Inhibition of cell adhesion by a Cadherin-11 antibody thwarts bone metastasis
Journal
Molecular Cancer Research
Journal Volume
11
Journal Issue
11
Pages
1401
Date Issued
2013-11
Author(s)
YU-CHEN LEE
MEHMET ASIM BILEN
GUOYU YU
SONG-CHANG LIN
ANGELICA ORTIZ
HYOJIN CHO
JIAN H. SONG
ROBERT L. SATCHER
JIAN KUANG
GARY E. GALLICK
LI-YUAN YU-LEE
Abstract
Cadherin-11 (CDH11) is a member of the cadherin superfamily mainly expressed in osteoblasts but not in epithelial cells. However, prostate cancer cells with a propensity for bone metastasis express high levels of cadherin-11 and reduced levels of E-cadherin. Downregulation of cadherin-11 inhibits interaction of prostate cancer cells with osteoblasts in vitro and homing of prostate cancer cells to bone in an animal model of metastasis. These findings indicate that targeting cadherin-11 may prevent prostate cancer bone metastasis. To explore this possibility, a panel of 21 monoclonal antibodies (mAb) was generated against the extracellular (EC) domain of cadherin-11. Two antibodies, mAbs 2C7 and 1A5, inhibited cadherin-11-mediated cell-cell aggregation in vitro using L-cells transfected with cadherin-11. Both antibodies demonstrated specificity to cadherin-11, and neither antibody recognized E-cadherin or N-cadherin on C4-2B or PC3 cells, respectively. Furthermore, mAb 2C7 inhibited cadherin-11-mediated aggregation between the highly metastatic PC3-mm2 cells and MC3T3-E1 osteoblasts. Mechanistically, a series of deletion mutants revealed a unique motif, aa 343-348, in the cadherin-11 EC3 domain that is recognized by mAb 2C7 and that this motif coordinated cell-cell adhesion. Importantly, administration of mAb 2C7 in a prophylactic setting effectively prevented metastasis of PC3-mm2 cells to bone in an in vivo mouse model. These results show that targeting the extracellular domain of cadherin-11 can limit cellular adhesion and metastatic dissemination of prostate cancer cells. Implications: Monotherapy using a cadherin-11 antibody is a suitable option for the prevention of bone metastases. ? 2013 American Association for Cancer Research.
SDGs
Other Subjects
cadherin; cadherin 11 antibody; monoclonal antibody; nerve cell adhesion molecule; protein antibody; unclassified drug; uvomorulin; animal cell; animal experiment; animal model; antibody specificity; article; bone metastasis; cell adhesion; cell aggregation; cell invasion; cell migration; controlled study; deletion mutant; epitope mapping; genetic transfection; mouse; nonhuman; osteoblast; phenotype; priority journal; prostate cancer; protein expression; protein localization; tumor volume; Animals; Antibodies, Monoclonal; Binding Sites, Antibody; Bone Neoplasms; Cadherins; Cell Adhesion; Cell Movement; Epitope Mapping; Humans; Male; Mice; Mice, SCID; Mutation; Neoplasm Metastasis; Prostatic Neoplasms
Type
journal article