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DNA damage induces GDNF secretion in the tumor microenvironment with paracrine effects promoting prostate cancer treatment resistance.

Huber RM, Lucas JM, Gomez-Sarosi LA, Coleman I, Zhao S, Coleman R, Nelson PS - Oncotarget (2015)

Bottom Line: Though metastatic cancers often initially respond to genotoxic therapeutics, acquired resistance is common.In studies designed to characterize the responses of prostate and bone stromal cells to genotoxic stress, we found that transcripts encoding glial cell line-derived neurotrophic factor (GDNF) increased several fold following exposures to cytotoxic agents including radiation, the topoisomerase inhibitor mitoxantrone and the microtubule poison docetaxel.Fibroblast GDNF exerted paracrine effects toward prostate cancer cells resulting in enhanced tumor cell proliferation and invasion, and these effects were concordant with the expression of known GDNF receptors GFRA1 and RET.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

ABSTRACT
Though metastatic cancers often initially respond to genotoxic therapeutics, acquired resistance is common. In addition to cytotoxic effects on tumor cells, DNA damaging agents such as ionizing radiation and chemotherapy induce injury in benign cells of the tumor microenvironment resulting in the production of paracrine-acting factors capable of promoting tumor resistance phenotypes. In studies designed to characterize the responses of prostate and bone stromal cells to genotoxic stress, we found that transcripts encoding glial cell line-derived neurotrophic factor (GDNF) increased several fold following exposures to cytotoxic agents including radiation, the topoisomerase inhibitor mitoxantrone and the microtubule poison docetaxel. Fibroblast GDNF exerted paracrine effects toward prostate cancer cells resulting in enhanced tumor cell proliferation and invasion, and these effects were concordant with the expression of known GDNF receptors GFRA1 and RET. Exposure to GDNF also induced tumor cell resistance to mitoxantrone and docetaxel chemotherapy. Together, these findings support an important role for tumor microenvironment damage responses in modulating treatment resistance and identify the GDNF signaling pathway as a potential target for improving responses to conventional genotoxic therapeutics.

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GDNF induces gene expression changes via the activation of transcription factor networksHeat map profiles of gene expression changes upon GDNF stimulation in (A) epithelial and stromal prostate cancer cells, (B) in M12 epithelial cells alone, and (C) in PSC27 PPFs alone. (D) Activation scores for transcription factor target gene groups after GDNF stimulation in PSC27 (black) and M12 (blue) cells. (E) Activation scores for RB, E2F1 and AR target gene groups after GDNF stimulation in epithelial CaP cells. (F) Gene expression changes of known E2F1 and AR target genes with enhancer modules regulated by GDNF stimulation.
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Figure 6: GDNF induces gene expression changes via the activation of transcription factor networksHeat map profiles of gene expression changes upon GDNF stimulation in (A) epithelial and stromal prostate cancer cells, (B) in M12 epithelial cells alone, and (C) in PSC27 PPFs alone. (D) Activation scores for transcription factor target gene groups after GDNF stimulation in PSC27 (black) and M12 (blue) cells. (E) Activation scores for RB, E2F1 and AR target gene groups after GDNF stimulation in epithelial CaP cells. (F) Gene expression changes of known E2F1 and AR target genes with enhancer modules regulated by GDNF stimulation.

Mentions: GDNF produced substantial changes in the phenotypes of both prostate epithelial and stromal cells. GDNF is known to regulate cellular behavior across a spectrum of tissues by indirectly influencing gene expression [8, 24, 25]. To identify the gene expression programs influenced by GDNF we used whole-genome microarrays to quantitate transcript abundance levels before and after GDNF exposure. We isolated RNA from M12 prostate epithelial cells and PSC27 prostate fibroblasts stimulated with 100 ng/ml hrGDNF for 48h in chemically defined culture medium. In M12 cells, 763 transcripts increased and 291 decreased following exposure to GDNF (FDR q≤0.01). In PSC27 fibroblasts, 735 transcripts increased and 383 decreased (FDR q≤0.01). Comparisons across the two cell lines identified 95 up-regulated and 25 down-regulated genes common to both gene sets (FDR q≤0.01). We performed unsupervised sample clustering based on these expression profiles. The primary attribute driving the sample grouping was cell type (Fig 6A) followed by absence (control) or presence of GDNF stimulation (Fig 6B, C) in both cell lines.


