Expression of Bioactive Chemerin by Keratinocytes Inhibits Late Stages of Tumor Development in a Chemical Model of Skin Carcinogenesis

Abstract

Chemerin is a multifunctional protein acting mainly through the G protein-coupled receptor ChemR23/CMKLR1/Chemerin1. Its expression is frequently downregulated in human tumors, including in melanoma and squamous cell carcinoma of the skin and anti-tumoral properties of chemerin were reported in mouse tumor graft models. In the present study, we report the development of spontaneous skin tumors in aged ChemR23-deficient mice. In order to test the potential therapeutic benefit of chemerin analogs, a transgenic model in which bioactive chemerin is over-expressed by basal keratinocytes was generated. These animals are characterized by increased levels of chemerin immunoreactivity and bioactivity in the skin and the circulation. In a chemical carcinogenesis model, papillomas developed later, were less numerous, and their progression to carcinomas was delayed. Temporal control of chemerin expression by doxycycline allowed to attribute its effects to late stages of carcinogenesis. The protective effects of chemerin were partly abrogated by ChemR23 invalidation. These results demonstrate that chemerin is able to delay very significantly tumor progression in a model that recapitulates closely the evolution of solid cancer types in human and suggest that the chemerin-ChemR23 system might constitute an interesting target for therapeutic intervention in the cancer field.

The antitumoral effects of chemerin are independent from leukocyte recruitment and mediated by inhibition of neoangiogenesis

“…To evaluate whether the site of expression of chemerin is of relevance for its anti-tumoral effects, we used a mouse model in which a bioactive form of chemerin is expressed under control of the keratin 5 promoter (K5-chemerin model). These mice were previously shown to express chemerin in basal keratinocytes of the skin, resulting in a significant increase of chemerin activity in the blood [ 40 ]. Following injection of B16 ( Figure 1C ) or LLC ( Figure 1D ) cells, K5-chemerin mice developed tumors significantly smaller than control mice in both tumor graft models.…”

“…Angiogenesis also plays a major role in tumor development, particularly in the late stages of progression in which chemerin was shown to act [ 40 ]. Histological analysis of the LLC and B16 tumors at different stages of growth uncovered the presence of necrotic areas predominating in the central parts of the tumors and increasing in size with time.…”

“…It is expected that an effect of chemerin mediated by the recruitment of a leukocyte subset would require the presence of a chemerin gradient attracting the cells, and would therefore be dependent on the expression of chemerin by the tumor itself. To investigate whether this hypothesis holds true, we used our previously described transgenic model in which a bioactive form of chemerin is expressed under the control of the keratin K5 promoter [ 40 ]. In contrast to prochemerin, which is constitutively produced by many cell types, the chemerin expressed in this transgenic model does not require proteolytic processing, as the codons encoding the last 6 amino acids of prochemerin have been removed from the transgene construct.…”

“…In contrast to prochemerin, which is constitutively produced by many cell types, the chemerin expressed in this transgenic model does not require proteolytic processing, as the codons encoding the last 6 amino acids of prochemerin have been removed from the transgene construct. Active chemerin is therefore produced by basal keratinocytes, and both chemerin immunoreactivity and bioactivity are significantly increased in the blood flow [ 40 ]. Grafting B16 and LLC cell lines in these mice resulted in a slower growth rate, similar to what was observed when chemerin is expressed by the tumor cells themselves.…”

Mechanical Loading-Driven Tumor Suppression Is Mediated by Lrp5-Dependent and Independent Mechanisms

“…The protein array analysis for cytokines and chemokines revealed that the levels of chemerin and nexin were mainly altered by knee loading in the serum of wild-type and knockout mice, as well as the responses to dopamine and cholesterol in tumor cells. It is reported that chemerin suppresses hepatocellular carcinoma metastasis, breast cancer growth, prostate cancer progression, skin carcinogenesis, and melanoma [ 36 , 37 , 38 , 39 , 40 ], while nexin is a stimulator of peritoneal metastasis in ovarian cancer [ 41 ], as well as the growth, migration, and invasion of breast cancer cells [ 42 ]. It is also reported that Wnt signaling in tumor cells is inhibited by chemerin while nexin is a downstream target of Wnt signaling [ 43 , 44 , 45 ].…”