Pretumor microenvironment of hepatocellular carcinoma: Cancerization or anticancerization?

Tumor microenvironment (TM) has been deeply concerned. However, the pretumor microenvironment (PTM) was poorly understood. The purpose in this study was to explore the possible pathophysiological features of PTM before hepatocellular carcinoma (HCC) appearance.

Mouse livers with no swelling but with tumors present elsewhere in the body after subcutaneous injection of H22 in the fore underarm were considered a PTM, HCC tumors presenting far away from the PTM were regarded as a TM, and the healthy livers of mice without injection of H22 were regarded as a physiological microenvironment (PM). The transcriptomes of samples were generated using RNA-seq and validated using RT-qPCR.

Overall, 4483 differentially expressed genes (DEGs) were found in the TM compared with the PTM (TM/PTM), but only 194 were altered in the PTM compared with the PM (PTM/PM). Among those 194 DEGs, 104 displayed upregulation and 90 downregulation. Some of these DEGs could promote the ability to resist cancerization or facilitate cancer metastasis, while others indicated liver impairment. The DEGs were involved in 16 relevant pathways. Additionally, the frequency of alternative splicing (AS) in the DEGs in various samples was positively related to the expression of those DEGs.

The PTM initiatively armed itself to combat cancerization when its indications appeared although the PTM did not manifest any tissue swelling. However, the cancer cells were negatively influencing immunity to prevent clearance and positively promoting transformation to construct a suitable environment. During transformation by cancer cells, some genes with acquired AS participated in the construction of the PTM. This alteration created an invadable space and an appropriate environment for cancer cells.