Experimental work during the period 1975-1986 revealed the crucial importance of the extracellular matrix (ECM) in tumor cell invasion and metastasis, and culminated in the three-step hypothesis of invasion. The first step is tumor cell attachment to the ECM. The second step is proteolytic degradation of the ECM, led by advancing protruding actin-rich pseudopods. The third step is migration of the tumor cell body through the remodeled matrix. This mechanistic scheme is widely accepted and continues to generate insights related to the large number of molecules, inside and outside invading cells, which all play a role in each of the three steps. Understanding the interaction of the tumor cells with the ECM has never been more clinically important. The ECM is not just a passive mechanical scaffold. Instead, the ECM is an active participant in neoplastic and physiologic invasion, and acts as an information highway, an immune sanctuary, and a storage depot supporting tumor growth and drug resistance. (C) 2016 AACR.
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