Open AccessTumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma
Author(s) -
Jee San Lee,
Jeong Eun Yoo,
Haeryoung Kim,
Hyungjin Rhee,
Myoung Ju Koh,
Ji Hae Nahm,
Jin Sub Choi,
Kee Ho Lee,
Young Nyun Park
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0171922
Subject(s) - hccs , hepatocellular carcinoma , senescence , pathology , immunohistochemistry , cancer research , sma* , hepatic stellate cell , biology , liver cancer , fibrosis , myofibroblast , medicine , endocrinology , mathematics , combinatorics
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), p21 Waf1/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 p21 Waf1/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 p21 Waf1/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.