Overview of Signal Transduction in Tumor Metastasis

Abstract

The signal transductions mediating each stage of tumor metastasis are gradually unraveled. A lot of growth factors and cytokines secreted in the tumor environment may trigger epithelial–mesenchymal transition (EMT), migration and invasion of the primary tumor via integration of multiple pathways. Further, TGF-β1/Smad signaling may switch the tumor cell from cohesive to single cell movement that facilitates the invasive tumor to enter blood circulation (intravasation). In the circulation, tumor cell may survive in an anchorage independent manner by developing signals counteracting the apoptotic machinery responsible for anoikis. In the extravasation stage, tumor cells that express higher selectin ligands my bind to platelet via P-selectin which facilitates the formation of tumor-platelet-leukocyte emboli. The arrested emboli may promote the E-selectin-mediated activation of ERK(MAPK) to trigger transendothelial passage. Moreover, various chemokine receptor/ligand pairs such as CCR4/CXCL12 can act to achieve organ preference in metastatic colonization. Distinct signaling pathways may also be responsible for determining the destination of tumor cells. The final change faced by the metastatic tumor cells is how to survive in the secondary loci. Recently, Src-mediated signaling was found to be responsible for metastatic breast cancer cells to survive in the bone marrow microenvironment. Blockade of the aforementioned molecular pathways for each stage of tumor progression could be one of the most effective strategies for prevention of metastasis.