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.
Highlights
Epithelial skin cancers, in particular basal and squamous cell carcinomas (BCC and SCC), are the most frequent types of cancer in humans, and they are diagnosed in 2–3 million people worldwide every year
To determine whether human papillomavirus 8 (HPV8)-induced tumorigenesis is associated with an increase in activin expression, we made use of mice expressing the oncogenes of HPV8 in keratinocytes under the control of the keratin 14 promoter (HPV8/wt mice)
We show a remarkable pro-tumorigenic effect of activin in the early phase of skin tumorigenesis, which is mediated via activininduced attraction of monocytes and their differentiation into a tumor-associated macrophages (TAM)-like phenotype
Summary
Epithelial skin cancers, in particular basal and squamous cell carcinomas (BCC and SCC), are the most frequent types of cancer in humans, and they are diagnosed in 2–3 million people worldwide every year. It is generally difficult to predict whether an AK lesion will progress to SCC, and it is important to identify biomarkers that indicate a high risk for malignant progression. This requires a thorough understanding of the pathomechanisms underlying AK development and progression and the identification and functional characterization of the involved cell types and genes/proteins. Some of them may represent novel targets for therapeutic intervention They include proteins that directly affect proliferation, survival and migration of keratinocytes and their malignant transformation, and proteins that act on various components of the tumor stroma. Activins signal via heterotetrameric receptor complexes consisting of type I and type II receptors, which are transmembrane serine/threonine kinases (Chen et al, 2006)
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