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 field-effect 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 (EGR-1), platelet-derived growth factor-A (PDGF-A), macrophage inhibitory cytokine-1 (MIC-1), 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 EGR-1 could be a key regulator of prostate field-effect formation by controlling the expression of PDGF-A, MIC-1, and FASN. Taking advantage of our extensive quantitative immunofluorescence data specific for EGR-1, PDGF-A, MIC-1, and FASN generated in disease-free, tumor-adjacent, 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 EGR-1 acts as a key regulator of prostate field effect through induction of pro-proliferative (PDGF-A and FASN), and suppression of pro-apoptotic (MIC-1) factors. These findings were corroborated by computational promoter analyses and cell transfection experiments in non-cancerous prostate epithelial cells with ectopically induced and suppressed EGR-1 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.

Molecular Characterization of Prostate Cancer with Associated Gleason Score Using Mass Spectrometry Imaging

“…The term "field cancerization," describes molecular alterations occur-ring in histologically normal tissue adjacent to tumors and has been previously described in prostate cancer and others (27)(28)(29)(40)(41)(42). A number of proteins including MIC-1 and PDGF-A have been found with elevated expression in tumor-adjacent tissues and it has been proposed that these secreted factors could promote tumorigenesis leading to tumor multifocality (40,43). Our observation of increasing lipid intensity in normal prostate tissue adjacent to tumor may indicate that metabolic alterations occur not just in tumor cells, but in surrounding tissue as well.…”

The Role of the Transcription Factor EGR1 in Cancer

“…As a transcription factor, EGR1 performs a regulatory function in cell growth, but the roles of EGR1 are different in different tumors. For example, EGR1 expression is higher in a prostate tumor than in surrounding prostate tissue ( 11 ), and the expression of EGR1 in the prostate tumor positively correlates with malignancy ( 12 ). Similar clinical associations have been found in gastric cancer ( 13 ).…”

Integrated transcriptomic analysis of distance-related field cancerization in rectal cancer patients

“…That is, the aberrant molecular alterations and environmental modifications are present throughout the organ that gives rise to the tumor [ 4 ]. This phenomenon has been studied in several epithelial tumors, including non-small cell lung cancer [ 5 , 6 ], colorectal cancer [ 7 , 8 ], breast cancer [ 9 ], head and neck cancer [ 10 ] and prostate cancer [ 11 , 12 ].…”