| 1. |
- Bengtsson, Axel, et al.
(författare)
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Organoid technology for personalized pancreatic cancer therapy
- 2021
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Ingår i: Cellular Oncology. - : Springer Science and Business Media LLC. - 2211-3428 .- 2211-3436. ; 44:2, s. 251-260
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Forskningsöversikt (refereegranskat)abstract
- Background: Pancreatic ductal adenocarcinoma has the lowest survival rate among all major cancers and is the third leading cause of cancer-related mortality. The stagnant survival statistics and dismal response rates to current therapeutics highlight the need for more efficient preclinical models. Patient-derived organoids (PDOs) offer new possibilities as powerful preclinical models able to account for interpatient variability. Organoid development can be divided into four different key phases: establishment, propagation, drug screening and response prediction. Establishment entails tailored tissue extraction and growth protocols, propagation requires consistent multiplication and passaging, while drug screening and response prediction will benefit from shorter and more precise assays, and clear decision-making tools. Conclusions: This review attempts to outline the most important challenges that remain in exploiting organoid platforms for drug discovery and clinical applications. Some of these challenges may be overcome by novel methods that are under investigation, such as 3D bioprinting systems, microfluidic systems, optical metabolic imaging and liquid handling robotics. We also propose an optimized organoid workflow inspired by all technical solutions we have presented.
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| 2. |
- Geessink, Oscar G. F., et al.
(författare)
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Computer aided quantification of intratumoral stroma yields an independent prognosticator in rectal cancer
- 2019
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Ingår i: Cellular Oncology. - : SPRINGER. - 2211-3428 .- 2211-3436. ; 42:3, s. 331-341
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Tidskriftsartikel (refereegranskat)abstract
- PurposeTumor-stroma ratio (TSR) serves as an independent prognostic factor in colorectal cancer and other solid malignancies. The recent introduction of digital pathology in routine tissue diagnostics holds opportunities for automated TSR analysis. We investigated the potential of computer-aided quantification of intratumoral stroma in rectal cancer whole-slide images.MethodsHistological slides from 129 rectal adenocarcinoma patients were analyzed by two experts who selected a suitable stroma hot-spot and visually assessed TSR. A semi-automatic method based on deep learning was trained to segment all relevant tissue types in rectal cancer histology and subsequently applied to the hot-spots provided by the experts. Patients were assigned to a stroma-high or stroma-low group by both TSR methods (visual and automated). This allowed for prognostic comparison between the two methods in terms of disease-specific and disease-free survival times.ResultsWith stroma-low as baseline, automated TSR was found to be prognostic independent of age, gender, pT-stage, lymph node status, tumor grade, and whether adjuvant therapy was given, both for disease-specific survival (hazard ratio=2.48 (95% confidence interval 1.29-4.78)) and for disease-free survival (hazard ratio=2.05 (95% confidence interval 1.11-3.78)). Visually assessed TSR did not serve as an independent prognostic factor in multivariate analysis.ConclusionsThis work shows that TSR is an independent prognosticator in rectal cancer when assessed automatically in user-provided stroma hot-spots. The deep learning-based technology presented here may be a significant aid to pathologists in routine diagnostics.
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| 3. |
- Huang, Shan, et al.
(författare)
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Dipyridamole enhances the anti-cancer ability of aspirin against colorectal cancer by inducing apoptosis in an unfolded protein response-dependent manner
- 2023
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Ingår i: Cellular Oncology. - : Springer Science and Business Media LLC. - 2211-3428 .- 2211-3436. ; 46:4, s. 953-967
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole.METHODS: Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, an Apc min/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms. RESULTS: We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect.CONCLUSIONS: Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as adjuvant agents.
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| 4. |
- Lillsunde-Larsson, Gabriella, 1971-, et al.
(författare)
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Digital droplet PCR (ddPCR) for the detection and quantification of HPV 16, 18, 33 and 45 : a short report
- 2017
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Ingår i: Cellular Oncology. - : Springer. - 2211-3428 .- 2211-3436. ; 40:5, s. 521-527
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Tidskriftsartikel (refereegranskat)abstract
- Human papilloma virus (HPV) infection is associated with several anogenital malignancies. Here, we set out to evaluate digital droplet PCR (ddPCR) as a tool for HPV 16, 18, 33 and 45 viral load quantification and, in addition, to compare the efficacy of the ddPCR assay for HPV 16 detection with that of quantitative real-time PCR (qPCR).Clinical samples, positive for HPV genotypes 16, 18, 33 and 45 were analyzed for viral load using ddPCR. Sample DNA was cleaved before droplet generation and PCR. Droplets positive for VIC and FAM fluorescence were read in a QX200 Droplet reader (TM) (BIO-RAD) after which the viral load was calculated using Quantasoft software.We found that DNAs extracted from formalin fixed paraffin embedded (FFPE) tissue samples yielded lower amplification signals compared to those obtained from liquid based cytology (LBC) samples, but they were clearly distinguishable from negative background signals. The viral limit of detection was 1.6 copies of HPV 16, 2.8 copies of HPV 18, 4.6 copies of HPV 33 and 1.6 copies of HPV 45. The mean inter-assay coefficients of variability (CV) for the assays ranged from 3.4 to 7.0%, and the mean intra-assay CV from 2.6 to 8.2%. The viral load in the different cohorts of tumor samples ranged from 154 to 340,200 copies for HPV 16, 244 to 31,300 copies for HPV 18 and 738 to 69,100 copies for HPV 33. One sample positive for HPV 45 contained 1331 viral copies. When comparing qPCR data with ddPCR copy number data, the qPCR values were found to be 1 to 31 times higher.Separation of fragments in nanodroplets may facilitate the amplification of fragmented human and viral DNA. The method of digital droplet PCR may, thus, provide a new and promising tool for evaluating the HPV viral load in clinical samples.
