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Osteoprotegerin in bone metastases: mathematical solution to the puzzle.

Ryser MD, Qu Y, Komarova SV - PLoS Comput. Biol. (2012)

Bottom Line: Consistently, systemic application of OPG decreases metastatic tumor burden in bone.However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth.The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics and Statistics, McGill University, Montréal, Québec, Canada.

ABSTRACT
Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

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OPG, RANKL and PTHrP expression in prostate cancer.Data from nine gene expression data sets [47]–[55] were combined and analyzed. A–C Expression of OPG (A), RANKL (B) and PTHrP (C) are shown in the box-plots where the lower whisker indicates the 1st percentile, the limits of the box indicate the 25th and 75th percentiles, and the upper whisker indicates the 99th percentile. Statistical significance is indicated by , , calculated using one-way ANOVA. D–F Data for the metastatic prostate samples were analyzed for the correlation in the expression of OPG and PTHrP (D), OPG and RANKL (E), and RANKL and PTHrP (F).
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pcbi-1002703-g009: OPG, RANKL and PTHrP expression in prostate cancer.Data from nine gene expression data sets [47]–[55] were combined and analyzed. A–C Expression of OPG (A), RANKL (B) and PTHrP (C) are shown in the box-plots where the lower whisker indicates the 1st percentile, the limits of the box indicate the 25th and 75th percentiles, and the upper whisker indicates the 99th percentile. Statistical significance is indicated by , , calculated using one-way ANOVA. D–F Data for the metastatic prostate samples were analyzed for the correlation in the expression of OPG and PTHrP (D), OPG and RANKL (E), and RANKL and PTHrP (F).

Mentions: We examined the expression of OPG, RANKL, and PTHrP in patient samples from normal prostate tissue, prostate carcinoma, and metastatic prostate carcinoma tissues, as reported in the studies [47]–[55]. We used the publicly available gene expression data analysis engine Oncomine Research Edition (www.oncomine.org), and processed data as described in Text S2 for details. We found that expression of osteoprotegerin was significantly increased in samples from metastatic prostate cancer compared to normal prostate (), as well as prostate carcinoma () (Figure 9-A). In contrast, expression of RANKL and PTHrP did not exhibit significant changes (Figures 9-B and 9-C).


Osteoprotegerin in bone metastases: mathematical solution to the puzzle.

Ryser MD, Qu Y, Komarova SV - PLoS Comput. Biol. (2012)

OPG, RANKL and PTHrP expression in prostate cancer.Data from nine gene expression data sets [47]–[55] were combined and analyzed. A–C Expression of OPG (A), RANKL (B) and PTHrP (C) are shown in the box-plots where the lower whisker indicates the 1st percentile, the limits of the box indicate the 25th and 75th percentiles, and the upper whisker indicates the 99th percentile. Statistical significance is indicated by , , calculated using one-way ANOVA. D–F Data for the metastatic prostate samples were analyzed for the correlation in the expression of OPG and PTHrP (D), OPG and RANKL (E), and RANKL and PTHrP (F).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475686&req=5

pcbi-1002703-g009: OPG, RANKL and PTHrP expression in prostate cancer.Data from nine gene expression data sets [47]–[55] were combined and analyzed. A–C Expression of OPG (A), RANKL (B) and PTHrP (C) are shown in the box-plots where the lower whisker indicates the 1st percentile, the limits of the box indicate the 25th and 75th percentiles, and the upper whisker indicates the 99th percentile. Statistical significance is indicated by , , calculated using one-way ANOVA. D–F Data for the metastatic prostate samples were analyzed for the correlation in the expression of OPG and PTHrP (D), OPG and RANKL (E), and RANKL and PTHrP (F).
Mentions: We examined the expression of OPG, RANKL, and PTHrP in patient samples from normal prostate tissue, prostate carcinoma, and metastatic prostate carcinoma tissues, as reported in the studies [47]–[55]. We used the publicly available gene expression data analysis engine Oncomine Research Edition (www.oncomine.org), and processed data as described in Text S2 for details. We found that expression of osteoprotegerin was significantly increased in samples from metastatic prostate cancer compared to normal prostate (), as well as prostate carcinoma () (Figure 9-A). In contrast, expression of RANKL and PTHrP did not exhibit significant changes (Figures 9-B and 9-C).

Bottom Line: Consistently, systemic application of OPG decreases metastatic tumor burden in bone.However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth.The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics and Statistics, McGill University, Montréal, Québec, Canada.

ABSTRACT
Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

Show MeSH
Related in: MedlinePlus