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  • 1.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Molecular heterogeneity of prostate cancer bone metastasis2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Castration-resistant prostate cancer (CRPC) develops after androgen deprivation therapy of advanced PC, often with metastatic growth in bone. Patients with metastatic CRPC have very poor prognosis. Growth of CRPC, in most but not all patients, seems to involve androgen receptor (AR) activity, despite castrate levels of serum testosterone. Multiple mechanisms behind AR activation in castrated patients have been described, such as AR amplification, AR mutations, expression of constitutively active AR variants, and intra-tumoral steroid synthesis. However, other mechanisms beside AR activation are also involved and CRPC patients with tumors circumventing the need for AR stimulation will probably not benefit from AR targeting therapies but will need alternative treatments.

    Available treatments for CRPC are chemotherapy, AR antagonists or inhibition of androgen-synthesis. Novel drugs are constantly under development and several new therapies has recently been approved for clinical use. These include, in addition to new AR targeting therapies also immunotherapy, osteoclast inhibitors and bone-targeting radiopharmaceuticals. Due to heterogeneous mechanisms behind CRPC and that newly developed therapies are based on different mechanisms of action, there are reasons to believe that CRPC patients show different therapy responses due to diverse molecular properties of individual tumors. Although there are promising prospects, no biomarkers are used today for patient stratification into different treatments. Another important aspect is that, when effective, any therapy will probably induce tumor responses that subsequently cause further molecular diversities and alternative paths for development of tumor relapse and castration-resistance. Such mechanisms are important to understand in order to develop new treatment strategies.

    In this thesis, global gene expression and methylation patterns were studied in bone metastases obtained from PC patients going through metastasis surgery for spinal cord compression. Gene expression patterns were analyzed by multivariate statistics and ontology analysis with the aim to identify subgroups of biological/pathological relevance. Interesting findings from array analysis were verified using qRT-PCR and immunohistochemical analysis. In addition, a xenograft mouse model was used to study the effects of abiraterone (steroidogenesis inhibitor) and cabazitaxel (taxane), and subsequently developed resistance mechanisms in the 22Rv1 PC cell line expressing high levels of AR-V7; a constitutively active AR splice variant associated with a poor prognosis and resistance to AR targeting therapies.

    In summary, results showed that the majority of CRPC bone metastases were AR-driven, defined from high levels of AR-regulated gene transcripts, while a smaller sub-group was non-AR-driven (paper I). AR-driven bone metastases had high metabolic activity in combination with downregulated immune responses while non-AR-driven cases had a more pronounced immune response (paper I) and higher bone cell activity (paper II). Paper III identified pronounced hypermethylation in primary prostate tumors probably causing a suppressed anti-tumor immune-response whereas metastases showed a different methylation pattern related to increased AR activity and patient outcome. In paper IV, 22Rv1 xenografts showed poor response to abiraterone and initially excellent response to cabazitaxel, but eventually resistance occurred probably due to an upregulation of the ABCB1 transporter protein. Anti-androgens partly reversed the resistance.

    In conclusion, we have identified molecular heterogeneities in clinical bone metastases associated with biological characteristics, which could perhaps be used both for stratifying patients into treatment modalities, and to aid in further development of effective therapies for CRPC.

  • 2.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nordstrand, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases2018Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 50-50Artikel i tidskrift (Övrigt vetenskapligt)
  • 3.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Egevad, Lars
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response2017Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, nr 5, s. 776-787Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives: To identify molecular subgroups of PC bone metastases of relevance for therapy.

    Design, setting, and participants: Fresh-frozen bone metastasis samples from men with CRPC (n = 40), treatment-naïve PC (n = 8), or other malignancies (n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation.

    Results and limitations: The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.

    Conclusions: Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.

  • 4.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Integrated DNA methylation and gene expression analysis of molecular heterogeneity in prostate cancer bone metastasisManuskript (preprint) (Övrigt vetenskapligt)
  • 5.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thellenberg-Karlsson, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Josefsson, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Excellent cabazitaxel response in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of resistance development by anti-androgensManuskript (preprint) (Övrigt vetenskapligt)
  • 6.
    Hörnberg, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 4, s. e19059-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote  the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.

