O Carpén

University of Turku, Turku, Province of Western Finland, Finland

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Publications (151)773.98 Total impact

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    ABSTRACT: Radiotherapy is a mainstay for treatment of many human cancer types, including head and neck squamous cell carcinoma (HNSCC). Thereby, it is clinically very relevant to understand the mechanisms determining radioresistance. Here, we identify CIP2A as an Oct4 target gene and provide evidence that they co-operate in radioresistance. Oct4 positively regulates CIP2A expression both in testicular cancer cell lines as well as in embryonic stem cells. To expand the relevance of these findings we show that Oct4 and CIP2A are co-expressed in CD24 positive side-population of patient-derived HNSCC cell lines. Most importantly, all Oct4 positive HNSCC patient samples were CIP2A positive and this double positivity was linked to poor differentiation level, and predicted for decreased patient survival among radiotherapy treated HNSCC patients. Oct4 and CIP2A expression was also linked with increased aggressiveness and radioresistancy in HNSCC cell lines. Together we demonstrate that CIP2A is a novel Oct4 target gene in stem cells and in human cancer cell lines. Clinically these results suggest that diagnostic evaluation of HNSCC tumors for Oct4 or Oct4/CIP2A positivity might help to predict HNSCC tumor radioresistancy. These results also identify both Oct4 and CIP2A as potential targets for radiosensitation.
    Oncotarget 12/2014; · 6.63 Impact Factor
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    ABSTRACT: Human epididymis protein 4 (HE4) is a novel tumour marker in epithelial ovarian cancer (EOC). Data on its profile and predictive potential for subsequent outcome after neoadjuvant chemotherapy (NACT) are still under investigation. The aim of this study was to compare CA125 and HE4 profiles with radiologic response after NACT and to evaluate their potential as predictors of clinical outcome in a primarily inoperable EOC patient cohort. Twenty-five EOC patients of high-grade subtype (HGSC) treated with NACT were enrolled in the study. Serum HE4 and CA125 samples were taken at the time of diagnosis and before interval debulking surgery (IDS). Pre-NACT and pre-IDS HE4 and CA125 and their percentage changes were compared with NACT response seen on CT and surgical outcome in IDS. We also evaluated the biomarkers' abilities to predict platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). All 25 patients were considered inoperable in laparoscopy at the time of diagnosis. HE4 and CA125 changes during NACT did not correlate with the changes seen on CT. Surgical outcome in IDS was associated with pre-IDS biomarker values but not with those taken before diagnosis. In IDS, 87 % had <1-cm residual tumour. In patients with HE4 change >80 and <80 % during NACT, the median OS was 3.38 and 1.60 years (p = 0.01), respectively. Serum HE4 is a promising additional tool when evaluating advanced HGSC patient's response to NACT. It may be helpful when deciding whether to proceed to IDS or to second-line chemotherapy.
    Tumor Biology 09/2014; 35(12). · 2.84 Impact Factor
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    ABSTRACT: Basal-like breast carcinomas, characterized by unfavorable prognosis and frequent metastases, are associated with epithelial-to-mesenchymal transition. During this process, cancer cells undergo cytoskeletal reorganization and up-regulate membrane-type-1 matrix metalloproteinase (MT1-MMP, MMP14), which functions in actin-based pseudopods to drive invasion by extracellular matrix degradation. However, the mechanisms that couple matrix proteolysis to the actin cytoskeleton in cell invasion have remained unclear. Based on a yeast two-hybrid screen for the MT1-MMP cytoplasmic tail-binding proteins, we identify here a novel Src-regulated protein interaction between the dynamic cytoskeletal scaffold protein palladin and MT1-MMP. These proteins were coexpressed in invasive human basal-like breast carcinomas and corresponding cell lines, where they were associated in the same matrix contacting and degrading membrane complexes. The silencing and overexpression of the 90-kDa palladin isoform revealed the functional importance of the interaction with MT1-MMP in pericellular matrix degradation and mesenchymal tumor cell invasion, whereas in MT1-MMP negative cells palladin overexpression was insufficient for invasion. Moreover, this invasion was inhibited in a dominant negative manner by an immunoglobulin-domain-containing palladin fragment lacking the dynamic scaffold and Src-binding domains. These results identify a novel protein interaction that links matrix degradation to cytoskeletal dynamics and migration signaling in mesenchymal cell invasion.
