Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

Abstract

Clinically and experimentally, primary tumor formation and metastasis are distinct processes -locally growing tumors can progress without the development of metastases. This observation prompted the hypothesis that the molecular processes regulating tumorigenicity and metastasis are distinguishable and could be targeted therapeutically. During the process of transformation and subsequent progression to a malignant phenotype, both genetic and epigenetic alterations alter a cell's ability to perceive and respond to signals that regulate normal tissue homeostasis. A minority of tumorigenic cells accrue the full complement of alterations that enables them to disseminate from the primary tumor, survive insults from the immune system and biophysical forces, and respond to growthpromoting and/or inhibitory signals from the distant tissues and thrive there. Identification of genes and proteins that specifically inhibit the ability of cells to form metastases (e.g., metastasis suppressors) is providing new insights into the molecular mechanisms that regulate this complex process. This review will highlight: (a) the functional identification of metastasis suppressors, (b) the signaling cascades and cellular phenotypes which are controlled or modulated by metastasis suppressors, and (c) opportunities for translation and clinical trials that are based on mechanistic studies regarding metastasis suppressors.

Peroxiredoxin 6 interferes with TRAIL-induced death-inducing signaling complex formation by binding to death effector domain caspase

“…TRAIL receptors are defined as metastasis suppressor proteins that reduce the metastatic propensity of tumor cells. 32,33 Inactivation of TRAIL signaling by mutation of TRAIL receptors, DR4 and DR5, was specifically observed in metastatic cancer, and downregulation of TRAIL receptors promotes metastasis of cancer cells. 34,35 Also, metastatic oral cancer cells showed greater TRAIL resistance than their primary oral tumors.…”

Targeting Tumor Metastasis by Regulating Nm23 Gene Expression

“…These genes are functionally defined by their ability to suppress in-vivo development of metastases without affecting the growth of the primary tumor. Since the identification of the first of these MSGs in 1988 the number of validated MSGs has increased to over 20s (Steeg et al, 1988;Steeg, 2003;Rinker-Schaeffer et al, 2006). The majority of these MSGs have been identified by their reduced expression in metastatic cancer cells compared to congenic, nonmetastatic cells using a wide variety of methods including microarray expression profiling, and subtractive library hybridization.…”

The microRNA network and tumor metastasis

“…The traditional view of metastasis includes the process of clonal selection in which rare variant clones within the primary tumor become capable of completing the complex multistep metastatic process (Fidler, 2003;Talmadge, 2007). Recently, expression profiling analyses have revealed various tumor metastasis genes and metastasis suppressor genes, which not only regulate the metastatic process (Dong et al, 1995(Dong et al, , 1996Bandyopadhyay et al, 2004;Nuyten and van de Vijver, 2006;Rinker-Schaeffer et al, 2006;Tomida et al, 2007;Albini et al, 2008;Kim et al, 2009;Lukes et al, 2009) but also maintain the microenvironment of tumor cells, and initiate the process of epithelial-mesenchymal transition (EMT).…”