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.

Surviving at a Distance: Organ-Specific Metastasis

“…Two WNT regulated genes, Lef1 and HoxB9, were specifically implicated in metastatic cell invasiveness and colony formation [20]. Brain metastases in patients show up-regulation of WNT target genes [94]. …”

Dishevelled: A masterful conductor of complex Wnt signals

“…DVL-1 and DVL-3 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 DVL-1 and 53.3% for DVL-3, and when DVL-1 and DVL-3 were up-regulated there was a significant increase in the number of cases with nuclear beta-catenin [163]. …”

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

“…Although SCLC is unique in that it has a high propensity for brain metastasis, limited attention has been paid to SCLC brain metastases. Recently, a clinical study indicated that high expression of chemokine receptor-4 may correlate with SCLC brain metastasis (8), and the altered expression of Dishevelled-1, Dishevelled-3, E-cadherin, and b-Catenin are present in brain metastases, which suggests that Wnt signaling is important in SCLC metastasis to the brain (9). Our previous study revealed that a role of the Rho/Rho-associated protein kinase signaling pathway in human brain microvascular endothelial cells (HBMECs) during SCLC cells migration across the BBB (10).…”