    Molecular Biology of the Cell 07/2014; · 4.55 Impact Factor
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    ABSTRACT: Anti-EGFR therapy is commonly used to treat colorectal cancer (CRC), although only a subset of patients benefit from the treatment. While KRAS mutation predicts non-responsiveness, positive predictive markers are not in clinical practice. We previously showed that immunohistochemistry (IHC)-guided EGFR gene copy number (GCN) analysis may identify CRC patients benefiting from anti-EGFR treatment. Here we tested the predictive value of such analysis in chemorefractory metastatic CRC, elucidated EGFR GCN heterogeneity within the tumors, and evaluated the association between EGFR GCN, KRAS status, and anti-EGFR antibody response in CRC cell lines. The chemorefractory patient cohort consisted of 54 KRAS wild-type (WT) metastatic CRC patients. EGFR GCN status was analyzed by silver in situ hybridization using a cut-off value of 4.0 EGFR gene copies/cell. KRAS-WT and KRAS mutant CRC cell lines with different EGFR GCN were used in in vitro studies. The chemorefractory CRC tumors with EGFR GCN increase (≥4.0) responded better to anti-EGFR therapy than EGFR GCN (<4.0) tumors (clinical benefit, P = 0.0004; PFS, HR = 0.23, 95% CI 0.12-0.46). EGFR GCN counted using EGFR IHC guidance was significantly higher than the value from randomly selected areas verifying intratumoral EGFR GCN heterogeneity. In CRC cell lines, EGFR GCN correlated with EGFR expression. Best anti-EGFR response was seen with KRAS-WT, EGFR GCN = 4 cells and poorest response with KRAS-WT, EGFR GCN = 2 cells. Anti-EGFR response was associated with AKT and ERK1/2 phosphorylation, which was effectively inhibited only in cells with KRAS-WT and increased EGFR GCN. In conclusion, IHC-guided EGFR GCN is a promising predictor of anti-EGFR treatment efficacy in chemorefractory CRC.
    PLoS ONE 06/2014; 9(6):e99590. · 3.53 Impact Factor
  • Clinical Cancer Research 05/2014; 19(19_Supplement):B43-B43. · 8.19 Impact Factor
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    ABSTRACT: Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with β1-integrin cytoplasmic tail positively regulates β1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer.
    Developmental Cell 05/2014; · 10.37 Impact Factor
  • Journal of Histochemistry and Cytochemistry 04/2014; · 2.40 Impact Factor
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    ABSTRACT: To assess the variation in ovarian carcinoma type diagnosis among gynaecological pathologists from Nordic countries, and whether a rationally designed panel of immunohistochemical markers could improve diagnostic reproducibility. Eight pathologists from four countries (Sweden, Denmark, Norway and Finland) received an educational lecture on diagnosis of ovarian carcinoma type. All tumour-containing slides from 54 ovarian carcinoma cases were independently reviewed by the participants, who 1) determined type based purely on histology, 2) indicated whether they would apply immunohistochemistry in their routine practice, and 3) determined type after reviewing the staining results. The results for 6 markers (WT1, TP53, P16, HNF-1beta, ARID1A and PR) were determined for all 54 cases, by staining a tissue microarray. The median concordance with central review diagnosis was 86%, significantly improving to 90% with incorporation of immunostaining results (p=0.0002). The median interobserver agreement was 78%, significantly improving to 85% with incorporation of immunostaining results. (p=0.0002). Use of the immunostaining results significantly improved both diagnostic accuracy and interobserver agreement. These results indicate that ovarian carcinoma type can be reliably diagnosed by pathologists from different countries, and further demonstrates that immunohistochemistry has an important role in improving diagnostic accuracy and agreement between pathologists. This article is protected by copyright. All rights reserved.
    Histopathology 12/2013; · 3.30 Impact Factor
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    ABSTRACT: Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.
