Publications by authors named "Markku Kallajoki"

54 Publications

Complement factor I upregulates expression of matrix metalloproteinase-13 and -2 and promotes invasion of cutaneous squamous carcinoma cells.

Exp Dermatol 2021 Apr 4. Epub 2021 Apr 4.

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.

The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing globally. Here, we have studied the functional role of complement factor I (CFI) in the progression of cSCC. CFI was knocked down in cSCC cells, and RNA-seq analysis was performed. Significant downregulation of genes in IPA biofunction categories Proliferation of cells and Growth of malignant tumor, in Gene Ontology (GO) terms Metallopeptidase activity and Extracellular matrix component, as well as Reactome Degradation of extracellular matrix was detected after CFI knockdown. Further analysis of the latter three networks, revealed downregulation of several genes coding for invasion-associated matrix metalloproteinases (MMPs) after CFI knockdown. The downregulation of MMP-13 and MMP-2 was confirmed at mRNA, protein and tissue levels by qRT-qPCR, Western blot and immunohistochemistry, respectively. Knockdown of CFI decreased the invasion of cSCC cells through type I collagen. Overexpression of CFI in cSCC cells resulted in enhanced production of MMP-13 and MMP-2 and increased invasion through type I collagen and Matrigel, and in increased ERK1/2 activation and cell proliferation. Altogether, these findings identify a novel mechanism of action of CFI in upregulation of MMP-13 and MMP-2 expression and cSCC invasion. These results identify CFI as a prospective molecular marker for invasion and metastasis of cSCC.
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http://dx.doi.org/10.1111/exd.14349DOI Listing
April 2021

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study.

Neoplasia 2020 09 22;22(9):333-342. Epub 2020 Jun 22.

Institute of Biomedicine, University of Turku and Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland.

Objectives: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines.

Materials And Methods: 176 surgically resected stage I-IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I-III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available.

Results: Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB ≥ 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB < 14 in multivariable analysis for overall (HR 0.284, 95% CI 0.14-0.59, P=0.001) and disease-specific survival (HR 0.213, 95% CI 0.08-0.56, P=0.002).

Conclusion: TMB was an independent biomarker of favorable prognosis in our cohort of lung adenocarcinoma despite being associated with predominant histological subtypes considered aggressive.
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http://dx.doi.org/10.1016/j.neo.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317687PMC
September 2020

p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous Squamous Cell Carcinoma via STAT3 Signaling.

Am J Pathol 2020 02 12;190(2):503-517. Epub 2019 Dec 12.

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; Cancer Research Laboratory, Western Cancer Centre of the Cancer Center Finland (FICAN West), University of Turku and Turku University Hospital, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland. Electronic address:

Long noncoding RNAs (lncRNAs) have emerged as putative biomarkers and therapeutic targets in cancer. The role of lncRNA LINC00346 in cutaneous squamous carcinoma (cSCC) was examined. The expression of LINC00346 was up-regulated in cSCC cells compared with normal human epidermal keratinocytes. Elevated expression of LINC00346 was noted in tumor cells in cSCC tissue sections in vivo, as compared with cSCC in situ, and actinic keratosis by RNA in situ hybridization; and the expression in seborrheic keratosis and normal skin was very low. Immunohistochemical analysis of cSCC tissue sections and functional assays of cSCC cells in culture showed that LINC00346 expression is down-regulated by p53. Knockdown of LINC00346 inhibited invasion of cSCC cells in culture and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00346 inhibited expression of activated STAT3 and resulted in down-regulation of the expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-10, and MMP-13. Based on these observations LINC00346 was named p53 regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT). These results identify PRECSIT as a new p53-regulated lncRNA, which promotes progression of cSCC via STAT3 signaling.
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http://dx.doi.org/10.1016/j.ajpath.2019.10.019DOI Listing
February 2020

Qualitative and Quantitative Reporting of a Unique Biparametric MRI: Towards Biparametric MRI-Based Nomograms for Prediction of Prostate Biopsy Outcome in Men With a Clinical Suspicion of Prostate Cancer (IMPROD and MULTI-IMPROD Trials).

J Magn Reson Imaging 2020 05 21;51(5):1556-1567. Epub 2019 Nov 21.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Background: Multiparametric MRI of the prostate has been shown to improve the risk stratification of men with an elevated prostate-specific antigen (PSA). However, long acquisition time, high cost, and inter-center/reader variability of a routine prostate multiparametric MRI limit its wider adoption.

Purpose: To develop and validate nomograms based on unique rapid biparametric MRI (bpMRI) qualitative and quantitative derived variables for prediction of clinically significant cancer (SPCa).

Study Type: Retrospective analyses of single (IMPROD, NCT01864135) and multiinstitution trials (MULTI-IMPROD, NCT02241122).

Population: 161 and 338 prospectively enrolled men who completed the IMPROD and MULTI-IMPROD trials, respectively.

Field Strength/sequence: IMPROD bpMRI: 3T/1.5T, T -weighted imaging, three separate diffusion-weighted imaging (DWI) acquisitions: 1) b-values 0, 100, 200, 300, 500 s/mm ; 2) b values 0, 1500 s/mm ; 3) values 0, 2000 s/mm .

Assessment: The primary endpoint of the combined trial analysis was the diagnostic accuracy of the combination of IMPROD bpMRI and clinical variables for detection of SPCa.

Statistical Tests: Logistic regression models were developed using IMPROD trial data and validated using MULTI-IMPROD trial data. The model's performance was expressed as the area under the curve (AUC) values for the detection of SPCa, defined as ISUP Gleason Grade Group ≥2.

Results: A model incorporating clinical variables had an AUC (95% confidence interval) of 0.83 (0.77-0.89) and 0.80 (0.75-0.85) in the development and validation cohorts, respectively. The corresponding values for a model using IMPROD bpMRI findings were 0.93 (0.89-0.97), and 0.88 (0.84-0.92), respectively. Further addition of the quantitative DWI-based score did not improve AUC values (P < 0.05).

