Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures through the Coordinated Regulation of Twist and the Transforming Growth Factor β (TGF-β)-Snail Signaling Axis

Chanmee, Theerawut; Ontong, Pawared; Mochizuki, Nobutoshi; Kongtawelert, Prachya; Konno, Kenjiro; Itano, Naoki

doi:10.1074/jbc.m114.564120

Cited by 79 publications

(85 citation statements)

References 41 publications

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“…HAS2 overexpression not only induces the EMT processes, but also provides additional stimulus driving the conversion to cancer stem cells (CSC) phenotype. Induction of HAS2 expression in HAS2 +Neo cells from transgenic mice resulted in frequent occurrence of CD44hi/CD24lo population 23. Our findings were in concordance with the observed functional effects of HAS2 in EMT and CSC in these studies.…”

Section: Discussionsupporting

confidence: 92%

“…However, recently, HAS2 has been described to promote EMT, independent of its enzymatic activity. HAS2 expression, independent of extracellular HA-CD44 interaction, was involved in EMT induction or the CSC conversion 7 23. In line with the observation, this study showed that the poor prognosis of HAS+AR− cancers was not dependent on CD44 expression.…”

Section: Discussionsupporting

confidence: 83%

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Hyaluronan synthase 2 is an adverse prognostic marker in androgen receptor-negative breast cancer

Zhang

Tsang

et al. 2016

J Clin Pathol

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 83%

Hyaluronan synthase 2 is an adverse prognostic marker in androgen receptor-negative breast cancer

Zhang

Tsang

et al. 2016

J Clin Pathol

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“…Adding to the heterogeneity of cancer cells, signals from stromal cells and extracellular matrix (ECM) components can also promote and maintain cancer stem/stem-like cells (CSCs) (Lu et al 2012; Chanmee et al 2014; Chen et al 2014a; Whatcott et al 2015b). CSCs represent a population of cancer cells thought to be responsible for tumor initiation and progression (Magee et al 2012).…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity

Martin

Fukumura

Duda

et al. 2016

Cold Spring Harb Perspect Med

132

117

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Solid tumors consist of cancer cells and stromal cells, including resident and transiting immune cells—all ensconced in an extracellular matrix (ECM)—nourished by blood vessels and drained by lymphatic vessels. The microenvironment constituents are abnormal and heterogeneous in morphology, phenotype, and physiology. Such irregularities include an inefficient tumor vascular network comprised of leaky and compressed vessels, which impair blood flow and oxygen delivery. Low oxygenation in certain tumor regions—or focal hypoxia—is a mediator of cancer progression, metastasis, immunosuppression, and treatment resistance. Thus, repairing an abnormal and heterogeneous microenvironment—and hypoxia in particular—can significantly improve treatments of solid tumors. Here, we summarize two strategies to reengineer the tumor microenvironment (TME)—vessel normalization and decompression—that can alleviate hypoxia. In addition, we discuss how these two strategies alone and in combination with each other—or other therapeutic strategies—may overcome the challenges posed by cancer heterogeneity.

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“…TGF-β-mediated EMT requires participation of HAS2 (Porsch et al, 2013). Overproduction of HA is needed to drive EMT via Twist and TGF-β–Snail signaling (Chanmee et al, 2014, 2016). TGF-β1 is growth-inhibitory to normal epithelial cells, whereas hyaluronidase PH-20 counteracts the effect of TGF-β1 (Chang, 1997), Chang (1998, 2002).…”

Section: Hyal-2 Is a Cognate Receptor For Tgf-β: Signaling Via Hyal-2mentioning

confidence: 99%

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Hsu

Chiang

Sze

et al. 2016

Front. Cell Dev. Biol.

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Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3− CD19− Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.

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Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures through the Coordinated Regulation of Twist and the Transforming Growth Factor β (TGF-β)-Snail Signaling Axis

Cited by 79 publications

References 41 publications

Hyaluronan synthase 2 is an adverse prognostic marker in androgen receptor-negative breast cancer

Hyaluronan synthase 2 is an adverse prognostic marker in androgen receptor-negative breast cancer

Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

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