    PLoS ONE 09/2013; 8(9):e74923. · 3.53 Impact Factor
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    ABSTRACT: The use of tumor debulking surgery in the management of epithelial ovarian cancer (EOC), which is often disseminated in the peritoneal cavity at the time of diagnosis, has a significant impact on prognosis. We compared (18)F-fluorodeoxyglucose (FDG) positron emission tomography/contrast-enhanced computed tomography (PET/CT) to contrast-enhanced CT for the detection of dissemination into the abdominal cavity preventing successful primary debulking surgery. Forty-one women with EOC underwent preoperative whole-body low-dose FDG-PET/CT followed by diagnostic high dose contrast-enhanced CT scan, and the results were compared with systematically recorded surgical findings as a reference standard. Both site-based and patient-based analyses were conducted. FDG-PET/CT was superior to conventional CT for the detection of carcinomatosis in subdiaphragmatic peritoneal surfaces (p=0.020) and in the bowel mesentery (p=0.001). Patient-based analysis of upper abdominal areas requiring extensive surgical procedures showed no significant differences between the two imaging methods. The sensitivity of PET/CT and CT was poor in certain areas of the peritoneal cavity (64 % vs. 27% in the small bowel mesentery and 65 % vs. 55 % in the right upper abdomen). Extra-abdominal disease spread was detected by PET/CT in 32 patients and by CT in 25 patients. PET/CT was not superior to CT for the detection of intra-abdominal disease spread. Patients with suspected EOC should be referred for upfront radical surgery regardless of the results of preoperative imaging studies. PET/CT is more effective for the detection of extra-abdominal disease than CT, but the clinical significance of this finding is unclear.
    Gynecologic Oncology 08/2013; · 3.69 Impact Factor
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    ABSTRACT: Abnormal translation of mRNAs frequently occurring during carcinogenesis is among the mechanisms that can affect the expression of proteins involved in tumor development and progression. Eukaryotic initiation factor eIF4E is a key regulator of translation of many cancer-related transcripts and its expression is altered in various cancers and has been associated with worse survival. We determined the eIF4E protein levels using immunohistochemistry (IHC) in 1,233 breast tumors on tissue microarrays. We analyzed the effects of the IHC expression level on tumor characteristics and patient survival, also with stratification by adjuvant chemotherapy treatment. In 1,085 successfully stained tumors, high level of eIF4E protein expression was associated with features of aggressive tumor phenotype, namely grade, estrogen and progesterone receptor negativity, HER2 receptor positivity, and high expression of p53 and Ki67, and with triple negative subtype (p < 0.001). High eIF4E expression was associated with worse breast cancer-specific survival with a hazard ratio (HR) of 1.99 (95 % CI 1.32-3.00, p = 0.0008) and was in a multivariate analysis an independent prognostic factor. High eIF4E expression was associated with worse outcome also after detection of distant metastasis (HR = 1.88, 95 % CI 1.20-2.94, p = 0.0060). In the subgroup analysis the survival effect was strongest among patients treated with anthracycline chemotherapy (HR = 3.34, 95 % CI 1.72-6.48, p = 0.0002), whereas no such effect was seen among patients who had not received anthracycline with significant difference in heterogeneity between the two groups (p = 0.0358). High expression of eIF4E is associated with adverse tumor characteristics and predicts poor breast cancer-specific survival. This effect is emphasized in patients treated with anthracycline chemotherapy. eIF4E as a treatment predictive factor warrants further studies.
    Breast Cancer Research and Treatment 08/2013; · 4.47 Impact Factor
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    ABSTRACT: OBJECTIVE: In endometrioid endometrial adenocarcinoma (EEA), the currently established prognostic factors in clinical guidelines are stage and grade. Many guidelines include lymphovascular invasion (LVI) and tumour size as prognostic factors. Although several studies have associated lack of estrogen (ER) and progesterone receptor (PR) expression with reduced outcome, the prognostic use of these markers is uncommon. Better prognostication of clinical behaviour would be useful in patients with early stage (I-II) disease. In this study we evaluated ER and PR as prognostic factors in EEA, and compared their expression with other potential biomarkers and clinical parameters. METHODS: Tissue microarrays were constructed from 182 patients with stage I-II EEA. ER, PR, p53, Ki-67, PTEN, MLH and HER-2 expression was assessed by immunohistochemical staining and HER-2 was confirmed with SISH. The results were correlated with clinicopathologic parameters and to disease-free survival. RESULTS: Eleven patients (6%) developed recurrent disease during a median follow up time of 62.8months. In univariate analysis FIGO grade (p=0.019), positive expression of p53 (p=0.010) and negative PR expression (p=0.001) were associated with a shorter disease-free survival. In multivariate analysis only negative PR expression (p=0.019) was significantly associated with a shorter disease-free survival. LVI and tumour size where not of prognostic value. CONCLUSIONS: Lack of PR expression is a strong, independent risk factor for tumour recurrence in patients with stage I-II endometrioid endometrial cancer. The use of this easily measurable biomarker as a prognostic factors in the clinical context should be considered and tested in a larger patient population.
