Targeting invadopodia for blocking breast cancer metastasis.

Dissemination of cancer cells from the primary tumor and their spread to distant sites of the body is the leading cause of mortality in metastatic cancer patients. Metastatic cancer cells invade surrounding tissues and blood vessels by forming F-actin-rich protrusions known as invadopodia, which degrade the extracellular matrix and enable invasion of tumor cells through it. Invadopodia have now been observed in vivo, and recent evidence demonstrates direct molecular links between assembly of invadopodia and cancer metastasis in both mouse models and in human patients. While significant progress has been achieved in the last decade in understanding the molecular mechanisms and signaling pathways regulating invadopodia formation and function, the application of this knowledge to development of prognostic and therapeutic approaches for cancer metastasis has not been discussed before. Here, we provide a detailed overview of current prognostic markers and tests for cancer metastasis and discuss their advantages, disadvantages, and their predicted efficiency. Using bioinformatic patient database analysis, we demonstrate, for the first time, a significant correlation between invadopodia-associated genes to breast cancer metastasis, suggesting that invadopodia could be used as both a prognostic marker and as a therapeutic target for blocking cancer metastasis. We include here a novel network interaction map of invadopodia-associated proteins with currently available inhibitors, demonstrating a central role for the recently identified EGFR-Pyk2-Src-Arg-cortactin invadopodial pathway, to which re-purposing of existent inhibitors could be used to block breast cancer metastasis. We then present an updated overview of current cancer-related clinical trials, demonstrating the negligible number of trials focusing on cancer metastasis. We also discuss the difficulties and complexity of performing cancer metastasis clinical trials, and the possible development of anti-metastasis drug resistance when using a prolonged preventive treatment with invadopodia inhibitors. This review presents a new perspective on invadopodia-mediated tumor invasiveness and may lead to the development of novel prognostic and therapeutic approaches for cancer metastasis.