl-2, p21WAF1, MIB-1, HER-2/neu, DNA ploidy and HPV16 or 18 infections with clinical parameters. HPV-DNA was evaluated in 171 early cervical carcinomas treated from 1965 to 1990 and detected by PCR (polymerase chain reaction) on paraffin specimens obtained before therapy was started. HPV-DNA of any type was detected in 78% (86/110) of all tumors, HPV16 was the predominant type and was seen in 56% (62/110), HPV18 in 8% (9/110) and HPV35 in 21% (23/110). Patients with HPV16 or 18 were significantly (P=0.011) younger than patients with tumors not containing these two HPV subtypes. Lymph node metastases were seen more frequently (P=0.047) in tumors expressing HPV16 or 18. Tumor size was associated with the HPV-type. The frequency of DNA aneuploidy was lower in high-risk HPV tumors than in tumors with other HPV subtypes (P=0.014). MIB-1 expression was highly significantly (P=0.00007) associated with presence of HPV16 or 18. The cancer-specific survival rate was lower for patients with HPV16 and 18 positive tumors, but the difference was not statistically significant. The overall 5-year survival rate of the complete series was 91%. In conclusion, the HPV DNA subtype was a prognostic factor in early stage cervical cancer and it was associated with age, positive lymph nodes, tumor size, DNA ploidy and the proliferation marker MIB-1.
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| 4. |
- Göstring, L., et al.
(författare)
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17AAG-induced internalisation of HER2-specific Affibody molecules
- 2016
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082 .- 1021-335X .- 1791-2431. ; 12:4, s. 2574-2580
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Tidskriftsartikel (refereegranskat)abstract
- The geldanamycin derivative 17-allylamino- 17-demethoxygeldanamycin (17-AAG) is known to induce internalisation and degradation of the otherwise internalisation-resistant human epidermal growth factor receptor 2 (HER2) receptor. In the present study, 17-AAG was used to increase internalisation of the HER2-specific Affibody molecule ABY-025. The cellular redistribution of halogen-labelled211At-ABY-025 and radiometal-labelled111In-ABY-025 following treatment with 17-AAG was studied. 17-AAG treatment of SKOV-3 human ovarian carcinoma and SKBR-3 human breast carcinoma cells to some extent shifted the localisation of 111In-ABY-025 from the cell surface to intracellular compartments in the two cell lines. ABY-025 labelled with the high-linear energy transfer α emitter211At was also internalised to a higher degree; however, due to its physiological properties, this nuclide was excreted faster. The results indicate that 17-AAG may be used to facilitate cell-specific intracellular localisation of a suitable cytotoxic or radioactive agent coupled to ABY-025 in HER2-overexpressing cells. © 2016, Spandidos Publications. All rights reserved.
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| 5. |
- Göthlin Eremo, Anna, 1980-, et al.
(författare)
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Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients
- 2013
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Ingår i: Oncology Reports. - Athens, Greece : Spandidos Publications. - 1021-335X .- 1791-2431. ; 29:4, s. 1467-1474
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Tidskriftsartikel (refereegranskat)abstract
- Reduced or absent Wwox expression has recently been associated with tamoxifen resistance in breast cancer and has also been proposed as a candidate predictive marker for treatment. We aimed to investigate the correlation of Wwox expression with the outcome of tamoxifen treatment by examining tissues from 912 randomized breast cancer patients. Paraffin-embedded tissues from patient tumors were arranged on tissue microarray, and Wwox protein was stained using immunohistochemistry. After microscopic examination, the results were analyzed with Cox regression, Kaplan-Meier survival curves and the log-rank test. In the group of cases having a tumor absent for Wwox expression, there was no difference in recurrence-free survival between treated and untreated patients (P=0.81). For treated cases with a tumor expressing moderate or strong Wwox protein, recurrence-free survival was improved (P=0.001 and P=0.003, respectively). The test for interaction between Wwox and treatment response demonstrated a decreased risk of recurrence for treated patients with a moderate or strong Wwox expression (HR=0.31, 95% CI 0.10-0.98 and HR=0.28, 95% CI 0.08-0.97, respectively). Our results indicate that patients with high expression of Wwox may gain more benefit from treatment with tamoxifen.
