Hepatocellular Carcinoma Metastasis and Circulating Tumor Cells

A hallmark of aggressive hepatocellular carcinomas (HCCs) is the ability to metastasize. Metastatic lesions are difficult to manage in clinical practice as the extent of disease typically precludes curative resection and resistance to systemic treatments is common [1, 2]. Metastasis is a multistage process in which cancer cells (1) delaminate from the primary site and locally invade the host stroma (initiation), (2) enter into blood and/or lymphatic vasculature (intravasation), (3) survive and exit the circulation into distant sites (extravasation), and (4) colonize the new microenvironment and proliferate to form a macroscopic secondary tumor (colonization) [3, 4]. This simplified model provides a framework for a sequence of biological properties that must be acquired during cancer dissemination. Different malignancies, however, demonstrate unique regulatory events in this process largely governed by the complex microenvironment in which the metastatic cells originate and that of the distant location(s) where the metastasis is established [5]. Given the anatomic and physiologic complexity of the liver, the HCC microenvironment is one of the most difficult to reproduce experimentally and, consequently, understand in its totality. In the context of this chapter, HCC metastasis is discussed, with an emphasis on the role of the hepatic microenvironment and the role of circulating cancer cells in the metastatic process.