Volume 144, Issue 3, Pages 512-527 (March 2013) Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma  Virginia Hernandez–Gea, Sara Toffanin, Scott L. Friedman, Josep M. Llovet  Gastroenterology  Volume 144, Issue 3, Pages 512-527 (March 2013) DOI: 10.1053/j.gastro.2013.01.002 Copyright © 2013 AGA Institute Terms and Conditions

Figure 1 Cellular components of the microenvironment and molecular mechanisms influencing tumor growth and progression. Interactions among stromal, inflammatory, and cancer cells create a complex, permissive microenvironment that favors tumor progression. TAFs, tumor associated fibroblasts; CSF-1, colony stimulating factor 1; EC, endothelial cells; KC, Kupffer cells; VEGF, vascular endothelial growth factor; FGF, Fibroblast growth factor; PDGF, platelet-derived endothelial cell growth factor; Tregs, regulatory T cells; HGF, Hepatocyte Growth Factor; EGFR, Epidermal Growth Factor Receptor; MMPs, metaloproteinases; TIMP, Tissue Inhibitor of Metalloproteinases; HIF-1, HIF-1, hypoxia-inducible factor 1; TAM, Tumor associated macrophages; SDF-1, stromal cell-derived factor 1; CSC, Cancer stem cells; DC, Dendritic cells; TNF, Tumor Necrosis Factor. Gastroenterology 2013 144, 512-527DOI: (10.1053/j.gastro.2013.01.002) Copyright © 2013 AGA Institute Terms and Conditions

Figure 2 Pathological features that may be present in hepatocellular carcinoma (HCC). (A) Poorly-differentiated HCC. Tumor cells have marked pleomorphic nuclei and an inflammatory infiltrate consisting of neutrophils. Ballooning degeneration and production of Mallory’s hyalines are also noted. H&E original magnification 400X. (B) Poorly-differentiated HCC with tumor cells arranged in a solid pattern. A focus of lymphocytic inflammatory infiltrate is present. H&E, original magnification 100X. (C) Well-differentiated multinodular HCC with dense fibrosis forming a wide septum that separate two HCC nodules. H&E, original magnification 40X. (D) Increased vascularization in HCC. Vessels are highlighted by CD34 immunostaining. These vessels are nourishing the tumor. Original magnification 100X. Images courtesy of Dr M. Isabel Fiel, Mount Sinai School of Medicine. Gastroenterology 2013 144, 512-527DOI: (10.1053/j.gastro.2013.01.002) Copyright © 2013 AGA Institute Terms and Conditions

Figure 3 Anatomic and cellular alterations leading to the development of HCC. (A) Normal liver parenchyma. Hepatocytes with microvilli and sinusoidal endothelial cells whose fenestrations favor metabolic exchange. Space of Disse with few quiescent stellate cells containing lipid droplets. (B) Fibrotic liver. Upon chronic liver injury, hepatocytes lose their microvilli, sinusoid endothelial cells become defenestrated, and stellate cells are activated, losing lipid droplets and secreting ECM. (C) HCC. Malignant transformation of hepatocytes with uncontrolled growth. Infiltration of inflammatory cells and cytokines with extensive fibrosis and recruitment of TAFs and CSCs. (D) Development of new vessels (neoangiogenesis) and distant metastases. Gastroenterology 2013 144, 512-527DOI: (10.1053/j.gastro.2013.01.002) Copyright © 2013 AGA Institute Terms and Conditions

Figure 4 Schematic representation of therapeutic opportunities and application of prognostic biomarkers in the management of patients with HCC and preneoplastic conditions. Gastroenterology 2013 144, 512-527DOI: (10.1053/j.gastro.2013.01.002) Copyright © 2013 AGA Institute Terms and Conditions