    Gynecologic Oncology 06/2013; · 3.69 Impact Factor
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    ABSTRACT: The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) associates with treatment resistance and adverse outcome in several human cancers. We studied ALDH1 expression in rectal cancer, with special emphasis on its association with treatment response and disease outcome. Immunohistochemical staining for ALDH1 was conducted for 64 biopsies and 209 operative samples from rectal cancer patients treated with short- (n = 89) or long-course (n = 46) (chemo)radiotherapy plus surgery, or with surgery only (n = 74). The staining results were compared to clinicopathological variables, tumor regression grade (TRG) and disease outcome. Nuclear β-catenin expression pattern was analyzed from 197 operative samples. Positive ALDH1 expression was present in 149 operative samples (71%), correlating with deficient nuclear β-catenin regulation (P = .018). In a pairwise comparison of respective biopsy and operative samples, ALDH1 expression remained stable or increased after preoperative (chemo)radiotherapy in most of the cases, while it decreased in few cases only (P = .02 for positive/negative category; P <.001 for intensity). ALDH1 expression did not, however, relate to tumor regression grade. In node-negative rectal cancer, ALDH1 expression was an independent predictor of short disease-free and disease-specific survival (P = .044; P = .049), specifically among patients treated with adjuvant chemotherapy. We conclude that ALDH1 associates with deregulated β-catenin signaling, supporting the role of ALDH1 in rectal cancer stemness. ALDH1 expression relates to poor outcome in early stage rectal cancer, a group where new prognostic tools are particularly needed, and may indicate chemo- and radioresistance.
    Human pathology 01/2013; · 2.81 Impact Factor
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    ABSTRACT: OBJECTIVE: Most cases of epithelial ovarian cancer (EOC) are diagnosed in an advanced stage. When the disease has spread intra-abdominally, complete surgical tumor debulking is the single most important prognostic factor. Neoadjuvant chemotherapy (NACT) before surgery can cause fibrosis and adhesions in the peritoneal cavity and may interfere with the perioperative evaluation of tumor spread. In this prospective study, we evaluated whether perioperative visual assessment of tumor dissemination is similar in patients undergoing primary and interval surgery for EOC. METHODS: Systematic visual evaluation of tumor spread was performed at the start of primary surgery/ diagnostic laparoscopy (n=39) or interval surgery (n=16). Peritoneal cavity was divided into 22 anatomical regions. The carefully documented results of the visual assessment were compared with the histopathological analysis of 220 biopsies from primary and 92 biopsies from interval surgery. RESULTS: In primary surgery, perioperative visual estimation of tumor spread showed 98% sensitivity, 76% specificity and 95% accuracy compared to histopathology. The corresponding figures after NACT were 86%, 76% and 84%, respectively. The difference in sensitivity and accuracy in primary and interval operations was statistically significant (p< 0.001). CONCLUSIONS: In advanced EOC, microscopically carcinomatous areas have a benign visual appearance more often after NACT than at primary surgery. NACT may interfere with the perioperative visual evaluation of tumor spread and thus lead to incomplete resection of tumor in potentially resectable areas.
    Gynecologic Oncology 11/2012; · 3.69 Impact Factor
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    ABSTRACT: High-grade cervical squamous intraepithelial lesions (CIN) as well as squamous cell carcinoma and adenocarcinoma of the cervix are associated with persistent high-risk human papillomavirus (HPV) infection. A number of cellular events play a role in HPV pathogenesis and in the development of cervical lesions, including alterations in cell adhesion and motility. The crucial plasma membrane - cytoskeleton linker protein ezrin of the Ezrin-Radixin-Moesin (ERM) protein family is involved in the regulation of cell morphology, cell adhesion and invasion. Based on our previous work on ERM proteins we sought out to study the expression of ezrin in cervical premalignant lesions. We also studied the expression of E-cadherin and β-catenin, which play an important role in epithelial cell adhesion. We observed intensifying expression of ezrin along with progressing grade of neoplasia. Ezrin staining was found to colocalize with p16 staining in high-risk HPV associated lesions. Expression of E-cadherin and β-catenin was found to be altered along with the severity of the lesion, similar to ezrin. Enhanced expression of ezrin in cervical HPV associated lesions suggests a role in the development of cervical neoplasia and cancer. Further clinical evaluation should reveal the feasibility of ezrin as a biomarker for the progression of cervical lesions. Keywords: CIN, ezrin; HPV, papillomavirus.
