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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
Hammarsten, P., Josefsson, A., Thysell, E., Lundholm, M., Hägglöf, C., Iglesias-Gato, D., . . . Bergh, A. (2019). Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome. Modern Pathology, 32(9), 1310-1319
Open this publication in new window or tab >>Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome
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2019 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 32, no 9, p. 1310-1319Article in journal (Refereed) Published
Abstract [en]

Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975-1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-163898 (URN)10.1038/s41379-019-0260-6 (DOI)000484437000009 ()30980038 (PubMedID)2-s2.0-85064215051 (Scopus ID)
Available from: 2019-10-07 Created: 2019-10-07 Last updated: 2019-11-14Bibliographically approved
Lionikaite, V., Henning, P., Drevinge, C., Shah, F. A., Palmquist, A., Wikström, P., . . . Lerner, U. H. (2019). Vitamin A decreases the anabolic bone response to mechanical loading by suppressing bone formation. The FASEB Journal, 33(4), 5237-5247
Open this publication in new window or tab >>Vitamin A decreases the anabolic bone response to mechanical loading by suppressing bone formation
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 4, p. 5237-5247Article in journal (Refereed) Published
Abstract [en]

Increased vitamin A consumption is associated with decreased cortical bone mass and increased fracture risk in humans. Rodent studies have demonstrated that hypervitaminosis A increases cortical bone resorption, whereas the importance of the effects on bone formation is less well defined. We used an experimental model of increased bone formation by loading of the tibiae to investigate the effect of vitamin A on bone formation. Control [retinol activity equivalents (RAE) 4.5 µg/g chow] or vitamin A (RAE 60 µg/g chow) diets were given to female C57BL/6N mice for 4 wk, after which the tibiae were subjected to axial loading on alternate days for 2 wk, while the diets were continued. Vitamin A inhibited the loading-induced increase in trabecular and cortical bone volume. This was attributed to inhibition of loading-induced increase in osteoblast number and activity, and expression of osteoblastic genes Sp7Alpl, and Col1a1 in cortical bone. Vitamin A, loading, and combination thereof also resulted in site-specific effects on bone composition measured by Raman spectroscopy. In summary, a clinically relevant dose of vitamin A suppresses the loading-induced gain of bone mass by decreasing bone formation. These observations may have implications for regulation of bone mass caused by physical activity and the risk of osteoporosis in humans.—Lionikaite, V., Henning, P., Drevinge, C., Shah, F. A., Palmquist, A., Wikström, P., Windahl, S. H., Lerner, U. H. Vitamin A decreases the anabolic bone response to mechanical loading by suppressing bone formation.

Bone remodeling is a continuous process throughout life that is balanced by bone-forming osteoblasts and bone-resorbing osteoclasts (1, 2). With age, the balance of remodeling is often disrupted, and bone resorption exceeds formation, leading to decreased bone mass and, eventually, osteoporosis and fractures (3–5). Although preventative measures can be taken to delay the onset and magnitude of bone loss (e.g., diet and exercise), bone loss can also be exacerbated by drugs such as glucocorticoids and vitamins such as vitamin A (retinol) if consumed in excess.

Vitamin A is found in foods such as meat, dairy products, and vegetables. A balanced diet is sufficient to maintain the nutritional needs; however, fortification of products as well as supplementation with vitamins leads to an increased risk of hypervitaminosis A and is becoming an increasing problem (6). Excess vitamin A consumption and elevated serum retinol levels have been associated with increased bone fragility and fracture risk in humans (7–10). This association indicates that increased vitamin A intake may be a risk factor for secondary osteoporosis.

The current recommended daily allowance for vitamin A consumption in adults is 900 and 700 µg retinol activity equivalents (RAE) per day in men and women, respectively (11). The upper tolerable limit of maximum vitamin A consumption that does not pose ill effects is 3000 µg/d (11). Supplements, whether single-ingredient or multimineral or multivitamin when combined with food or each other, often contain over 100% of the recommended daily allowance of 1 or more nutrients (12). Besides professional athletes (13), the elderly (aged 60 y and over) are the highest users of supplements (12). For this reason, supplementation of vitamin A or constituents high in vitamin A (e.g., liver oil), in addition to an already balanced diet, may exacerbate bone loss.

