Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth.
In the tumor microenvironment, CD11b(+)Gr1(+) bone marrow-derived cells are a predominant source of protumorigenic factors such as matrix metalloproteinases (MMP), but how distal tumors regulate these cells in the bone marrow is unclear. Here we addressed the hypothesis that the parathyroid hormone-related protein (PTHrP) potentiates CD11b(+)Gr1(+) cells in the bone marrow of prostate tumor hosts. In two xenograft models of prostate cancer, levels of tumor-derived PTHrP correlated with CD11b(+)Gr1(+) cell recruitment and microvessel density in the tumor tissue, with evidence for mediation of CD11b(+)Gr1(+) cell-derived MMP-9 but not tumor-derived VEGF-A. CD11b(+)Gr1(+) cells isolated from mice with PTHrP-overexpressing tumors exhibited relatively increased proangiogenic potential, suggesting that prostate tumor-derived PTHrP potentiates this activity of CD11b(+)Gr1(+) cells. Administration of neutralizing PTHrP monoclonal antibody reduced CD11b(+)Gr1(+) cells and MMP-9 in the tumors. Mechanistic investigations in vivo revealed that PTHrP elevated Y418 phosphorylation levels in Src family kinases in CD11b(+)Gr1(+) cells via osteoblast-derived interleukin-6 and VEGF-A, thereby upregulating MMP-9. Taken together, our results showed that prostate cancer-derived PTHrP acts in the bone marrow to potentiate CD11b(+)Gr1(+) cells, which are recruited to tumor tissue where they contribute to tumor angiogenesis and growth.
Authors' Affiliations: Departments of Medicine and Cancer Biology; Center for Bone Biology; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry; Comprehensive Cancer Center Biostatistics Core; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
Serk In
SI
Park
Changki
C
Lee
W David
WD
Sadler
Amy J
AJ
Koh
Jacqueline
J
Jones
Jung Won
JW
Seo
Fabiana N
FN
Soki
Sun Wook
SW
Cho
Stephanie D
SD
Daignault
Laurie K
LK
McCauley
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology*; D039481:CD11b Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004285:Dogs; D025461:Feedback, Physiological / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D044162:Parathyroid Hormone-Related Protein / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D059016:Tumor Microenvironment / Q000502:physiology
D000954:Antigens, Surface; D039481:CD11b Antigen; D044162:Parathyroid Hormone-Related Protein