    Methodology/Principal Findings: Hormone-naı¨ve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from  40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.

    Conclusions/Significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

  • 7.
    Jernberg, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rudolfsson, Stina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 11, s. e77407-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Intra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated withcastration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels ofsteroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation toexpression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables.

    Methodology/Principal Findings: Untreated, hormone-naıve (HN, n = 9) and CRPC bone metastases samples (n = 45) wereobtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry andimmunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases.Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases thanin non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNAlevels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which wasnot due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only oneexception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with highAKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individualbone metastases.

    Conclusions/Significance: Induced capacity of converting adrenal-gland derived steroids into more potent androgens wasindicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage ofmetastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs,which might be of relevance for patient response to 2nd line androgen-deprivation therapy.

  • 8.
    Nordstrand, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition at Institute for Medicine, Sahlgrenska Academy at University of Gothenburg.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity2018Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, nr 4, artikel-id 1223Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Nordstrand, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bovinder-Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastasesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Prostate cancer often metastasizes to bone and the metastases are generally classified as osteoblastic, although a mixed osteoblastic/osteolytic bone response may exist. The present study aimed to characterize the bone remodeling activity in clinical bone metastasis samples, with the overall hypothesis that diversities exist that may be of importance for clinical response to current therapies. Specifically, we aimed to study bone remodeling activity in relation to tumor cell androgen receptor (AR) activity. Metastasis tissue obtained from treatment-naïve (n=11) and castration-resistant (n=28) patients during surgery for spinal cord compression was characterized using whole-genome expression analysis followed by multivariate modeling and functional enrichment analysis as well as by histological evaluation. By analyzing expression levels of a predefined set of markers representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST), we found high osteoblast activity to be coupled to a high osteoclast activity. Immunohistochemistry verified a significant correlation between RUNX2 positive osteoblasts and TRAP (ACP5) positive osteoclasts lining metastatic bone surfaces in close contact to tumor cells. No difference in bone remodeling activity was seen between treatment naïve and castration-resistant patients, while the bone remodeling activity was inversely correlated to AR activity within the tissue (measured as expression of the AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2) and patient serum PSA levels. Ontology analysis suggested enriched BMP signaling in metastases with high bone remodeling activity and, accordingly, BMP4 mRNA expression was significantly higher in bone metastases with than without ongoing bone formation, as determined from histological evaluation of van Gieson-stained sections. In conclusion, we have observed diversities in bone remodeling activity among clinical samples of prostate cancer bone metastases that may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered. The importance of the BMP signaling system for the development of sclerotic metastasis lesion deserve further exploration.

  • 10.
    Nordstrand, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Halin Bergström, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder-Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition at Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone2017Ingår i: Clinical and Experimental Metastasis, ISSN 0262-0898, E-ISSN 1573-7276, Vol. 34, nr 3-4, s. 261-271Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.

  • 11.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    A Systems Approach to Prostate Cancer Classification: Letter2017Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, nr 24, s. 7131-7132Artikel i tidskrift (Refereegranskat)
  • 12.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Clinically relevant molecular subgroups of prostate cancer bone metastases2018Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 123-123Artikel i tidskrift (Övrigt vetenskapligt)
  • 13.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Iglesias-Gato, Diego
    Flores-Morales, Amilcar
    Stattin, Pär
    Egevad, Lars
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor2019Ingår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, nr 8, s. 1763-1777Artikel i tidskrift (Refereegranskat)
    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.

  • 14.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ylitalo, Erik B.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-872017Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, nr 4, s. e104-e105Artikel i tidskrift (Refereegranskat)
  • 15.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ylitalo, Erik B.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-872017Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, nr 4, s. E104-E105Artikel i tidskrift (Refereegranskat)
1 - 15 av 15
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