Osteopontin-positive infiltrating tumor-associated macrophages in bulky ampullary cancer predict survival

Abstract

Purpose: Tumor-associated macrophages (TAMs) promote cancer cell proliferation and distant metastases. Osteopontin (OPN) is overexpressed in several human cancer cells and in TAMs. Therefore, we set out to determine the role of OPN-expressing macrophages in cancer. Experimental Design: Specimens from ampullary cancer patients at National Cheng Kung University Hospital were collected for immunohistochemistry. Plasma OPN was measured by enzyme-linked immunosorbent assay. Tumor and normal epithelial cells from fresh tissues were separated by laser-assisted microdissection for reverse-transcription polymerase chain reaction and quantitative real-time PCR analyses. Results: In 100 ampullary cancers, diffuse cytoplasmic positivity for OPN was found in infiltrating TAMs in 36 patients and marginal TAMs in 32 patients; OPN+ macrophages were absent in 32 patients. Expression patterns of OPN in TAMs were associated with pancreatic invasion, tumor stage, TNM stage, lymphovascular invasion and recurrence with peritoneal carcinomatosis. Patients were stratified according to a median tumor size of 2 cm. Patients with tumor sizes ≥2 cm and OPN+ infiltrating TAMs had a poorer disease-specific survival rate than those with OPN+ marginal TAMs. Macrophage-associated cytokine expression in ampullary cancer cells was also assessed; levels of macrophage migration inhibitory factor (MIF) in cancer cells were higher than in normal duodenal mucosa. Conclusions: Expression of OPN and location of TAMs in bulky ampullary cancer predict recurrence. In addition, cytoplasmic staining of MIF is enhanced in ampullary cancer cells. Patients with bulky tumor, OPN+ infiltrating TAMs and MIF expression had a worst disease-specific survival.