Inhibition of Systemic Hyaluronan Synthesis Exacerbates Murine Hepatic Carcinogenesis

Mikami, Koji; Endo, Tetsu; Sawada, Naoya; Igarashi, Go; Kimura, Masayo; Sakuraba, Hirotake; Fukuda, Shinsaku

doi:10.21873/invivo.11234

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…Some reports have shown that 4-MU inhibits the properties of CSCs by the inhibition of HA, accompanied by a reduction of CSC markers, like transmembrane glycoproteins CD44 and CD133, as well as CD90 and EpCAM cells, indicating a possible mechanism which involves HA in cell-to-cell and cell-to-matrix interactions (52,53). In contrast to these reports, Mikami et al showed that systemic inhibition of HA synthesis by oral 4-MU administration promotes the development of tumor in mice with liver tumors induced by administration of thioacetamide (TAA) (79). A possible explanation for this opposite result could be associated with the HCC model used by the authors.…”

Section: Hepatocellular Carcinomamentioning

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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Section: Hepatocellular Carcinomamentioning

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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“…However, 4-MU treatment is not specific for any particular HAS, and can partially affect the synthesis of other GAG chains [102]. It is reported that 4-MU causes potential detrimental effects, as described for glycocalyx alteration in atherosclerotic animal models [109] and increased tumorigenicity in hepatocellular carcinoma mouse models [110]. Recently, the potential limited systemic efficacy of 4-methylumbelliferyl glucuronide (4-MUG) was tested in mice.…”

Section: Has Inhibition By 4-mumentioning

confidence: 99%

Effects of Hyaluronan on Breast Cancer Aggressiveness

Parnigoni

Moretto

Viola

et al. 2023

Cancers

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The expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells is critical for determining tumor aggressiveness and targeting therapies. The presence of such receptors allows for the use of antagonists that effectively reduce breast cancer growth and dissemination. However, the absence of such receptors in triple-negative breast cancer (TNBC) reduces the possibility of targeted therapy, making these tumors very aggressive with a poor outcome. Cancers are not solely composed of tumor cells, but also include several types of infiltrating cells, such as fibroblasts, macrophages, and other immune cells that have critical functions in regulating cancer cell behaviors. In addition to these cells, the extracellular matrix (ECM) has become an important player in many aspects of breast cancer biology, including cell growth, motility, metabolism, and chemoresistance. Hyaluronan (HA) is a key ECM component that promotes cell proliferation and migration in several malignancies. Notably, HA accumulation in the tumor stroma is a negative prognostic factor in breast cancer. HA metabolism depends on the fine balance between HA synthesis by HA synthases and degradation yielded by hyaluronidases. All the different cell types present in the tumor can release HA in the ECM, and in this review, we will describe the role of HA and HA metabolism in different breast cancer subtypes.

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“…Long-term treatment with TAA alone has been demonstrated to induce HCC within 14-16 weeks in rats (69,70). Murine studies are much rarer in the literature and describe HCC development after 26 weeks to 12 months of TAA treatment (71)(72)(73)(74). Figure 2 illustrates tumor histology and characteristics of TAA-induced HCC development compared to CDE-mediated HCC development in mice after 7 months of treatment.…”

Section: Thioacetamide (Taa)mentioning

confidence: 99%

Mouse Models of Hepatocellular Carcinoma

Carlessi

Köhn-Gaone

Olynyk

et al. 2019

Hepatocellular Carcinoma

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Hepatocellular carcinoma (HCC) represents a major and steadily increasing global health challenge as the most common primary liver malignancy and leading cause of death in cirrhotic patients. The only hope for curative treatment or significant increase in life expectancy is early detection. Once patients have progressed towards end-stage HCC, effective treatment options are extremely limited on the background of a very high degree of heterogeneity in clinical presentation and outcome. Experimental chronic liver injury and cancer have been used extensively to mimic the human disease. In particular, mouse studies have advanced the field due to the ability to easily manipulate the mouse genome and transcriptome for mechanistic evaluations. In addition, they offer the opportunity to screen new therapeutic strategies cost-effectively

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Inhibition of Systemic Hyaluronan Synthesis Exacerbates Murine Hepatic Carcinogenesis

Abstract: Abstract. Background

Cited by 4 publications

References 37 publications

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

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

Effects of Hyaluronan on Breast Cancer Aggressiveness

Mouse Models of Hepatocellular Carcinoma

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