Down-regulation of CXCL1 inhibits growth of colorectal liver metastases

Colorectal cancer is the fourth most abundant type of cancer in the world. Most of the CRC patients die from metastases, predominantly in the liver. Metastasis results from a complex cascade of events, necessitating the involvement of numerous tumor cell–derived factors and microenvironmental molecules, including specific chemokines. In addition to their activities in the haematopoietic context, the possible role of chemokines to regulate tumor growth and metastasis in different ways-either by promoting or inhibiting these processes has motivated us to investigate the hypothesis that chemokines may not only affect the tumor microenvironment, but also directly regulate malignancy-associated properties in the tumor cells.

Examination of gene expression profile between tumor cells of the invasion front and those from the inner parts of the tumor revealed an up regulation of pro-angiogenic molecules at the invasion front which was further confirmed by qPCR. shRNA mediated inhibition of CXCL1 showed inhibition of CXCL1 expression as judged by quantitative real-time PCR and Western blotting. In the proliferation assay, shCXCL1 cells in which CXCL1 expression has been ablated showed a much decreased proliferation rate compared to nontargeting controls (shNTC). ShRNA-mediated inhibition of CXCL1 resulted in 6-fold decrease in cell migration. shNTC cells consistently showed levels of invasion similar to those observed for the parental LS174T cells.

Transplantation of shCXCL1, shNTC or LS174T cells to the livers of nude mice produced large tumors in animals injected with shNTC cells similar to the parental LS174T cells whereas shCXCL1 clones seemed to have lost this tumorigenic potential.

Taken together, these data suggest that down regulation of CXCL1 results in reduced tumor growth and it may be a potential target to develop novel therapeutic strategies for some tumors.

CXCL1 - Colorectal liver metasatasis - Invasion front