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1.
Matrix Biol ; 88: 53-68, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31812535

RESUMO

Heparanase is known to enhance the progression of many cancer types and is associated with poor patient prognosis. We recently reported that after patients with multiple myeloma were treated with high dose chemotherapy, the tumor cells that emerged upon relapse expressed a much higher level of heparanase than was present prior to therapy. Because tumor cells having stemness properties are thought to seed tumor relapse, we investigated whether heparanase had a role in promoting myeloma stemness. When plated at low density and grown in serum-free conditions that support survival and expansion of stem-like cells, myeloma cells expressing a low level of heparanase formed tumor spheroids poorly. In contrast, cells expressing a high level of heparanase formed significantly more and larger spheroids than did the heparanase low cells. Importantly, heparanase-low expressing cells exhibited plasticity and were induced to exhibit stemness properties when exposed to recombinant heparanase or to exosomes that contained a high level of heparanase cargo. The spheroid-forming heparanase-high cells had elevated expression of GLI1, SOX2 and ALDH1A1, three genes known to be associated with myeloma stemness. Inhibitors that block the heparan sulfate degrading activity of heparanase significantly diminished spheroid formation and expression of stemness genes implying a direct role of the enzyme in regulating stemness. Blocking the NF-κB pathway inhibited spheroid formation and expression of stemness genes demonstrating a role for NF-κB in heparanase-mediated stemness. Myeloma cells made deficient in heparanase exhibited decreased stemness properties in vitro and when injected into mice they formed tumors poorly compared to the robust tumorigenic capacity of cells expressing higher levels of heparanase. These studies reveal for the first time a role for heparanase in promoting cancer stemness and provide new insight into its function in driving tumor progression and its association with poor prognosis in cancer patients.


Assuntos
Regulação para Baixo , Glucuronidase/genética , Mieloma Múltiplo/patologia , Células-Tronco Neoplásicas/patologia , Família Aldeído Desidrogenase 1/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Exossomos/enzimologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Mieloma Múltiplo/genética , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Retinal Desidrogenase/genética , Fatores de Transcrição SOXB1/genética , Esferoides Celulares/citologia , Proteína GLI1 em Dedos de Zinco/genética
2.
Clin Cancer Res ; 17(6): 1382-93, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21257720

RESUMO

PURPOSE: Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action. EXPERIMENTAL DESIGN: The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo. RESULTS: SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase-induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment. CONCLUSIONS: These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma.


Assuntos
Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glucuronidase/metabolismo , Heparina/análogos & derivados , Heparina/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Neovascularização Patológica , Sindecana-1/metabolismo , Animais , Linhagem Celular Tumoral , Dexametasona/farmacologia , Feminino , Glucuronidase/antagonistas & inibidores , Heparina/química , Heparina/farmacologia , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos SCID , Transplante de Neoplasias , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
J Biol Chem ; 284(38): 26085-95, 2009 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-19596856

RESUMO

Myeloma tumors are characterized by high expression of syndecan-1 (CD138), a heparan sulfate proteoglycan present on the myeloma cell surface and shed into the tumor microenvironment. High levels of shed syndecan-1 in the serum of patients are an indicator of poor prognosis, and numerous studies have implicated syndecan-1 in promoting the growth and progression of this cancer. In the present study we directly addressed the role of syndecan-1 in myeloma by stable knockdown of its expression using RNA interference. Knockdown cells that were negative for syndecan-1 expression became apoptotic and failed to grow in vitro. Knockdown cells expressing syndecan-1 at approximately 28% or approximately 14% of normal levels survived and grew well in vitro but formed fewer and much smaller subcutaneous tumors in mice compared with tumors formed by cells expressing normal levels of syndecan-1. When injected intravenously into mice (experimental metastasis model), knockdown cells formed very few metastases as compared with controls. This indicates that syndecan-1 may be required for the establishment of multi-focal metastasis, a hallmark of this cancer. One mechanism of syndecan-1 action occurs via stimulation of tumor angiogenesis because tumors formed by knockdown cells exhibited diminished levels of vascular endothelial growth factor and impaired development of blood vessels. Together, these data indicate that the effects of syndecan-1 on myeloma survival, growth, and dissemination are due, at least in part, to its positive regulation of tumor-host interactions that generate an environment capable of sustaining robust tumor growth.


Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/metabolismo , Proteínas de Neoplasias/biossíntese , Neovascularização Patológica/metabolismo , Sindecana-1/biossíntese , Animais , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos SCID , Metástase Neoplásica , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Interferência de RNA , Sindecana-1/genética
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