COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis.

Autor:	Zheng Y; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Comaills V; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Burr R; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Boulay G; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Miyamoto DT; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Wittner BS; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Emmons E; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Sil S; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Koulopoulos MW; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Broderick KT; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Tai E; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Rengarajan S; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Kulkarni AS; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Shioda T; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Wu CL; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Ramaswamy S; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129., Ting DT; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Toner M; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.; Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospital for Children, Boston, MA 02114., Rivera MN; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Maheswaran S; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114., Haber DA; Massachusetts General Hospital Cancer Center,Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129; dhaber@mgh.harvard.edu.; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.; Howard Hughes Medical Institute, Chevy Chase, MD 20815.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Mar 19; Vol. 116 (12), pp. 5223-5232. Date of Electronic Publication: 2019 Feb 28.
DOI:	10.1073/pnas.1819303116
Abstrakt:	Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression. Competing Interests: Conflict of interest statement: Massachusetts General Hospital has filed for patent protection for the circulating tumor cell inertial focusing (iChip) technology. (Copyright © 2019 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu