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Thysell, Elin
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Publications (10 of 38) Show all publications
Thysell, E., Vidman, L., Bovinder Ylitalo, E., Jernberg, E., Crnalic, S., Iglesias-Gato, D., . . . Wikström, P. (2019). Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor. Molecular Oncology, 13(8), 1763-1777
Open this publication in new window or tab >>Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor
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2019 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, no 8, p. 1763-1777Article in journal (Refereed) Published
Abstract [en]

Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
bone metastasis, gene expression, gene set enrichment analysis, morphology, survival, unsupervised cluster analysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-162668 (URN)10.1002/1878-0261.12526 (DOI)000478600200009 ()31162796 (PubMedID)
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-05Bibliographically approved
Watts, E. L., Perez-Cornago, A., Appleby, P. N., Albanes, D., Ardanaz, E., Black, A., . . . Travis, R. C. (2019). The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies. International Journal of Cancer
Open this publication in new window or tab >>The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Epub ahead of print
Abstract [en]

Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Keywords
IGFBPs, IGFs, correlates, pooled analysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-157847 (URN)10.1002/ijc.32276 (DOI)30873591 (PubMedID)
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-04-05
Nordstrand, A., Bovinder Ylitalo, E., Thysell, E., Jernberg, E., Crnalic, S., Widmark, A., . . . Wikström, P. (2018). Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity. International Journal of Molecular Sciences, 19(4), Article ID 1223.
Open this publication in new window or tab >>Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity
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2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 4, article id 1223Article in journal (Refereed) Published
Abstract [en]

Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-naïve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
prostate cancer, bone, metastasis, androgen receptor, osteoblast, osteoclast, BMP
National Category
Orthopaedics
Identifiers
urn:nbn:se:umu:diva-146973 (URN)10.3390/ijms19041223 (DOI)000434978700302 ()29670000 (PubMedID)2-s2.0-85045938451 (Scopus ID)
Available from: 2018-04-24 Created: 2018-04-24 Last updated: 2018-11-21Bibliographically approved
Bovinder Ylitalo, E., Nordstrand, A., Thysell, E., Jernberg, E., Crnalic, S., Widmark, A., . . . Wikström, P. (2018). Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 50-50
Open this publication in new window or tab >>Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 50-50Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-151399 (URN)000441803800065 ()
Conference
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Note

Supplement: S, Meeting Abstract: A048

Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved
Thysell, E., Bovinder Ylitalo, E., Jernberg, E., Crnalic, S., Widmark, A., Bergh, A. & Wikström, P. (2018). Clinically relevant molecular subgroups of prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 123-123
Open this publication in new window or tab >>Clinically relevant molecular subgroups of prostate cancer bone metastases
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 123-123Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-151398 (URN)000441803800194 ()
Conference
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Note

 Supplement: S, Meeting Abstract: B081

Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved
Iglesias-Gato, D., Thysell, E., Crnalic, S., Mann, M., Widmark, A., Bergh, A., . . . Wikström, P. (2018). The proteome of prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 91-92
Open this publication in new window or tab >>The proteome of prostate cancer bone metastases
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 91-92Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-151400 (URN)000441803800138 ()
Conference
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Note

Supplement: S, Meeting Abstract: B025

Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved
Iglesias-Gato, D., Thysell, E., Tyanova, S., Crnalic, S., Santos, A., Lima, T. S., . . . Wikström, P. (2018). The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications. Clinical Cancer Research, 24(21), 5433-5444
Open this publication in new window or tab >>The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications
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2018 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 21, p. 5433-5444Article in journal (Refereed) Published
Abstract [en]

Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.

Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.

Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid b-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.

Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. (C) 2018 AACR.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-153547 (URN)10.1158/1078-0432.CCR-18-1229 (DOI)000448895100025 ()30042207 (PubMedID)
Funder
Swedish Research Council, K2013-64X-20407-04-3Swedish Cancer Society, CAN 2015/732Swedish Cancer Society, CAN 2016/824Swedish Cancer Society, CAN 2013/1324Swedish Cancer Society, 130293Swedish Foundation for Strategic Research , RB13-0119Novo Nordisk, NNF14CC0001
Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2018-11-22Bibliographically approved
Thysell, E., Bovinder Ylitalo, E., Jernberg, E., Bergh, A. & Wikström, P. (2017). A Systems Approach to Prostate Cancer Classification: Letter [Letter to the editor]. Cancer Research, 77(24), 7131-7132
Open this publication in new window or tab >>A Systems Approach to Prostate Cancer Classification: Letter
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 24, p. 7131-7132Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-143503 (URN)10.1158/0008-5472.CAN-16-3231 (DOI)000418189800029 ()29212852 (PubMedID)
Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-06-09Bibliographically approved
Strömvall, K., Thysell, E., Halin Bergström, S. & Bergh, A. (2017). Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis. PLoS ONE, 12(5), Article ID e0176679.
Open this publication in new window or tab >>Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176679Article in journal (Refereed) Published
Abstract [en]

In order to grow and spread tumors need to interact with adjacent tissues. We therefore hypothesized that small but aggressive prostate cancers influence the rest of the prostate and regional lymph nodes differently than tumors that are more indolent. Poorly metastatic (Dunning AT1) or highly metastatic (Dunning MLL) rat prostate tumor cells were injected into the ventral prostate lobe of immunocompetent rats. After 10 days-when the tumors occupied about 30% of the prostate lobe and lymph node metastases were undetectable- the global gene expression in tumors, benign parts of the prostate, and regional iliac lymph nodes were examined to define tumor-induced changes related to preparation for future metastasis. The tumors induced profound effects on the gene expression profiles in the benign parts of the prostate and these were strikingly different in the two tumor models. Gene ontology enrichment analysis suggested that tumors with high metastatic capacity were more successful than less metastatic tumors in inducing tumor-promoting changes and suppressing anti-tumor immune responses in the entire prostate. Some of these differences such as altered angiogenesis, nerve density, accumulation of T-cells and macrophages were verified by immunohistochemistry. Gene expression alterations in the regional lymph nodes suggested decreased quantity and activation of immune cells in MLL-lymph nodes that were also verified by immunostaining. In summary, even when small highly metastatic prostate tumors can affect the entire tumor-bearing organ and pre-metastatic lymph nodes differently than less metastatic tumors. When the kinetics of these extratumoral influences (by us named TINT = tumor instructed normal tissue) are more precisely defined they could potentially be used as markers of disease aggressiveness and become therapeutic targets.

Place, publisher, year, edition, pages
Public library science, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-135971 (URN)10.1371/journal.pone.0176679 (DOI)000400648500061 ()28472073 (PubMedID)
Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2018-06-09Bibliographically approved
Djusberg, E., Jernberg, E., Thysell, E., Golovleva, I., Lundberg, P., Crnalic, S., . . . Wikström, P. (2017). High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases. The Prostate, 77(6), 625-638
Open this publication in new window or tab >>High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases
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2017 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 6, p. 625-638Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2017
Keywords
androgen receptor variant 7, AKR1C3, extracellular vesicles, exosomes, blood coagulation
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-131817 (URN)10.1002/pros.23307 (DOI)000397496300007 ()28144969 (PubMedID)
Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2018-06-09Bibliographically approved
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