Thrombin-processed Ecrg4 recruits myeloid cells and induces antitumorigenic inflammation.
BACKGROUND
Extensive infiltration of brain tumors by microglia and macrophages is a hallmark of tumor progression, and yet the overall tumor microenvironment is characterized by an immunosuppressive phenotype. Here we identify esophageal cancer-related gene 4 (Ecrg4) as a novel thrombin-processed monocyte chemoattractant that recruits myeloid cells, promotes their activation, and leads to a blockade of tumor progression.


METHODS
Both xenograft glioma and syngeneic glioma models were used to measure orthotopic tumor progression and overall survival. Flow cytometry and immunohistochemical analyses were performed to assess myeloid cell localization, recruitment, and activation.


RESULTS
Ecrg4 promotes monocyte recruitment and activation of microglia in a T-/B-cell-independent mechanism, which leads to a reduction in glioma tumor burden and increased survival. Mutational analysis reveals that the biological activity of Ecrg4 is dependent on a thrombin-processing site at the C-terminus, inducing monocyte invasion in vivo and in vitro. Furthermore, tumor-induced myeloid cell recruitment is impaired in Ecrg4 knockout mice, leading to increased tumor burden and decreased survival.


CONCLUSIONS
Together, these results identify Ecrg4 as a paracrine factor that activates microglia and is chemotactic for monocytes, with potential as an antitumor therapeutic.
Department of Surgery, University of California San Diego School of Medicine, San Diego, California (J.L., X.D., A.B., R.C., A.B., B.P.E.).
Jisook
J
Lee
Department of Surgery, University of California San Diego School of Medicine, San Diego, California (J.L., X.D., A.B., R.C., A.B., B.P.E.).
Xitong
X
Dang
Department of Surgery, University of California San Diego School of Medicine, San Diego, California (J.L., X.D., A.B., R.C., A.B., B.P.E.).
Alexandra
A
Borboa
Department of Surgery, University of California San Diego School of Medicine, San Diego, California (J.L., X.D., A.B., R.C., A.B., B.P.E.).
Raul
R
Coimbra
Department of Surgery, University of California San Diego School of Medicine, San Diego, California (J.L., X.D., A.B., R.C., A.B., B.P.E.).
Andrew
A
Baird
Department of Surgery, University of California San Diego School of Medicine, San Diego, California (J.L., X.D., A.B., R.C., A.B., B.P.E.).
Brian P
BP
Eliceiri
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D005910:Glioma / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis; D013917:Thrombin / Q000378:metabolism*; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins
C476999:ECRG4 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D013917:Thrombin
Ecrg4; glioma; macrophage; microglia; monocyte