József Tímár

Semmelweis University, Budapeŝto, Budapest, Hungary

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Publications (242)738.4 Total impact

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    ABSTRACT: Ectopic lymphoid structures have been described in several tumor types including metastatic lesions, but not primary tumors, of patients with melanoma. Here we present evidence of B-cell follicles in primary cutaneous melanomas, being present in 39 of 147 cases (27 %). B-cell clusters were associated with T lymphocytes, most of which belonging to CD45RO(+) memory T cells. A network of CD21(+) follicular dendritic cells was demonstrated in 8 of 22 cases studied (36 %). MECA-79(+) HEV-like venules were observed in the neighborhood of the follicles in the majority of cases, however, their presence was not confined to tumors hosting ectopic lymphoid structures. The appearance of B-cell aggregates did not show association with the outcome of the disease, although a trend for their higher prevalence was observed in thicker tumors. Our results show that neogenesis of lymphoid structures does occur in primary melanomas, albeit with lower frequency compared to that reported in metastases.
    Pathology & Oncology Research 04/2014; · 1.56 Impact Factor
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    ABSTRACT: Platinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy. 505 Caucasian stage III-IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed. Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P=0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P=0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P=0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233days; versus 175days in the G12x group; P=0.145). While KRAS mutation status per se is neither prognostic nor predictive in stage III-IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions.
    European journal of cancer (Oxford, England: 1990) 04/2014; · 4.12 Impact Factor
  • József Tímár
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    ABSTRACT: There are conflicting data on the potential prognostic and predictive role of mutant KRAS in nonsmall cell lung cancer (NSCLC). KRAS is the most frequently mutated oncogene in lung adenocarcinoma patients of non-Asian ethnicity. Novel data also revealed that allelic variants of mutant KRAS are different concerning their biochemistry, which may influence their prognostic and predictive role in NSCLC. Though mutant KRAS is not the target of molecular therapy yet, a molecular diagnostic algorithm involving KRAS determination can define a subgroup of tumors where no further diagnostic test is necessary due to the exclusivity of this driver oncogene mutation. Recent data indicated that the prognostic role of mutant KRAS in lung adenocarcinomas in Asian patients is evident, while more research is neccessary in non-Asian populations. Studies also suggest the potential predictive role of mutant KRAS in the context of chemosensitivity of NSCLC which may depend on the individual drug types. Recent data on the negative predictive role of KRAS mutation on the efficacy of EGFR tyrosine kinase inhibitor (TKI) therapies confirm previous findings. Studies on the prognostic and predictive role of mutant KRAS in lung adenocarcinoma must be extended to the analysis of the potential role for allelic variants.
    Current opinion in oncology 01/2014; · 4.09 Impact Factor
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    ABSTRACT: Background Platinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy. Methods 505 Caucasian stage III–IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed. Results Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P = 0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P = 0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P = 0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233 days; versus 175 days in the G12x group; P = 0.145). Conclusions While KRAS mutation status per se is neither prognostic nor predictive in stage III–IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions.
    European Journal of Cancer. 01/2014;
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    ABSTRACT: Tumor angiogenesis and receptor tyrosine kinases (RTK) are major novel targets in anticancer molecular therapy. Accordingly, we characterized the vascular network and the expression pattern of angiogenic RTK in the most frequent pediatric brain tumors. In a retrospective collection of 44 cases (14 astrocytoma, 16 ependymoma and 14 medulloblastoma), immunohistochemistry for VEGFR1, VEGFR2, PDGFRα, PDGFRβ, and c-Kit as well as microvessel labeling with CD34 and SMA were conducted on surgical specimens. We found a significantly higher vascular density in ependymoma. Glomeruloid formations were abundant in medulloblastoma but rare or almost absent in astrocytoma and ependymoma, respectively. C-Kit and VEGFR2 labeled blood vessels were more abundant in ependymoma than in the other two types of tumors. In contrast, medulloblastoma contained higher number of PDGFRα expressing vessels. In tumor cells, we found no VEGFR2 but VEGFR1 expression in all three tumor types. PDGFRα was strongly expressed on the tumor cells in all three malignancies, while PDGFRβ tumor cell expression was present in the majority of medulloblastoma cases. Interestingly, small populations of c-Kit expressing cancer cells were found in a number of medulloblastoma and ependymoma cases. Our study suggests that different angiogenic mechanisms are present in ependymoma and medulloblastoma. Furthermore ependymoma patients may benefit from anti-angiogenic therapies based on the high vascularization as well as the endothelial expression of c-kit and VEGFR2. The expression pattern of the receptors on tumor cells also suggests the targeting of specific angiogenic tyrosine kinase receptors may have direct antitumor activity. Further preclinical and biomarker driven clinical investigations are needed to establish the application of tyrosine kinase inhibitors in the treatment of pediatric brain tumors.