    Neoplasma 10/2012; · 1.64 Impact Factor
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    ABSTRACT: Proteinases play a pivotal role in wound healing by regulating cell-matrix interactions and availability of bioactive molecules. The role of matrix metalloproteinase-13 (MMP-13) in granulation tissue growth was studied in subcutaneously implanted viscose cellulose sponge in MMP-13 knockout (Mmp13(-/-)) and wild type (WT) mice. The tissue samples were harvested at time points day 7, 14 and 21 and subjected to histological analysis and gene expression profiling. Granulation tissue growth was significantly reduced (42%) at day 21 in Mmp13(-/-) mice. Granulation tissue in Mmp13(-/-) mice showed delayed organization of myofibroblasts, increased microvascular density at day 14, and virtual absence of large vessels at day 21. Gene expression profiling identified differentially expressed genes in Mmp13(-/-) mouse granulation tissue involved in biological functions including inflammatory response, angiogenesis, cellular movement, cellular growth and proliferation and proteolysis. Among genes linked to angiogenesis, Adamts4 and Npy were significantly upregulated in early granulation tissue in Mmp13(-/-) mice, and a set of genes involved in leukocyte motility including Il6 were systematically downregulated at day 14. The expression of Pdgfd was downregulated in Mmp13(-/-) granulation tissue in all time points. The expression of matrix metalloproteinases Mmp2, Mmp3, Mmp9 was also significantly downregulated in granulation tissue of Mmp13(-/-) mice compared to WT mice. Mmp13(-/-) mouse skin fibroblasts displayed altered cell morphology and impaired ability to contract collagen gel and decreased production of MMP-2. These results provide evidence for an important role for MMP-13 in wound healing by coordinating cellular activities important in the growth and maturation of granulation tissue, including myofibroblast function, inflammation, angiogenesis, and proteolysis.
    PLoS ONE 08/2012; 7(8):e42596. · 3.53 Impact Factor
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    ABSTRACT: Prolyl oligopeptidase (PREP) is a serine protease that hydrolyzes peptides shorter than 30-mer, and it has been connected with multiple physiological and pathological conditions. PREP has been mostly studied in the brain, but significant PREP activities have been measured in peripheral tissues. Moreover, increased PREP activities have been found in tumors. In this study, the authors studied the immunohistochemical distribution of PREP protein in human peripheral tissues and in ovarian and colorectal tumors. PREP was found to be widely distributed in human peripheral tissues and specifically in certain cells. The most intense PREP expression was seen in the testis, ovaries, liver, and some parts of the skin. At the cellular level, high PREP levels were seen as a rule in secreting epithelial cells and cells involved in reproduction. Increased PREP expression was seen in most of the tumors studied. PREP expression was higher in malignant than benign tumors, and in ovarian epithelial cancers, there was a trend for increased PREP staining with increased malignancy grade. Results suggest that PREP may be associated with secretory processes as well as in reproduction. A more abundant expression of PREP in malignant than benign tumors suggests that PREP may be associated with expansion and metastasis of tumors.
