Histopathological growth pattern evolution of tumor in VX2 liver cancer model.

The histopathological growth pattern (HGP) is a morphological reflection of interactions between cancer cells and the surrounding tissue, and has been identified with a remarkably predictive value in liver metastases. However, there is still a lack of studies on HGP of primary liver cancer even furtherly on HGP evolution. We employed VX2 tumor-bearing rabbits as the primary liver cancer model of which tumor size and distant metastasis were investigated. HGP assessment and computed tomography scanning was performed in four cohorts of different time points to map the HGP evolution. Additionally, Fibrin deposition and neovascularization were evaluated by Masson staining and immunohistochemical analysis of CD31, hypoxia-inducible factor-1 alpha (HIF1A) and vascular endothelial growth factor (VEGF). Tumors displayed exponential growth in the VX2 liver cancer model, but these tumor-bearing animals did not show any visible metastasis until they reached a specific stage of development. Correspondingly, the components of HGPs changed along with the tumor growth. The proportion of desmoplastic HGP (dHGP) decreased initially and then grew, but in contrast, the level of replacement HGP (rHGP) rose from the 7th day, reached a peak at around the 21st day, and then appeared drop. Importantly, the collagen deposition and expression of HIF1A and VEGF correlated with dHGP, while CD31 did not. HGP evolution presents a two-way switch including dHGP to rHGP and rHGP to dHGP, in which the emergence of rHGP may be linked to metastases. HIF1A-VEGF partially participates in the HGP evolution and presumably plays a key role in the formation of dHGP.