Evolved Resistance to Placental Invasion Secondarily Confers Increased Survival in Melanoma Patients

Abstract

Mammals exhibit large differences in rates of cancer malignancy, even though the tumor formation rates may be similar. In placental mammals, rates of malignancy correlate with the extent of placental invasion. Our Evolved Levels of Invasibility (ELI) framework links these two phenomena identifying genes that potentially confer resistance in stromal fibroblasts to limit invasion, from trophoblasts in the endometrium, and from disseminating melanoma in the skin. Herein, using patient data from The Cancer Genome Atlas (TCGA), we report that these anti-invasive genes may be crucial in melanoma progression in human patients, and that their loss is correlated with increased cancer spread and lowered survival. Our results suggest that, surprisingly, these anti-invasive genes, which have lower expression in humans compared to species with non-invasive placentation, may potentially prevent stromal invasion, while a further reduction in their levels increases the malignancy and lethality of melanoma. Our work links evolution, comparative biology, and cancer progression across tissues, indicating new avenues for using evolutionary medicine to prognosticate and treat human cancers.

The value of broad taxonomic comparisons in evolutionary medicine: Disease is not a trait but a state of a trait!

“…For instance, the expression of TGFb1 in stromal fibroblasts is correlated with higher invasibility by both, cancer cells as well as trophoblast cells, and is also associated with worse outcome for cancer patients 32 . That this pattern is not only anecdotal has been show in recent studies comparing genes associated with placental phenotype and cancer malignancy across a sample of mammalian species 33,34 . That these insights do hold translational potential is shown by the fact that modulating gene expression in human cells to make them more like bovine fibroblasts can increase their ability to resist cancer cell invasion 31 …”

“…32 That this pattern is not only anecdotal has been show in recent studies comparing genes associated with placental phenotype and cancer malignancy across a sample of mammalian species. 33,34 That these insights do hold translational potential is shown by the fact that modulating gene expression in human cells to make them more like bovine fibroblasts can increase their ability to resist cancer cell invasion. 31…”

A SNP affects Wnt4 expression in endometrial stroma, with antagonistic implications for pregnancy, endometriosis and reproductive cancers

“…We suggest that the reported correlated associations of the mutation with reproductive cancers and endometriosis may be mediated through the second prong: the enhancement of proimplantation processes, which make stroma more permissive to invasion by embryo but also by cancer and ectopic endometriotic tissue. This suggestion is inspired by the correlation across species between endometrial permissiveness to embryo implantation and vulnerability of peripheral stroma to cancer invasion, where species with more invasive placentation are more prone to invasion by metastases [68][69][70][71] . Here we hypothesize that this relationship is not only a species-level phenomenon but applies within human populations; individuals with increased uterine embryo invasibility may be more prone to cancer metastasis and endometriosis.…”

Experimental and phylogenetic evidence for correlated gene expression evolution in endometrial and skin fibroblasts

“… 16 This model has been called ELI for “Evolved Levels of Invasibility,” where the term “invasibility” denotes the vulnerability of a tissue to invasion by some cell type. 17 This term is well established in ecology, where it describes the vulnerability of a habitat to be invaded by foreign species. 18 , 19 In the case of tissues, the invasive cell type can be a cancer cell population, the extra villous trophoblast cells of the placenta or a leukocyte.…”