Data Conclusion: A prediction model using qualitative IMPROD bpMRI findings demonstrated high accuracy for predicting SPCa in men with an elevated PSA. Online risk calculator: http://petiv.utu.fi/multiimprod/ Level of Evidence: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1556-1567.
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http://dx.doi.org/10.1002/jmri.26975DOI Listing
May 2020

Prostate Cancer Risk Stratification in Men With a Clinical Suspicion of Prostate Cancer Using a Unique Biparametric MRI and Expression of 11 Genes in Apparently Benign Tissue: Evaluation Using Machine-Learning Techniques.

J Magn Reson Imaging 2020 05 6;51(5):1540-1553. Epub 2019 Oct 6.

Institute of Biomedicine, University of Turku and Department of Pathology, Turku University Hospital, Turku, Finland.

Background: Accurate risk stratification of men with a clinical suspicion of prostate cancer (cSPCa) remains challenging despite the increasing use of MRI.

Purpose: To evaluate the diagnostic accuracy of a unique biparametric MRI protocol (IMPROD bpMRI) combined with clinical and molecular markers in men with cSPCa.

Study Type: Prospective single-institutional clinical trial (NCT01864135).

Subjects: Eighty men with cSPCa.

Field Strength/sequence: 3T, surface array coils. Two T -weighted and three diffusion-weighted imaging (DWI) acquisitions: 1) b-values 0, 100, 200, 300, 500 s/mm ; 2) b-values 0,1500 s/mm ; 3) b-values 0, 2000 s/mm .

Assessment: IMPROD bpMRI examinations were qualitatively (IMPROD bpMRI Likert score) and quantitatively (DWI-based Gleason grade score) prospectively reported. Men with IMPROD bpMRI Likert 3-5 had two targeted biopsies followed by 12-core systematic biopsies (SB); those with IMPROD bpMRI Likert 1-2 had only SB. Additionally, 2-core from normal-appearing prostate areas were obtained for the mRNA expression of ACSM1, AMACR, CACNA1D, DLX1, PCA3, PLA2G7, RHOU, SPINK1, SPON2, TMPRSS2-ERG, and TDRD1 measured by quantitative reverse-transcription polymerase chain reaction.

Statistical Tests: Univariate and multivariate analysis using regularized least-squares, feature selection and tournament leave-pair-out cross-validation (TLPOCV), as well as 10 random splits of the data in training-testing sets, were used to evaluate the mRNA, clinical and IMPROD bpMRI parameters in detecting clinically significant prostate cancer (SPCa) defined as Gleason score ≥ 3 + 4. The evaluation metric was the area under the curve (AUC).

Results: IMPROD bpMRI Likert demonstrated the highest TLPOCV AUC of 0.92. The tested clinical variables had AUC 0.56-0.73, while the mRNA and additional IMPROD bpMRI parameters had AUC 0.50-0.67 and 0.65-0.89 respectively. The combination of clinical and mRNA biomarkers produced TLPOCV AUC of 0.87, the highest TLPOCV performance without including IMPROD bpMRI Likert.

Data Conclusion: The qualitative IMPROD bpMRI Likert score demonstrated the highest accuracy for SPCa detection compared with the tested clinical variables and mRNA biomarkers.

Level Of Evidence: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1540-1553.
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http://dx.doi.org/10.1002/jmri.26945DOI Listing
May 2020

Positive STAT5 Protein and Locus Amplification Status Predicts Recurrence after Radical Prostatectomy to Assist Clinical Precision Management of Prostate Cancer.

Cancer Epidemiol Biomarkers Prev 2019 10 10;28(10):1642-1651. Epub 2019 Jul 10.

Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: A significant fraction of prostate cancer patients experience post-radical prostatectomy (RP) biochemical recurrence (BCR). New predictive markers are needed for optimizing postoperative prostate cancer management. is an oncogene in prostate cancer that undergoes amplification in 30% of prostate cancers during progression.

Methods: We evaluated the significance of a positive status for nuclear STAT5 protein expression versus locus amplification versus combined positive status for both in predicting BCR after RP in 300 patients.

Results: Combined positive STAT5 status was associated with a 45% disadvantage in BCR in Kaplan-Meier survival analysis in all Gleason grade patients. Patients with Gleason grade group (GG) 2 and 3 prostate cancers and combined positive status for STAT5 had a more pronounced disadvantage of 55% to 60% at 7 years after RP in univariate analysis. In multivariate analysis, including the Cancer of the Prostate Risk Assessment Postsurgical nomogram (CAPRA-S) variables, combined positive STAT5 status was independently associated with a shorter BCR-free survival in all Gleason GG patients (HR, 2.34; = 0.014) and in intermediate Gleason GG 2 or 3 patients (HR, 3.62; = 0.021). The combined positive STAT5 status improved the predictive value of the CAPRA-S nomogram in both ROC-AUC analysis and in decision curve analysis for BCR.

Conclusions: Combined positive status for STAT5 was independently associated with shorter disease-free survival in univariate analysis and was an independent predictor for BCR in multivariate analysis using the CAPRA-S variables in prostate cancer.

Impact: Our results highlight potential for a novel precision medicine concept based on a pivotal role of STAT5 status in improving selection of prostate cancer patients who are candidates for early adjuvant interventions to reduce the risk of recurrence.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774884PMC
October 2019

Validation of IMPROD biparametric MRI in men with clinically suspected prostate cancer: A prospective multi-institutional trial.

PLoS Med 2019 06 3;16(6):e1002813. Epub 2019 Jun 3.

Department of Urology, University of Turku and Turku University Hospital, Turku, Finland.

Background: Magnetic resonance imaging (MRI) combined with targeted biopsy (TB) is increasingly used in men with clinically suspected prostate cancer (PCa), but the long acquisition times, high costs, and inter-center/reader variability of routine multiparametric prostate MRI limit its wider adoption.

