In patients with
multiple myeloma, the
heparan sulfate proteoglycan syndecan-1 (CD138) is shed from the surface of
tumor cells and accumulates in the serum and within the extracellular matrix of the bone marrow where it promotes
tumor growth and
metastasis. In the present study we discovered that commonly used anti-myeloma drugs stimulate
syndecan-1 shedding both in vitro and in animals bearing myeloma
tumors. Enhanced shedding is accompanied by increased
syndecan-1 synthesis prior to
drug induced
tumor cell death. Addition of a
caspase inhibitor blocks the
drug-induced shedding of
syndecan-1 in vitro indicating that shedding is linked to the onset of apoptosis. ADAM inhibitors or
siRNA targeting ADAMs blocked
drug-induced shedding suggesting that upregulation or activation of ADAMs is responsible for cleaving
syndecan-1 from the
tumor cell surface. These results reveal that myeloma
chemotherapy stimulates synthesis and shedding of
syndecan-1, a potentially negative side effect that may lead to the accumulation of high levels of
syndecan-1 to establish a microenvironment that nurtures relapse and promotes
tumor progression. Interestingly, we also found that chemotherapeutic drugs stimulated
syndecan-1 shedding from
pancreatic cancer cells as well, indicating that
drug-induced shedding of
syndecan-1 may occur in many
cancer types. Overall, our results indicate that the use of
metalloproteinase inhibitors (to inhibit
syndecan-1 shedding) in combination with
chemotherapy may represent a novel therapeutic strategy to prevent re-establishment of a microenvironment conducive for
tumor relapse.