Interfering with hyaluronic acid metabolism suppresses glioma cell proliferation by regulating autophagy

Yan, Tao; Chen, Xin; Zhan, Hua; Yao, Penglei; Wang, Ning; He, Yang; Zhang, Cheng; Hu, Hanqing; Li, Jiafeng; Sun, Jian; Dong, Yunsheng; Lu, Enzhou; Zheng, Zhixing; Zhang, Ruotian; Wang, Xiaoxiong; Ma, Jichao; Gao, Ming; Ye, Junyi; Liu, Huailei

doi:10.1038/s41419-021-03747-z

Cited by 23 publications

(31 citation statements)

References 35 publications

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“…Clinically, 4MU is often used to relieve biliary spasm [ 25 ]. Moreover, we confirmed that 4MU as HA inhibitor could suppress glioma growth in previous research [ 20 ]. Meanwhile, CD47 expression in hepatic cancer stem cells can be inhibited by 4MU [ 26 ], and CD47-SIRPα axis exerts an inhibitory effect on the ability of macrophages to phagocytose cancer cells [ 27 ].…”

Section: Resultssupporting

confidence: 88%

“…In previous study, we confirmed that glioblastoma growth could be inhibited by 4MU treatment or HAS3 silencing via inhibiting HA synthesis [ 20 ]. To confirm whether the HA abnormal accumulation in glioblastoma could regulate macrophages polarization, U251 and LN229 cell lines were subjected to 4MU treatment or HAS3 silencing in vitro for 48 h. Then, the culture supernatant was collected and mixed with RPMI-1640 to obtain different conditioned medium (CM).…”

Section: Resultssupporting

confidence: 59%

“…In our previous research, we demonstrated that CD44, as an important HA receptor, binds to HA, which is crucial for glioma progression [ 20 ]. Moreover, HA binding to CD44 could regulate T cell activation and tumor progression, and the effect of HA fragment in macrophages could be partially inhibited by anti-CD44 antibodies [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…Thus, modulating TAMs polarization is a feasible approach to improve the effects of immunotherapy in glioma. HA is closely associated with the tumor microenvironment [ 28 ], and our previous studies demonstrated that blocking the HA pathway can inhibit glioma growth [ 20 ]. However, whether the HA pathway influences TAMs remains to be further clarified in glioma.…”

Section: Discussionmentioning

confidence: 99%

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Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma

Yan

et al. 2022

Cell Death Discov.

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Immunosuppressive tumor microenvironment is a crucial factor that impedes the success of tumor immunotherapy, and tumor-associated macrophages (TAMs) are essential for the formation of tumor immunosuppressive microenvironment. Hyaluronic acid (HA) is highly important brick for glioblastoma microenvironment, but whether it contributes to TAM polarization and glioblastoma immunosuppressive microenvironment is less well known. In our study, we observed that disrupting glioblastoma HA synthesis or blocking HA binding to its receptor CD44 on macrophages increased the proportion of M1 macrophages by upregulating SIRPα in macrophages, the underlying mechanism was elevated SIRPα enhanced STAT1 phosphorylation and suppressed STAT3 phosphorylation in macrophages. Subsequently, the induced macrophages could inhibit glioblastoma growth via a feedback effect. In addition, 4-methylumbelliferone (4MU), a cholecystitis drug, can disrupt the CD47/SIRPα axis by disturbing glioblastoma HA synthesis. Collectively, these findings indicated that HA plays a crucial role in macrophages polarization and CD47/SIRPα signaling between glioblastoma cells and macrophages, and suppressing the HA pathway may be a new immunotherapeutic approach for glioblastoma.

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Section: Resultssupporting

confidence: 88%

Section: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma

Yan

et al. 2022

Cell Death Discov.