Methods And Findings: The aim was to validate a previously developed unique MRI acquisition and reporting protocol, IMPROD biparametric MRI (bpMRI) (NCT01864135), in men with a clinical suspicion of PCa in a multi-institutional trial (NCT02241122). IMPROD bpMRI has average acquisition time of 15 minutes (no endorectal coil, no intravenous contrast use) and consists of T2-weighted imaging and 3 separate diffusion-weighed imaging acquisitions. Between February 1, 2015, and March 31, 2017, 364 men with a clinical suspicion of PCa were enrolled at 4 institutions in Finland. Men with an equivocal to high suspicion (IMPROD bpMRI Likert score 3-5) of PCa had 2 TBs of up to 2 lesions followed by a systematic biopsy (SB). Men with a low to very low suspicion (IMPROD bpMRI Likert score 1-2) had only SB. All data and protocols are freely available. The primary outcome of the trial was diagnostic accuracy-including overall accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value-of IMPROD bpMRI for clinically significant PCa (SPCa), which was defined as a Gleason score ≥ 3 + 4 (Gleason grade group 2 or higher). In total, 338 (338/364, 93%) prospectively enrolled men completed the trial. The accuracy and NPV of IMPROD bpMRI for SPCa were 70% (113/161) and 95% (71/75) (95% CI 87%-98%), respectively. Restricting the biopsy to men with equivocal to highly suspicious IMPROD bpMRI findings would have resulted in a 22% (75/338) reduction in the number of men undergoing biopsy while missing 4 (3%, 4/146) men with SPCa. The main limitation is uncertainty about the true PCa prevalence in the study cohort, since some of the men may have PCa despite having negative biopsy findings.

Conclusions: IMPROD bpMRI demonstrated a high NPV for SPCa in men with a clinical suspicion of PCa in this prospective multi-institutional clinical trial.

Trial Registration: ClinicalTrials.gov NCT02241122.
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http://dx.doi.org/10.1371/journal.pmed.1002813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546206PMC
June 2019

ANO7 is associated with aggressive prostate cancer.

Int J Cancer 2018 11 22;143(10):2479-2487. Epub 2018 Sep 22.

Institute of Biomedicine, University of Turku, Turku, Finland.

Prostate cancer is one of the most common and heritable human cancers. Our aim was to find germline biomarkers that can predict disease outcome. We previously detected predisposing signals at 2q37, the location of the prostate specific ANO7 gene. To investigate, in detail, the associations between the ANO7 gene and PrCa risk and disease aggressiveness, ANO7 was sequenced in castration resistant tumors together with samples from unselected PrCa patients and unaffected males. Two pathogenic variants were discovered and genotyped in 1769 patients and 1711 unaffected males. Expression of ANO7 vs. PrCa aggressiveness was investigated. Different databases along with Swedish and Norwegian cohorts were used for validation. Case-control and aggressive vs. nonaggressive association analyses were performed against risk and/or cancer aggressiveness. The ANO7 mRNA level and patient survival were analyzed using expression data from databases. Variant rs77559646 showed both risk (OR 1.40; p = 0.009, 95% CI 1.09-1.78) and association with aggressive PrCa (Genotype test p = 0.04). It was found to be an eQTL for ANO7 (Linear model p-values for Finnish patients p = 0.009; Camcap prostate tumor p = 2.53E-06; Stockholm prostate tumor cohort p = 1.53E-13). rs148609049 was not associated with risk, but was related to shorter survival (HR 1.56; 95% CI 1.03-2.36). High ANO7 expression was independently linked to poor survival (HR 18.4; 95% CI 1.43-237). ANO7 genotypes correlate with expression and biochemical relapse, suggesting that ANO7 is a potential PrCa susceptibility gene and that its elevated expression correlates with disease severity and outcome.
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http://dx.doi.org/10.1002/ijc.31746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589920PMC
November 2018

New prostate cancer grade grouping system predicts survival after radical prostatectomy.

Hum Pathol 2018 05 13;75:159-166. Epub 2018 Feb 13.

Department of Pathology, Medicum, University of Helsinki, 00014 Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland; Department of Pathology, HUSLAB, Helsinki University Hospital, 00029 Helsinki, Finland,. Electronic address:

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http://dx.doi.org/10.1016/j.humpath.2018.01.027DOI Listing
May 2018

Intensity of F-FDG PET Uptake in Culture-Negative and Culture-Positive Cases of Chronic Osteomyelitis.

Contrast Media Mol Imaging 2017 11;2017:9754293. Epub 2017 Oct 11.

Orthopaedic Research Unit, Department of Orthopaedic Surgery and Traumatology, Turku University Hospital, University of Turku, Turku, Finland.

Microbiologic cultures are not infrequently negative in patients with a histopathologic diagnosis of chronic osteomyelitis. Culture-negative cases may represent low-grade infections with a lower metabolic activity than culture-positive cases. F-FDG PET could potentially detect such a difference. We determined whether the level of F-FDG PET uptake differs in patients with culture-negative and culture-positive osteomyelitis. We reviewed the clinical charts of 40 consecutive patients, who had diagnostic F-FDG PET for a suspected bone infection. Twenty-six patients were eligible with a confirmed diagnosis based on microbiologic cultures and/or histopathologic examination. Sixteen of 26 patients had chronic osteomyelitis. Eight of them had positive cultures, seven had negative cultures, and one patient had no cultures of the biopsy specimen. The patients with histologically and/or microbiologically proven osteomyelitis were correctly interpreted as true positive in the routine clinical reading of F-FDG PET images. There was no relationship between the level of F-FDG PET uptake and the presence of positive or negative bacterial cultures. The result favors the concept that that culture-negative cases of osteomyelitis are false-negative infections due to nonculturable microbes. F-FDG PET may help to confirm the presence of metabolically active infection in these patients and guide their appropriate treatment.
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http://dx.doi.org/10.1155/2017/9754293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660764PMC
July 2018

Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma.

