A hyaluronan synthase suppressor, 4‐methylumbelliferone, inhibits liver metastasis of melanoma cells

Yoshihara, Shuichi; Kon, Atsushi; Kudo, Daisuke; Nakazawa, Hideaki; Kakizaki, Ikuko; Sasaki, Makoto; Endo, Masahiko; Takagaki, Keiichi

doi:10.1016/j.febslet.2005.03.079

Cited by 117 publications

(101 citation statements)

References 20 publications

(36 reference statements)

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“…Previous studies found that forced expression of HAS increased tumor cell proliferation and metastasis, whereas inhibition of HAS prevented proliferation and metastasis (23,24,30). These experiments suggested that HA promotes tumor proliferation and metastasis, whereas our results indicate that HA prevents metastasis.…”

Section: Discussioncontrasting

confidence: 56%

Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis

Hirose¹,

Saijou²,

Sugano³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hyaluronic acid (HA) has been implicated in the proliferation and metastasis of tumor cells. However, most previous studies were conducted on extracellular matrix or pericellular HA, and the role of circulating HA in vivo has not been studied. HA is rapidly cleared from the bloodstream. The scavenger receptor Stabilin-2 (Stab2) is considered a major clearance receptor for HA. Here we report a dramatic elevation in circulating HA levels in Stab2-deficient mice without any overt phenotype. Surprisingly, the metastasis of B16F10 melanoma cells to the lungs was markedly suppressed in the Stab2-deficient mice, whereas cell proliferation was not affected. Furthermore, administration of an anti-Stab2 antibody in Stab2 + mice elevated serum HA levels and prevented the metastasis of melanoma to the lung, and also suppressed spontaneous metastasis of mammary tumor and human breast tumor cells inoculated in the mammary gland. Administration of the antibody or high-dose HA in mice blocked the lodging of melanoma cells to the lungs. Furthermore, HA at high concentrations inhibited the rolling/tethering of B16 cells to lung endothelial cells. These results suggest that blocking Stab2 function prevents tumor metastasis by elevating circulating HA levels. Stab2 may be a potential target in antitumor therapy.cancer | hyaluronan | imaging | antibody therapy | sinusoid

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Section: Discussioncontrasting

confidence: 56%

Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis

Hirose¹,

Saijou²,

Sugano³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, it is also known that 4-MU can act by reducing levels of HAS mRNA in breast, melanoma and ovarian cancer cells (27). Some studies have shown anticancer effects of 4-MU through decreased HA synthesis in vitro and in vivo (28,29). However, to our knowledge, no study examining the anticancer effect of 4-MU on canine mammary tumors has been published.…”

Section: -Methylumbelliferone Leads To Growth Arrest and Apoptosis Imentioning

confidence: 69%

“…In recent studies, 4-MU has shown anticancer effects involving apoptotic, anti-invasive and anti-angiogenic pathways in vitro and in vivo (28,29,36,37). We hypothesized that treatment of canine CF33 mammary tumor cells with 4-MU might decrease the HA matrix, leading to the inhibition of tumor cell growth and the induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

4-Methylumbelliferone leads to growth arrest and apoptosis in canine mammary tumor cells

et al. 2012

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Abstract. Hyaluronan (HA), a major component of the extracellular matrix (ECM), is synthesized by HA synthase (HAS) 1, HAS2 and HAS3 and is intricately involved in cell growth and metastasis. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) has been reported to exhibit anticancer properties in various types of malignant tumors. However, the underlying mechanisms at the molecular and cellular levels remain unclear. In this study, to establish an animal model for studying the function of HA in human breast cancer, we investigated the antitumor effects of 4-MU using canine mammary tumor (CF33) cells. First, we investigated the effects of 4-MU on HA production in CF33 cells. Quantitative analysis of HA in culture media showed that 4-MU inhibited HA synthesis, accompanied by downregulation of HAS2 mRNA levels, in a dose-dependent manner at 24-72 h. Additionally, we observed a 4-MU-mediated decrease in the extent of the cell-associated HA matrix. We examined the effect of 4-MU on cell growth and apoptosis in CF33 cells. 4-MU markedly inhibited cell proliferation and induced apoptosis in CF33 cells. In particular, our experiments showed that the mechanism of 4-MU-induced apoptosis in CF33 cells involved increased levels of expression of pro-apoptotic BAX mRNA and protein molecules. These data suggest that 4-MU may be a candidate therapeutic agent for the treatment of canine mammary tumors. Furthermore, this study provides the first indication that the canine mammary tumor may be a suitable model for comparative study of the function of HA in human breast cancer. IntroductionMammary tumors in dogs occur at a frequency of 3 times the incidence of mammary tumors in humans and have recorded a higher incidence rate than other livestock (1). Mammary tumors are the most frequent cutaneous neoplasms in female dogs, and approximately 50% are diagnosed as malignant tumors (2). Following surgical excision, approximately 48% of the affected dogs die or are euthanized within 1 year due to tumor recurrence or metastasis (3). Canine mammary tumors are heterogeneous, and the different clinical and biological features (4) make it difficult to determine a prognosis and treatment for affected dogs, as is often the case in humans. Additional and reliable tools for effective therapy are required in veterinary medicine. Furthermore, a recent study revealed clear evidence of a similarity between human and dog tumors in regard to the deregulation of several cancer-related genes, including PI3K/Akt, PTEN and Wnt-β catenin and MAPK signaling (5). Accordingly, canine mammary tumors can also provide a suitable natural model for the comparative study of human breast cancer (5-7).Hyaluronan (HA) is a non-sulfated linear glycosaminoglycan that consists of repeating disaccharide subunits of glucuronic acid and N-acetylglucosamine (8,9). It is ubiquitously distributed in the extra-and pericellular spaces of most animal tissues (8,9). HA plays a critical role in regulating matrix assembly, cell migration, differentiation and proliferation (9-11)...

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“…Because we found that treatment with 4-MU robustly attenuates the migratory ability of PDAC cells, inhibiting HA production could be an ideal therapeutic strategy to prevent invasion and/or metastasis of PDAC. In fact, inhibition of HA synthesis by treatment with 4-MU, or its derivative 4-methylesculetin, has demonstrated antitumor activity in a variety of cancers, including PDAC [32][33][34][35][36][37]. Of particular importance, 4-MU (or hymecromone) is a dietary supplement for improving liver health and can be administered orally without any toxicities [38].…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan stimulates pancreatic cancer cell motility

et al. 2016

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A hyaluronan synthase suppressor, 4‐methylumbelliferone, inhibits liver metastasis of melanoma cells

Cited by 117 publications

References 20 publications

Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis

Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis

4-Methylumbelliferone leads to growth arrest and apoptosis in canine mammary tumor cells

Hyaluronan stimulates pancreatic cancer cell motility

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