Abstract
Prostate cancer is the most common form of cancer in men. It is the second leading cause of cancer death in men in the UK and USA after lung cancer. In a variety of tumors, including breast, ovarian, colorectal, and gastric carcinomas, the neoplastic cell population is often outnumbered by CD68-positive tumor-associated macrophages (TAM). TAM are a form of macrophages with an immature phenotype, that are characterized by low expression of carboxypeptidase M and tumor necrosis factor-a and high expression of interleukin (IL)-1 and IL-6, thereby reducing their tumoricidial activities. It also appears that exposure to hypoxia in poorly vascularized areas of tumors may stimulate TAM to release cytokines and enzymes that drive tumor growth, invasion, angiogenesis, and metastasis. Although prostate carcinomas contain significant areas of hypoxia and large numbers of TAM, to date, neither the distribution of TAM relative to blood vessels (and thus hypoxia) nor their expression of hypoxia-inducible factors (HIFs) 1 and 2 has been examined in such tumors. Study design Forty patients with prostate adenocarcinoma were included this study. The sections were double immunostained for the vascular endothelial marker factor VIII, the pan-macrophage marker CD68, and HIF-1a and HIF-2a. The three most vascular areas (vascular ‘hotspots’) were assessed for mean microvessel density using a 25-point Chalkley array graticule at 250 magnification (field area 0.189 mm2 ). Thereafter, they were assessed for macrophage density. Macrophage and microvessel densities were similarly assessed in the three areas of highest macrophage density (macrophage ‘hotspots’). The same method was applied for the analysis of HIF-1a and HIF-2a proteins as well as CD68-positive macrophages. Results This study shows that macrophages are prominent in prostate carcinoma and accumulate in hypoxic areas of tissues as there is a significant and reciprocal relationship between angiogenesis and macrophage infiltration in prostate cancer. HIF-1a and HIF-2a were shown to be expressed in small subsets of macrophages, with a higher expression of HIFs in avascular (35 and 40%) areas when compared with vascular areas (18 and 21%). Conclusion The study gives a valuable indication that TAMs can be used to deliver hypoxically-activated therapeutic DNA constructs to prostate tumors. However, further studies are required to detect the expression of other hypoxia-induced transcription factors in macrophages, which might play a role in activating gene expression in hypoxic tumor areas.