Wolf et al., Supplemental Material
Etiologies of inflammation-driven carcinogenesis
Besides chronic inflammation - a newly added hallmark of cancer - evading apoptosis, self-sufficiency
in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis, limitless
replicative potential and sustained angiogenesis are the hallmarks of cancer
Chronic inflammation can be caused by viruses, such as hepatitis B and C viruses (HBV, HCV) which
drive chronic hepatitis leading to hepatocellular carcinoma (HCC) (Llovet et al., 2003) or by pathogenic
bacteria, such as Helicobacter pylori, which promotes gastric inflammation thereby increasing the risk
of developing gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma (Cover and
Blaser 2009). Infections with parasites (e.g. schistosoma) can also favor chronic inflammation
consequently driving bladder carcinoma, liver cancer or colorectal cancer development (Mostafa et al.,
1999). Moreover, it has been reported that autoimmune diseases accompanied by chronic
inflammation contribute to cancer development: Autoimmune hepatitis is involved in HCC development
(Nishiyama et al., 2004) and inflammatory bowel diseases (e.g. ulcerative colitis, Crohn’s disease) can
precede colon cancer (Pohl et al., 2000). Furthermore, primary sclerotizing cirrhosis can lead to
cholangiocellular carcinoma (CCC) (Maggs and Chapman 2008). Finally, in addition to pathogenic and
autoimmune mediators, chronic or acute intoxication (e.g. alcohol, drug abuse, aflatoxin-b) can cause
inflammation-induced carcinogenesis (Fan and Farrell 2009).
Hepatic LT R signaling and pathogen infection
LT has been demonstrated to directly act on hepatocytes expressing high levels of LTR but little LT
(Browning and French 2002; Haybaeck et al., 2009): T-cell-derived LT and LIGHT signaling to
hepatocytes was demonstrated to control lipoprotein homeostasis (Lo et al., 2007) and LTR signaling
was shown to be important for liver regeneration through T-cell-derived LT expression (Tumanov et
al., 2009). Ruddell and colleagues demonstrated that LTR signaling regulates hepatic stellate cell
function and wound healing (Ruddell et al., 2009). Thus, hepatic LTR signaling seems to control liver
homeostasis, in both health and disease.
Indeed pharmacological inhibition of LTR signaling in the context of pathogen infections has recently
demonstrated that virus-, bacteria- and concavalin A-induced liver injury could be significantly reduced
(An et al., 2006; Anand et al., 2006; Puglielli et al., 1999). An involvement of LTR signaling in the host
response to liver infection was studied in the case of HCV in vivo and in vitro. Increased LT
expression in human livers was found to correlate with HCV-infection especially in liver progenitor
(oval) cells but also in small portal hepatocytes as well as immune cells (Lowes et al., 2003). In
addition, LT was reported to be upregulated as a consequence of HBV X protein expression in liver
cell lines (Lee et al., 2005) and siRNA knock-down of various components of the LTR signaling
pathway (e.g. LT; Rel A) was shown to interfere with HCV replication in vitro (Ng et al., 2007).
Indeed, several reports point towards an interaction of the HCV core protein with the LTR, leading to
the modulation of the LTR-signaling pathway (Chen et al., 1997; Matsumoto et al., 1997; Zhu et al.,
1998). The causal link between HCV- or HBV-infection, sustained LTR signaling and liver cancer
development will be further discussed in the main section of this review.
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