    Pathology & Oncology Research 11/2013; · 1.56 Impact Factor
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    ABSTRACT: Established clinicopathologic characteristics of non-small cell lung cancer patients define a subgroup responding better to EGFR-TK inhibitors: adenocarcinoma histology, ethnicity, sex, smoking status, presence of activating EGFR mutation, and/or K-RAS wild type. However, EGFR mutation does not automatically lead to increased activity of the protein influenced by several factors. As adenocarcinoma can be further divided into histologic subclasses, we have compared adenocarcinomas without lepidic growth pattern (NLAC) to those characterized by pure or predominant lepidic growth (LAC) for EGFR protein expression and autophosphorylation activity (Y1173), as determined by immunohistochemistry. This pretarget therapy cohort comprised a total of 110 surgically operated patients of stage I non-small cell lung cancer: 49 NLAC and 61 LAC variants. The LAC group had a significantly better prognosis and the incidence of phospho-EGFR-positive tumors was significantly higher compared with NLAC. Patient sex did not influence EGFR activity, but the incidence of pEGFR-positive tumors was significantly lower among smoker patients. There was no statistically significant difference in EGFR or KRAS mutation frequencies between the 2 groups. In NLAC, pEGFR-positive tumors occurred exclusively among EGFR-mutant/K-RAS wild-type tumors. On the contrary, in LAC tumors, pEGFR-positive tumors were similarly frequent in the EGFR or K-RAS mutant groups indicating an interesting feedback activation of EGFR signaling in K-RAS mutant tumors. Our data also indicate that EGFR mutation leads to EGFR autophosphorylation only in a small fraction of adenocarcinoma patients, which might have clinical significance.
    Diagnostic molecular pathology: the American journal of surgical pathology, part B 11/2013; · 1.58 Impact Factor
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    ABSTRACT: The mortality of patients with solid tumors is mostly due to metastasis that relies on the interplay between migration and proliferation. The "go or grow" hypothesis postulates that migration and proliferation spatiotemporally excludes each other. We evaluated this hypothesis on thirty-five cell lines (12 mesothelioma, 13 melanoma and 10 lung cancer) on both the individual cell and population levels. Following three-day-long videomicroscopy, migration, proliferation and cytokinesis-length were quantified. We found a significantly higher migration in mesothelioma cells compared to melanoma and lung cancer while tumor types did not differ in mean proliferation or duration of cytokinesis. Strikingly, we found in melanoma and lung cancer a significant positive correlation between mean proliferation and migration. Furthermore, non-dividing melanoma and lung cancer cells displayed slower migration. In contrast, in mesothelioma there were no such correlations. Interestingly, negative correlation was found between cytokinesis-length and migration in melanoma. FAK activation was higher in melanoma cells with high motility. We demonstrate that the cancer cells studied do not defer proliferation for migration. Of note, tumor cells from various organ systems may differently regulate migration and proliferation. Furthermore, our data is in line with the observation of pathologists that highly proliferative tumors are often highly invasive.
    Experimental Cell Research 08/2013; · 3.56 Impact Factor
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    ABSTRACT: Malignant melanoma biologically can be divided into non-metastatic and metastatic forms which cannot be predicted precisely using classical clinicopathological parameters, therefore studies on novel genetic or protein markers are abundant in the literature. These studies did not result in clinically useful markers because mostly ignored the results of studies on the genetic basis of metastatic potential of malignant melanoma. Accordingly, the list of promising novel markers is short (BCL2, CDK2, MART-1, OPN). Similar to other solid malignancies, introduction of targeted therapy into clinical practice of melanoma turned the attention toward the genetic basis of resistance to chemo- and targeted therapies. These novel data could lead to the development of molecular diagnostics which can help in designing more effective therapeutic strategies of malignant melanoma.
    Magyar Onkológia 06/2013; 57(2):79-83.