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| 6. |
- Hemmingsson, Oskar, 1975-, et al.
(författare)
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Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA1
- 2009
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 22:4, s. 869-875
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Tidskriftsartikel (refereegranskat)abstract
- Platinating agents constitute the first line treatment for ovarian cancer but treatment failure is common because of intrinsic and acquired resistance. Cancer cells develop the RASP-phenotype (cross resistance against arsenite, antimonite and platinum) associated with decreased accumulation of cisplatin and arsenite. ASNA1 is a possible subunit of a transport system for cisplatin and arsenite due to homology to arsA, an ATPase in the E. coli ars-complex responsible for efflux of arsenite and antimonite. Eukaryotic ASNA1 is a targeting factor for membrane insertion of tail-anchored proteins involved in the secretory pathway and cellular stress responses. The purpose with this study was to evaluate if ASNA1 expression influenced cisplatin, carboplatin, oxaliplatin or arsenite sensitivity in ovarian cancer. Human ovarian cancer cell line 2008 was transfected with a sense or an antisense ASNA1 construct. ASNA1 downregulated and overexpressing clones were identified by Western blots. Cell growth and chemosensitivity was determined by the MTT assay. Down-regulated ASNA1 expression was associated with retarded growth and increased sensitivity to cisplatin, carboplatin, oxaliplatin and arsenite whereas the cisplatin resistant 2008/A overexpresses ASNA1. These observations support the hypothesis that ASNA1 is a target to overcome platinum resistance in ovarian cancer.
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| 7. |
- Khan, Maria, et al.
(författare)
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Reduced tumor growth in EP2 knockout mice is related to signaling pathways favoring an increase local anti-tumor immunity in the tumor stroma
- 2022
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 47:6
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Tidskriftsartikel (refereegranskat)abstract
- Inflammatory signaling through prostaglandin E2 receptor subtype 2 (EP2) is associated with malignant tumor growth in both experimental models and cancer patients. Thus, the absence of EP2 receptors in host tissues appears to reduce tumor growth and systemic inflammation by inducing major alterations in gene expression levels across tumor tissue compartments. However, it is not yet well‑established how signaling pathways in tumor tissue relate to simultaneous signaling alterations in the surrounding tumor‑stroma, at conditions of reduced disease progression due to decreased host inflammation. In the present study, wild‑type tumor cells, producing high levels of prostaglandin E2 (MCG 101 cells, EP2+/+), were inoculated into EP2 knockout (EP2‑/‑) and EP2 wild‑type (EP2+/+) mice. Solid tumors were dissected into tumor‑ and tumor‑stroma tissue compartments for RNA expression microarray screening, followed by metabolic pathway analyses. Immunohistochemistry was used to confirm adequate dissections of tissue compartments, and to assess cell proliferation (Ki‑67), prostaglandin enzymes (cyclooxygenase 2) and immunity biomarkers (CD4 and CD8) at the protein level. Microarray analyses revealed statistically significant alterations in gene expression in the tumor‑stroma compartment, while significantly less pathway alterations occurred in the tumor tissue compartment. The host knockout of EP2 receptors led to a significant downregulation of cell cycle regulatory factors in the tumor‑stroma compartment, while interferon γ‑related pathways, chemokine signaling pathways and anti‑tumor chemokines [chemokine (C‑X‑C motif) ligand 9 and 10] were upregulated in the tumor compartment. Thus, such gene alterations were likely related to reduced tumor growth in EP2‑deficient hosts. On the whole, pathway analyses of both tumor‑ and tumor‑stroma compartments suggested that absence of host EP2 receptor signaling reduces ‘remodeling’ of tumor microenvironments and increase local immunity, probably by decreased productions of stimulating growth factors, perhaps similar to well‑recognized physiological observations in wound healing.
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| 8. |
- Lagerstedt-Robinson, K., et al.
(författare)
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Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population
- 2016
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 36:5, s. 2823-2835
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Tidskriftsartikel (refereegranskat)abstract
- Lynch syndrome caused by constitutional mismatch-repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.
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| 9. |
- Milkina, Elena, et al.
