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MIF antagonist (CPSI-1306) protects against UVB-induced squamous cell carcinoma

Significance Statement

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that has been implicated in acute inflammatory states and chronic inflammatory diseases. It has also been shown to play a crucial role in the progression of several malignancies, as well as in the induction / maintenance of cancer associated inflammation in tumors.

MIF is upregulated in skin after exposure to sunlight and is expressed at high levels in cutaneous squamous cell carcinomas (SCC). In addition, MIF receptors are expressed at appreciable levels in epidermal keratinocytes and inflammatory cells, through which MIF contributes to maintenance of transformed cells and hence, promotion of SCC. To evaluate if inhibition of MIF can alleviate these processes, two studies were conducted.

In the first study, mice were pre-treated with a MIF antagonist (CPSI) or vehicle, following which they were exposed to a single dose of ultraviolet B light (UVB). Direct UVB-induced DNA damage (measured by cyclo-pyrimidine dimers, CPD) was reduced in CPSI-treated mice when compared to vehicle-treated mice. The epidermal keratinocytes of these mice also displayed early induction and increased expression of p53 protein, lower Ki67 proliferation index and enhanced apoptosis. In addition, cutaneous UVB-induced inflammatory response was also decreased in CPSI-treated mice. Thus, inhibition of MIF resulted in an overall reduction in epidermal DNA damage, supported by lower phospho-histone {Gamma}H2A.X expression.

In the second study, mice were exposed to UVB for a prolonged period of time to mimic the average lifetime sun exposure in adult humans and then treated with CPSI or vehicle. CPSI-treated mice developed smaller and less aggressive tumors (premalignant). Epidermal keratinocytes of non-tumor bearing skin displayed lower proliferation rate and decreased levels of mutant p53 protein, as demonstrated by fewer p53 foci. Thus, inhibition of MIF can reduce the development of UVB-induced squamous cell carcinomas.

These studies provide biological evidence that disruption of MIF function can alleviate the adverse effects of acute and chronic UVB exposure. Therefore, MIF is a potential target in patients at high-risk for developing squamous cell carcinomas.

Figure legend: Inhibition of MIF decreases ultraviolet light (UVB)-induced DNA damage and squamous carcinogenesis. A. Exposure to UVB causes DNA damage (initiation), which leads to the development of p53 foci, containing mutant p53 (red nuclei). These cells may develop into premalignant tumors and acquire additional mutations (purple nuclei) and eventually, develop into squamous cell carcinomas. B. Treatment with a MIF antagonist increases the expression of wild type p53 (green nuclei) in response to UVB exposure and decreases UVB-induced DNA damage. Though these mice can develop premalignant squamous papillomas, disruption of MIF function inhibits the development of malignant tumors, probably by preventing the acquisition of additional alterations in genomic DNA.

MIF antagonist (CPSI-1306) protects against UVB-induced squamous cell carcinoma

Nagarajan P1, Tober KL1, Riggenbach JA1, Kusewitt DF2, Lehman AM3, Sielecki T4, Pruitt J4, Satoskar AR1, Oberyszyn TM5.

Mol Cancer Res. 2014 ;12(9):1292-302.

 

1Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.and

2Department of Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, Texas.

3Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio.

4Cytokine PharmaSciences, King of Prussia, Pennsylvania.

5Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio. [email protected]

 

Abstract

Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light-induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX ({Gamma}-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non-tumor-bearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306-treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure.

IMPLICATIONS:

Macrophage migration inhibitory factor is a viable target for the prevention of UVB-induced cutaneous SSCs.

©2014 American Association for Cancer Research.

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