ABSTRACT
As the frequency of melanoma increases, current treatment strategies are struggling to significantly impact patient survival. One of the critical issues in designing efficient therapies is understanding the composition of heterogeneous melanoma tumors in order to target cancer stem cells (CSCs) and drug-resistant subpopulations. In this review, we summarize recent findings pertinent to the reemergence of the embryonic Nodal signaling pathway in melanoma and its significance as a prognostic biomarker and therapeutic target. In addition, we offer a novel molecular approach to studying the functional relevance of Nodal-expressing subpopulations and their CSC phenotype.
Subject(s)
Gene Expression Regulation, Neoplastic , Melanoma/metabolism , Neoplastic Stem Cells/cytology , AC133 Antigen , Animals , Antigens, CD/metabolism , Biomarkers , Biomarkers, Tumor , Cell Differentiation , Cell Line, Tumor , Cell Separation , Cytological Techniques , Flow Cytometry , Genetic Techniques , Glycoproteins/metabolism , Humans , Immunohistochemistry , Mice , Neoplastic Stem Cells/metabolism , Nodal Protein/metabolism , Peptides/metabolism , Phenotype , Prognosis , Signal Transduction , Time Factors , Treatment OutcomeABSTRACT
Gap junctional intercellular communication (GJIC) regulates cellular homeostasis by propagating signaling molecules, exchanging cellular metabolites, and coupling electrical signals. In cancer, cells exhibit altered rates of GJIC which may play a role in neoplastic progression. K(ATP) channels help maintain membrane polarity and linkages between K(ATP) channel activity and rates of GJIC have been established. The mechanistic relationship has not been fully elucidated. We report the effects of treatment with multiple K(ATP) antagonist compounds on GJIC in metastatic cell lines demonstrating an increase in communication rates following treatment with compounds possessing specificities towards the SUR2 subunit of K(ATP). These effects remained consistent using cell lines with different expression levels of SUR1 and SUR2, suggesting possible off target effects on GJIC by these compounds.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , KATP Channels/antagonists & inhibitors , Mediator Complex/metabolism , Potassium Channel Blockers/pharmacology , Potassium Channels, Inwardly Rectifying/metabolism , Receptors, Drug/metabolism , Cell Communication/drug effects , Cell Line, Tumor/pathology , Gap Junctions/metabolism , Humans , Neoplasm Metastasis , Sulfonylurea ReceptorsABSTRACT
As the frequency of melanoma diagnosis increases, current treatment strategies are still struggling to significantly impact patient survival. Some promise has been shown in treating certain melanomas by targeting activated signaling pathways resulting from specific mutations in proteins, such as BRAF and NRAS. Recently, the identification of embryonic signaling pathways in melanoma has helped us better understand certain biological characteristics, such as cellular heterogeneity and phenotypic plasticity, and has provided novel insight pertinent to diagnosis and therapy. For instance, our studies have shown that the TGF-ß family member, Nodal, is expressed in melanoma and is responsible, at least in part, for tumor cell plasticity and aggressiveness. Since the majority of normal adult tissues do not express Nodal, we reason that this embryonic morphogen could be used to identify and target aggressive melanoma cells. We have also identified that molecular cross-talk between the Notch and Nodal pathways may represent a mechanism responsible for the overexpression of Nodal in melanoma. Further exploitation of the relationship between embryonic signaling pathways and cancer pathogenesis could lead to novel approaches for diagnosis and therapy in cancers, such as melanoma.
