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Key Roles of Hyaluronan and Its CD44 Receptor in the Stemness and Survival of Cancer Stem Cells.

Chanmee T, Ontong P, Kimata K, Itano N - Front Oncol (2015)

Bottom Line: For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition.CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals.We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University , Kyoto , Japan.

ABSTRACT
Cancer stem cells (CSCs) represent a unique subpopulation of self-renewing oncogenic cells that drive cancer initiation and progression. CSCs often acquire multidrug and oxidative stress resistance and are thereby thought to be responsible for tumor recurrence following treatment and remission. Although the mechanisms responsible for CSC generation, maintenance, and expansion have become a major focus in cancer research, the molecular characteristics of CSCs remain poorly understood. The stemness and subsequent expansion of CSCs are believed to be highly influenced by changes in microenvironmental signals as well as genetic and epigenetic alterations. Hyaluronan (HA), a major component of the extracellular matrix, has recently been demonstrated to provide a favorable microenvironment for the self-renewal and maintenance of stem cells. HA directly and indirectly affects CSC self-renewal by influencing the behavior of both cancer and stromal cells. For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition. The importance of HA in mediating CSC self-renewal has been strengthened by the finding that interactions between HA and its receptor, CD44, propagate the stemness of CSCs. HA-CD44 interactions evoke a wide range of signals required for CSC self-renewal and maintenance. CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals. Thus, a better understanding of the molecular mechanisms involved in HA and CD44 control of CSC stemness may help in the design of more effective therapies for cancer patients. In this review, we address the key roles of HA and CD44 in CSC self-renewal and maintenance. We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

No MeSH data available.


Related in: MedlinePlus

Involvement of HA in the induction of EMT and CSC self-renewal. An alternative mechanism of HA–CD44 interaction-promoted EMT relying on activation of the lysyl oxidase promoter leads to the up-regulation of Twist. HA overproduction also induces EMT through the coordinated regulation of Twist and TGF-β-Snail signaling. In addition, TGF-β facilitates EMT by increasing the expression of HAS2. This stimulatory effect requires the activation of Smad and p38 MAPK. CD44 maintains the self-renewal ability of CSCs through Nanog and GSK3β. HA and CD44 promote Nanog protein association with CD44 followed by activation of the stem-cell regulators Rex1 and Sox2. CD44 also inhibits the phosphorylation of GSK3β to maintain the functional indicators of cancer stemness, including EMT and stem-cell markers (e.g., Oct4, Sox2, and Nanog).
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Figure 2: Involvement of HA in the induction of EMT and CSC self-renewal. An alternative mechanism of HA–CD44 interaction-promoted EMT relying on activation of the lysyl oxidase promoter leads to the up-regulation of Twist. HA overproduction also induces EMT through the coordinated regulation of Twist and TGF-β-Snail signaling. In addition, TGF-β facilitates EMT by increasing the expression of HAS2. This stimulatory effect requires the activation of Smad and p38 MAPK. CD44 maintains the self-renewal ability of CSCs through Nanog and GSK3β. HA and CD44 promote Nanog protein association with CD44 followed by activation of the stem-cell regulators Rex1 and Sox2. CD44 also inhibits the phosphorylation of GSK3β to maintain the functional indicators of cancer stemness, including EMT and stem-cell markers (e.g., Oct4, Sox2, and Nanog).

Mentions: A close link between EMT and CSC properties has emerged to enable a greater understanding of the molecular mechanisms underlying the expansion and maintenance of CSCs in tumor masses. Increasing evidence suggests that HA plays a central role in EMT during embryonic development and malignant progression. Zoltan-Jones et al. demonstrated that forced HAS2 expression induced Madin–Darby canine kidney and MCF-10A human mammary epithelial cells to acquire mesenchymal-like phenotype as defined by a down-regulation of E-cadherin at intercellular boundaries, up-regulation of vimentin, and fibroblast-like morphology (66). Ectopic expression of murine Has2 in non-HA-producing mesothelioma cells also invoked conversion to fibroblastic morphology (67). In vivo experiments have confirmed the importance of HA in the induction of EMT. Disruption of the Has2 gene abrogated normal cardiac morphogenesis and HA-mediated transformation of epithelium to mesenchyme (68). We produced conditional transgenic mice carrying the murine Has2 gene and observed that HA overproduction in spontaneous mammary tumors resulted in a loss of epithelial phenotype in tumor cells by down-regulation of E-cadherin and induced nuclear translocation of β-catenin, both of which are hallmarks of EMT (40). Transcriptional networks that drive EMT (e.g., Snail, Twist, and Zeb1) have also been found to dynamically change during HA-induced EMT. We witnessed that HA overproduction up-regulated Snail and Twist expression in a mammary carcinoma cell (Figure 2) (69). Furthermore, HA association with CD44 was suggested to induce Twist expression following CD44 nuclear translocation and activation of the lysyl oxidase promoter in human breast cancer (Figure 2) (70).


Key Roles of Hyaluronan and Its CD44 Receptor in the Stemness and Survival of Cancer Stem Cells.