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“…These authors demonstrated that, in the GL26 murine GBM cell line, 4-MU diminished HA synthesis while increasing apoptosis and decreasing cell proliferation and migration (66). Yan et al found that alterations in HA metabolism, by silencing HAS3 or by treating with 4-MU, inhibited glioma cell proliferation by affecting the autophagy flux (67). Although these new results are encouraging, more investigations are needed to understand the action and mechanism of 4-MU in GBM cells.…”

Section: Glioblastomamentioning

confidence: 99%

Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

et al. 2021

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In antineoplastic therapy, one of the challenges is to adjust the treatment to the needs of each patient and reduce the toxicity caused by conventional antitumor strategies. It has been demonstrated that natural products with antitumoral properties are less toxic than chemotherapy and radiotherapy. Also, using already developed drugs allows developing substantially less costly methods for the discovery of new treatments than traditional drug development. Candidate molecules proposed for drug repositioning include 4-methylumbelliferone (4-MU), an orally available dietetic product, derivative of coumarin and mainly found in the plant family Umbelliferae or Apiaceae. 4-MU specifically inhibits the synthesis of glycosaminoglycan hyaluronan (HA), which is its main mechanism of action. This agent reduces the availability of HA substrates and inhibits the activity of different HA synthases. However, an effect independent of HA synthesis has also been observed. 4-MU acts as an inhibitor of tumor growth in different types of cancer. Particularly, 4-MU acts on the proliferation, migration and invasion abilities of tumor cells and inhibits the progression of cancer stem cells and the development of drug resistance. In addition, the effect of 4-MU impacts not only on tumor cells, but also on other components of the tumor microenvironment. Specifically, 4-MU can potentially act on immune, fibroblast and endothelial cells, and pro-tumor processes such as angiogenesis. Most of these effects are consistent with the altered functions of HA during tumor progression and can be interrupted by the action of 4-MU. While the potential advantage of 4-MU as an adjunct in cancer therapy could improve therapeutic efficacy and reduce toxicities of other antitumoral agents, the greatest challenge is the lack of scientific evidence to support its approval. Therefore, crucial human clinical studies have yet to be done to respond to this need. Here, we discuss and review the possible applications of 4-MU as an adjunct in conventional antineoplastic therapies, to achieve greater therapeutic success. We also describe the main proposed mechanisms of action that promote an increase in the efficacy of conventional antineoplastic strategies in different types of cancer and prospects that promote 4-MU repositioning and application in cancer therapy.

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The effects of sulfated hyaluronan in breast, lung and colorectal carcinoma and monocytes/macrophages cells: Its role in angiogenesis and tumor progression

et al. 2022

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Hyaluronan (HA) is a component of the extracellular matrix (ECM) it is the main non‐sulfated glycosaminoglycan able to modulate cell behavior in the healthy and tumor context. Sulfated hyaluronan (sHA) is a biomaterial derived from chemical modifications of HA, since this molecule is not naturally sulfated. The HA sulfation modifies several properties of the native molecule, acquiring antitumor properties in different cancers. In this study, we evaluated the action of sHA of ~30–60 kDa with different degrees of sulfation (0.7 sHA1 and 2.5 sHA3) on tumor cells of a breast, lung, and colorectal cancer model and its action on other cells of the tumor microenvironment, such as endothelial and monocytes/macrophage cells. Our data showed that in breast and lung tumor cells, sHA3 is able to modulate cell viability, cytotoxicity, and proliferation, but no effects were observed on colorectal cancer cells. In 3D cultures of breast and lung cancer cells, sHA3 diminished the size of the tumorsphere and modulated total HA levels. In these tumor models, treatment of monocytes/macrophages with sHA3 showed a downregulation of the expression of angiogenic factors. We also observed a decrease in endothelial cell migration and modulation of the hyaluronan‐binding protein TSG‐6. In the breast in vivo xenograft model, monocytes/macrophages preincubated with sHA1 or sHA3 decreased tumor vasculature, TSG‐6 and HA levels. Besides, in silico analysis showed an association of TSG‐6, HAS2, and IL‐8 with biological processes implicated in the progression of the tumor. Taken together, our data indicate that sHA in a breast and lung tumor context is able to induce an antiangiogenic action on tumor cells as well as in monocytes/macrophages (Mo/MØ) by modulation of endothelial migration, angiogenic factors, and vessel formation.

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Interfering with hyaluronic acid metabolism suppresses glioma cell proliferation by regulating autophagy

Cited by 23 publications

References 35 publications

Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma

Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma

Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

The effects of sulfated hyaluronan in breast, lung and colorectal carcinoma and monocytes/macrophages cells: Its role in angiogenesis and tumor progression

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