TY - JOUR
T1 - Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone
AU - Kolonin, Mikhail G.
AU - Sergeeva, Anna
AU - Staquicini, Daniela I.
AU - Smith, Tracey L.
AU - Tarleton, Christy A.
AU - Molldrem, Jeffrey J.
AU - Sidman, Richard L.
AU - Marchiò, Serena
AU - Pasqualini, Renata
AU - Arap, Wadih
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a nonproteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short timeframe. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention.
AB - Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a nonproteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short timeframe. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention.
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U2 - 10.1158/0008-5472.CAN-16-0708
DO - 10.1158/0008-5472.CAN-16-0708
M3 - Article
C2 - 28428279
AN - SCOPUS:85021049351
SN - 0008-5472
VL - 77
SP - 3144
EP - 3150
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -