Peritumoral activated hepatic stellate cells are associated with hepatic recurrence for resectable colorectal adenocarcinoma liver metastasis following resection

The formation of the pre-metastatic niche (PMN), which precedes the establishment of tumor lesions, plays a critical role in cancer recurrence and metastasis. Hepatic stellate cells (HSCs), a critical liver stromal cell component, can be induced to facilitate metastasis by modeling liver PMN formation. In the present study, activated HSCs were observed in the peritumor non-cancerous liver tissues (PNLT) colorectal adenocarcinoma liver metastasis (CRALM), and the density of activated HSCs was higher in PNLT compared with that in normal liver tissues (NLT). High density of activated HSC in the PNLT was positively associated with the number of tumor liver metastases (P=0.036), maximum diameter of liver metastases (P=0.002), and recurrence following synchronous radical resection (P=0.003). High density of activated HSCs in the PNLT was identified as a significant and independent prognostic factor for disease-free survival (HR, 2.083; 95% CI, 1.504–2.885; P=0.016) and overall survival (HR, 2.039; 95% CI, 1.312–3.169; P=0.019). Functionally, in vitro assays revealed that activated HSCs facilitated colorectal adenocarcinoma (CRA) cells to colonize the liver. Molecularly, it was demonstrated that the pro-recurrence of activated HSCs depended on paracrine hepatic growth factor. Taken together, the present results showed that high density of activated HSCs in the PNLT was an independent predictor for CRALM recurrence following resection, and they exerted their roles via their effect on CRA cell recruitment and proliferation by paracrine HGF.