Oncotarget 2017 Jul;8(28):45825-45836

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. Inflammation is a typical feature in cSCC progression. Analysis of the expression of inflammasome components in cSCC cell lines and normal human epidermal keratinocytes revealed upregulation of the expression of AIM2 mRNA and protein in cSCC cells. Elevated levels of AIM2 mRNA were noted in cSCCs in vivo compared with normal skin. Strong and moderate tumor cell specific expression of AIM2 was detected with immunohistochemistry (IHC) in sporadic human cSCCs in vivo, whereas expression of AIM2 was moderate in cSCC in situ (cSCCIS) and low or absent in actinic keratosis (AK) and normal skin. IHC of cSCCs, cSCCIS and AKs from organ transplant recipients also revealed strong and moderate tumor cell specific expression of AIM2 in cSCCs. Knockdown of AIM2 resulted in reduction in viability of cSCC cells and onset of apoptosis. RNA-seq and pathway analysis after knockdown of AIM2 in cSCC cells revealed downregulation of the biofunction category Cell cycle and upregulation of the biofunction category Cell Death and Survival. Knockdown of AIM2 also resulted in reduction in invasion of cSCC cells and downregulation in production of invasion proteinases MMP1 and MMP13. Knockdown of AIM2 resulted in suppression of growth and vascularization of cSCC xenografts in vivo. These results provide evidence for the role of AIM2 in the progression of cSCC and identify AIM2 inflammasome function as a potential therapeutic target in these invasive and metastatic tumors.
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http://dx.doi.org/10.18632/oncotarget.17573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542230PMC
July 2017

Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma.

Am J Pathol 2017 May 17;187(5):1186-1197. Epub 2017 Mar 17.

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland. Electronic address:

Cutaneous squamous cell carcinoma (cSCC) is one of the most common metastatic skin cancers with increasing incidence. We examined the roles of complement component C3 and complement factor B (CFB) in the growth of cSCC. Analysis of cSCC cell lines (n = 8) and normal human epidermal keratinocytes (n = 11) with real-time quantitative PCR and Western blotting revealed up-regulation of C3 and CFB expression in cSCC cells. Immunohistochemical staining revealed stronger tumor cell-specific labeling for C3 and CFB in invasive cSCCs (n = 71) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n = 11) than in cSCC in situ (n = 69), actinic keratoses (n = 63), and normal skin (n = 5). Significant up-regulation of C3 and CFB mRNA expression was noted in chemically induced mouse cSCCs, compared to benign papillomas. Knockdown of C3 and CFB expression inhibited migration and proliferation of cSCC cells and resulted in potent inhibition of extracellular signal-regulated kinase 1/2 activation. Knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the roles of C3 and CFB in the development of cSCC and identify them as biomarkers and potential therapeutic targets in this metastatic skin cancer.
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http://dx.doi.org/10.1016/j.ajpath.2017.01.006DOI Listing
May 2017

Novel biparametric MRI and targeted biopsy improves risk stratification in men with a clinical suspicion of prostate cancer (IMPROD Trial).

J Magn Reson Imaging 2017 10 6;46(4):1089-1095. Epub 2017 Feb 6.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

Purpose: To evaluate the role of a 3T biparametric magnetic resonance imaging (bpMRI), T -weighted imaging, and three separate diffusion-weighted imaging acquisitions combined with targeted biopsy (TB) for improving risk stratification of men with elevated prostate-specific antigen (PSA).

Materials And Methods: Between March 2013 and February 2015, 175 men with a clinical suspicion of prostate cancer (PCa) were offered bpMRI (NCT01864135) based on a suspicion of PCa (two repeated PSA measurements in the range 2.5-20.0 ng/ml and/or abnormal digital rectal examination). Men with an equivocal to high suspicion of PCa had two TBs of the dominant lesion using cognitive ultrasound guidance, followed by systematic biopsy (SB). Men with a low to very low suspicion had only SB. In total, 161 (161/175, 92%) prospectively enrolled men completed the trial and were included in the final analyses. The primary endpoint of the trial was the cancer detection rate (CDR) of TB and SB. Clinically significant cancer (SPCa) was defined as Gleason score ≥3 + 4.

Results: TB compared with SB had higher CDR for SPCa (45%, 72/161 vs. 39%, 63/161, respectively; P > 0.05) and a lower CDR for Gleason score 3 + 3 (8%, 15/161 vs. 16%, 30/161; P < 0.05). Restricting biopsy to men with equivocal to highly suspicious bpMRI findings would have resulted in a 24% (38/161) reduction in the number of men undergoing biopsy, while missing 4 (2%) with SPCa. All anonymized datasets, including bpMRI reports and follow up information, are freely available on the trial server.

Conclusion: Prebiopsy bpMRI and TB in men with a clinical suspicion of PCa improved risk stratification.

Level Of Evidence: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:1089-1095.
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http://dx.doi.org/10.1002/jmri.25641DOI Listing
October 2017

Expression of claudin-11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ.

Exp Dermatol 2017 09 10;26(9):771-777. Epub 2017 Apr 10.

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.

The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing, and the prognosis of patients with metastatic disease is poor. There is an emerging need to identify molecular markers for predicting aggressive behaviour of cSCC. Here, we have examined the role of tight junction (TJ) components in the progression of cSCC. The expression pattern of mRNAs for TJ components was determined with RNA sequencing and oligonucleotide array-based expression analysis from cSCC cell lines (n=8) and normal human epidermal keratinocytes (NHEK, n=5). The expression of CLDN11 was specifically elevated in primary cSCC cell lines (n=5), but low or absent in metastatic cSCC cell lines (n=3) and NHEKs. Claudin-11 was detected in cell-cell contacts of primary cSCC cells in culture by indirect immunofluorescence analysis. Analysis of a large panel of tissue samples from sporadic UV-induced cSCC (n=65), cSCC in situ (n=56), actinic keratoses (n=31), seborrhoeic keratoses (n=7) and normal skin (n=16) by immunohistochemistry showed specific staining for claudin-11 in intercellular junctions of keratinizing tumor cells in well and moderately differentiated cSCCs, whereas no staining for claudin-11 was detected in poorly differentiated tumors. The expression of claudin-11 in cSCC cells was dependent on the activity of p38δ MAPK and knock-down of claudin-11 enhanced cSCC cell invasion. These findings provide evidence for the role of claudin-11 in regulation of cSCC invasion and suggest loss of claudin-11 expression in tumor cells as a biomarker for advanced stage of cSCC.
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http://dx.doi.org/10.1111/exd.13278DOI Listing
September 2017

Long Noncoding RNA PICSAR Promotes Growth of Cutaneous Squamous Cell Carcinoma by Regulating ERK1/2 Activity.

