Roles for endothelin receptor B and BCL2A1 in spontaneous CNS metastasis of melanoma.

Abstract

Metastatic spread of melanoma to the central nervous system (CNS) is a common and devastating manifestation of disease progression, which, despite its clinical importance, remains poorly understood with respect to underlying molecular mechanisms. Using a recently developed preclinical model of spontaneous melanoma CNS metastasis, we have identified alterations in expression of endothelin receptor B (EDNRB) as a potential factor that influences brain metastatic potential. Induced overexpression of this gene mediated enhanced overall metastatic disease, and resulted in an increased incidence of spontaneous CNS metastases. In contrast, the overexpression of other highlighted genes, such as BCL2A1, did not affect the incidence of CNS metastases but nevertheless appears to facilitate intracranial tumor growth. The prometastatic effect in the CNS associated with EDNRB appears to be mediated by the interaction with its ligands resulting in enhanced tumor cell proliferation and thus intracranial melanoma growth. That EDNRB contributes to melanoma metastasis is underscored by the fact that its therapeutic inhibition by the EDNRB-specific inhibitor A192621 translated into improved outcomes when treating mice with either visceral metastases or intracranial tumors. The identification of an influential role of EDNRB in CNS melanoma spontaneous metastasis may provide both a target for therapeutic intervention as well as a potential prognostic marker for patients having an increased predisposition for incidence of CNS melanoma metastases.

• Authors: William Cruz-Muñoz, Maria L Jaramillo, Shan Man, Ping Xu, Myriam Banville, Catherine Collins, Andre Nantel, Giulio Francia, Sherif S Morgan, Lee D Cranmer, Maureen D O'Connor-McCourt, Robert S Kerbel
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 19 Pg. 4909-19 (Oct 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22865454 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• A 192621
• BCL2-related protein A1
• Endothelin B Receptor Antagonists
• Minor Histocompatibility Antigens
• Proto-Oncogene Proteins c-bcl-2
• Pyrrolidines
• Receptor, Endothelin B

Topics

• Animals
• Cell Line, Tumor
• Central Nervous System Neoplasms (drug therapy, genetics, secondary)
• Endothelin B Receptor Antagonists
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Melanoma (drug therapy, genetics, pathology)
• Mice
• Mice, SCID
• Minor Histocompatibility Antigens
• Oligonucleotide Array Sequence Analysis
• Prognosis
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Pyrrolidines (pharmacology)
• Receptor, Endothelin B (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis
• Tumor Burden (genetics)
• Xenograft Model Antitumor Assays