Abstract
A key cellular process associated with the invasive or metastatic program in many cancers is the transformation of epithelial cells toward a mesenchymal state, a process called epithelial to mesenchymal transition or EMT. Actin-dependent protrusion of cell pseudopodia is a critical element of mesenchymal cell migration and therefore of cancer metastasis. However, whether EMT occurs in human cancers and, in particular, whether it is a prerequisite for tumor cell invasion and metastasis, remains a subject of debate. Microarray and proteomic analysis of actin-rich pseudopodia from six metastatic human tumor cell lines identified 384 mRNAs and 64 proteins common to the pseudopodia of six metastatic human tumor cell lines of various cancer origins leading to the characterization of 19 common pseudopod-specific proteins. Four of these (AHNAK, septin-9, eIF4E, and S100A11) are shown to be essential for pseudopod protrusion and tumor cell migration and invasion. Knockdown of each of these proteins in metastatic cells resulted in reduced actin cytoskeleton dynamics and induction of mesenchymal-epithelial transition (MET) that could be prevented by the stabilization of the actin cytoskeleton. Actin-dependent pseudopodial protrusion and tumor cell migration are therefore determinants of EMT. Protein regulators of pseudopodial actin dynamics may represent unique molecular targets to induce MET and thereby inhibit the metastatic potential of tumor cells.
Highlights
Tumor progression is a complex process that invokes multimodal parameters that enable tumor cells to evade host defense mechanisms and to migrate and establish new colonies or metastases
We report here the transcriptome/proteome analysis of six metastatic human tumor cell lines and identify four tumor cell pseudopod–specific proteins (AHNAK, Septin-9, eIF4E, and S100A11) whose expression is critical for pseudopod protrusion, actin cytoskeleton dynamics, and tumor cell migration and invasion
Pseudopod and cell body mRNA fractions were prepared from the six cell lines and analyzed by Affymetrix microarray analysis
Summary
Tumor progression is a complex process that invokes multimodal parameters that enable tumor cells to evade host defense mechanisms and to migrate and establish new colonies or metastases. Dynamic actin cytoskeleton remodeling and stabilization of de novo substrate contacts drive pseudopodial protrusion and represent the basic mechanism by which cells migrate [1]. Pseudopodial protrusion, and the formation of related invadopodia, has long been associated with tumor cell migration and invasion [2, 3]. Expression of regulators of local actin reorganization critical for pseudopod protrusion, such as Wiskott-Aldrich syndrome protein family proteins, the Arp2/3 complex, Eps 8, α-actinin, fascin, filamin, LIMkinase/cofilin, and cortactin, are closely associated with tumor cell migration and invasion and overexpressed in various. Increased expression of Arp2/3 and WAVE2 correlates with poor prognosis in breast and liver carcinomas underlining the relevance of actin-dependent membrane protrusion and pseudopodia formation in cancer progression [7, 8]. Proteins required for pseudopodial extension may represent potential therapeutic targets to suppress tumor cell invasion and metastasis
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