Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma

Abstract

Senescence secretome was recently reported to promote liver cancer in an obese mouse model. Steatohepatitic hepatocellular carcinoma (SH-HCC), a new variant of HCC, has been found in metabolic syndrome patients, and pericellular fibrosis, a characteristic feature of SH-HCC, suggests that alteration of the tumor stroma might play an important role in SH-HCC development. Clinicopathological characteristics and tumor stroma showing senescence and senescence-associated secretory phenotype (SASP) were investigated in 21 SH-HCCs and 34 conventional HCCs (C-HCCs). The expression of α-smooth muscle actin (α-SMA), p21Waf1/Cif1, γ-H2AX, and IL-6 was investigated by immunohistochemistry or immunofluorescence. SH-HCCs were associated with older age, higher body mass index, and a higher incidence of metabolic syndrome, compared to C-HCC (P <0.05, all). The numbers of α-SMA-positive cancer-associated fibroblasts (CAFs) (P = 0.049) and α-SMA-positive CAFs co-expressing p21Waf1/Cif1 (P = 0.038), γ-H2AX (P = 0.065), and IL-6 (P = 0.048) were greater for SH-HCCs than C-HCCs. Additionally, non-tumoral liver from SH-HCCs showed a higher incidence of non-alcoholic fatty liver disease and a higher number of α-SMA-positive stellate cells expressing γ-H2AX and p21Waf1/Cif1 than that from C-HCCs (P <0.05, all). In conclusion, SH-HCCs are considered to occur more frequently in metabolic syndrome patients. Therein, senescent and damaged CAFs, as well as non-tumoral stellate cells, expressing SASP including IL-6 may contribute to the development of SH-HCC.

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

“…Yoshimoto et al related these findings to an increase in gut microbiota population, which produces the DNA‐damaging metabolite deoxycholic acid, promoting SASP in HSCs . Moreover, in human NASH‐related HCC, cancer‐associated fibroblasts and nontumoral HSCs demonstrated increased expression of senescence markers and SASP markers compared with those deriving from conventional HCC . Further mechanistic studies are needed to elucidate the role of senescence in NASH‐associated HCC.…”

Senescent cells: a therapeutic target for cardiovascular disease

“…Normally, SASP factors target senescent cells (SNCs) for removal by the immune system, clearing adjacent, nonsenescent preneoplastic cells in the process and therefore providing tumor-suppressive benefits that are supe-rior to apoptosis (6). However, long-term persistence of SNCs and their secretome drives cancer, atherosclerosis 7, and other major age-related diseases, in addition to aging itself (8)(9)(10). The solidifying link between SNCs, cardiovascular aging, and CVD depends on four lines of evidence.…”

An update on the histological subtypes of hepatocellular carcinoma

“…It was noted that around 60% (14 of 22) SH-HCCs was associated with one more known risk factor for non-alcoholic fatty liver disease (NAFLD) [10] . The association with and NAFLD and metabolic syndrome was consolidated in other studies [13,14] . While most studies suggested a link of fatty liver disease with this subtype, in 2015 Yeh et al [15] looked at a series of SH-HCC and identified a group of patients without any underlying causes for metabolic disease.…”

“…Immunohistochemical expression of serum amyloid A and CRP was significantly higher in this subtype than conventional HCC as revealed by another study [16] . It was also found that the cancer-associated fibroblasts in SH-HCC more frequently expressed senescence-associated secretory phenotype by immunohistochemical staining [14] . On genetic and genomic levels, SH-HCC was shown to associate with IL6/JAK/STAT pathway activation, as well as wild type CTNNB1 [8,17] and TP53 [8] .…”