  • József Tímár, Judit Hársing, Beáta Somlai
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    ABSTRACT: Pathological classification of malignant melanoma did not change in the past decade, it was just completed with UV-induced skin alterations. A new feature, however, is the establishment of molecular classification of melanoma indicating that beside the most frequent genetic alterations (BRAF, NRAS, CKIT mutations) there is a wide variety of rare molecular subclasses. Unfortunately, none of these genetic alterations can be used to discriminate benign lesions from malignant ones. The frequently used "melanoma" markers are mostly melanosomal markers, therefore they are not helpful for this diagnostic purpose either. More recently, novel FISH kits have been developed analyzing characteristic copy number alterations specific for malignant melanoma. Though melanosomal markers are helpful in differencial diagnostics, the presence of normal melanocytes in various tissues (lymph nodes, intestine or brain) requires application of molecular techniques when melanoma metastasis is in question.
    Magyar Onkológia 06/2013; 57(2):73-8.
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    ABSTRACT: Metastasis of human cancer is an organ-selective process that is determined by anatomical and biological factors as well as by specific microenvironmental properties. Dissemination of visceral malignancies to the skin is rather rare and usually occurs in a later stage of the disease. Using statistical approaches, both positive (renal and lung cancers) and negative (pancreatic and liver cancers) organ preferences can be identified in a variety of cancers. While certain cancer types are characterized by random distribution for skin metastasis (liver cancer), a number of cancers demonstrate a colonization preference to the region of origin: lung cancer to the supradiaphragmatic (mostly chest) and colorectal cancers to the infradiaphragmatic (abdominal) skin regions. In certain cases, however, skin metastasis develops more frequently at specific distant locations, as evidenced by the dissemination of renal cancer at the head and neck region. These findings are clinically relevant and useful especially in patients where skin metastasis is the first indication of a malignancy. Nevertheless, it is a strong argument for the predominant role of microenvironmental factors in cancer dissemination. On the other hand, skin metastases of visceral cancers provide a unique model to analyze the pathomechanisms determining organ selectivity, including the organ-specific vascularization, the dermatome-specific innervation, or immunological and developmental factors.
    CANCER AND METASTASIS REVIEW 05/2013; · 9.35 Impact Factor
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    ABSTRACT: Background: Grade 2 breast carcinomas do not form a uniform prognostic group. Aim: To extend the number of patients and the investigated genes of a previously identified prognostic signature described by the authors that reflect chromosomal instability in order to refine characterization of grade 2 breast cancers and identify driver genes. Methods: Using publicly available databases, the authors selected 9 target and 3 housekeeping genes that are capable to divide grade 2 breast carcinomas into prognostic groups. Gene expression was investigated by polymerase chain reaction in 249 formalin-fixed, paraffin-embedded breast tumors. The results were correlated with relapse-free survival. Results: Histologically grade 2 carcinomas were split into good and a poor prognosis groups. Centroid-based ranking showed that 3 genes, FOXM1, TOP2A and CLDN4 were able to separate the good and poor prognostic groups of grade 2 breast carcinomas. Conclusion: Using appropriately selected control genes, a limited set of genes is able to split prognostic groups of breast carcinomas independently from their grade. Orv. Hetil., 2013, 154, 627-632.
    Orvosi Hetilap 04/2013; 154(16):627-32.
  • József Tímár
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    ABSTRACT: Due to the developments of pathology in the past decades (immunohistochemistry and molecular pathology) classification of cancers changed fundamentally, laying a ground for personalized management of cancer patients. Our picture of cancer is more complex today, identifying the genetic basis of the morphological variants. On the other hand, this picture has a much higher resolution enabling us to subclassify similar histological cancer types based on molecular markers. This redefined classification of cancers helps us to better predict the possible biological behavior of the disease and/or the therapeutic sensitivity, opening the way toward a more personalized treatment of this disease. The redefined molecular classification of cancer may affect the universal application of treatment protocols. To achieve this goal molecular diagnostics must be an integral and reimbursed part of the routine pathological diagnostics. On the other hand, it is time to extend the multidisciplinary team with molecular pathologist to improve the decision making process of the management of cancer patients.
    Magyar Onkológia 04/2013; 57(1):26-32.
