Bv8 mediates myeloid cell migration and enhances malignancy of colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most predominant malignancy in the world. Although the importance of immune system in cancer development has been well established, the underlying mechanisms remain to be investigated further. My PhD project studied a novel protein prokineticin 2 (Prok2, also known as Bv8) as a key pro-tumoural factor in CRC progression in in vitro and ex vivo settings. Immunostaining of human samples collected from cancer patients indicated myeloid cell infiltration (especially neutrophils) and Bv8 accumulation in colorectal tumour tissue. Bv8 shows chemotactic effects on human neutrophils through real-time chemotaxis assay, with neutrophils presenting a Bv8 gradient-dependent movement pattern. CRC cells produced reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF) that were triggered by myeloid cells and Bv8. ROS and VEGF acted as pro-angiogenesis buffer in myeloid cell-infiltrated CRC microenvironment. Moreover, leukocytes from studied patients with malignant tumours were more susceptible to produce ROS compared to patients with benign tumours. Myeloid cell or Bv8 enhanced energy consumption of glycolysis ATP and mitochondria ATP of CRC cells. Interestingly, cell-cell interaction between myeloid cells and CRC cells increased CRC cell viability but decreased the viability of myeloid cells (U937 cells). On the other hand, Bv8 showed no effect on cell viability and proliferation of CRC cells. ERK signalling pathway in CRC cells was activated by both Bv8 and co-cultured myeloid cells, indicating its regulatory role in Bv8-induced effects on CRC cells. Further data potentially suggested that Bv8 was negatively regulated in the tumour microenvironment of CRC, being maintained at a delicate level with a maximum pro-tumoural potential. In conclusion, my PhD PhD Thesis Xiaomeng Li 5 project presents the vital roles of Bv8 in myeloid cell infiltration and CRC development, suggesting that Bv8 is a potential therapeutic target for cancer-related immunotherapy.