Chanmee T, Ontong P, Kimata K, Itano N - Front Oncol (2015)

Involvement of HA in the induction of EMT and CSC self-renewal. An alternative mechanism of HA–CD44 interaction-promoted EMT relying on activation of the lysyl oxidase promoter leads to the up-regulation of Twist. HA overproduction also induces EMT through the coordinated regulation of Twist and TGF-β-Snail signaling. In addition, TGF-β facilitates EMT by increasing the expression of HAS2. This stimulatory effect requires the activation of Smad and p38 MAPK. CD44 maintains the self-renewal ability of CSCs through Nanog and GSK3β. HA and CD44 promote Nanog protein association with CD44 followed by activation of the stem-cell regulators Rex1 and Sox2. CD44 also inhibits the phosphorylation of GSK3β to maintain the functional indicators of cancer stemness, including EMT and stem-cell markers (e.g., Oct4, Sox2, and Nanog).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4530590&req=5

Figure 2: Involvement of HA in the induction of EMT and CSC self-renewal. An alternative mechanism of HA–CD44 interaction-promoted EMT relying on activation of the lysyl oxidase promoter leads to the up-regulation of Twist. HA overproduction also induces EMT through the coordinated regulation of Twist and TGF-β-Snail signaling. In addition, TGF-β facilitates EMT by increasing the expression of HAS2. This stimulatory effect requires the activation of Smad and p38 MAPK. CD44 maintains the self-renewal ability of CSCs through Nanog and GSK3β. HA and CD44 promote Nanog protein association with CD44 followed by activation of the stem-cell regulators Rex1 and Sox2. CD44 also inhibits the phosphorylation of GSK3β to maintain the functional indicators of cancer stemness, including EMT and stem-cell markers (e.g., Oct4, Sox2, and Nanog).
Mentions: A close link between EMT and CSC properties has emerged to enable a greater understanding of the molecular mechanisms underlying the expansion and maintenance of CSCs in tumor masses. Increasing evidence suggests that HA plays a central role in EMT during embryonic development and malignant progression. Zoltan-Jones et al. demonstrated that forced HAS2 expression induced Madin–Darby canine kidney and MCF-10A human mammary epithelial cells to acquire mesenchymal-like phenotype as defined by a down-regulation of E-cadherin at intercellular boundaries, up-regulation of vimentin, and fibroblast-like morphology (66). Ectopic expression of murine Has2 in non-HA-producing mesothelioma cells also invoked conversion to fibroblastic morphology (67). In vivo experiments have confirmed the importance of HA in the induction of EMT. Disruption of the Has2 gene abrogated normal cardiac morphogenesis and HA-mediated transformation of epithelium to mesenchyme (68). We produced conditional transgenic mice carrying the murine Has2 gene and observed that HA overproduction in spontaneous mammary tumors resulted in a loss of epithelial phenotype in tumor cells by down-regulation of E-cadherin and induced nuclear translocation of β-catenin, both of which are hallmarks of EMT (40). Transcriptional networks that drive EMT (e.g., Snail, Twist, and Zeb1) have also been found to dynamically change during HA-induced EMT. We witnessed that HA overproduction up-regulated Snail and Twist expression in a mammary carcinoma cell (Figure 2) (69). Furthermore, HA association with CD44 was suggested to induce Twist expression following CD44 nuclear translocation and activation of the lysyl oxidase promoter in human breast cancer (Figure 2) (70).

Bottom Line: For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition.CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals.We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University , Kyoto , Japan.

ABSTRACT
Cancer stem cells (CSCs) represent a unique subpopulation of self-renewing oncogenic cells that drive cancer initiation and progression. CSCs often acquire multidrug and oxidative stress resistance and are thereby thought to be responsible for tumor recurrence following treatment and remission. Although the mechanisms responsible for CSC generation, maintenance, and expansion have become a major focus in cancer research, the molecular characteristics of CSCs remain poorly understood. The stemness and subsequent expansion of CSCs are believed to be highly influenced by changes in microenvironmental signals as well as genetic and epigenetic alterations. Hyaluronan (HA), a major component of the extracellular matrix, has recently been demonstrated to provide a favorable microenvironment for the self-renewal and maintenance of stem cells. HA directly and indirectly affects CSC self-renewal by influencing the behavior of both cancer and stromal cells. For instance, HA in the tumor microenvironment modulates the function of tumor-associated macrophages to support CSC self-renewal, and excessive HA production promotes the acquisition of CSC signatures through epithelial-to-mesenchymal transition. The importance of HA in mediating CSC self-renewal has been strengthened by the finding that interactions between HA and its receptor, CD44, propagate the stemness of CSCs. HA-CD44 interactions evoke a wide range of signals required for CSC self-renewal and maintenance. CD44 also plays a critical role in the preservation and multidrug resistance (MDR) of CSCs by transmitting survival and anti-apoptotic signals. Thus, a better understanding of the molecular mechanisms involved in HA and CD44 control of CSC stemness may help in the design of more effective therapies for cancer patients. In this review, we address the key roles of HA and CD44 in CSC self-renewal and maintenance. We also discuss the involvement of CD44 in the oxidative stress and MDR of CSCs.

No MeSH data available.


Related in: MedlinePlus