title: DNA Damage Induces a Secretory Program in the Quiescent TME that Fosters Adverse Cancer Phenotypes.
abstract: Carcinomas develop in complex environments that include a diverse spectrum of cell types that influence tumor cell behavior. These microenvironments represent dynamic systems that contribute to pathologic processes. Damage to DNA is a notable inducer of both transient and permanent alterations in cellular phenotypes. Induction of a DNA damage secretory program is known to promote adverse tumor cell behaviors such as proliferation, invasion, metastasis, and treatment resistance. However, prior studies designed to identify genotoxic stress-induced factors evaluated actively proliferatingin vitrocultures of cells such as fibroblasts as experimental models. Conversely, the vast majority of benign cells in a typical tumor microenvironment (TME) are not proliferating but rather exist in quiescent (i.e., G0) or in terminally differentiated states. In this study, the diversity and magnitude of transcriptional responses to genotoxic damage in quiescent prostate fibroblasts were assessed using gene expression profiling. The secretory damage response in quiescent cells was highly concordant with that of actively dividing cells. Quiescent human prostate stroma exposed to genotoxic agents (e.g., mitoxantrone)in vivoresulted in significant upregulation (2.7- to 5.7-fold;P≤ 0.01) of growth factors and cytokines including IL1β, MMP3, IL6, and IL8. The paracrine effects of damaged quiescent cells consistently increased the proliferation and invasion of prostate cancer cells and promoted cell survival and resistance to apoptosis following exposure to chemotherapy.Implications:Benign quiescent cells in the TME respond to genotoxic stress by inducing a secretory program capable of promoting therapy resistance. Developing approaches to suppress the secretory program may improve treatment responses.Mol Cancer Res; 15(7); 842-51. ©2017 AACR.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Luis
authors.initials: L
authors.lastname: Gomez-Sarosi
authors.affiliation: Shanghai Institutes for Biology Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Daniella
authors.initials: D
authors.lastname: Bianchi-Frias
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. pnelson@fhcrc.org.|Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D008942:Mitoxantrone / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics
chemical_list: C508606:CXCL8 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D008942:Mitoxantrone; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3