Expression of Intercellular Adhesion Molecule 1 by Hepatocellular Carcinoma Stem Cells and Circulating Tumor Cells

Abstract

Intercellular adhesion molecule 1 (ICAM-1) is believed to be involved in metastasis of hepatocellular carcinoma (HCC) cells. Cancer stem cells promote tumor relapse and metastasis. We investigated whether ICAM-1 is a marker of HCC stem cells. Sphere formation and tumor formation assays were performed to investigate the stem cell properties of ICAM-1(+) cells in vitro and in vivo. A specific targeting system that inhibits ICAM-1 expression and hepatitis B virus transgenic mice (M-TgHBV) were used to investigate whether inhibition of ICAM-1 reduced tumor incidence and metastasis in vivo. We used real-time polymerase chain reaction and immunoblot analysis to assess ICAM-1 and Nanog expression in tumor cell lines, and flow cytometry analysis was used to investigate ICAM-1 expression in HCC and blood samples. ICAM-1 was expressed on a minor cell population in HCC tumor cell lines, as well as in tumor tissues and circulating tumor cells isolated from patients and transgenic mice. ICAM-1(+) tumor cells had greater sphere-forming and tumorigenic capacities and increased expression of stemness-related genes compared with ICAM-1(-) tumor cells. The specific inhibition of ICAM-1 reduced formation and metastasis in M-TgHBV mice. ICAM-1 was found to be a marker of circulating tumor cells from patients and M-TgHBV mice. Increased numbers of CD45(-)ICAM-1(+) cells in blood samples of patients with HCC correlated with worse clinical outcomes. The stem cell transcription factor Nanog regulated expression of ICAM-1 in HCC stem cells. ICAM-1 is a marker of HCC stem cells in humans and mice; ICAM-1 inhibitors slow tumor formation and metastasis in mice. ICAM-1 expression is regulated by the stem cell transcription factor Nanog.