DNA damage induces GDNF secretion in the tumor microenvironment with paracrine effects promoting prostate cancer treatment resistance.

Huber RM, Lucas JM, Gomez-Sarosi LA, Coleman I, Zhao S, Coleman R, Nelson PS - Oncotarget (2015)

GDNF induces gene expression changes via the activation of transcription factor networksHeat map profiles of gene expression changes upon GDNF stimulation in (A) epithelial and stromal prostate cancer cells, (B) in M12 epithelial cells alone, and (C) in PSC27 PPFs alone. (D) Activation scores for transcription factor target gene groups after GDNF stimulation in PSC27 (black) and M12 (blue) cells. (E) Activation scores for RB, E2F1 and AR target gene groups after GDNF stimulation in epithelial CaP cells. (F) Gene expression changes of known E2F1 and AR target genes with enhancer modules regulated by GDNF stimulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385841&req=5

Figure 6: GDNF induces gene expression changes via the activation of transcription factor networksHeat map profiles of gene expression changes upon GDNF stimulation in (A) epithelial and stromal prostate cancer cells, (B) in M12 epithelial cells alone, and (C) in PSC27 PPFs alone. (D) Activation scores for transcription factor target gene groups after GDNF stimulation in PSC27 (black) and M12 (blue) cells. (E) Activation scores for RB, E2F1 and AR target gene groups after GDNF stimulation in epithelial CaP cells. (F) Gene expression changes of known E2F1 and AR target genes with enhancer modules regulated by GDNF stimulation.
Mentions: GDNF produced substantial changes in the phenotypes of both prostate epithelial and stromal cells. GDNF is known to regulate cellular behavior across a spectrum of tissues by indirectly influencing gene expression [8, 24, 25]. To identify the gene expression programs influenced by GDNF we used whole-genome microarrays to quantitate transcript abundance levels before and after GDNF exposure. We isolated RNA from M12 prostate epithelial cells and PSC27 prostate fibroblasts stimulated with 100 ng/ml hrGDNF for 48h in chemically defined culture medium. In M12 cells, 763 transcripts increased and 291 decreased following exposure to GDNF (FDR q≤0.01). In PSC27 fibroblasts, 735 transcripts increased and 383 decreased (FDR q≤0.01). Comparisons across the two cell lines identified 95 up-regulated and 25 down-regulated genes common to both gene sets (FDR q≤0.01). We performed unsupervised sample clustering based on these expression profiles. The primary attribute driving the sample grouping was cell type (Fig 6A) followed by absence (control) or presence of GDNF stimulation (Fig 6B, C) in both cell lines.

Bottom Line: Though metastatic cancers often initially respond to genotoxic therapeutics, acquired resistance is common.In studies designed to characterize the responses of prostate and bone stromal cells to genotoxic stress, we found that transcripts encoding glial cell line-derived neurotrophic factor (GDNF) increased several fold following exposures to cytotoxic agents including radiation, the topoisomerase inhibitor mitoxantrone and the microtubule poison docetaxel.Fibroblast GDNF exerted paracrine effects toward prostate cancer cells resulting in enhanced tumor cell proliferation and invasion, and these effects were concordant with the expression of known GDNF receptors GFRA1 and RET.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

ABSTRACT
Though metastatic cancers often initially respond to genotoxic therapeutics, acquired resistance is common. In addition to cytotoxic effects on tumor cells, DNA damaging agents such as ionizing radiation and chemotherapy induce injury in benign cells of the tumor microenvironment resulting in the production of paracrine-acting factors capable of promoting tumor resistance phenotypes. In studies designed to characterize the responses of prostate and bone stromal cells to genotoxic stress, we found that transcripts encoding glial cell line-derived neurotrophic factor (GDNF) increased several fold following exposures to cytotoxic agents including radiation, the topoisomerase inhibitor mitoxantrone and the microtubule poison docetaxel. Fibroblast GDNF exerted paracrine effects toward prostate cancer cells resulting in enhanced tumor cell proliferation and invasion, and these effects were concordant with the expression of known GDNF receptors GFRA1 and RET. Exposure to GDNF also induced tumor cell resistance to mitoxantrone and docetaxel chemotherapy. Together, these findings support an important role for tumor microenvironment damage responses in modulating treatment resistance and identify the GDNF signaling pathway as a potential target for improving responses to conventional genotoxic therapeutics.

Show MeSH
Related in: MedlinePlus