STEROID ENZYMES AND CANCER Inflammation and Liver Cancer New Molecular Links C. Berasain, J. Castillo, M.J. Perugorria, M.U. Latasa, J. Prieto, and M.A. Avila Division of Hepatology and Gene Therapy, CIMA-Universidad de Navarra, Pamplona, Spain A connection between inflammation and cancer has been long suspected. Epidemio- logical studies have established that many tumors occur in association with chronic infectious diseases, and it is also known that persistent inflammation in the absence of infections increases the risk and accelerates the development of cancer. One clear example of inflammation-related cancer is hepatocellular carcinoma (HCC). HCC is a type tumor that slowly unfolds on a background of chronic inflammation mainly triggered by exposure to infectious agents (hepatotropic viruses) or to toxic compounds (ethanol). The molecular links that connect inflammation and cancer are not completely known, but evidences gathered over the past few years are beginning to define the pre- cise mechanisms. In this article we review the most compelling evidences on the role of transcription factors such as NF-κB and STAT3, cytokines like IL-6 and IL-1α, lig- ands of the EGF receptor and other inflammatory mediators in cancer development, with special emphasis in HCC. The molecular dissection of the pathways connecting the inflammatory reaction and neoplasia will pave the way for better therapies to treat cancers. Key words: hepatocellular carcinoma; inflammation; nuclear factor-κB (NF-κB); STAT3; IL-6; epidermal growth factor receptor; amphiregulin; Toll-like receptor (TLR); pattern recognition receptors (PRRs) Inflammation and Cancer Development The implication of inflammatory mecha- nisms in the development of malignancies was first suggested in the nineteenth century by the Prussian scientist Rudolph Virchow. 1 Among his observations was that tumors frequently de- Address for correspondence: Dr. M.A. Avila or Prof. J. Prieto, Division of Hepatology and Gene Therapy. CIMA. Universidad de Navarra. Avda. Pio XII, N55. 31008 Pamplona, Spain. Voice: +34-948-194700; fax: +34- 948-194717. maavila@unav.es or jprieto@unav.es Work in the authors’ laboratory is supported by the agreement between FIMA and the “UTE project CIMA.” Red Tem´ atica de Investigaci´ on Cooperativa en C´ ancer RD06 00200061, and CIBERehd (to JP) from Instituto de Salud Carlos III. Grants FIS PI040819, PI070392, PI070402 from Ministerio de Sanidad y Consumo. Fundaci´ on Mutua Madrile˜ na. Grant Ort´ ız de Landazuri from Gobierno de Navarra. MJP, MUL, and JC were supported by a fellowship, a Juan de la Cierva contract and a Torres Quevedo contract from Ministerio de Educaci´ on y Ciencia, respectively. veloped on sites of sustained inflammation, and that tumoral tissues often contained inflam- matory infiltrates. His early insights have not been given further attention until recent years, when data collected in epidemiological studies and observations made in genetic experimen- tal models of cancer confirmed the association between chronic inflammation and cancer. 2–4 Indeed, cumulative evidence indicates that in- flammatory diseases predispose to the devel- opment of different types of cancer, and it has been estimated that about 15% of the total can- cer deaths may be attributable to underlying infections. 5 On the other hand, there is evi- dence indicating that the use of nonsteroidal anti-inflammatory agents decreases the inci- dence of various tumors. 4 Among the infectious agents related to the pathogenesis of cancer we find bacteria such as Helicobacter pylori in gastric Steroid Enzymes and Cancer: Ann. N.Y. Acad. Sci. 1155: 206–221 (2009). doi: 10.1111/j.1749-6632.2009.03704.x C  2009 New York Academy of Sciences. 206