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There is growing evidence that supports the role of the tumor microenvironment in the development and progression of hepatocellular carcinoma. The tumor microenvironment is composed of cellular components, bioactive substances, and extracellular matrix comprising of proteins such as collagens, proteoglycans, and the linear glycosaminoglycan hyaluronan. Hepatocellular carcinoma generally arises from fibrotic or cirrhotic liver, characterized by alteration in extracellular matrix components. In addition, non-tumoral cells such as mesenchymal stem/stromal cells (MSCs) are typically recruited to the injured or hypoxic area within the tumor. Besides the secretion of immunoregulatory proteins, growth factors, and cytokines, MSCs and hepatic stellate cells can also synthesize hyaluronan, amongst other components, which affects several tumor-associated processes. The tumor microenvironment also contains different types of immune cells. A key component in the genesis of hepatocellular carcinoma is the macrophages, as tumor-associated macrophages (TAM). This chapter provides an overview of the interaction of MSCs-hyaluronan-TAMs and tumor cells, and how this interaction potentially contributes to the development and progression of hepatocellular carcinoma.
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