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    ABSTRACT: Nearly 30% of prostate cancer (PCa) patients treated with potentially curative doses relapse at the sites of irradiation. How some tumor cells acquire radioresistance is poorly understood. The platelet-type 12-lipoxygenases (12-LOX)-mediated arachidonic acid metabolism is important in PCa progression. Here we show that 12-LOX confers radioresistance upon PCa cells. Treatment with 12-LOX inhibitors baicalein or BMD122 sensitizes PCa cells to radiation, without radiosensitizing normal cells. 12-LOX inhibitors and radiation, when combined, have super additive or synergistic inhibitory effects on the colony formation of both androgen-dependent LNCaP and androgen-independent PC-3 PCa cells. In vivo, the combination therapy significantly reduced tumor growth.
    Cancer letters 03/2013; · 4.86 Impact Factor
  • K A Kovács, I Kenessey, J Tímár
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    ABSTRACT: Skin metastatization of internal cancers are rare and a few studies are available analyzing its clinicopathological features. The reported incidence of skin metastasis is influenced by two factors: the relative proportion of cancers covered by skin in the various cohorts and the large differences in the prevalences of various cancer types. Futhermore, the anatomical distribution of skin metastases of various cancer types is aslo not well known. Therefore we have collected a skin metastasis cohort of biopsy and authopsy cases (n = 80) from the archive of our department and analysed its clinicopathologic features. The adjusted skin metastasis prevalence data of various inner cancers indicated that kidney-, lung- and colorectal cancers have a strong positive preference for skin metastatisation while pancreatic cancer has a negative one. We have provided evidences that lower gastrointestinal- and genitourinary cancers preferred infradiaphragmatic skin regions unlike upper gastrointestinal cancers while lung- and kidney cancers preferred supradiaphragmatic regions. We have also detected that ventral skin regional metastasis is slightly more prevalent irrespective of the cancer type. Our study provide the first statistical data for the variations in skin preference of metastatisation among various cancer types as well as for the significant variations in their regional distributions.
    Pathology & Oncology Research 03/2013; · 1.56 Impact Factor
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    ABSTRACT: Abstract Malignant melanoma is the most aggressive cancer in humans and understanding this unique biological behavior may help to design better prognosticators and more efficient therapies. However, malignant melanoma is a heterogenous tumor etiologically (UV-induced or not), morphologically and genetically driven by various oncogens (B-RAF, N-RAS, KIT) and suppressor genes (CDKN2A, p53, PTEN). There are a significant number of studies in which prognostic gene and protein signatures were defined based on either analysis of the primary tumors (metastasis initiating gene set) or melanoma metastases (metastasis maintenance gene set) affecting progression of the disease or survival of the patient. These studies provided prognostic signatures of minimal overlap. Here we demonstrate consensus prognostic gene and protein sets derived from primary and metastatic tumor tissues. It is of note that although there were rare overlaps concerning the composing individual genes in these sets, network analysis defined the common pathways driving melanoma progression: cell proliferation, apoptosis, motility, and immune mechanisms. Malignant melanoma is chemoresistant, the genetic background of which has been unknown for a long time, but new genomic analyses have identified complex genetic alterations responsible for this phenotype involving DNA repair genes and oncogene signaling pathways. The advent of immunotherapy of melanoma placed the previously defined immune signature-associated genomic prognosticators into a new perspective, suggesting that it might also be a powerful predictor. Target therapy of malignant melanoma has changed the standard therapy based on IFN and dacarbazine. Target therapy of B-RAF and KIT mutated melanomas is based on careful selection of tumors with activating/sensitizing mutations, but has immediately raised the issue of genetic basis of constitutive or acquired resistances.
    02/2013: pages 47-76; , ISBN: 978-94-007-5841-4 ; 978-94-007-5842-1 (eBook)
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    ABSTRACT: The role of CD44 in the progression of human melanoma has mostly been characterised by qualitative changes in expression of its individual variable exons. These exons however, may be expressed to form a number of molecules, the alternative splice variants of CD44, which may be structurally and functionally different. Using real-time PCR measurements with variable exon specific primers we have determined that all are expressed in human melanoma. To permit comparison between different tumours we identified a stable CD44 variable exon (CD44v) expression pattern, or CD44 ‘fingerprint’. This was found to remain unchanged in melanoma cell lines cultured in different matrix environments. To evaluate evolution of this fingerprint during tumour progression we established a scid mouse model, in which the pure expression pattern of metastatic primary tumours, circulating cells and metastases, non-metastatic primary tumours and lung colonies could be studied. Our analyses demonstrated, that although the melanoma CD44 fingerprint is qualitatively stable, quantitative changes are observed suggesting a possible role in tumour progression.
