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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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MIC-1 (A-C) and PDGF-A (D-F) detection in human prostate tissues (UNMH/CHTN cohort).Representative cases of prostate tumors (A and D) and adjacent tissues (B and E), as well as cases of disease-free control tissues unrelated to cancer (C and F) are shown; pictures represent overlays of nuclear staining by DAPI (blue) and Alexa Fluor 633 immunostaining (yellow/white); the insets are Alexa Fluor 633 immunostaining only; white bars represent 10 micrometers. The diamonds, closed arrows, and open arrows in B and E denote a typical lumen, epithelial cell compartment, and stromal cell compartment, respectively.
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pone.0119314.g001: MIC-1 (A-C) and PDGF-A (D-F) detection in human prostate tissues (UNMH/CHTN cohort).Representative cases of prostate tumors (A and D) and adjacent tissues (B and E), as well as cases of disease-free control tissues unrelated to cancer (C and F) are shown; pictures represent overlays of nuclear staining by DAPI (blue) and Alexa Fluor 633 immunostaining (yellow/white); the insets are Alexa Fluor 633 immunostaining only; white bars represent 10 micrometers. The diamonds, closed arrows, and open arrows in B and E denote a typical lumen, epithelial cell compartment, and stromal cell compartment, respectively.

Mentions: Upon ensuring that unspecific control IgG antibodies did not generate any measurable fluorescence, all immunostainings with specific primary antibodies were performed under identical conditions. Figs. 1A-C show representative immunostainings for MIC-1 in tumor (cancerous), tumor adjacent, and disease-free tissues, respectively. Visual inspection indicated that typically, MIC-1 expression, was similar in tumor and adjacent tissues, as well as elevated compared to disease-free prostate tissues from individuals without cancer. Although a preferential staining in epithelial compartments was observed, the staining was diffuse in appearance, seemingly both intra- and extra-cellular in nature, which is in accordance with MIC-1 being a secreted cytokine [13,14] (Figs. 1A and B). Very little, if any, MIC-1 immunostaining was observed in disease-free prostate tissues from autopsies unrelated to cancer (Fig. 1C). Likewise, immunostaining for PDGF-A was similar in tumor and adjacent tissues (Figs. 1D and E), elevated compared to disease-free tissues (Fig. 1F), and predominantly epithelial but diffuse, in agreement with a secreted growth factor [15].


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)

MIC-1 (A-C) and PDGF-A (D-F) detection in human prostate tissues (UNMH/CHTN cohort).Representative cases of prostate tumors (A and D) and adjacent tissues (B and E), as well as cases of disease-free control tissues unrelated to cancer (C and F) are shown; pictures represent overlays of nuclear staining by DAPI (blue) and Alexa Fluor 633 immunostaining (yellow/white); the insets are Alexa Fluor 633 immunostaining only; white bars represent 10 micrometers. The diamonds, closed arrows, and open arrows in B and E denote a typical lumen, epithelial cell compartment, and stromal cell compartment, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119314.g001: MIC-1 (A-C) and PDGF-A (D-F) detection in human prostate tissues (UNMH/CHTN cohort).Representative cases of prostate tumors (A and D) and adjacent tissues (B and E), as well as cases of disease-free control tissues unrelated to cancer (C and F) are shown; pictures represent overlays of nuclear staining by DAPI (blue) and Alexa Fluor 633 immunostaining (yellow/white); the insets are Alexa Fluor 633 immunostaining only; white bars represent 10 micrometers. The diamonds, closed arrows, and open arrows in B and E denote a typical lumen, epithelial cell compartment, and stromal cell compartment, respectively.
Mentions: Upon ensuring that unspecific control IgG antibodies did not generate any measurable fluorescence, all immunostainings with specific primary antibodies were performed under identical conditions. Figs. 1A-C show representative immunostainings for MIC-1 in tumor (cancerous), tumor adjacent, and disease-free tissues, respectively. Visual inspection indicated that typically, MIC-1 expression, was similar in tumor and adjacent tissues, as well as elevated compared to disease-free prostate tissues from individuals without cancer. Although a preferential staining in epithelial compartments was observed, the staining was diffuse in appearance, seemingly both intra- and extra-cellular in nature, which is in accordance with MIC-1 being a secreted cytokine [13,14] (Figs. 1A and B). Very little, if any, MIC-1 immunostaining was observed in disease-free prostate tissues from autopsies unrelated to cancer (Fig. 1C). Likewise, immunostaining for PDGF-A was similar in tumor and adjacent tissues (Figs. 1D and E), elevated compared to disease-free tissues (Fig. 1F), and predominantly epithelial but diffuse, in agreement with a secreted growth factor [15].

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