(författare)
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Interaction of hematopoietic CD34(+) CD45(+) stem cells and cancer cells stimulated by TGF-beta 1 in a model of glioblastoma in vitro
- 2018
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Ingår i: Oncology Reports. - : SPANDIDOS PUBL LTD. - 1021-335X .- 1791-2431. ; 40:5, s. 2595-2607
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Tidskriftsartikel (refereegranskat)abstract
- The majority of modern treatment methods for malignant brain tumors are not sufficiently effective, with a median survival time varying between 9 and 14 months. Metastatic and invasive processes are the principal characteristics of malignant tumors. The most important pathogenic mechanism is epithelial-mesenchymal transition (EMT), which causes epithelial cells to become more mobile, and capable of invading the surrounding tissues and migrating to distant organs. Transforming growth factor-beta 1 (TGF-beta 1) serves a key role in EMT-inducing mechanisms. The current study presented the interaction between hematopoietic stem cells and glioblastoma cells stimulated by TGF-beta 1 in vitro. The materials for the study were hematopoietic progenitor cell antigen CD34(+) hematopoietic stem cells (HSCs) and U87 glioblastoma cells. Cell culture methods, automated monitoring of cell-cell interactions, confocal laser microscopy, flow cytometry and electron microscopy were used. It was demonstrated that U87 cells have a complex communication system, including adhesive intercellular contacts, areas of interdigitation with dissolution of the cytoplasm, cell fusion, communication microtubes and microvesicles. TGF-beta 1 affected glioblastoma cells by modifying the cell shape and intensifying their exocrine function. HSCs migrated to glioblastoma cells, interacted with them and exchanged fluorescent tags. Stimulation of cancer cells with TGF-beta 1 weakened the ability of glioblastoma cells to attract HSCs and exchange a fluorescent tag. This process stimulated cancer cell proliferation, which is an indication of the ability of HSCs to 'switch' the proliferation and invasion processes in glioblastoma cells.
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| 10. |
- Mitran, Bogdan, et al.
(författare)
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Affibody-mediated imaging of EGFR expression in prostate cancer using radiocobalt-labeled DOTA-Z(EGFR:2377)
- 2019
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 41:1, s. 534-542
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Tidskriftsartikel (refereegranskat)abstract
- The epidermal growth factor receptor (EGFR) is often overexpressed during prostate cancer (PCa) progression towards androgen-independence after hormone therapy, but the overexpression is lower than in other types of cancers. Despite the low expression, EGFR has emerged as a promising therapeutic target for patients with castration-resistant PCa. Non-invasive methods for determination of EGFR expression in PCa can serve for patient stratification and therapy response monitoring. Radionuclide imaging probes based on affibody molecules (7 kDa) provide high contrast imaging of cancer-associated molecular targets. We hypothesized that the anti-EGFR affibody molecule DOTA-Z(EGFR:2377) labeled with Co-55 (positron-emitter, T1/2=17.5 h) would enable imaging of EGFR expression in PCa xenografts. The human PCa cell line DU-145 was used for in vitro and in vivo experiments and Co-57 was used as a surrogate for Co-55 in the present study. Binding of Co-57-DOTA-Z(EGFR:2377) to EGFR-expressing xenografts was saturable with anti-EGFR monoclonal antibody cetuximab, which would motivate the use of this tracer for monitoring the receptor occupancy during treatment. A significant dose-dependent difference in radioactivity accumulation in tumors and normal organs was observed when the biodistribution was studied 3 h after the injection of 10 and 35 mu g of Co-57-DOTA-Z(EGFR:2377): At lower doses the tumor uptake was 2-fold higher although tumor-to-organ ratios were not altered. For clinically relevant organs for PCa, tumor-to-organ ratios increased with time, and at 24 h pi were 2.2 +/- 0.5 for colon, 7 +/- 2 for muscle, and 4.0 +/- 0.7 for bones. Small animal SPECT/CT images confirmed the capacity of radiocobalt labeled DOTA-Z(EGFR:2377) to visualize EGFR expression in PCa. In conclusion, the present study demonstrated the feasibility of using the radiocobalt labeled anti-EGFR affibody conjugate Z(EGFR:2377) as an imaging agent for in vivo visualization of low EGFR-expressing tumors, like PCa, and for monitoring of receptor occupancy during cetuximab therapy as well as the importance of optimal dosing in order to achieve higher sensitivity molecular imaging.
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