    Journal of Histochemistry and Cytochemistry 06/2012; 60(9):706-15. · 2.40 Impact Factor
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    ABSTRACT: Epithelial ovarian cancer (EOC) spreads intra-abdominally and to the retroperitoneal lymph nodes. A greater number of distant metastases are revealed by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) compared to conventional imaging methods. We aimed to investigate the presence and anatomic distribution of supradiaphragmatic lymph node metastasis (LNM) detected with pretreatment FDG PET/CT. Thirty women with advanced stage (IIC-IV) EOC were scanned with whole body contrast-enhanced FDG PET/CT prior to surgery/neoadjuvant chemotherapy. We performed PET/CT analysis qualitatively and quantitatively. Additionally, contrast-enhanced CT was analyzed blinded to PET/CT scan. Intra-abdominal dissemination was verified by surgery and histopathology. Metabolically active lymph nodes were biopsied when possible. The clinical characteristics of patients with and without supradiaphragmatic LNM were compared. In 20/30 patients (67%) FDG PET/CT detected supradiaphragmatic LNM in one or more locations, whereas conventional CT found LNM in 10 patients (33%). Fourteen patients had parasternal, 14 cardiophrenic, 8 other mediastinal, 6 axillar, and 1 subclavian LNM. Microscopy of all four biopsied lymph nodes (three axillar and one subclavian) confirmed metastatic dissemination. The patients with supradiaphragmatic LNM had significantly more ascites (p<0.01), higher CA 125 levels, and more frequent subdiaphragmal carcinomatosis (p<0.03) compared to patients without supradiaphragmatic LNM in preoperative FDG PET/CT. A significant number of patients with advanced EOC showed supradiaphragmatic LNM in pre-treatment PET/CT. Our findings suggest that the route of EOC cells from the peritoneal cavity to the lymphatic system permeates the diaphragm mainly to the cardiophrenic and continues to parasternal lymph nodes.
    Gynecologic Oncology 04/2012; 126(1):64-8. · 3.69 Impact Factor
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    ABSTRACT: The Neurofibromatosis 2 (NF2) gene product merlin is a tumour suppressor, which in addition to inhibiting cell proliferation regulates cell morphology. The morphogenic properties of merlin may play a role in tumour suppression, as patient-derived tumour cells demonstrate cytoskeletal abnormalities. However, it is still unclear how these functions are linked. The N-terminal FERM-domain of merlin is highly homologous to the oncogenic protein ezrin, while the C-termini are less conserved, suggesting that the opposite effect of the proteins on proliferation could be mediated by their distinct C-terminal regions. In this study we characterize the role of the most C-terminal residues of merlin in the regulation of proliferation, cytoskeletal organization, phosphorylation and intramolecular associations. In addition to the two full-length merlin isoforms and truncating mutations found in patients, we focused on the evolutionally conserved C-terminal residues 545-547, also harbouring disease-causing mutations. We demonstrate that merlin induces cell extensions, which result from impaired retraction of protrusions rather than from increased formation of filopodia. The residues 538-568 were found particularly important for this morphogenic activity. The results further show that both merlin isoforms are able to equally inhibit proliferation, whereas C-terminal mutants affecting residues 545-547 are less effective in growth suppression. This study demonstrates that the C-terminus contains distinct but overlapping functional domains important for regulation of the morphogenic activity, intramolecular associations and cell proliferation.
    Journal of Cellular and Molecular Medicine 02/2012; 16(9):2161-75. · 3.70 Impact Factor
  • British Journal of Cancer 12/2011; · 5.08 Impact Factor

Publication Stats

5k Citations
773.98 Total Impact Points


  • 2005–2014
    • University of Turku
      • Department of Pathology
      Turku, Province of Western Finland, Finland
  • 1986–2012
    • University of Helsinki
      • • Division of Pharmacology and Toxicology
      • • Department of Pathology
      • • Department of Otorhinolaryngology
      • • Department of Bacteriology and Immunology
      Helsinki, Province of Southern Finland, Finland
  • 2009
    • Turku University Hospital
      Turku, Province of Western Finland, Finland
    • International Centre for Genetic Engineering and Biotechnology
      Trst, Friuli Venezia Giulia, Italy
  • 2008
    • Mayo Foundation for Medical Education and Research
      • Department of Neurology
      Scottsdale, AZ, United States
  • 2000–2006
    • Helsinki University Central Hospital
      • • Department of Pathology
      • • Division of Plastic Surgery
      • • Department of Obstetrics and Gynaecology
      Helsinki, Southern Finland Province, Finland
  • 2004
    • University of North Carolina at Chapel Hill
      • Department of Cell Biology and Physiology
      Chapel Hill, NC, United States
  • 2003
    • Finnish Institute of Occupational Health
      • Centre of Expertise for Health and Work Ability
      Helsinki, Southern Finland Province, Finland
  • 2001
    • Winston-Salem State University
      Winston-Salem, North Carolina, United States
  • 1989–1994
    • Harvard Medical School
      • Department of Pathology
      Boston, MA, United States
  • 1993
    • Karolinska Institutet
      Solna, Stockholm, Sweden