    PLoS ONE 01/2013; 8(1):e53883. · 3.73 Impact Factor
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    ABSTRACT: The possibility that endocrine factors may influence the clinical course of malignant melanoma is suggested by the superior survival data of women. In preclinical models we observed a higher rate of colony formation by human melanoma cells in male compared to female SCID mice, but only in the case of the liver and not in other organs. The gender difference could be seen at an early phase of colony formation. On the other hand, in our human melanoma cell lines we failed to detect steroid receptor protein expression, and treatment with sex hormones did not considerably influence their in vitro behavior. Investigating the possible contribution of host cells to the observed gender difference, we performed in vivo blocking experiments applying pretreatment of the animals with Kupffer cell inhibitor gadolinium chloride and the NK cell inhibitor anti-asialo GM1 antibody. While Kupffer cell blockade enhanced melanoma liver colonization equally in the two sexes, a more prominent increase was observed in female than in male mice in the case of NK cell inhibition. Further supporting the importance of NK cells in the lower liver colonization efficiency of melanoma cells in females, gender difference in colony formation was lost in NSG mice lacking NK activity. Although in humans no organ selectivity of gender difference in melanoma progression has been observed according to data in the literature, our results possibly indicate a contribution of natural host defense mechanisms to gender difference in survival of patients with melanoma or other tumor types as well.
    Clinical and Experimental Metastasis 12/2012; · 3.46 Impact Factor
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    ABSTRACT: BACKGROUND: CD44 is considered as 'a' metastasis associated gene, despite the fact that it is an umbrella term for a group of molecules produced from a single gene by alternative splicing. However, little consideration is given to the above in the literature of colorectal carcinomas as well as other tumour types, leading to confusion and contradictory results about its possible role in tumour progression. METHODS: We compared the CD44 alternative splice pattern (ASP) of three genetically different human colorectal cancer cell lines (HT25, HT29, HCT116) using a series of PCR reactions and next- generation sequencing method, as well as identified a colorectal adenocarcinoma specific CD44 ASP. This ASP was further investigated in terms of its qualitative and quantitative stability in our experimental iso- and xenograft mouse models for colorectal cancer progression. A complex preclinical experimental set-up was established to separately test the different steps of tumour progression and the role of tumour microenvironment, respectively, focusing on the role of 'CD44' in this process. RESULTS: We managed to present a colorectal cancer-specific CD44 ASP, which remained unchanged from cell lines throughout primary tumour formation and metastatic progression. Furthermore, we report a unique roster of all expressed CD44 variant isoforms characteristic to colorectal cancer. Finally, on quantitative assessment of the variable exons v3 and v6, higher co-expression levels were found to be characteristic to metastatically potent tumour cells. CONCLUSION: Particular CD44 variant isoforms seem to act as "metastasis genes" via tumour microenvironment-driven shifts in v3 and v6 expressions. However, this function may just affect a minority of tumour subclones. This fact and the huge potential number of different CD44 splice variants that can contain v3 and v6 domains can explain incoherence of clinical studies regarding functional asessment of CD44 variants, as well as diminish the chances of using CD44 variants for predictive purpose.
    Molecular Cancer 11/2012; 11(1):83. · 5.13 Impact Factor
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    ABSTRACT: The 180 kDa transmembrane collagen XVII is known to anchor undifferentiated keratinocytes to the basement membrane in hemidesmosomes while constitutively shedding a 120 kDa ectodomain. Inherited mutations or auto-antibodies targeting collagen XVII cause blistering skin disease. Collagen XVII is down-regulated in mature keratinocytes but re-expressed in skin cancer. By recently detecting collagen XVII in melanocyte hyperplasia, here we tested its expression in benign and malignant melanocytic tumors using endodomain and ectodomain selective antibodies. We found the full-length collagen XVII protein in proliferating tissue melanocytes, basal keratinocytes and squamous cell carcinoma whereas resting melanocytes were negative. Furthermore, the cell-residual 60 kDa endodomain was exclusively detected in 62/79 primary and 15/18 metastatic melanomas, 8/9 melanoma cell lines, HT199 metastatic melanoma xenografts and atypical nests in 8/63 dysplastic nevi. The rest of 19 nevi including common, blue and Spitz subtypes were also negative. In line with the defective ectodomain, sequencing of COL17A1 gene revealed aberrations in the ectodomain coding region including point mutations. Collagen XVII immunoreaction-stained spindle cell melanomas, showed partly overlapping profiles with those of S100B, Melan A and HMB45. It was concentrated at vertical melanoma fronts and statistically associated with invasive phenotype. Antibody targeting the extracellular aa507-529 terminus of collagen XVII endodomain promoted apoptosis and cell adhesion, while inhibiting proliferation in HT199 cells. These results suggest that the accumulation of collagen XVII endodomain in melanocytic tumors is associated with malignant transformation to be a potential marker of malignancy and a target for antibody-induced melanoma apoptosis.