J Invest Dermatol 2016 08 2;136(8):1701-1710. Epub 2016 Apr 2.

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland. Electronic address:

Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing globally. Long noncoding RNAs (lncRNA) are involved in various biological processes, and their role in cancer progression is emerging. Whole transcriptome analysis of cSCC cells (n = 8) and normal human epidermal keratinocytes (n = 4) revealed overexpression of long intergenic ncRNA (LINC00162) in cSCC cells. The expression of LINC00162 in cSCC cells was upregulated by inhibition of the p38α and p38δ mitogen-activated protein kinases. Analysis of tissue sections by RNA in situ hybridization showed that LINC00162 is specifically expressed by tumor cells in cSCCs but not by keratinocytes in normal skin in vivo. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells, and suppressed the growth of human cSCC xenografts in vivo. Furthermore, knockdown of LINC00162 inhibited extracellular signal-regulated kinase 1/2 activity and upregulated expression of dual specificity phosphatase 6 (DUSP6) in cSCC cells. Based on these observations, LINC00162 was named p38 inhibited cutaneous squamous cell carcinoma associated lincRNA (PICSAR). Our results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of extracellular signal-regulated kinase 1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a biomarker and putative therapeutic target in cSCC.
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http://dx.doi.org/10.1016/j.jid.2016.03.028DOI Listing
August 2016

Increased expression of fibroblast growth factor 13 in prostate cancer is associated with shortened time to biochemical recurrence after radical prostatectomy.

Int J Cancer 2016 Jul 12;139(1):140-52. Epub 2016 Mar 12.

Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland.

Fibroblast growth factor homologous factors (FHFs) belong to the fibroblast growth factor (FGF) superfamily, which plays an important role in prostate cancer (PCa). Mining of public database suggests that FGF13 (FHF2) mRNA expression is altered in over 30% of PCa cases. This study examined the FGF13 expression pattern in human PCa specimens and evaluated its potential as a biomarker for patient outcome after radical prostatectomy (RP). Immunohistochemistry (IHC) showed that FGF13 was detectable in the majority of human PCa samples, and FGF13 IHC scores were higher in high-grade prostatic intraepithelial neoplasia, in primary PCa and in metastatic PCa than in benign prostatic tissue. There was a significant association between high cytoplasmic FGF13 staining and a risk of biochemical recurrence (BCR) after RP. This was also evident in the intermediate to high-risk patient groups. In contrast, positive nuclear FGF13 staining along with low cytoplasmic FGF13 group showed a decreased BCR risk. Multivariate regression analysis indicated that high cytoplasmic FGF13 staining was associated with BCR and that this could serve as an independent prognostic marker in PCa. Several PCa cell lines showed increased FGF13 expression at the mRNA and protein levels compared to the immortalized prostate epithelial cell line PNT1a. Analysis of co-labeled cells suggested a possible interaction of FGF13 with α-tubulin and the voltage-gated sodium channel proteins (Na(V)s/VGSCs). Our data indicate that, for PCa patients after RP, FGF13 serves as a potential novel prognostic marker that improves prediction of BCR-free survival, in particular if combined with other clinical parameters.
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http://dx.doi.org/10.1002/ijc.30048DOI Listing
July 2016

Stratification of aggressive prostate cancer from indolent disease-Prospective controlled trial utilizing expression of 11 genes in apparently benign tissue.

Urol Oncol 2016 06 5;34(6):255.e15-22. Epub 2016 Feb 5.

Department of Biotechnology, University of Turku, Turku, Finland.

Background: The aim of the study was to evaluate the diagnostic power of molecular markers in men with a clinical suspicion of prostate cancer (PCa) using apparently benign areas as targeted by magnetic resonance imaging (MRI).

Methods: In the study, 99 consecutive men with clinical suspicion of PCa in a prospective controlled trial (IMPROD, NCT01864135) were included. In addition to 12-core systematic and MRI-targeted biopsies, cores from normal-appearing prostate areas, based on clinical examination, ultrasound, and biparametric prostate MRI, were obtained. The RNA transcript levels of ACSM1, AMACR, CACNA1D, DLX1, KLK3, PCA3, PLA2G7, RHOU, SPINK1, SPON2, TMPRSS2-ERG, and TDRD1 were measured with quantitative reverse-transcription polymerase chain reaction.

Results: Of the 99 men, 69 were diagnosed with PCa, 31 with primary Gleason pattern 3 and 38 with primary Gleason 4 or 5. TDRD1 messenger RNA (mRNA) levels were 1.3 times higher (P = 0.029) and the presence of TMPRSS2-ERG mRNAs more frequent in biopsies from men diagnosed with PCa (27/69, 39%) than in men without (5/30, 16%) (P = 0.035). The 2 markers identified aggressive PCa defined as Gleason sum≥7 at biopsy: median TDRD1 mRNA level was 1.4 higher (P = 0.005) and TMPRSS2-ERG expression more frequent (P<0.001) in high-grade cancer. A multivariate analysis of mRNA expression of 11 candidate genes combined with KLK3, serum prostate-specific antigen (PSA), percentage-free PSA, and prostate volume improved the discrimination between aggressive and nonaggressive PCa (area under the curve = 0.77) compared with the use of the candidate genes or clinical parameters alone. However, serum PSA, percentage-free PSA, and prostate volume resulted in the best discrimination between non-organ-confined PCa (T3) from organ-confined PCa (T2) and healthy prostate (area under the curve = 0.86).

Conclusions: Of the 11 studied genes, TDRD1 and TMPRSS2-ERG were able to statistically significantly differentiate men with PCa from men without it as single markers. However, a multivariate analysis using 15 features outperformed each individual marker in identifying aggressive PCa.
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http://dx.doi.org/10.1016/j.urolonc.2015.12.014DOI Listing
June 2016

[Diagnosis of soft tissue tumors--multidisciplinary collaboration].

