Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

Abstract

Inadequate dietary Zn consumption increases susceptibility to esophageal and other cancers in humans and model organisms. Since Zn supplementation can prevent cancers in rodent squamous cell carcinoma (SCC) models, we were interested in determining if it could have a preventive effect in a rodent skin cancer model, as a preclinical basis for considering a role for Zn in prevention of human nonmelanoma skin cancers, the most frequent cancers in humans. We used the 7,12‐dimethyl benzanthracene carcinogen/phorbol myristate acetate tumor promoter treatment method to induce skin tumors in Zn‐sufficient wild‐type and Fhit (human or mouse protein) knockout mice. Fhit protein expression is lost in >50% of human cancers, including skin SCCs, and Fhit‐deficient mice show increased sensitivity to carcinogen induction of tumors. We hypothesized that: (1) the skin cancer burdens would be reduced by Zn supplementation; (2) Fhit −/−(Fhit, murine fragile histidine triad gene) mice would show increased susceptibility to skin tumor induction versus wild‐type mice. 30 weeks after initiating treatment, the tumor burden was increased ~2‐fold in Fhit −/− versus wild‐type mice (16.2 versus 7.6 tumors, P < 0.001); Zn supplementation significantly reduced tumor burdens in Fhit −/− mice (males and females combined, 16.2 unsupplemented versus 10.3 supplemented, P = 0.001). Most importantly, the SCC burden was reduced after Zn supplementation in both strains and genders of mice, most significantly in the wild‐type males (P = 0.035). Although the mechanism(s) of action of Zn supplementation in skin tumor prevention is not known in detail, the Zn‐supplemented tumors showed evidence of reduced DNA damage and some cohorts showed reduced inflammation scores. The results suggest that mild Zn supplementation should be tested for prevention of skin cancer in high‐risk human cohorts.

Influence of environmental risk factors on the development of wounds associated with squamous cell carcinoma

“…Males were discovered to be significantly more susceptible to developing SCC lesions than females. Males have higher incidence of SCC than females, presumably due to differences in sun exposure behaviours, hormonal factors and genetic predispositions 1,17 . This finding is consistent with this notion.…”

“…Males have higher incidence of SCC than females, presumably due to differences in sun exposure behaviours, hormonal factors and genetic predispositions. 1,17 This finding is consistent with this notion. This gender-specific prevalence necessitates gender-specific screening and preventative measures.…”

A Topical Zinc Ionophore Blocks Tumorigenic Progression in UV‐exposed SKH‐1 High‐risk Mouse Skin

“…ZnT, ZIP, MT family members) is dysregulated during tumorigenesis, playing a key role in malignant progression, relevant to various malignancies including breast, prostate and pancreatic cancer . Interestingly, dietary zinc supplementation has shown efficacy in a murine model of chemical‐induced cutaneous SCC, and cumulative evidence suggests the efficacy of topical or dietary supplemental zinc administration in skin environmental stress protection, wound healing and cancer prevention . In the context of ZnPT‐based skin cancer photochemoprevention as reported here for the first time, it should also be mentioned that earlier research has reported ZnPT‐induced suppression of UVB‐induced murine epidermal hyperplasia, an effect that was attributed to stabilization of HIF‐1α, but the obvious role of ZnPT‐induced modulation of cellular zinc homeostasis was not addressed experimentally in these studies .…”

Zinc treatment reverses and anti-Zn-regulated miRs suppress esophageal carcinomas in vivo

“…A limitation of this study is the absence thus far of well-designed human clinical trials showing efficacy of Zn supplementation in preventing cancer development or reducing cancer burdens in ESCCs, oral cancers, or skin cancers where animal models ( 13 , 28 , 50 ) have suggested efficacy. It seems this would be especially useful for the skin cancers predictably developed in immunosuppressed transplant patients.…”