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| 5. |
- Naber, Hildegonda P H, et al.
(författare)
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BMP-7 inhibits TGF-β-induced invasion of breast cancer cells through inhibition of integrin β(3) expression
- 2012
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Ingår i: Cellular Oncology. - : Springer. - 2211-3428 .- 2211-3436. ; 35:1, s. 19-28
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The transforming growth factor (TGF)-β superfamily comprises cytokines such as TGF-β and Bone Morphogenetic Proteins (BMPs), which have a critical role in a multitude of biological processes. In breast cancer, high levels of TGF-β are associated with poor outcome, whereas inhibition of TGF-β-signaling reduces metastasis. In contrast, BMP-7 inhibits bone metastasis of breast cancer cells. METHODS: In this study, we investigated the effect of BMP-7 on TGF-β-induced invasion in a 3 dimensional invasion assay. RESULTS: BMP-7 inhibited TGF-β-induced invasion of the metastatic breast cancer cell line MCF10CA1a, but not of its premalignant precursor MCF10AT in a spheroid invasion model. The inhibitory effect appears to be specific for BMP-7, as its closest homolog, BMP-6, did not alter the invasion of MCF10CA1a spheroids. To elucidate the mechanism by which BMP-7 inhibits TGF-β-induced invasion, we analyzed invasion-related genes. BMP-7 inhibited TGF-β-induced expression of integrin α(v)β(3) in the spheroids. Moreover, targeting of integrins by a chemical inhibitor or knockdown of integrin β(3) negatively affected TGF-β-induced invasion. On the other hand, overexpression of integrin β(3) counteracted the inhibitory effect of BMP7 on TGF-β-induced invasion. CONCLUSION: Thus, BMP-7 may exert anti-invasive actions by inhibiting TGF-β-induced expression of integrin β(3).
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| 6. |
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| 7. |
- Sillars-Hardebol, Anke H., et al.
(författare)
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CSE1L, DIDO1 and RBM39 in colorectal adenoma to carcinoma progression
- 2012
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Ingår i: Cellular Oncology. - : Springer Science and Business Media LLC. - 2211-3428 .- 2211-3436. ; 35:4, s. 293-300
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Tidskriftsartikel (refereegranskat)abstract
- Background Gain of chromosome 20q is an important factor in the progression from colorectal adenomas to carcinomas. Genes that drive 20q gain are expected to show correlation of mRNA and protein expression levels with 20q DNA copy number status while functionally influencing cancer processes. CSE1L, DIDO1 and RBM39 are located on the 20q amplicon and affect processes such as cell viability and anchorage-independent growth in colorectal cancer. This study aimed to investigate whether CSE1L, DIDO1 and RBM39 may drive 20q amplification.Methods Protein expression levels were examined by immunohistochemical evaluation of tissue microarrays containing a series of colorectal adenoma and carcinoma samples, which were characterized by genome-wide (microarray-based) DNA and mRNA profiling.Results CSE1L, DIDO1 and RBM39 mRNA expression levels correlated with chromosome 20q DNA copy number status. CSE1L protein expression was not associated with 20q gain, although its expression was increased in carcinomas compared to adenomas. DIDO1 and RBM39 protein expression was quite strong in the majority of tumors irrespective of 20q DNA copy number status.Conclusion The lack of correlation between protein expression levels and 20q DNA copy number status implies that CSE1L, DIDO1 and RBM39 are merely passengers rather than drivers of chromosome 20q gain in colorectal adenoma-to-carcinoma progression.
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| 8. |
- Sobti, R. C., et al.
