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.
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