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Human vulnerability to cancer malignancy is enhanced by evolution of higher mesenchymal CD44 expression compared to other mammals
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.08.03.234617v1?rss=1
Authors: Ma, X., Dighe, A., Maziarz, J., Neumann, E., Erkenbrack, E., Hei, Y.-Y., Liu, Y., Suhail, Y., Kshitiz, K., Levchenko, A., Wagner, G.
Abstract:
CD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution of CD44 expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase of CD44 expression in SF and ESF is due to cis-regulatory effects in the proximal promoter of CD44 as well as trans-regulatory factors. We identify CEBPB as a putative lineage specific positive regulatory factor of CD44 expression in skin fibroblasts. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increased CD44 expression in primate skin fibroblasts. The trans-regulatory factors are, to some degree, cell type specific, as supported by statistical analysis of reporter experiments as well as the fact that CEBPB does not affect CD44 expression in human ESF. All these results suggest that selective modulation of CD44 expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.
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Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.08.03.234617v1?rss=1
Authors: Ma, X., Dighe, A., Maziarz, J., Neumann, E., Erkenbrack, E., Hei, Y.-Y., Liu, Y., Suhail, Y., Kshitiz, K., Levchenko, A., Wagner, G.
Abstract:
CD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution of CD44 expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase of CD44 expression in SF and ESF is due to cis-regulatory effects in the proximal promoter of CD44 as well as trans-regulatory factors. We identify CEBPB as a putative lineage specific positive regulatory factor of CD44 expression in skin fibroblasts. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increased CD44 expression in primate skin fibroblasts. The trans-regulatory factors are, to some degree, cell type specific, as supported by statistical analysis of reporter experiments as well as the fact that CEBPB does not affect CD44 expression in human ESF. All these results suggest that selective modulation of CD44 expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.
Copy rights belong to original authors. Visit the link for more info