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- Henriksson, Eva, et al.
(author)
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Comparison of cisplatin sensitivity and the 18F fluoro-2-deoxy 2 glucose uptake with proliferation parameters and gene expression in squamous cell carcinoma cell lines of the head and neck
- 2009
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In: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 28
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Journal article (peer-reviewed)abstract
- Background: The survival of patients with locally advanced head and neck cancer is still poor, with 5-year survival rates of 24-35%. The identification of prognostic and predictive markers at the molecular and cellular level could make it possible to find new therapeutic targets and provide "taylor made" treatments. Established cell lines of human squamous cell carcinoma (HNSCC) are valuable models for identifying such markers. The aim of this study was to establish and characterize a series of cell lines and to compare the cisplatin sensitivity and 18F fluoro-2 deoxy 2 glucose (18F-FDG) uptake of these cell lines with other cellular characteristics, such as proliferation parameters and TP53 and CCND1 status. Methods: Explant cultures of fresh tumour tissue were cultivated, and six new permanent cell lines were established from 18 HNSCC cases. Successfully grown cell lines were analysed regarding clinical parameters, histological grade, karyotype, DNA ploidy, and index and S-phase fraction (Spf). The cell lines were further characterized with regard to their uptake of 18F-FDG, their sensitivity to cisplatin, as measured by a viability test ( crystal violet), and their TP53 and CCND1 status, by fluorescence in situ hybridization (FISH), polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) with DNA sequencing and, for cyclin D1, by immunohistochemistry. Results: Patients with tumours that could be cultured in vitro had shorter disease-free periods and overall survival time than those whose tumours did not grow in vitro, when analysed with the Kaplan-Meier method and the log-rank test. Their tumours also showed more complex karyotypes than tumours from which cell lines could not be established. No correlation was found between TP53 or CCND1 status and 18F-FDG uptake or cisplatin sensitivity. However, there was an inverse correlation between tumour cell doubling time and 18F-FDG uptake. Conclusion: In vitro growth of HNSCC cells seem to be an independent prognostic factor, with cell lines being more readily established from aggressive tumours, a phenomenon more dependent on the molecular genetic characteristics of the tumour cells than on tumour location or TNM status.
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| 4. |
- Omerovic, Elmir, 1968, et al.
(author)
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Aqueous fish extract increases survival in the mouse model of cytostatic toxicity
- 2008
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In: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966 .- 0392-9078. ; 4:27
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Journal article (peer-reviewed)abstract
- Background: Treatment of cancer patients with anthracycline antibiotic doxorubicin (DOX) may be complicated by development of acute and chronic congestive heart failure (CHF), malignant arrhythmias and death. The aim of this study was to test whether an aqueous low molecular weight (LMW) extract from cod muscle decreases acute mortality in the mouse model of acute CHF caused by DOX. Methods: A LMW fraction (< 500 Da) of the aqueous phase of cod light muscle (AOX) was used for treatment of male BALB/c mice (similar to 25 g, n = 70). The animals were divided into four groups, DOX + AOX (n = 20), DOX + saline (NaCl) (n = 30), NaCl + AOX (n = 10) and NaCl only (n = 10). Echocardiography was performed in the separate subgroups (DOX treated n = 6 and controls n = 6) to verify the presence and the grade of acute CHF. The cod extract was delivered by subcutaneously implanted osmotic minipumps over the period of 2 weeks. High-dose injection of DOX was administered to randomly selected animals. The animals received single intraperitoneal injection of DOX (25 mg/kg) and were followed over two weeks for mortality. Results: Mortality rate was 68% lower (p < 0.05) in the mice treated with the extract. The analyses of cod extract have shown strong antioxidative effect in vitro. Conclusion: The aqueous LMW cod muscles extract decreases mortality in the mouse model of DOX induced acute CHF. This effect may be mediated by cardioprotection through antioxidative mechanisms.
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- Shao, Linus Ruijin, 1964, et al.
