A Review of the Current Status and Concept of the Emerging Implications of Zinc and Zinc Transporters in the Development of Pancreatic Cancer

Leslie C Costello,Renty B Franklin

doi:10.4172/2165-7092.s4-002

Leslie C Costello, Renty B Franklin

Open Access

https://doi.org/10.4172/2165-7092.s4-002

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Abstract

Pancreatic cancer (adenocarcinoma) remains a deadly untreatable cancer with no effective early detection procedure. Little is known concerning the factors involved in the development of pancreatic malignancy, which impedes advancements in its treatment and detection. Altered cellular zinc has been implicated in several cancers. Recent studies provide evidence that zinc and zinc transporters are important factors in pancreatic cancer. This review discusses the current information relating to the status of zinc and zinc transporters in human pancreatic adenocarcinoma. Relationships of the physiology and biochemistry of zinc in mammalian cells are presented, which should be applied to the conduct, interpretation, and translational application of human studies and experimental models. Evidence from human pancreatic tissue studies supports a new concept of the role of zinc in the development of pancreatic adenocarcinoma. The zinc level of the normal ductal and acinar epithelium is markedly decreased in the development of the malignant cells and the premalignant PanIN cells. ZIP3 is identified as the likely zinc uptake transporter, which is down regulated concurrently with the loss of zinc. Ras responsive binding protein (RREB1) is identified as the possible transcription factor involved in the silencing of ZIP3 expression. The evidence supports the current views of transdifferentiation of PanIN epithelium to ductal adenocarcinoma, and the possibility that acinar epithelial dedifferentiation might be a source of premalignant cells. These zinc-associated events occur early in oncogenesis to protect the malignant cells from the cytotoxic effects of zinc levels that exist in the normal cells. Hopefully, this presentation will stimulate interest in and support for much needed research into the implications of zinc and zinc transporters as important events in pancreatic carcinogenesis. The potential exists for the RREB1-ZIP3-zinc concept and/or other implications of zinc as new approaches for the development of effective treatment and for diagnostic biomarkers for pancreatic cancer.

Highlights

Pancreatic cancer is expected to result in ~44,000 new cases/year in theU.S, of which ~38,000 deaths will occur [1]
Li et al [17] in studies with with human pancreatic cancer and normal tissue analyses reported that ZIP4 transporter is upregulated in ductal adenocarcinoma; and ZIP4 is localized at the plasma membrane
The consistent decrease in zinc that is apparent in the PanIN lesions, well-differentiated malignancy, and progressing malignancy leads to the likely conclusion that cellular zinc levels that exist in the normal ductal/acinar epithelium are potentially cytotoxic in malignant cells

Summary

Introduction

Pancreatic cancer (adenocarcinoma) is expected to result in ~44,000 new cases/year in theU.S, of which ~38,000 deaths will occur [1]. Li et al [17] in studies with with human pancreatic cancer and normal tissue analyses reported that ZIP4 transporter is upregulated in ductal adenocarcinoma; and ZIP4 is localized at the plasma membrane.

Results

Conclusion