Macrophage migration inhibitory factor (MIF) plays a critical role in pathogenesis of ultraviolet‐B (UVB) ‐induced nonmelanoma skin cancer (NMSC)

Abstract

Mounting evidence suggests that macrophage migration inhibitory factor (MIF) may serve as an important link between chronic inflammation and cancer development. The proinflammatory and proangiogenic activities of MIF position it as a potentially important player in the development and progression of nonmelanoma skin cancer (NMSC). To assess the role of MIF in the development and progression of NMSC, we exposed MIF(-/-) BALB/c mice to acute and chronic ultraviolet B (UVB) irradiation. Our studies demonstrate that MIF(-/-) BALB/c mice have a significantly diminished acute inflammatory response to UVB exposure compared to wild-type mice, as measured by myeloperoxidase activity, dermal neutrophil infiltration, and edematous response. Relative to wild-type mice, MIF(-/-) mice also show significantly lower vascular endothelial growth factor (VEGF) concentrations in whole skin and significantly lower 8-oxo-dG adduct concentrations in epidermal DNA following UVB exposure. Furthermore, MIF(-/-) mice showed significant increases in p53 activity, epidermal thickness, and epidermal cell proliferation following acute UVB insult. In response to chronic UVB exposure, MIF(-/-) mice showed a 45% reduction in tumor incidence, significantly less angiogenesis, and delayed tumor progression when compared to their wild-type counterparts. These data indicate that MIF plays an important role in UVB-induced NMSC development and progression.

Pathobiology of actinic keratosis: Ultraviolet-dependent keratinocyte proliferation

“…Mice lacking macrophage migration inhibiting factor (MIF À/À ), as compared with wild-type mice, have a diminished acute inflammatory response to UVB exposure, increased p53 activity, and a significantly reduced tumor burden in response to chronic exposure. 15 In contrast, transgenic mice that overexpress MIF display reduced expression of the apoptosis regulatory genes p53 and p21, fewer apoptotic epidermal cells in response to acute UVB exposure, and both an earlier onset and higher numbers of skin tumors compared with wild-type mice. 16 Immunohistochemical analyses of MIF in human skin samples demonstrated a progressive increase in expression of MIF from normal-appearing skin, to AK, to SCC.…”

25 Years On: A Retrospective on Migration Inhibitory Factor in Tumor Angiogenesis

“…In mouse models, MIF-deficient mice crossed to adenomatous polyposis coli (ApcMin/+) oncomice are characterized by significant reductions in both the number and size of adenomas that correspond to diminished tumor microvessel density (50). Moreover, MIF-deficient mice show a 45% reduction in chronic ultraviolet B (UVB) irradiation-induced epidermal tumorigenesis (51). The decreased tumor incidence and delayed tumor outgrowth in these MIF-deficient mice exposed to UVB correlated with significantly less VEGF expression and intratumoral microvessel density (51).…”

“…Moreover, MIF-deficient mice show a 45% reduction in chronic ultraviolet B (UVB) irradiation-induced epidermal tumorigenesis (51). The decreased tumor incidence and delayed tumor outgrowth in these MIF-deficient mice exposed to UVB correlated with significantly less VEGF expression and intratumoral microvessel density (51). Thus, one of the most consistent phenotypes associated with loss or inhibition of MIF in tumorigenesis is decreased angiogenic growth factor expression leading to microvascular density.…”

MIF Antagonist (CPSI-1306) Protects against UVB-Induced Squamous Cell Carcinoma

“…Compared with their wild-type (WT) counterparts, these mice also had diminished tumor number and burden, slower tumor progression, and lower VEGF levels (20). On the other hand, transgenic mice that overexpressed MIF were highly susceptible to UVB-induced carcinogenesis.…”