Evolution of higher mesenchymal CD44 expression in the human lineage A gene linked to cancer malignancy

Lay Summary While all multicellular organisms can develop tumors, cancer mortality is, to a large degree, determined by the tendency of tumors to progress to malignant cancer, i.e. the spread of cancer cells to other parts of the body. There are large differences in the rate of cancer malignancy, with many hoofed animals (cow, horses, etc.), for instance, less vulnerable to malignancy than say humans. In order to understand the species differences in cancer malignancy, we investigated the evolutionary changes in the expression of a gene that has been implicated in cancer malignancy, called CD44. We find that the primate lineage has evolved high levels of CD44 expression, while that in other animals remained comparatively modest. This result suggests that the expression of this gene might explain, in part, the human vulnerability to malignant cancer. CD44 is an extracellular matrix receptor implicated in cancer progression. CD44 increases the invasibility of skin (SF) and endometrial stromal fibroblasts (ESF) by cancer and trophoblast cells. We reasoned that the evolution of CD44 expression can affect both, the fetal-maternal interaction through CD44 in ESF as well as vulnerability to malignant cancer through expression in SF. We studied the evolution of CD44 expression in mammalian SF and ESF and demonstrate that in the human lineage evolved higher CD44 expression. Isoform expression in cattle and human is very similar suggesting that differences in invasibility are not due to the nature of expressed isoforms. We then asked whether the concerted gene expression increase in both cell types is due to shared regulatory mechanisms or due to cell type-specific factors. Reporter gene experiments with cells and cis-regulatory elements from human and cattle show that the difference of CD44 expression is due to cis effects as well as cell type-specific trans effects. These results suggest that the concerted expression increase is likely due to selection acting on both cell types because the evolutionary change in cell type-specific factors requires selection on cell type-specific functions. This scenario implies that the malignancy enhancing effects of elevated CD44 expression in humans likely evolved as a side-effect of positive selection on a yet unidentified other function of CD44. A possible candidate is the anti-fibrotic effect of CD44 but there are no reliable data showing that humans and primates are less fibrotic than other mammals.