From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence

Abstract

Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-κB, STAT3 and JNK as possible missing links. In addition, the "inflammasome" (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver.

Keywords: Cellular senescence; Cirrhosis; Genetic/Epigenetic landscape; Hepatocellular carcinoma; Inflammasomes.

Fig. 1

Diagrammatic representation of various pathological changes associated with liver disease progression. Necroinflammation and telomere shortening are hallmarks of the early stages of chronic liver disease that finally lead to fibrosis and cirrhosis. Some regenerating nodules in the cirrhotic liver show atypical cells that progress toward dysplasia and culminate as a neoplastic lesion. Neoplasia is accompanied with telomerase activation and accumulations of genetic/epigenetic alterations (see fig. 5).

Fig. 2

Chronological representation of histopathological events during progression toward HCC. The majority of HCC lesions occur against a cirrhotic background (green asterisk), whereas in rare instances it can also occur against a noncirrhotic background (red asterisk). Typical histopathology sections during disease progression are shown: (a) normal liver (×200), (b) chronic hepatitis with marked portal/peri-portal chronic inflammation (×100), (c) cirrhosis with regenerating parenchymal nodules separated by active fibrous septa (×40), (d1) ductular reaction in cirrhosis (×100), (d2) ductular reaction with different stages of differentiation toward hepatocytes in a regenerating nodule (×200), (d3) large cell changes in regenerating nodule in cirrhosis (×100), (e1) large cell dysplasia (×200), (e2) small cell dysplasia (×200), (f1) HCC with thick trabeculae of malignant hepatocytes (×200) and (f2) HCC with trabeculae and pseudoacinar transformation in a noncirrhotic background (×40).

Fig. 3

Inflammation is a hallmark of injured liver. The inflammatory response, caused by viral (microbial attack) or nonviral etiologies (sterile attacks), leads to production of proinflammatory cytokines such as IL6, TNF-α, IL1 and IL18 through inflammasome-independent or -dependent pathways. The inflammasome component provides a platform for activation of caspase, which in turn cleaves Pro-IL1/IL18 to their active forms. Proinflammatory cytokines, through activation of transcription factors or by yet unknown mechanisms, make the hepatic milieu a fertile zone for cellular transformation. The accompanying pathological stages are shown in the right panel. DAMPS= damage-associated molecular patterns.

Fig. 4

Graphical representation showing Notch/TGF-β signaling and T cell activation during liver disease progression through phases of acute and chronic HBV infection with respect to the later stages of end-stage liver disease, i.e., cirrhosis and HCC. Activation is seen during the acute and end stages of liver disease, whereas attenuation is noted during the chronic stage of infection [28].

Fig. 5

Genetic/epigenetic landscape together with associated hallmarks of cirrhotic liver and HCC. S³ refers to the seven signature single nucleotide polymorphisms that are usually seen in HCV-related cirrhosis, in addition to mutation in P53. EMT = epithelial-to-mesenchymal transition. The classification of genetic changes in HCC is as has been described by Guichard et al [64].

Fig. 6

Opposing roles of cellular senescence depending on cell type and the pathological state of the liver. The secretome phenotype of senescent cells makes them active immunomodulators. In a cirrhotic background, the senescence of HSCs is beneficial for the resolution of fibrosis; in contrast, accumulation of hepatocyte senescence is a hallmark of cirrhosis. The senescent hepatocyte, through its secretome activity, can help in clearing neoplastic cells and thus have an anticarcinogenic effect; however, in later stages of disease progression, the secretome can act as a procarcinogen influencing the proliferation of neighboring parenchymal cells or stem cells. ROS = reactive oxygen species.

Fig. 7

Hepatic senescence. (a) HCC cell line Huh7 without (a1) or with doxorubicin treatment (a2). Note that the senescent cells (a2) showed an enlarged morphology, a typical feature of stress-induced premature senescence, as a result of the action of doxorubicin. Cells were stained with hematoxylin and eosin. Scale bar =10 µM. (b) Cirrhotic liver tissue stained positive for senescent associated β-galactosidase activity. The dotted lines and arrow indicate the cirrhotic nodules. Note the blue staining in the cirrhotic liver.