In experimental rat studies, a 142-fold increase in vitamin A intake (RAE vitamin A 510 µg/g chow) has been illustrated to induce hypervitaminosis A and vitamin A toxicity determined by serum retinol status, reduced food intake, and reduction in weight gain (14–16). In rats receiving oral gavage of a 200–500-fold increase of vitamin A levels (RAE vitamin A 3000–7500 µg/d), spontaneous long-bone fractures have been reported (17). Short-term hypervitaminosis A in rodents decreases cortical bone because of an increased number of osteoclasts on the periosteal bone (14, 17–19) and a decreased number on the endocortical bone (14).

The effects of vitamin A on bone formation have been less well studied. In 2 studies, rats fed hypervitaminosis A diet containing 1700 IU (RAE vitamin A 510 µg/g chow) for 7 d have decreased osteoblast activity and number on the periosteal bone of the femur (15) and on the pericranial side of the calvaria (16). In another study, mice given daily injections of 125 µg/kg of the retinoid Ro 13-6295 for 4 d had a reduced number of osteoblasts with no effect on their activity (19).

Although the doses of vitamin A used in rodent studies are high, they are not necessarily reflective of human consumption in either quantity or duration. More recently, we have shown that a clinically relevant dose of vitamin A (RAE 60 µg/g chow), which is only 13 times higher than control diet, decreased periosteal bone formation after 1 wk and also increased endocortical bone formation after 1 and 4 wk of treatment in mice (20). Thus, via concomitant increase in bone resorption and decrease in bone formation, excess vitamin A can lead to decreased bone strength (14, 21) and increased risk of fractures (8, 9, 22–24).

Bone strength is dependent on size, architecture, and composition. Loading of the skeleton during physical activity leads to recruitment of bone-forming osteoblasts in order to adapt the bones to the applied strain, thereby increasing bone strength (25). Bone is composed of organic (mainly collagen type 1 fibers) and inorganic (hydroxyapatite, calcium, phosphate) compounds that reflect the quality of the bone. Axial mechanical loading of the tibia in rodents is the gold standard of studying bone response to load (26). It is also a good model of impact sports and can be used against a background of various dietary supplements. Often it is noted that the opportune time to enhance bone strength and reduce the risk of fractures later in life is during childhood and puberty; however, implementation of exercise in postmenopausal women has also shown increases in bone mineral density (BMD) at the lumbar spine and femoral neck (27–31).

We hypothesized that a clinically relevant dose of vitamin A may inhibit the bone-forming effects of mechanical loading in mice, in addition to activation of bone resorption. Therefore, we assessed the loading response in bone with and without prior and concurrent treatment with a clinically relevant dose of vitamin A.

Place, publisher, year, edition, pages
Federation of American Societies for Experimental Biology, 2019
Keywords
osteoblasts retinoids, physical activity, Raman spectroscopy
National Category
Orthopaedics
Identifiers
urn:nbn:se:umu:diva-158085 (URN)10.1096/fj.201802040R (DOI)000462888500049 ()30668919 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-04-15Bibliographically approved
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
Erlandsson, A., Carlsson, J., Andersson, S.-O., Vyas, C., Wikström, P., Andrén, O., . . . Rider, J. R. (2018). High inducible nitric oxide synthase in prostate tumor epithelium is associated with lethal prostate cancer. Scandinavian journal of urology, 52(2), 129-133
Open this publication in new window or tab >>High inducible nitric oxide synthase in prostate tumor epithelium is associated with lethal prostate cancer
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2018 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 2, p. 129-133Article in journal (Refereed) Published
Abstract [en]

