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Prostate field cancerization: deregulated expression of macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) in tumor adjacent tissue.

Jones AC, Antillon KS, Jenkins SM, Janos SN, Overton HN, Shoshan DS, Fischer EG, Trujillo KA, Bisoffi M - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: University of New Mexico Health Sciences Center, Department of Biochemistry and Molecular Biology, Albuquerque, New Mexico, United States of America.

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.

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Quantitative immunofluorescence of PDGF-A in human prostate tissues.(A-D) PDGF-A expression levels (indicated as signal intensities [pixel count]) in disease-free, tumor adjacent, and tumor tissues; the types of analysis were the following (as per Materials and Methods): (A and B) Whole slide analysis (WSA) for values above (A) and below (B) the median of the values of all cases in the UNMH/CHTN cohort; (C and D) region of interest (ROI) analysis for values above (A) and below (B) the median of the values of all cases in the UNMH/CHTN cohort. Individual data points are shown as small black squares (partially overlapping); the boxes represent group medians (line across middle) and quartiles (25th and 75th percentiles) at its ends; lines above and below boxes indicate 10th and 90th percentiles, respectively. For each analysis, the number of images and cases is indicated; p values above the panels denote the level of statistical significance for the differences between groups, as calculated by the student’s t-test (p(t)) and by the Wilcoxon rank sums test (p(WRS)).
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pone.0119314.g004: Quantitative immunofluorescence of PDGF-A in human prostate tissues.(A-D) PDGF-A expression levels (indicated as signal intensities [pixel count]) in disease-free, tumor adjacent, and tumor tissues; the types of analysis were the following (as per Materials and Methods): (A and B) Whole slide analysis (WSA) for values above (A) and below (B) the median of the values of all cases in the UNMH/CHTN cohort; (C and D) region of interest (ROI) analysis for values above (A) and below (B) the median of the values of all cases in the UNMH/CHTN cohort. Individual data points are shown as small black squares (partially overlapping); the boxes represent group medians (line across middle) and quartiles (25th and 75th percentiles) at its ends; lines above and below boxes indicate 10th and 90th percentiles, respectively. For each analysis, the number of images and cases is indicated; p values above the panels denote the level of statistical significance for the differences between groups, as calculated by the student’s t-test (p(t)) and by the Wilcoxon rank sums test (p(WRS)).

Mentions: 1 Ratio is based on the mean of all pixel intensities (expression) in the indicated group. The number of images utilized to calculate the ratio and the difference in expression are partially indicated in Table 1 and Figs. 2 and 4.


Prostate field cancerization: deregulated expression of macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) in tumor adjacent tissue.

Jones AC, Antillon KS, Jenkins SM, Janos SN, Overton HN, Shoshan DS, Fischer EG, Trujillo KA, Bisoffi M - PLoS ONE (2015)

Quantitative immunofluorescence of PDGF-A in human prostate tissues.(A-D) PDGF-A expression levels (indicated as signal intensities [pixel count]) in disease-free, tumor adjacent, and tumor tissues; the types of analysis were the following (as per Materials and Methods): (A and B) Whole slide analysis (WSA) for values above (A) and below (B) the median of the values of all cases in the UNMH/CHTN cohort; (C and D) region of interest (ROI) analysis for values above (A) and below (B) the median of the values of all cases in the UNMH/CHTN cohort. Individual data points are shown as small black squares (partially overlapping); the boxes represent group medians (line across middle) and quartiles (25th and 75th percentiles) at its ends; lines above and below boxes indicate 10th and 90th percentiles, respectively. For each analysis, the number of images and cases is indicated; p values above the panels denote the level of statistical significance for the differences between groups, as calculated by the student’s t-test (p(t)) and by the Wilcoxon rank sums test (p(WRS)).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358924&req=5

pone.0119314.g004: Quantitative immunofluorescence of PDGF-A in human prostate tissues.(A-D) PDGF-A expression levels (indicated as signal intensities [pixel count]) in disease-free, tumor adjacent, and tumor tissues; the types of analysis were the following (as per Materials and Methods): (A and B) Whole slide analysis (WSA) for values above (A) and below (B) the median of the values of all cases in the UNMH/CHTN cohort; (C and D) region of interest (ROI) analysis for values above (A) and below (B) the median of the values of all cases in the UNMH/CHTN cohort. Individual data points are shown as small black squares (partially overlapping); the boxes represent group medians (line across middle) and quartiles (25th and 75th percentiles) at its ends; lines above and below boxes indicate 10th and 90th percentiles, respectively. For each analysis, the number of images and cases is indicated; p values above the panels denote the level of statistical significance for the differences between groups, as calculated by the student’s t-test (p(t)) and by the Wilcoxon rank sums test (p(WRS)).
Mentions: 1 Ratio is based on the mean of all pixel intensities (expression) in the indicated group. The number of images utilized to calculate the ratio and the difference in expression are partially indicated in Table 1 and Figs. 2 and 4.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: University of New Mexico Health Sciences Center, Department of Biochemistry and Molecular Biology, Albuquerque, New Mexico, United States of America.

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.

Show MeSH
Related in: MedlinePlus