title: c-Jun N-Terminal Kinases Mediate a Wide Range of Targets in the Metastatic Cascade.
abstract: Disseminated cancer cells rely on intricate interactions among diverse cell types in the tumor-associated stroma, vasculature, and immune system for survival and growth. Ubiquitous expression of c-Jun N-terminal kinase (jnk) genes in various cell types permits their control of metastasis. In early stages of metastasis, JNKs affect tumor-associated inflammation and angiogenesis as well as tumor cell migration and intravasation. Within the tumor stroma, JNKs are essential for the release of growth factors that promote epithelial-to-mesenchymal transition (EMT) in tumor cells. JNK3, the least ubiquitous isoform, facilitates angiogenesis by increasing endothelial cell migration. Importantly, JNK expression in tumor cells integrates stromal signals to promote tumor cell invasion. However, JNK isoforms differentially regulate migration toward the endothelial barrier. Once tumor cells enter the bloodstream, JNKs increase circulating tumor cell (CTC) survival and homing to tissues. By promoting fibrosis, JNKs improve CTC attachment to the endothelium. Once anchored, JNKs stimulate EMT to facilitate tumor cell extravasation and enhance the secretion of endothelial barrier disrupters. Tumor cells attract barrier-disrupting macrophages by JNK-dependent transcription of macrophage chemoattractant molecules. In the secondary tissue, JNKs are instrumental in the premetastatic niche and stimulate tumor cell proliferation. JNK expression in cancer cells stimulates tissue-remodeling macrophages to improve tumor colonization. However, in T-cells, JNKs alter cytokine production that increases tumor surveillance and inhibits the recruitment of tissue-remodeling macrophages. Therapeutically targeting JNKs for metastatic disease is attractive considering their promotion of metastasis; however, specific JNK tools are needed to determine their definitive actions within the context of the entire metastatic cascade.
authors.affiliation: Institute of Cellular & Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Ebelt
authors.affiliation: Institute of Cellular & Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cantrell
authors.affiliation: Institute of Cellular & Molecular Biology, The University of Texas at Austin, Austin, TX, USA ; Division of Pharmacology & Toxicology, Dell Pediatric Research Institute, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Carla L
authors.initials: CL
authors.lastname: Van Den Berg
keywords: JNK; cancer; metastasis