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

Abstract

Prostate field cancerization denotes molecular alterations in histologically normal tissues adjacent to tumors. Such alterations include deregulated protein expression, as we have previously shown for the key transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS). Here we add the two secreted factors macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) to the growing list of protein markers of prostate field cancerization. Expression of MIC-1 and PDGF-A was measured quantitatively by immunofluorescence and comprehensively analyzed using two methods of signal capture and several groupings of data generated in human cancerous (n = 25), histologically normal adjacent (n = 22), and disease-free (n = 6) prostate tissues. A total of 208 digitized images were analyzed. MIC-1 and PDGF-A expression in tumor tissues were elevated 7.1x to 23.4x and 1.7x to 3.7x compared to disease-free tissues, respectively (p<0.0001 to p = 0.08 and p<0.01 to p = 0.23, respectively). In support of field cancerization, MIC-1 and PDGF-A expression in adjacent tissues were elevated 7.4x to 38.4x and 1.4x to 2.7x, respectively (p<0.0001 to p<0.05 and p<0.05 to p = 0.51, respectively). Also, MIC-1 and PDGF-A expression were similar in tumor and adjacent tissues (0.3x to 1.0x; p<0.001 to p = 0.98 for MIC-1; 0.9x to 2.6x; p<0.01 to p = 1.00 for PDGF-A). All analyses indicated a high level of inter- and intra-tissue heterogeneity across all types of tissues (mean coefficient of variation of 86.0%). Our data shows that MIC-1 and PDGF-A expression is elevated in both prostate tumors and structurally intact adjacent tissues when compared to disease-free specimens, defining field cancerization. These secreted factors could promote tumorigenesis in histologically normal tissues and lead to tumor multifocality. Among several clinical applications, they could also be exploited as indicators of disease in false negative biopsies, identify areas of repeat biopsy, and add molecular information to surgical margins.

miRNA-186 inhibits prostate cancer cell proliferation and tumor growth by targeting YY1 and CDK6

“…The majority of these candidates are irregularly expressed in PCa compared with normal tissue or related to cell proliferation (15–17). Next, RT-qPCR was used to detect the expression of these target genes in PC-3/pCDH or PC-3/miR-186.…”

Comparison of quantitative apparent diffusion coefficient parameters with prostate imaging reporting and data system V2 assessment for detection of clinically significant peripheral zone prostate cancer

“…in areas where no visible tumor by mpMRI) are significantly different in those patients with pathologically confirmed aggressive PC elsewhere in the prostate compared to those with less aggressive tumors, has not been previously reported. We speculate that these findings may be due to field cancerization, a known phenomenon in the histopathology literature, and currently being evaluated in the prostate [36]. …”

MicroRNA-375 inhibits oral squamous cell carcinoma cell migration and invasion by targeting platelet-derived growth factor-A

“…PDGF-A serves a key role in the regulation of multiple biological functions, including vascularization, cell migration and invasion, and tumor development. Emerging evidence implicates PDGF-A as a potential prognostic marker, independent of the traditional pathologic parameters (19,20). The promoter of this gene is a potential target for an efficient and selective antineoplastic gene therapy in multiple cancer types, including breast cancer and osteosarcoma (21,22); however, the biological functions of PDGF-A in OSCC remain to be determined.…”