title: DNA damage induces GDNF secretion in the tumor microenvironment with paracrine effects promoting prostate cancer treatment resistance.
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.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Huber
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Lucas
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Gomez-Sarosi
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Coleman
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008942:Mitoxantrone / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D043823:Taxoids / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects / Q000528:radiation effects; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects
chemical_list: D000970:Antineoplastic Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D043823:Taxoids; D000077143:Docetaxel; D008942:Mitoxantrone