Early growth response 1 and fatty acid synthase expression is altered in tumor adjacent prostate tissue and indicates field cancerization

Abstract

BACKGROUND Field cancerization denotes the occurrence of molecular alterations in histologically normal tissues adjacent to tumors. In prostate cancer, identification of field cancerization has several potential clinical applications. However, prostate field cancerization remains ill defined. Our previous work has shown up-regulated mRNA of the transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS) in tissues adjacent to prostate cancer. METHODS Immunofluorescence data were analyzed quantitatively by spectral imaging and linear unmixing to determine the protein expression levels of EGR-1 and FAS in human cancerous, histologically normal adjacent, and disease-free prostate tissues. RESULTS EGR-1 expression was elevated in both structurally intact tumor adjacent (1.6× on average) and in tumor (3.0× on average) tissues compared to disease-free tissues. In addition, the ratio of cytoplasmic versus nuclear EGR-1 expression was elevated in both tumor adjacent and tumor tissues. Similarly, FAS expression was elevated in both tumor adjacent (2.7× on average) and in tumor (2.5× on average) compared to disease-free tissues. CONCLUSIONS EGR-1 and FAS expression is similarly deregulated in tumor and structurally intact adjacent prostate tissues and defines field cancerization. In cases with high suspicion of prostate cancer but negative biopsy, identification of field cancerization could help clinicians target areas for repeat biopsy. Field cancerization at surgical margins on prostatectomy specimen should also be looked at as a predictor of cancer recurrence. EGR-1 and FAS could also serve as molecular targets for chemoprevention.

Heterogeneous patterns of DNA methylation-based field effects in histologically normal prostate tissue from cancer patients

“…In contrast, detection of molecular cancer field effects that are not microscopically visible to the pathologist could increase sensitivity for occult PC and ensure early diagnosis of potentially aggressive tumours. PC associated field effects have previously been detected at various molecular levels, including RNA3031, protein3334 and DNA (mutations)32. Here, we focused specifically on epigenetic field effects since aberrant DNA methylation has been found to be an early and highly recurrent event in PC16.…”

“…So far, field effects in relation to PC have been reported at various molecular levels, including RNA3031, DNA32, protein3334, and DNA methylation35363738, where the latter seems particularly promising. Indeed, a commercial test (ConfirmMDx for Prostate Cancer, MDx Health), based on APC (Adenomatous Polyposis Coli), GSTP1 , and RASSF1 (Ras Association (RalGDS/AF-6) Domain Family Member 1) hypermethylation in cancer-negative biopsies, offers a negative predictive value of 90%39.…”

Prostate Field Cancerization: Deregulated Expression of Macrophage Inhibitory Cytokine 1 (MIC-1) and Platelet Derived Growth Factor A (PDGF-A) in Tumor Adjacent Tissue

“…Quantitative immunofluorescence was performed as described in our previous work [ 12 ]. Briefly, paraffin-embedded prostate tissue sections were deparaffinized with xylene and rehydrated with decreasing concentrations of ethanol.…”

“…Accordingly, a number of genetic, epigenetic, and biochemical alterations in structurally intact cells of both epithelial and stromal origin that reside in histologically normal tissues adjacent to prostate adenocarcinomas (“field cancerized” tissues) have been recently identified by us and others and postulated to be of value as clinical indicators of disease (reviewed in [ 7 – 10 ]). We have previously identified, among others, the key transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS) as distinct markers of prostate field cancerization [ 11 , 12 ]. Of note, growth factors and cytokines have not been previously described in the context of field cancerization.…”

Angiomotin decreases lung cancer progression by sequestering oncogenic YAP/TAZ and decreasing Cyr61 expression

“…Two representative regions of interest (defined as areas with robust immunostaining,~100 μm 2 each) per slide were chosen, and the cumulative florescence intensity specific for Dyligh 488 (green) was determined. 52 Animal model/immunohistochemical reactions The LLC cells were transplanted into C57BL/6 mice by tail vein injection. The animals were then killed on day 20 after LLC transplantation, and the LLC cells in the lungs were isolated by mincing, collagenase type I digestion and filtering.…”