Duodecim 2015 ;131(8):769-80

The number of soft tissue sarcomas found in Finland yearly is around 200 cases. Benign soft tissue tumors are common. The patients having a tumor with a deep location in the tissue or a large superficial tumor should be readily referred for imaging studies and consultations with the sarcoma teams of university hospitals. The diagnosis of sarcoma is based on medical history, clinical examination, imaging, examination of a biopsy, and frequently also on molecular genetic analyses. In imaging, the best resolution is provided by MRI. Targeting of the biopsy is an essential part of imaging. Gradus is the most important histology-based factor affecting the prognosis and treatment of the tumor.
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August 2015

EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma.

J Invest Dermatol 2015 Jul 19;135(7):1882-1892. Epub 2015 Mar 19.

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland. Electronic address:

Keratinocyte-derived skin cancer, cutaneous squamous cell carcinoma (cSCC), is the most common metastatic skin cancer. We have examined the role of Eph/ephrin signaling in the progression of cSCC. Analysis of the expression of EPH and EFN families in cSCC cells and normal epidermal keratinocytes revealed overexpression of EPHB2 mRNA in cSCC cells and cSCC tumors in vivo. Tumor cell-specific overexpression of EphB2 was detected in human cSCCs and in chemically induced mouse cSCCs with immunohistochemistry, whereas the expression of EphB2 was low in premalignant lesions and normal skin. Knockdown of EphB2 expression in cSCC cells suppressed growth and vascularization of cSCC xenografts in vivo and inhibited proliferation, migration, and invasion of cSCC cells in culture. EphB2 knockdown downregulated expression of genes associated with biofunctions cell viability, migration of tumor cells, and invasion of tumor cells. Among the genes most downregulated by EphB2 knockdown were MMP1 and MMP13. Moreover, activation of EphB2 signaling by ephrin-B2-Fc enhanced production of invasion proteinases matrix metalloproteinase-13 (MMP13) and MMP1, and invasion of cSCC cells. These findings provide mechanistic evidence for the role of EphB2 in the early progression of cSCC to the invasive stage and identify EphB2 as a putative therapeutic target in this invasive skin cancer.
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http://dx.doi.org/10.1038/jid.2015.104DOI Listing
July 2015

Complement factor I promotes progression of cutaneous squamous cell carcinoma.

J Invest Dermatol 2015 Feb 3;135(2):579-588. Epub 2014 Sep 3.

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland. Electronic address:

The incidence of cutaneous squamous cell carcinoma (cSCC) is rising worldwide. We have examined the role of complement components in the progression of cSCC. Analysis of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=11) with whole transcriptome profiling (SOLiD), quantitative real-time reverse transcriptase-PCR, and western blotting revealed marked overexpression of complement factor I (CFI) in cSCC cells. Immunohistochemical analysis for CFI in vivo showed stronger tumor cell-specific labeling intensity in invasive sporadic cSCCs (n=83) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n=7) than in cSCC in situ (n=65), premalignant epidermal lesions (actinic keratoses, n=64), benign epidermal papillomas (seborrheic keratoses, n=39), and normal skin (n=9). The expression of CFI was higher in the aggressive Ha-ras-transformed cell line (RT3) than in less tumorigenic HaCaT cell lines (HaCaT, A5, and II-4). The expression of CFI by cSCC cells was upregulated by IFN-γ and IL-1β. Knockdown of CFI expression inhibited proliferation and migration of cSCC cells and resulted in inhibition of basal extracellular signal-regulated kinase (ERK) 1/2 activation. Knockdown of CFI expression potently inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the role of CFI in the progression of cSCC and identify it as a potential therapeutic target in this nonmelanoma skin cancer.
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http://dx.doi.org/10.1038/jid.2014.376DOI Listing
February 2015

Complement factor H: a biomarker for progression of cutaneous squamous cell carcinoma.

J Invest Dermatol 2014 Feb 12;134(2):498-506. Epub 2013 Aug 12.

Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland. Electronic address:

The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing globally. We have studied the expression of complement system components in cSCC. Expression profiling of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=5) with Affymetrix and quantitative real-time PCR (qPCR) revealed upregulation of complement factor H (CFH) and factor H-like protein-1 (FHL-1) in cSCC cell lines. The expression of CFH and FHL-1 mRNAs was also significantly higher in cSCC tumors (n=6) than in normal skin (n=11). Analysis of CFH and FHL-1 expression in vivo in invasive cSCCs (n=65), in situ cSCCs (n=38), and premalignant lesions (actinic keratoses, n=37) by immunohistochemistry showed that they were specifically expressed by tumor cells in cSCCs and the staining intensity was stronger in cSCCs than in in situ cSCCs and actinic keratoses. The expression of CFH by cSCC cells was upregulated by IFN-γ and the basal CFH and FHL-1 expression was dependent on extracellular signal-regulated kinase (ERK)1/2 and p38 signaling. Knockdown of CFH and FHL-1 expression inhibited proliferation and migration of cSCC cells and inhibited basal ERK1/2 activation. These results provide evidence for a role of CFH and FHL-1 in cSCC progression and identify them as progression markers and potential therapeutic targets in SCCs of skin.
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http://dx.doi.org/10.1038/jid.2013.346DOI Listing
February 2014

In vivo imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86-7548.

Clin Cancer Res 2013 Oct 9;19(19):5434-43. Epub 2013 Aug 9.

Authors' Affiliations: Department of Surgery, Division of Urology, Departments of Clinical Physiology and Nuclear Medicine, Oncology and Radiotherapy, and Pathology, Turku University Hospital; Turku PET Centre; Department of Diagnostic Radiology, University of Turku, Turku, Finland; Departments of Medical Oncology and Nuclear Medicine, University Hospital of Zurich; Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland; Bayer Pharma AG, Berlin, Germany.

Purpose: A novel [(68)Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer.

Experimental Design: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [(11)C]-acetate (n = 2) or [(18)F]-fluoromethylcholine (n = 1) PET/CT.

Results: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [(11)C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [(18)F]-fluoromethylcholine PET/CT.

Conclusion: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3490DOI Listing
October 2013

Unusual case of inflammatory myofibroblastic tumor in maxilla.

Case Rep Dent 2013 16;2013:876503. Epub 2013 Apr 16.

