Circuitos celulares y moleculares regulados por cx3cl1 en el cancer de mama y la neurodegeneración

Abstract

CX3CL1, the sole chemokine belonging to the CX3C group, is an atypical chemokine that is synthesised by epithelial cells, endothelial cells and neurons as a transmembrane protein and can be processed to yield a soluble form. These characteristics enable CX3CL1 to enhance both the adhesion and migration of cells expressing its only known physiologic receptor, CX3CR1, which include different types of leukocytes, cells of the microglia in the central nervous system (C.N.S.) and endothelial cells. Besides its role in the chemotaxis of leukocytes, the axis CX3CL1-CX3CR1 has also been implicated in cancer, both promoting and inhibiting tumor progression. Previous data from the literature show that CX3CL1 expression is downregulated in samples of breast cancer comparing to those of healthy donors, so our goal has been to define the role of CX3CL1 in breast cancer. Our results show that CX3CL1 is expressed in the mammary gland of FVB/N mice, with the highest expression corresponding to luminal epithelial cells. In FVB/N-Tg(MMTVneu)202Mul/J mice, which spontaneously develop breast cancer tumors due to the overexpression of the protooncogene neu in the mammary gland, we have observed a downregulation of CX3CL1 in tumoral cells. However, CX3CL1 overexpression, achieved by intratumoral infection with adenoviral vectors, has not suppressed tumor progression but increased the number of tumors per animal found in these mice. We show that CX3CL1 is capable of inducing Epithelial to Mesenchymal Transition (EMT) in a human breast cancer cell line expressing CX3CR1. Nevertheless, this is not the mechanism mediating the increase in the number of tumors per mice after CX3CL1 overexpression, as we have not been able to detect tumoral cells invading the lymph nodes that drain the infected. We have generated FVB/NTg MMTVneu mice lacking CX3CL1 in which tumoral onset has shown significant delay both in CX3CL1 knockout and heterozygous mice compared to wild type mice, which argues for a protumoral role of CX3CL1 in breast cancer. Intriguingly, we have observed a high incidence of “sudden death” in mice lacking CX3CL1 starting at the eight week of age. This “sudden death” has also been observed in non-transgenic FVB/N CX3CL1 knockout mice and shares some characteristics with a neurologic disorder arising in aged FVB/N mice. We have shown the presence of gross neuronal lesions in the C.N.S. of mice lacking CX3CL1 correlating with a high activation of astroglia and microglia cells. These results provide evidence for a role of CX3CL1 in breast cancer, possibly promoting tumor progression. Besides, the finding of a neurologic disorder arising specifically in FVB/N CX3CL1 knockout mice, but not in those of the C57BL/6 background, has shown promising results as a model to investigate the interactions between neurons, astroglia cells and microglia.