    Histochemie 06/2012; 138(4):653-67. · 2.61 Impact Factor
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    ABSTRACT: Negative ion desorption electrospray ionization (DESI) was used for the analysis of an ex vivo tissue sample set comprising primary colorectal adenocarcinoma samples and colorectal adenocarcinoma liver metastasis samples. Frozen sections (12 μm thick) were analyzed by means of DESI imaging mass spectrometry (IMS) with spatial resolution of 100 μm using a computer-controlled DESI imaging stage mounted on a high resolution Orbitrap mass spectrometer. DESI-IMS data were found to predominantly feature complex lipids, including phosphatidyl-inositols, phophatidyl-ethanolamines, phosphatidyl-serines, phosphatidyl-ethanolamine plasmalogens, phosphatidic acids, phosphatidyl-glycerols, ceramides, sphingolipids, and sulfatides among others. Molecular constituents were identified based on their exact mass and MS/MS fragmentation spectra. An identified set of molecules was found to be in good agreement with previously reported DESI imaging data. Different histological tissue types were found to yield characteristic mass spectrometric data in each individual section. Histological features were identified by comparison to hematoxylin-eosin stained neighboring sections. Ions specific to certain histological tissue types (connective tissue, smooth muscle, healthy mucosa, healthy liver parenchyma, and adenocarcinoma) were identified by semi-automated screening of data. While each section featured a number of tissue-specific species, no potential global biomarker was found in the full sample set for any of the tissue types. As an alternative approach, data were analyzed by principal component analysis (PCA) and linear discriminant analysis (LDA) which resulted in efficient separation of data points based on their histological types. A pixel-by-pixel tissue identification method was developed, featuring the PCA/LDA analysis of authentic data set, and localization of unknowns in the resulting 60D, histologically assigned LDA space. Novel approach was found to yield results which are in 95% agreement with the results of classical histology. KRAS mutation status was determined for each sample by standard molecular biology methods and a similar PCA/LDA approach was developed to assess the feasibility of the determination of this important parameter using solely DESI imaging data. Results showed that the mutant and wild-type samples fully separated. DESI-MS and molecular biology results were in agreement in 90% of the cases.
    Analytical and Bioanalytical Chemistry 03/2012; 403(8):2315-25. · 3.66 Impact Factor

Publication Stats

3k Citations
738.40 Total Impact Points

Institutions

  • 1985–2014
    • Semmelweis University
      • • First Department of Pathology and Experimental Cancer Research
      • • Department of Otorhinolaryngology, Head and Neck Surgery
      • • Department of Orthopaedics
      Budapeŝto, Budapest, Hungary
  • 2013
    • Medical University of Graz
      Gratz, Styria, Austria
  • 2002–2013
    • National Institute of Oncology
      Budapeŝto, Budapest, Hungary
  • 2010
    • Medical University of Vienna
      Wien, Vienna, Austria
  • 2005–2010
    • National Koranyi Institute of TB and Pulmoology
      Budapeŝto, Budapest, Hungary
  • 2005–2009
    • Gottsegen György Országos Kardiológiai Intézet
      Budapeŝto, Budapest, Hungary
  • 2008
    • The Christie NHS Foundation Trust
      • Medical Oncology
      Manchester, ENG, United Kingdom
  • 2007
    • University of Debrecen
      • Department of Physiology
      Debrecen, Hajdu-Bihar, Hungary
  • 1991–2006
    • Wayne State University
      • • Department of Radiation Oncology
      • • Department of Pathology
      Detroit, MI, United States
    • Institute of Cancer Research
      Londinium, England, United Kingdom
  • 1998–2003
    • Hungarian Academy of Sciences
      • Department of Molecular Pharmacology
      Budapest, Budapest fovaros, Hungary
  • 2000
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
  • 1992
    • Harper University Hospital
      Detroit, Michigan, United States
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, MD, United States