Department of Oral Pathology and Oral Radiology, Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, 20520 Turku, Finland ; Cell Biology Program, Research Institute, Hospital for Sick Children, University of Toronto, Room 7142, 555 University Avenue, Toronto, ON, Canada M5G 1X8.

Inflammatory myofibroblastic tumor (IMT) is a rare lesion found mostly in children and young adults and originates from the lung, abdominopelvic region, and retroperitoneum. Clinical manifestations of IMT or imaging are nonspecific and diagnosis is based on histopathological and immunohistochemical findings. Minority of all IMTs will metastasize. IMT in the oral cavity is an extreme rarity and this is a first case report of IMT in maxilla causing delayed tooth eruption and multiple cervical root resorption with an 11-year-old child. The IMT reported here was positive for smooth muscle actin, vimentin, and anaplastic lymphoma kinase (ALK1) with immunohistochemistry. Only three IMTs of the jaws have been reported so far and none of them had delayed root eruption and tooth resorption. This unusual case of IMT in a child was also ALK1- positive supporting neoplastic origin of her tumor. The case presented here underscores the importance of histopathological examination of the tissue found in any root resorption especially in the case of multiple resorptions.
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http://dx.doi.org/10.1155/2013/876503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652139PMC
May 2013

Characterization of hepatic tumors using [11C]metomidate through positron emission tomography: comparison with [11C]acetate.

EJNMMI Res 2013 Feb 27;3(1):13. Epub 2013 Feb 27.

Turku PET Centre, Turku University Hospital, University of Turku, Kiinamyllynkatu 4-8, Turku 20521, Finland.

Background: Using positron emission tomography (PET), we compared two tracers, [11C]metomidate ([11C]MTO) and [11C]acetate ([11C]ACE), for the characterization of hepatic tumors.

Methods: Thirty-three patients underwent PET with [11C]MTO and [11C]ACE and magnetic resonance imaging (MRI). Based on the histology of the tumor biopsy, 14 patients had hepatocellular carcinoma (HCC), 9 patients had focal nodular hyperplasia (FNH), and 10 patients had other types of hepatic tumors. Tumor uptake was evaluated by calculating the maximum and mean standardized uptake value and tumor-to-liver ratio.

Results: Altogether, 120 hepatic lesions (59 HCC, 18 FNH, 30 metastases of different primaries, 9 adenomas, and 4 regenerating nodules of liver cirrhosis) were detected by MRI. The overall tumor detection rate was slightly higher for [11C]MTO (39%) than for [11C]ACE (33%). [11C]ACE was more sensitive for HCC detection (50% versus 43%, respectively), whereas [11C]MTO was more sensitive for FNH detection (78% versus 44%, respectively). In HCC patients, the tumor grade correlated with [11C]ACE, but not with [11C]MTO. All of the patients with liver metastases, from various primary tumors (n = 10), were negative for both tracers.

Conclusions: Due to low sensitivity, [11C]MTO and [11C]ACE PET have only limited value in diagnosing hepatic tumors.
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http://dx.doi.org/10.1186/2191-219X-3-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598556PMC
February 2013

[Mesenterial fibrosis--could it be desmoidi?].

Duodecim 2012 ;128(24):2562-8

TYKS:n naistenklinikka.

Desmoid tumors are rare benign fibrous tumors, which have a tendency to invade locally. A minority of desmoids are mesenterial. The symptoms of mesenterial desmoids are misleading, and diagnosis can be delayed. A complete surgical excision is the preferred treatment, but the mesenterial location of the tumor makes radical surgery complicated. Patients whose tumors are not amenable to surgical treatment, have been treated with antiestrogens, nonsteroidal anti-inflammatorics and various chemotherapeutics. Good responses have been observed with pegylated liposomal doxorubicin. In most cases, the quality of life can be maintained even in incurable situations.
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March 2013

Systemic analysis of gene expression profiles identifies ErbB3 as a potential drug target in pediatric alveolar rhabdomyosarcoma.

PLoS One 2012 5;7(12):e50819. Epub 2012 Dec 5.

Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.

Pediatric sarcomas, including rhabdomyosarcomas, Ewing's sarcoma, and osteosarcoma, are aggressive tumors with poor survival rates. To overcome problems associated with nonselectivity of the current therapeutic approaches, targeted therapeutics have been developed. Currently, an increasing number of such drugs are used for treating malignancies of adult patients but little is known about their effects in pediatric patients. We analyzed expression of 24 clinically approved target genes in a wide variety of pediatric normal and malignant tissues using a novel high-throughput systems biology approach. Analysis of the Genesapiens database of human transcriptomes demonstrated statistically significant up-regulation of VEGFC and EPHA2 in Ewing's sarcoma, and ERBB3 in alveolar rhabdomyosarcomas. In silico data for ERBB3 was validated by demonstrating ErbB3 protein expression in pediatric rhabdomyosarcoma in vitro and in vivo. ERBB3 overexpression promoted whereas ERBB3-targeted siRNA suppressed rhabdomyosarcoma cell gowth, indicating a functional role for ErbB3 signaling in rhabdomyosarcoma. These data suggest that drugs targeting ErbB3, EphA2 or VEGF-C could be further tested as therapeutic targets for pediatric sarcomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050819PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515522PMC
May 2013

Ewing's sarcoma family of tumors in Finland during 1990-2009: a population-based study.

Acta Oncol 2013 May 22;52(4):767-75. Epub 2012 Nov 22.

Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Background: Ewing's sarcoma family of tumors (ESFTs) are rare bone and soft tissue tumors characterized by specific genetic alterations. Our aim was to carry out a nationwide analysis of ESFT, to survey the treatments used and to report the five-year disease specific and event-free survival rates (EFS and DSS).

Material And Methods: The study data was gathered from the Finnish National Cancer Registry and all five University Hospitals and consisted of 76 bone and soft tissue ESFT patients diagnosed during 1990-2009. Their medical records were reviewed and data on their disease, treatments, complications and outcome were analyzed.

Results: The five-year EFS and DSS of patients with localized disease at diagnosis (n = 57) were 70% and 60%, respectively. Factors contributing to DSS and EFS were the axial vs. peripheral site of primary tumor and adequate surgical resection of the primary tumor. DSS was also affected by patient's age at diagnosis and the treatment employed. The five-year DSS of patients with metastatic disease at diagnosis (n = 19) was 33% and both preoperative and high dose chemotherapy were associated with improved survival.

