CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy.
Growing evidence suggests that tumor-associated macrophages (TAM) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix-remodeling, and immunosuppression. In this study, prostate cancer under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to prostate cancer disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF1 or CSF1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF1 signaling through its receptor, CSF1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared with ABT alone.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Jemima
J
Escamilla
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Shiruyeh
S
Schokrpur
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Connie
C
Liu
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, California.
Saul J
SJ
Priceman
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Diana
D
Moughon
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Ziyue
Z
Jiang
Department of Surgery, Urology Division, Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada.
Frederic
F
Pouliot
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Clara
C
Magyar
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
James L
JL
Sung
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Jingying
J
Xu
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California.
Gang
G
Deng
Plexxikon Inc., Berkeley, California.
Brian L
BL
West
Plexxikon Inc., Berkeley, California.
Gideon
G
Bollag
Department of Surgery, Urology Division, Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada.
Yves
Y
Fradet
Department of Surgery, Urology Division, Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada.
Louis
L
Lacombe
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California.
Michael E
ME
Jung
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Jiaoti
J
Huang
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. lwu@mednet.ucla.edu.
Lily
L
Wu
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D063646:Carcinogenesis; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*
D000726:Androgen Antagonists; D016186:Receptor, Macrophage Colony-Stimulating Factor