Association and regulation of protein factors of field effect in prostate tissues.

ABSTRACT

Field effect or field cancerization denotes the presence of molecular aberrations in structurally intact cells residing in histologically normal tissues adjacent to solid tumors. Currently, the etiology of prostate field­effect formation is unknown and there is a prominent lack of knowledge of the underlying cellular and molecular pathways. We have previously identified an upregulated expression of several protein factors representative of prostate field effect, i.e., early growth response-1 (EGR­1), platelet-derived growth factor­A (PDGF­A), macrophage inhibitory cytokine­1 (MIC­1), and fatty acid synthase (FASN) in tissues at a distance of 1 cm from the visible margin of intracapsule prostate adenocarcinomas. We have hypothesized that the transcription factor EGR­1 could be a key regulator of prostate field­effect formation by controlling the expression of PDGF­A, MIC­1, and FASN. Taking advantage of our extensive quantitative immunofluorescence data specific for EGR­1, PDGF­A, MIC­1, and FASN generated in disease­free, tumor­adjacent, and cancerous human prostate tissues, we chose comprehensive correlation as our major approach to test this hypothesis. Despite the static nature and sample heterogeneity of association studies, we show here that sophisticated data generation, such as by spectral image acquisition, linear unmixing, and digital quantitative imaging, can provide meaningful indications of molecular regulations in a physiologically relevant in situ environment. Our data suggest that EGR­1 acts as a key regulator of prostate field effect through induction of pro­proliferative (PDGF­A and FASN), and suppression of pro­apoptotic (MIC­1) factors. These findings were corroborated by computational promoter analyses and cell transfection experiments in non­cancerous prostate epithelial cells with ectopically induced and suppressed EGR­1 expression. Among several clinical applications, a detailed knowledge of pathways of field effect may lead to the development of targeted intervention strategies preventing progression from pre-malignancy to cancer.