A strategy for the identification of paracrine regulators of cancer cell migration.

We hypothesized that the correlation of the whole transcriptome with quantifiable phenotypes may unveil genes contributing to the regulation of the corresponding response. We tested this hypothesis in cultured fibroblasts exposed to diverse pharmacological and biological agents, to identify genes influencing chemoattraction of breast cancer cells. Our analyses revealed several genes that correlated, either positively or negatively with cell migration, suggesting that they may operate as activators or inhibitors of this process. Survey of the scientific literature showed that genes exhibiting positive or negative association with cell migration had frequently been linked to cancer and metastasis before, while those with minimal association were not. The current methodology may formulate the basis for the development of novel strategies linking genes to quantifiable phenotypes.

Beneficial effects of CCL8 inhibition at lipopolysaccharide-induced lung injury.

CCL8 (MCP-2) is a chemoattractive cytokine associated with various immune-related pathologies. Recent studies show that CCL8 is significantly stimulated during acute respiratory distress syndrome in severely ill patients with COVID-19, making the inhibition of CCL8 activity a promising treatment. Lipopolysaccharide (LPS)-induced lung injury was evaluated in mice using a neutralizing antibody (1G3E5) against human CCL8. Pharmacokinetic studies indicated that following IP administration, 1G3E5 was sustained at higher levels and for a longer period compared to IV administration. CCL8 expression in the lungs was not enhanced by LPS, but CCR2 and CCR5 receptors were significantly stimulated. 1G3E5-mediated inhibition of CCL8 was associated with the reduction of pulmonary inflammation and suppression of various pro-inflammatory cytokines. These results point to a previously unrecognized, permissive role for CCL8 in mediating cytokine induction and ultimately sustaining inflammation. Disruption of CCL8 activity may provide a strategy for mitigating pulmonary inflammation during lung injury when related to abnormal cytokine induction.