title: Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin.
abstract: The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p=0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p=0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain.
authors.affiliation: Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000 Zagreb, Croatia. anja.kafka@mef.hr.
authors.forename: Anja
authors.initials: A
authors.lastname: Kafka
authors.affiliation: Ljudevit Jurak Department of Pathology, University Hospital "Sisters of Charity", 10000 Zagreb, Croatia. davor.tomas@kbcsm.hr.
authors.forename: Davor
authors.initials: D
authors.lastname: Tomas
authors.affiliation: Department of Neurosurgery, University Hospital "Sisters of Charity", 10000 Zagreb, Croatia. viliberos@gmail.com.
authors.forename: Vili
authors.initials: V
authors.lastname: Beroš
authors.affiliation: Department of Radiology, University Hospital "Sisters of Charity", 10000 Zagreb, Croatia. hipecina@gmail.com.
authors.forename: Hrvoje Ivan
authors.initials: HI
authors.lastname: Pećina
authors.affiliation: Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000 Zagreb, Croatia. martina.zeljko2@gmail.com.
authors.forename: Martina
authors.initials: M
authors.lastname: Zeljko
authors.affiliation: Laboratory of Neuro-Oncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000 Zagreb, Croatia. nina@mef.hr.
authors.forename: Nives
authors.initials: N
authors.lastname: Pećina-Šlaus
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D000072261:Dishevelled Proteins; D015536:Down-Regulation; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; C000606578:DVL1 protein, human; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D051176:beta Catenin