Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer.

Avigdor Leftin,Nir Ben-Chetrit,Johanna A Joyce,Jason A Koutcher,Florian Klemm,Aamir Ahmad

doi:10.1371/journal.pone.0184765

Abstract

Iron-deposition is a metabolic biomarker of macrophages in both normal and pathological situations, but the presence of iron in tumor and metastasis-associated macrophages is not known. Here we mapped and quantified hemosiderin-laden macrophage (HLM) deposits in murine models of metastatic breast cancer using iron and macrophage histology, and in vivo MRI. Iron MRI detected high-iron pixel clusters in mammary tumors, lung metastasis, and brain metastasis as well as liver and spleen tissue known to contain the HLMs. Iron histology showed these regions to contain clustered macrophages identified by their common iron status and tissue-intrinsic association with other phenotypic macrophage markers. The in vivo MRI and ex vivo histological images were further processed to determine the frequencies and sizes of the iron deposits, and measure the number of HLMs in each deposit to estimate the in vivo MRI sensitivity for these cells. Hemosiderin accumulation is a macrophage biomarker and intrinsic contrast source for cellular MRI associated with the innate function of macrophages in iron metabolism systemically, and in metastatic cancer.

Highlights

Macrophage accumulation is an emerging hallmark of the breast tumor and metastasis microenvironment [1,2,3,4]
We found that hemosiderin iron is a metabolic biomarker of a population of macrophage deposits, and that the association of these iron(III)+ CD68+ macrophages with pro-inflammatory and anti-inflammatory subsets varies according to tissue type
The function of macrophages in storing iron is highlighted in the livers and spleens, organs known to harbor hemosiderin-laden macrophage (HLM) and are central to iron homeostasis

Summary

Introduction

Macrophage accumulation is an emerging hallmark of the breast tumor and metastasis microenvironment [1,2,3,4]. Histological evaluation of cells stained for macrophage surface receptor markers such as CD68 can provide a score of immune cell accumulation, or infiltration, that has been correlated with disease stage [7,8,9,10,11,12], and can provide predictive information on expected outcomes of therapeutic intervention [13]. Iron imaging in metastatic breast cancer study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion