Parallel Analysis of Transcript and Translation Profiles:  Identification of Metastasis-Related Signal Pathways Differentially Regulated by Drug and Genetic Modifications

Abstract

Tumor metastasis is a complex multi-step process normally involving dysregulation of multiple signal transduction pathways. In this study we developed a novel approach to efficiently define dysreguated pathways associated with metastasis by comparing global gene and protein expressions of two distinct metastasis-suppressed models. Consequently, we identified common features shared by the two models which are potentially associated with metastasis.The efficiency of metastasis from the highly aggressive polyoma middle T-induced mouse mammary tumors was suppressed by either prolonged caffeine exposure or by breeding the animal to a low metastastic mouse strain. Molecular profiles of the primary tumors from both metastasis-suppressed classes were then derived to identify molecules and pathways that might underlie a common mechanism of metastasis. A number of differentially regulated genes and proteins were identified, including genes encoding basement membrane components, which were inversely related to metastatic efficiency. In addition, the analysis revealed that the Stat signal transduction pathways were potentially associated with metastasis inhibition, as demonstrated by enhanced Stat1 activation, and decreased Stat5 phosphorylation in both genetic and pharmacological modification models. Tumor cells of low-metastatic genotypes also demonstrated anti-apoptotic properties. The common changes of these pathways in all of the metastasis-suppressed systems suggest that they may be critical components in the metastatic cascade, at least in this model system. Our data demonstrate that analysis of common changes in genes and proteins in a metastatic-related context greatly decrease the complexity of data analysis, and may serve as a screening tool to identify biological important factors from large scale data.

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

“…This result is consistent with the finding that JAK-mediated activation of STAT1 suppresses metastasis of other types of tumors [24,66]. In contrast, JAK-mediated activation of STAT3 or STAT5 increases metastasis of other tumors [24].…”

A systems biology approach to defining metastatic biomarkers and signaling pathways

“…An additional ICAT study revealed 240 differentially expressed proteins between the metastatic gastric cancer TMC-1 cell line and the noninvasive gastric cancer SC-M1 cell line [60]. Further, when ICAT and microarray gene expression analysis were combined, Stat signal transduction pathways and differential expression of many basement membrane proteins were linked to metastasis inhibition [61]. Taken together, these studies support the application of ICAT to identify differentially expressed proteins related to metastasis.…”

Manipulation of prostate cancer metastasis by locus-specific modification of the CRMP4 promoter region using chimeric TALE DNA methyltransferase and demethylase

“…Among many genes involved in the development of metastasis, MSGs are responsible for negative regulation of metastasis by interfering with cancer cell dissemination, tissue invasion, survival, and growth [10,11,[36][37][38][39]. The underlying molecular mechanisms employed by MSGs remain obscure.…”

“…Similarly, there is a dire need for improved prognostic metastatic biomarkers to determine whether primary prostate cancers are potentially aggressive or indolent; in the latter case, patients can be spared from over treatment [9]. www.impactjournals.com/oncotarget Metastasis suppressor genes (MSGs) are negative regulators of metastasis [10,11]. Compelling evidence indicates that modifications of DNA methylation and histones can silence the expression of MSGs, leading to the development of metastasis [12][13][14].…”