Imaging and Characterization of Macrophage Distribution in Mouse Models of Human Prostate Cancer.

Abstract

Prostate carcinoma consists of tumor epithelium and malignant stroma. Until recently, diagnostic and therapeutic efforts have focused exclusively on targeting characteristics of the tumor epithelium, ignoring opportunities to target inflammatory infiltrate and extracellular matrix components. Prostate tumors are rich in tumor-associated macrophages (TAMs), which can be either of the cytotoxic M1 or protumorigenic M2 phenotype. We have quantified the proportion of each in seven common human prostate tumor lines grown subcutaneously in athymic nude mice and have imaged macrophage densities in vivo in xenografts derived from these lines. A panel of seven human prostate cancer xenografts was generated in intact male athymic nude mice reflecting variable expression of the androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Mice were imaged ex vivo using near-infrared fluorescence (NIRF) imaging for PSMA expression and total macrophage densities to enable direct comparison between the two. Tumors were harvested for sectioning and additional staining to delineate M1 and M2 phenotype along with vascular density. Macrophage polarization analysis of sections revealed that all xenografts were > 94% M2 phenotype, and the few M1-polarized macrophages present were confined to the periphery. Xenografts displaying the fastest growth were associated with the highest densities of macrophages while the slowest growing tumors were characterized by focal, tumor-infiltrating macrophage densities. Xenograft sections displayed a strong positive spatial relationship between macrophages, vasculature, and PSMA expression. Prostate TAM disposition can be imaged ex vivo and is associated with growth characteristics of a variety of tumor subtypes regardless of PSMA or AR expression.