This measurement tool can be used as the primary outcome in clinical trials evaluating treatments in this patient population, although its features are equally attractive for monitoring patients' progress in clinical practice.
Epithelial tumor cells transit to a mesenchymal state in response to extracellular cues, in a process known as epithelial-to-mesenchymal transition (EMT). The precise nature of these cues has not been fully defined, an important issue given that EMT is an early event in tumor metastasis. Here, we have found that a population of metastasis-prone mouse lung adenocarcinoma cells expresses Notch and Notch ligands and that the Notch ligand Jagged2 promotes metastasis. Mechanistically, Jagged2 was found to promote metastasis by increasing the expression of GATA-binding (
IntroductionLung cancer is the foremost cause of cancer-related death in Western countries, and metastasis is the leading cause of death in patients with lung cancer. Improving clinical outcomes will require a better understanding of the biological processes that initiate metastasis. Toward that goal, mouse models have been generated that develop lung adenocarcinomas with high or low propensities for invasion and metastasis. Mice that express K-ras G12D alleles inducibly, conditionally, or somatically develop lung adenocarcinomas with low invasive and metastatic potential (1-5), whereas mice that express K-ras G12D and p53 R172H alleles develop lung adenocarcinomas that metastasize widely (6-9). Thus, K-ras-driven mouse models of lung cancer acquire metastatic potential with the addition of a second mutation commonly found in lung cancer.Investigators have used mouse models of cancer to study the biological basis of metastasis. In one working hypothesis, epithelial tumor cells acquire the ability to invade and disseminate by undergoing epithelial-to-mesenchymal transition (EMT), which is characterized by a loss of cell-cell attachments and apical-basal polarization and gain of mesenchymal and invasive properties (10-19). The process of EMT is regulated by several transcriptional suppressor families, including the zinc-finger proteins Snail1 and Snail2, the 2-handed zinc-finger δEF1 family factors
The microRNA-200 (miR-200) family is part of a gene expression signature that predicts poor prognosis in lung cancer patients. In a mouse model of K-ras/p53-mutant lung adenocarcinoma, miR-200 levels are suppressed in metastasis-prone tumor cells, and forced miR-200 expression inhibits tumor growth and metastasis, but the miR-200 target genes that drive lung tumorigenesis have not been fully elucidated. Here, we scanned the genome for putative miR-200 binding sites and found them in the 3′-untranslated region (3′-UTR) of 35 genes that are amplified in human cancer. Mining of a database of resected human lung adenocarcinomas revealed that the levels of one of these genes, Flt1/VEGFR1, correlate inversely with duration of survival. Forced miR-200 expression suppressed Flt1 levels in metastasis-prone lung adenocarcinoma cells derived from K-ras/p53-mutant mice, and negatively regulated the Flt1 3′-UTR in reporter assays. Cancer-associated fibroblasts (CAFs) isolated from murine lung adenocarcinomas secreted abundant VEGF and enhanced tumor cell invasion in coculture studies. CAF-induced tumor cell invasion was abrogated by VEGF neutralization or Flt1 knockdown in tumor cells. Flt1 knockdown decreased the growth and metastasis of tumor cells in syngeneic mice. We conclude that miR-200 suppresses lung tumorigenesis by targeting Flt1.
Huntingtin interacting protein 1 (HIP1) is a recently identi®ed component of clathrin-coated vesicles that plays a role in clathrin-mediated endocytosis. To explore the normal function of HIP1 in vivo, we created mice with targeted mutation in the HIP1 gene (HIP1 ±/± ). HIP1 ±/± mice develop a neurological phenotype by 3 months of age manifest with a failure to thrive, tremor and a gait ataxia secondary to a rigid thoracolumbar kyphosis accompanied by decreased assembly of endocytic protein complexes on liposomal membranes. In primary hippocampal neurons, HIP1 colocalizes with GluR1-containing AMPA receptors and becomes concentrated in cell bodies following AMPA stimulation. Moreover, a profound dosedependent defect in clathrin-mediated internalization of GluR1-containing AMPA receptors was observed in neurons from HIP1 ±/± mice. Together, these data provide strong evidence that HIP1 regulates AMPA receptor traf®cking in the central nervous system through its function in clathrin-mediated endocytosis.
With the numbers available for this study, the authors found betamethasone to be no more effective in improving the quality of life, range of motion, or impingement sign than xylocaine alone in patients with chronic rotator cuff tendinosis for all follow-up time intervals evaluated.
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