PMID- 27742687
OWN - NLM
STAT- MEDLINE
DCOM- 20170724
LR  - 20180411
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 77
IP  - 2
DP  - 2017 Jan 15
TI  - Lysyl Oxidase Is a Strong Determinant of Tumor Cell Colonization in Bone.
PG  - 268-278
LID - 10.1158/0008-5472.CAN-15-2621 [doi]
AB  - Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase whose primary 
      function is to drive collagen crosslinking and extracellular matrix stiffness. 
      LOX in colorectal cancer synergizes with hypoxia-inducible factor-1 (HIF-1) to 
      promote tumor progression. Here we investigated whether LOX/HIF1 endows 
      colorectal cancer cells with full competence for aggressive colonization in bone. 
      We show that a high LOX expression in primary tumors from patients with 
      colorectal cancer was associated with poor clinical outcome, irrespective of 
      HIF-1 In addition, LOX was expressed by tumor cells in the bone marrow from 
      colorectal cancer patients with bone metastases. In vivo experimental studies 
      show that LOX overexpression in colorectal cancer cells or systemic delivery of 
      the conditioned medium from LOX-overexpressing colorectal cancer cells promoted 
      tumor cell dissemination in the bone marrow and enhanced osteolytic lesion 
      formation, irrespective of HIF-1 Conversely, silencing or pharmacologic 
      inhibition of LOX activity blocked dissemination of colorectal cancer cells in 
      the bone marrow and tumor-driven osteolytic lesion formation. In vitro, 
      tumor-secreted LOX supported the attachment and survival of colorectal cancer 
      cells to and in the bone matrix, and inhibited osteoblast differentiation. LOX 
      overexpression in colorectal cancer cells also induced a robust production of 
      IL6. In turn, both LOX and IL6 were acting in concert to promote RANKL-dependent 
      osteoclast differentiation, thereby creating an imbalance between bone resorption 
      and bone formation. Collectively, our findings show that LOX supports colorectal 
      cancer cell dissemination in the bone marrow and they reveal a novel mechanism 
      through which LOX-driven IL6 production by colorectal cancer cells impairs bone 
      homeostasis. Cancer Res; 77(2); 268-78. (c)2016 AACR.
CI  - (c)2016 American Association for Cancer Research.
FAU - Reynaud, Caroline
AU  - Reynaud C
AD  - INSERM, UMR1033, Lyon, France. philippe.clezardin@inserm.fr 
      caroline.reynaud@inserm.fr.
AD  - University of Lyon, Villeurbanne, France.
FAU - Ferreras, Laura
AU  - Ferreras L
AD  - INSERM, UMR1033, Lyon, France.
AD  - University of Lyon, Villeurbanne, France.
FAU - Di Mauro, Paola
AU  - Di Mauro P
AD  - INSERM, UMR1033, Lyon, France.
AD  - University of Lyon, Villeurbanne, France.
FAU - Kan, Casina
AU  - Kan C
AD  - INSERM, UMR1033, Lyon, France.
AD  - University of Lyon, Villeurbanne, France.
FAU - Croset, Martine
AU  - Croset M
AD  - INSERM, UMR1033, Lyon, France.
AD  - University of Lyon, Villeurbanne, France.
FAU - Bonnelye, Edith
AU  - Bonnelye E
AD  - INSERM, UMR1033, Lyon, France.
AD  - University of Lyon, Villeurbanne, France.
FAU - Pez, Floriane
AU  - Pez F
AD  - CNRS, UMR5305, IBCP, Lyon, France.
FAU - Thomas, Clemence
AU  - Thomas C
AD  - Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 
      Massachusetts.
FAU - Aimond, Geraldine
AU  - Aimond G
AD  - CNRS, UMR5305, IBCP, Lyon, France.
FAU - Karnoub, Antoine E
AU  - Karnoub AE
AD  - Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 
      Massachusetts.
FAU - Brevet, Marie
AU  - Brevet M
AD  - INSERM, UMR1033, Lyon, France.
AD  - Department of Pathology, Groupement Hospitalier Est, Hospices Civils de Lyon, 
      Lyon, France.
FAU - Clezardin, Philippe
AU  - Clezardin P
AD  - INSERM, UMR1033, Lyon, France. philippe.clezardin@inserm.fr 
      caroline.reynaud@inserm.fr.
AD  - University of Lyon, Villeurbanne, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20161014
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Interleukin-6)
RN  - EC 1.4.3.13 (Protein-Lysine 6-Oxidase)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Bone Neoplasms/*secondary
MH  - Bone and Bones/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Colorectal Neoplasms/*enzymology/*secondary
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Heterografts
MH  - Humans
MH  - Immunohistochemistry
MH  - Interleukin-6/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Neoplasm Invasiveness/*pathology
MH  - Protein-Lysine 6-Oxidase/*metabolism
MH  - Real-Time Polymerase Chain Reaction
EDAT- 2016/10/16 06:00
MHDA- 2017/07/25 06:00
CRDT- 2016/10/16 06:00
PHST- 2015/09/22 00:00 [received]
PHST- 2016/09/28 00:00 [revised]
PHST- 2016/09/30 00:00 [accepted]
PHST- 2016/10/16 06:00 [pubmed]
PHST- 2017/07/25 06:00 [medline]
PHST- 2016/10/16 06:00 [entrez]
AID - 0008-5472.CAN-15-2621 [pii]
AID - 10.1158/0008-5472.CAN-15-2621 [doi]
PST - ppublish
SO  - Cancer Res. 2017 Jan 15;77(2):268-278. doi: 10.1158/0008-5472.CAN-15-2621. Epub 
      2016 Oct 14.