Objective: The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) in lethal prostate cancer (PCa) by studying the iNOS immunoreactivity in tumor tissue from men diagnosed with localized PCa. Materials and methods: This study is nested within a cohort of men diagnosed with incidental PCa undergoing transurethral resection of the prostate (the Swedish Watchful Waiting Cohort). To investigate molecular determinants of lethal PCa, men who died from PCa (n = 132) were selected as cases; controls (n = 168) comprised men with PCa who survived for at least 10 years without dying from PCa during follow-up. The immunoreactivity of iNOS in prostate tumor epithelial cells and in cells of the surrounding stroma was scored as low/negative, moderate or high. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for lethal PCa according to iNOS category. Results: There was no association between iNOS immunoreactivity in stroma and lethal disease. However, when comparing high versus low/negative iNOS immunoreactivity in epithelial cells, the OR for lethal PCa was 3.80 (95% CI 1.45-9.97). Conclusion: Patients with localized PCa have variable outcomes, especially those with moderately differentiated tumors. Identifying factors associated with long-term PCa outcomes can elucidate PCa tumor biology and identify new candidate prognostic markers. These findings support the hypothesis that high iNOS in tumor epithelium of the prostate is associated with lethal disease.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
Inducible nitric oxide synthase, iNOS, nitric oxide, prognostic marker, prostate cancer
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-152926 (URN)10.1080/21681805.2017.1421261 (DOI)000446242100009 ()29307261 (PubMedID)
Available from: 2018-10-30 Created: 2018-10-30 Last updated: 2018-10-30Bibliographically approved
Tjon-Kon-Fat, L.-A., Lundholm, M., Schröder, M., Wurdinger, T., Thellenberg-Karlsson, C., Widmark, A., . . . Nilsson, R. J. (2018). Platelets harbor prostate cancer biomarkers and the ability to predict therapeutic response to abiraterone in castration resistant patients. The Prostate, 78(1), 48-53
Open this publication in new window or tab >>Platelets harbor prostate cancer biomarkers and the ability to predict therapeutic response to abiraterone in castration resistant patients
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2018 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, no 1, p. 48-53Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. This study used circulating biomarker analysis to follow cancer-derived transcripts implicated in therapy resistance.

METHOD: The isolated platelet population of blood samples and digital-PCR were used to identify selected biomarker transcripts in patients with CRPC prior chemo- or androgen synthesis inhibiting therapy.

RESULTS: Fifty patients received either docetaxel (n = 24) or abiraterone (n = 26) therapy, with therapy response rates of 54% and 48%, respectively. Transcripts for the PC-associated biomarkers kallikrein-related peptidase-2 and -3 (KLK2, KLK3), folate hydrolase 1 (FOLH1), and neuropeptide-Y (NPY) were uniquely present within the platelet fraction of cancer patients and not detected in healthy controls (n = 15). In the abiraterone treated cohort, the biomarkers provided information on therapy outcome, demonstrating an association between detectable biomarkers and short progression free survival (PFS) (FOLH1, P < 0.01; KLK3, P < 0.05; and NPY, P < 0.05). Patients with biomarker-negative platelets had the best outcome, while FOLH1 (P < 0.05) and NPY (P = 0.05) biomarkers provided independent predictive information in a multivariate analysis regarding PFS. KLK2 (P < 0.01), KLK3 (P < 0.001), and FOLH1 (P < 0.05) biomarkers were associated with short overall survival (OS). Combining three biomarkers in a panel (KLK3, FOLH1, and NPY) made it possible to separate long-term responders from short-term responders with 87% sensitivity and 82% specificity.

CONCLUSION: Analyzing tumor-derived biomarkers in platelets of CRPC patients enabled prediction of the outcome after abiraterone therapy with higher accuracy than baseline serum PSA or PSA response.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2018
Keywords
biomarkers, liquid biopsy, personalized medicine, platelet, prostate cancer, therapy stratification
National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-142384 (URN)10.1002/pros.23443 (DOI)000417131400007 ()29094381 (PubMedID)
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2018-06-09Bibliographically 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
Projects
Biomarkers for aggressive prostate cancer [2009-04892_VR]; Umeå UniversityBiomarkers for Prostate Cancer Prognosis and Prediction of Therapy Response [2012-02179_VR]; Umeå UniversityBiomarkers for prostate cancer prognosis and prediction of therapy response [2015-02393_VR]; Umeå UniversityBiomarkers for improved prognostics and therapeutics of aggressive prostate cancer [2018-02594_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6347-1999

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