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.