Chemotherapy stimulates syndecan-1 shedding: A potentially negative effect of treatment that may promote tumor relapse

Abstract

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. ADAMs inhibitors or siRNA targeting ADAMs blocked drug-induced shedding suggesting that up regulation 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 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 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.

Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype

“…We recently demonstrated that chemotherapy elevates shedding of syndecan-1 in myeloma [16]. Because heparanase (HPSE) is known to enhance syndecan-1 shedding, we investigated whether chemotherapy was inducing heparanase expression.…”

“…In addition, chemotherapy often has undesirable side effects and in some cases chemotherapy has been shown to actually lead to enhanced tumor growth and resistance [14, 15]. We recently demonstrated that chemotherapy induces syndecan-1 shedding from tumor cells [16]. We also recently demonstrated that in myeloma patients, tumor cells that survive past chemotherapy had dramatically elevated levels of heparanase expression compared to cells harvested prior to therapy [17].…”

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

“…In addition, the use of ADAM10 and ADAM17 inhibitors was shown to ameliorate the response to chemotherapy treatments in different in vivo models of cancer (57,58), and ADAM inhibitors were used in clinical trials in breast cancer patients (59). Of interest, combined treatment using chemotherapy and metalloproteinase inhibitors recently was proposed as a therapeutic regimen in MM, because drug-induced ADAM-mediated CD138 release was shown to promote tumor growth (60). Overall, our findings suggest that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses.…”

The novel biomarker of alternative macrophage activation, soluble mannose receptor (sMR/sCD206): Implications in multiple myeloma

“…Soluble CD163 is, at least in part, generated as a result of cleavage by the enzyme a disintegrin and metalloproteinase 17 (ADAM17) [26], which may also be involved in shedding of CD138/syndecan-1 from MM plasma cells [27]. The mechanism for generation of sMR in humans is not known.…”