(författare)
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Aberrant promoter methylation and loss of suppressor of cytokine signalling-1 gene expression in the development of uterine cervical carcinogenesis
- 2011
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Ingår i: Cellular Oncology. - : Springer Science and Business Media LLC. - 2211-3428 .- 2211-3436. ; 34:6, s. 533-43
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cervical cancer is a leading cause of cancer related deaths in women worldwide caused due to infection of high-risk human papillomaviruses. As JAK/STAT signalling pathway has been shown to play an important role during carcinogenesis, we studied the role of silencing of Suppressor of Cytokine Signalling-1 (SOCS-1) gene, a negative regulator of JAK/STAT pathway in cervical cancer.METHODS: The expression pattern of SOCS-1 mRNA and protein was analyzed in different stages of cervical tumor biopsies while normal cervical tissues served as controls. RT-PCR, immunohistochemistry and methylation-specific PCR (MSP) were performed to assess the expression pattern and promoter methylation of SOCS-1 gene in a total of 120 fresh surgically resected cervical tissue specimens comprising precancer (n = 12), cancer (n = 78) and normal controls (n = 30).RESULTS: Compared with expression of SOCS-1 in normal tissues, 64% of the tumor tissues expressed either undetectable or reduced expression. Aberrant promoter methylation of SOCS-1 was found in 61% of the cervical tumor tissues. SOCS-1 expression and methylation were significantly associated with severity of the disease (p < 0.01).CONCLUSION: We demonstrate for the first time the transcriptional inactivation of SOCS-1 gene due to hypermethylation and synergism with HPV infection which may play an important role in cervical carcinoma.
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| 9. |
- Wiechec, Emilia, et al.
(författare)
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Chromosome 1q25.3 copy number alterations in primary breast cancers detected by multiplex ligation-dependent probe amplification and allelic imbalance assays and its comparison with fluorescent in situ hybridization assays
- 2013
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Ingår i: Cellular Oncology. - : Springer Netherlands. - 2211-3428 .- 2211-3436. ; 36:2, s. 113-120
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Tidskriftsartikel (refereegranskat)abstract
- Background: Breast cancer is characterized by a complex pattern of chromosomal alterations, which is in accordance with its heterogeneous character. Simultaneous gains of 1q and losses of 16q represent early events in breast tumourigenesis and have been related to clinical outcome. Here, we evaluated the accuracy of 1q25.3 copy number detection in conjunction with allelic imbalance (AI) detection in a series of primary breast tumours.METHODS:We compared previously obtained AI results from the 1q25.3 region in a series of 222 primary breast tumours with newly obtained MLPA and FISH results. To this end, a novel 1q25.3 MLPA probe set was designed and a commercially available 1q25.3/1p35.2 dual color FISH probe set was used.RESULTS:MLPA revealed 1q25.3 copy number gains and copy number losses in subsets of the tumour samples tested. Next, tumour samples were examined by FISH and scored for the level of 1q25.3 alterations. Non-tumourigenic nuclei from healthy individuals were used to establish cut-off levels for 1q25.3 copy numbers. By doing so, we found a 100 % concordance between the FISH results in breast tumour samples displaying similar 1q25.3 copy number alterations as determined by MLPA and, previously, AI. Furthermore, FISH was found to be instrumental in determining 1q25.3 copy number alterations in samples exhibiting discordances between AI and MLPA.CONCLUSIONS:This study shows that both AI and MLPA assays can be employed to map regions exhibiting copy number alterations in cancer genomes, and that the results obtained are in concordance with FISH assays.
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| 10. |
- Zhang, Hanzhao, et al.
(författare)
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Inhibition of high level E2F in a RB1 proficient MYCN overexpressing chicken retinoblastoma model normalizes neoplastic behaviour
- 2024
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Ingår i: Cellular Oncology. - : Springer. - 2211-3428 .- 2211-3436. ; 47:1, s. 209-227
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Tidskriftsartikel (refereegranskat)abstract
- PurposeRetinoblastoma, a childhood cancer, is most frequently caused by bi-allelic inactivation of RB1 gene. However, other oncogenic mutations such as MYCN amplification can induce retinoblastoma with proficient RB1. Previously, we established RB1-proficient MYCN-overexpressing retinoblastoma models both in human organoids and chicken. Here, we investigate the regulatory events in MYCN-induced retinoblastoma carcinogenesis based on the model in chicken.MethodsMYCN transformed retinal cells in culture were obtained from in vivo MYCN electroporated chicken embryo retina. The expression profiles were analysed by RNA sequencing. Chemical treatments, qRT-PCR, flow cytometry, immunohisto- and immunocytochemistry and western blot were applied to study the properties and function of these cells.ResultsThe expression profile of MYCN-transformed retinal cells in culture showed cone photoreceptor progenitor signature and robustly increased levels of E2Fs. This expression profile was consistently observed in long-term culture. Chemical treatments confirmed RB1 proficiency in these cells. The cells were insensitive to p53 activation but inhibition of E2f efficiently induced cell cycle arrest followed by apoptosis.ConclusionIn conclusion, with proficient RB1, MYCN-induced high level of E2F expression dysregulates the cell cycle and contributes to retinoblastoma carcinogenesis. The increased level of E2f renders the cells to adopt a similar mechanistic phenotype to a RB1-deficient tumour.
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