(author)
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Direct effects of metformin in the endometrium: a hypothetical mechanism for the treatment of women with PCOS and endometrial carcinoma
- 2014
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In: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 33:41
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Research review (peer-reviewed)abstract
- Abstract Although a number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and antimetastatic effects of metformin in multiple cancer cell types, its cellular and molecular mechanisms of anti-cancer action in the endometrium of women with polycystic ovary syndrome (PCOS) have not yet been fully elucidated. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are known to be involved in metformin uptake and excretion in cells. In this article, we discuss the novel therapeutic possibilities for early-stage endometrial carcinoma (EC) in women with PCOS focusing on metformin, which might have a direct effect in the endometrium through the OCTs and MATEs. We then review the molecular mechanism(s) of the action of metformin in the endometrium and highlight possible mechanistic insights into the inhibition of cell proliferation and tumor growth and, ultimately, the reversal of early-stage EC into normal endometria in women with PCOS.
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- Albjerg Venning, Freja, et al.
(author)
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Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer
- 2021
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In: Journal of Experimental and Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 40:1, s. 1-1
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Journal article (peer-reviewed)abstract
- BackgroundCancer-associated fibroblasts (CAFs) comprise a heterogeneous population of stromal cells within the tumour microenvironment. CAFs exhibit both tumour-promoting and tumour-suppressing functions, making them exciting targets for improving cancer treatments. Careful isolation, identification, and characterisation of CAF heterogeneity is thus necessary for ex vivo validation and future implementation of CAF-targeted strategies in cancer.MethodsMurine 4T1 (metastatic) and 4T07 (poorly/non-metastatic) orthotopic triple negative breast cancer tumours were collected after 7, 14, or 21 days. The tumours were analysed via flow cytometry for the simultaneous expression of six CAF markers: alpha smooth muscle actin (αSMA), fibroblast activation protein alpha (FAPα), platelet derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ), CD26/DPP4 and podoplanin (PDPN). All non-CAFs were excluded from the analysis using a lineage marker cocktail (CD24, CD31, CD45, CD49f, EpCAM, LYVE-1, and TER-119). In total 128 murine tumours and 12 healthy mammary fat pads were analysed.ResultsWe have developed a multicolour flow cytometry strategy based on exclusion of non-CAFs and successfully employed this to explore the temporal heterogeneity of freshly isolated CAFs in the 4T1 and 4T07 mouse models of triple-negative breast cancer. Analysing 128 murine tumours, we identified 5–6 main CAF populations and numerous minor ones based on the analysis of αSMA, FAPα, PDGFRα, PDGFRβ, CD26, and PDPN. All markers showed temporal changes with a distinct switch from primarily PDGFRα+ fibroblasts in healthy mammary tissue to predominantly PDGFRβ+ CAFs in tumours. CD26+ CAFs emerged as a large novel subpopulation, only matched by FAPα+ CAFs in abundance.ConclusionWe demonstrate that multiple subpopulations of CAFs co-exist in murine triple negative breast cancer, and that the abundance and dynamics for each marker differ depending on tumour type and time. Our results form the foundation needed to isolate and characterise specific CAF populations, and ultimately provide an opportunity to therapeutically target specific CAF subpopulations.
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- Ali, Zaheer, et al.
(author)
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Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer
- 2022
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In: Journal of Experimental & Clinical Cancer Research. - : BMC. - 1756-9966. ; 41:1
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Journal article (peer-reviewed)abstract
- Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days. Methods Using a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients. Results The resulting ZTX models responded to Erlotinib and Paclitaxel, with similar potency as in mouse-PDX models and the patients themselves, and resistant tumors similarly failed to respond to these drugs in the ZTX system. Drug response was coupled to elevated expression of EGFR, Mdm2, Ptch1 and Tsc1 (Erlotinib), or Nras and Ptch1 (Paclitaxel) and reduced expression of Egfr, Erbb2 and Foxa (Paclitaxel). Importantly, ZTX models retained the invasive phenotypes of the tumors and predicted lymph node involvement of the patients with 91% sensitivity and 62% specificity, which was superior to clinically used tests. The biopsies from all four patient tested implanted successfully, and treatment outcome and dissemination were quantified for all patients in only 3 days. Conclusions We conclude that the ZTX platform provide a fast, accurate, and clinically relevant system for evaluation of treatment outcome and invasion/dissemination of PDX models, providing an attractive platform for combined mouse-zebrafish PDX trials and personalized medicine.
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