Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

Abstract

Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2‐positive monocytes. Gene expression profiling of macrophages from pre‐tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor‐associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody‐mediated depletion of macrophages, which strongly suppressed activin‐induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation.

Regulatory T cells are required for normal and activin‐promoted wound repair in mice

“…Dendritic epidermal T cells (DETC; CD3 hi TCRβ − ) were significantly less abundant in the presence of the activin transgene (Fig. F), which is consistent with the DETC depletion in Act mice during skin tumorigenesis . A reduction in DETCs also occurred following Treg depletion (Fig.…”

“…Activin is as a potent accelerator of the wound healing response , but the underlying cellular mechanisms are still largely unknown. Consistent with the effect of activin on Treg numbers in skin tumors and on Treg differentiation in the periphery , the percentage of CCR6 + effector cells among the Tregs was increased in wounds of Act mice. Expression levels of several proinflammatory cytokines, in particular of IL‐6, were increased in 7‐day wounds of Act mice.…”

“…One of them is the growth and differentiation factor activin, a member of the TGF‐β superfamily with important roles in inflammation, tissue repair, and cancer . We previously showed that wound healing is accelerated in mice overexpressing activin A in keratinocytes, since the highly diffusible activin A activates various types of stromal cells .…”

“…Interestingly, enhanced levels of activin result in depletion of epidermal γδ T cells, but accumulation of αβ T cells—in particular Tregs—in mouse skin carcinogenesis models , suggesting that activin may also regulate T cells during wound healing. The knowledge about the function of T cells in this process is, however, still limited.…”

Increased Serum Activin A Levels in Mycosis Fungoides and Sézary Syndrome

“…It has been shown that activin A plays important roles in the development and progression of solid tumors including breast carcinoma (1), ovarian carcinoma (2), and colorectal carcinoma (3). In addition, a recent study has revealed that activin overexpression is an early event in murine and human skin tumorigenesis via attracting tumor-associated macrophages (4). Tumorassociated macrophages are thought to have important roles in progression of not only skin solid tumors but also cutaneous T-cell lymphoma, based on the reports which describe that the depletion of tumor-associated macrophages delays tumor formation of cutaneous T-cell lymphoma cells in skin (5) and that cutaneous T-cell lymphoma patients with an increased number of tumor-associated macrophages had worse prognosis (6).…”