Login to Access Video or Poster Abstract: MP39-14
Sources of Funding: This work was supported by the Roswell Park Cancer Institute Alliance Foundation and National Cancer Institute grant P30CA016056

Introduction

The von Hippel Lindau-hypoxia inducible factor axis underlying clear cell renal cell carcinoma (RCC) is centrally involved in iron and oxygen metabolism. Iron is a key catalyst for DNA synthesis, an abundant ingredient of tobacco, and a potent cause of oxidative stress-induced RCC in rodents. Yet the role of iron in human RCC carcinogenesis is largely unknown. We investigated whether levels of iron and the main iron uptake protein, transferrin receptor 1 (TfR1/CD71), are altered during human RCC tumorigenesis and progression.

Methods

Over 1500 core sections from 587 tissues (272 primary tumors, 240 benign kidney, 75 metastases) of 288 RCC patients were stained for iron and TfR1 protein using Prussian Blue and immunohistochemistry, respectively. 178 tissue cores from 14 different body sites of non-cancer patients were included as controls. Staining was scored by a clinically blinded genitourinary pathologist based on the product of intensity and tissue percentage (Z-score), and tested for association with clinicopathologic features and survival using a Mann-Whitney U test, Kruskal Wallis test and Cox regression model.

Results

Renal epithelium from non-cancer patients had low iron content (mean Z-score, MZS= 0.1), but by far the highest TfR1 levels of any tissue site in the body (MZS= 153). Compared to non-cancer patients, iron content in RCC patients increased mildly (4-fold) in benign renal epithelium (MZS= 0.6) and dramatically (>100 fold) in primary tumors (MZS= 21, p< 0.001). Higher tumor iron content was accompanied by moderate TfR1 downregulation (MZS= 21, p< 0.001) and associated with clear cell and papillary histologies, male gender and tobacco usage (p< 0.05 each). Opposite to changes observed with tumorigenesis, iron and TfR1 levels decreased and increased, respectively, with progression in tumor size, grade, pT stage and metastatic stage (all p< 0.05). Iron loss and TfR1 upregulation were most apparent in metastatic lesions (MZS= 5 and 111, respectively) and each associated with patient anemia and worse RCC-specific survival (all p< 0.05).

Conclusions

Benign renal epithelium has uniquely high levels of the iron import protein, TfR1, potentially priming these cells for dysregulated iron uptake and large intracellular iron increases (>100 fold) during tumorigenesis. Reduction in iron content during RCC progression to metastasis, despite TfR1 increases, may reflect lower systemically available iron in advanced RCC patients and raises the possibility that these cancers might have increased susceptibility to iron deprivation as a novel therapeutic strategy.

Funding

This work was supported by the Roswell Park Cancer Institute Alliance Foundation and National Cancer Institute grant P30CA016056