Conclusion: Population-based studies including both bone and soft tissue ESFTs are few. In this nationwide, population-based study on Finnish bone and soft tissue ESFT patients, we find their treatment successful and results comparable to those previously published. Absence of metastases, young age at diagnosis and a peripheral primary tumor site were associated with a better prognosis. It seems that surgical resection of the primary tumor should be performed whenever adequate resection margins can be achieved. The role of high dose chemotherapy merits further studies in this setting.
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http://dx.doi.org/10.3109/0284186X.2012.728714DOI Listing
May 2013

Melanoma-associated cancer-testis antigen 16 (CT16) regulates the expression of apoptotic and antiapoptotic genes and promotes cell survival.

PLoS One 2012 21;7(9):e45382. Epub 2012 Sep 21.

Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland.

Cancer-testis (CT) antigens are predominantly expressed in testis or placenta, but absent in most adult tissues. During malignant transformation CT genes are often activated. CT antigen 16 (CT16, PAGE5) is frequently expressed in advanced melanoma but its biological function has been unknown. To examine the role of CT16 in cell survival we knocked it down in A2058 melanoma cells using specific siRNAs and exposed the cells to cancer drug cisplatin known to induce apoptosis. As a result, cell survival was markedly decreased. To study the effects of CT16 on cell survival in more detail, the cellular gene expression profiles were investigated after CT16 silencing in CT16 positive A2058 melanoma cells, as well as after CT16 overexpression in CT16 negative WM-266-4 melanoma cells. Among the 11 genes both upregulated by CT16 silencing and downregulated by CT16 overexpression or vice versa, 4 genes were potentially apoptotic or antiapoptotic genes. CT16 was recognized as a positive regulator of antiapoptotic metallothionein 2A and interleukin 8 genes, whereas it inhibited the expression of apoptosis inducing dickkopf 1 (DKK1) gene. In addition CT16 enhanced the expression of fatty acid binding protein 7, a known promoter of melanoma progression. The effect of CT16 on DKK1 expression was p53 independent. Furthermore, CT16 did not regulate apoptotic genes via DNA methylation. In twenty melanoma metastasis tissue samples average DKK1 mRNA level was shown to be significantly (p<0.05) lower in high CT16 expressing tumors (n = 3) when compared to the tumors with low CT16 expression (n = 17). Thus, our results indicate that CT16 promotes the survival of melanoma cells and is therefore a potential target for future drug development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045382PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448647PMC
February 2013

c-Jun N-terminal kinase phosphorylation of MARCKSL1 determines actin stability and migration in neurons and in cancer cells.

Mol Cell Biol 2012 Sep 2;32(17):3513-26. Epub 2012 Jul 2.

Turku Centre for Biotechnology, Åbo Akademi and University of Turku, BioCity, Turku, Finland.

Cell migration is a fundamental biological function, critical during development and regeneration, whereas deregulated migration underlies neurological birth defects and cancer metastasis. MARCKS-like protein 1 (MARCKSL1) is widely expressed in nervous tissue, where, like Jun N-terminal protein kinase (JNK), it is required for neural tube formation, though the mechanism is unknown. Here we show that MARCKSL1 is directly phosphorylated by JNK on C-terminal residues (S120, T148, and T183). This phosphorylation enables MARCKSL1 to bundle and stabilize F-actin, increase filopodium numbers and dynamics, and retard migration in neurons. Conversely, when MARCKSL1 phosphorylation is inhibited, actin mobility increases and filopodium formation is compromised whereas lamellipodium formation is enhanced, as is cell migration. We find that MARCKSL1 mRNA is upregulated in a broad range of cancer types and that MARCKSL1 protein is strongly induced in primary prostate carcinomas. Gene knockdown in prostate cancer cells or in neurons reveals a critical role for MARCKSL1 in migration that is dependent on the phosphorylation state; phosphomimetic MARCKSL1 (MARCKSL1(S120D,T148D,T183D)) inhibits whereas dephospho-MARCKSL1(S120A,T148A,T183A) induces migration. In summary, these data show that JNK phosphorylation of MARCKSL1 regulates actin homeostasis, filopodium and lamellipodium formation, and neuronal migration under physiological conditions and that, when ectopically expressed in prostate cancer cells, MARCKSL1 again determines cell movement.
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http://dx.doi.org/10.1128/MCB.00713-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421996PMC
September 2012

CIP2A promotes proliferation of spermatogonial progenitor cells and spermatogenesis in mice.

PLoS One 2012 26;7(3):e33209. Epub 2012 Mar 26.

Turku Centre for Biotechnology, University of Turku, Turku, Finland.

Protein phosphatase 2A (PP2A) is a critical regulator of protein serine/threonine phosphorylation. However, the physiological and developmental roles of different PP2A complexes are very poorly understood. Here, we show that a newly characterized PP2A inhibitory protein CIP2A is co-expressed with ki-67 and with self-renewal protein PLZF in the spermatogonial progenitor cell (SPC) population in the testis. CIP2A and PLZF expression was shown also to correlate Ki-67 expression in human testicular spermatogonia. Functionally, CIP2A mutant mouse testes exhibited smaller number of PLZF-positive SPCs and reduced sperm counts. Moreover, seminiferous tubuli cells isolated from CIP2A mutant mice showed reduced expression of Plzf and other renewal genes Oct-4 and Nanog at mRNA level. However, PLZF-deficient testes did not show altered CIP2A expression. Importantly, spermatogonia-specific restoration of CIP2A expression rescued PLZF expression and sperm production defects observed in CIP2A mutant mice. Taken together, these results reveal first physiological function for an emerging human oncoprotein CIP2A, and provide insights into maintenance of PLZF-positive progenitors. Moreover, demonstration that CIP2A expression can be systematically inhibited without severe consequences to normal mouse development and viability may have clinical relevance regarding targeting of oncogenic CIP2A for future cancer therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033209PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312892PMC
June 2012
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