Interleukin-12 Deficiency Is Permissive for Angiogenesis in UV Radiation-Induced Skin Tumors

Abstract

We have shown previously that endogenous deficiency of interleukin (IL)-12 promotes photocarcinogenesis in mice. To characterize the role of IL-12 deficiency in tumor angiogenesis, we developed IL-12p35 knockout (IL-12 KO) mice on a C3H/HeN background. IL-12 KO mice and their wild-type (WT) counterparts were subjected to a photocarcinogenesis protocol. When tumor yield was stabilized, samples of tumor and tumoruninvolved UVB-exposed skin were collected and subjected to immunohistochemistry, gelatinolytic zymography, real-time PCR, and Western blot analysis of angiogenic factors. We found that the protein, mRNA expression and/or activity of the matrix metalloproteinases (MMP)-2, MMP-3, MMP-7, and MMP-9, and basic fibroblast growth factor, which play crucial roles in tumor growth, were significantly higher in UVBexposed skin and tumors of IL-12 KO mice compared with WT mice. With respect to the tumor vasculature, the expression of CD31-positive cells and the expression of vascular endothelial growth factor were higher in the tumors of IL-12 KO mice than WTs. The proliferative capacity of tumor cells of the IL-12 KO mice was significantly higher than their WT counterparts when determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by analyzing the expression of cyclin D1. The level of the proinflammatory cytokine IL-6 and the expression of IL-23 in tumors of IL-12 KO mice were markedly higher than in the tumors of WT mice. IL-23 has been shown to promote tumor growth. Together, these data indicate for the first time that IL-12 deficiency promotes proangiogenic stimuli in UVB-induced skin tumors and suggest that endogenous enhancement of IL-12 levels may be effective in the prevention and treatment of UV-induced skin cancers. [Cancer Res 2007;67(8):3785-93]

The antiproliferative function of violacein‐like purple violet pigment (PVP) from an Antarctic Janthinobacterium sp. Ant5‐2 in UV‐induced 2237 fibrosarcoma

“…The liquid chromatography, mass spectrometry and 1 H NMR results of the PVP (3-[5-(3-hydroxyl-1H-indol-3yl)-2-R 1 -1H-pyrrol-3-ylidene]-2-R 1 -1H-indol) (Fig. 1a) from Antarctic Janthinobacterium sp.…”

“…The ultraviolet B (UVB) (290-320 nm) component of the solar radiation causes cumulative damage of the skin cells resulting in immunosuppression that leads to skin cancer. 1 It has been reported that the exposure to UV radiation increases risk of both the melanoma and non-melanoma skin cancers in humans. 2 Moreover, it has been estimated that approximately one million new cases of nonmelanoma skin cancers were diagnosed in 2008 in USA alone causing nearly 1000 deaths (National Cancer Institute, http://www.cancer.gov/).…”

Accelerated wound healing phenotype in Interleukin 12/23 deficient mice

“…The presence of IL-12 has been associated with down-regulation of MMP-9 [15,47-49] which directly affects endothelial cell function and inhibits angiogenesis [49]. MMP-9 facilitates angiogenesis by breaking down the ECM, allowing endothelial cells to migrate, proliferate and differentiate into new capillaries [50].…”

Application of Angiogenesis to Clinical Dermatology

“…The reason for this difference remains unclear, but may explain why BCC is usually less aggressive than SCC. Both tumors require an angiogenic switch between local inhibitors of angiogenesis (interferon alpha, interleukin-12) and local stimulators of angiogenesis (bFGF, VEGF) (80,81). Angiogenesis inhibitors are already in use for the treatment of nonmelanoma skin cancers.…”