Hyaluronan facilitates invasion of colon carcinoma cells in vitro via interaction with CD Siegelman, M. Lamontagne, C. Cell Res. Thomas, L. CD44H regulates tumor cell migration on hyaluronate-coated substrate.
Bustelo, X. Regulatory and signaling properties of the Vav family. Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine macrophage-colony stimulating factor production and breast tumor progression. Marhaba, R. In vivo CDCD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance.
Nagano, O. Mechanism and biological significance of CD44 cleavage. Cancer Sci. Nakamura, H. Sugahara, K. Proteolytic cleavage of the CD44 adhesion molecule in multiple human tumors.
Jung, T. CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11 , — Desai, B. CD44v 3 , 8—10 is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase MMP-9 association in metastatic breast cancer cells. Yu, Q. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CDmediated tumor invasion. Wilson, T. Cathepsin G. Hill, A. The emerging role of CD44 in regulating skeletal micrometastasis.
Cancer Lett. CAS Google Scholar. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Cathepsin G-mediated activation of pro-matrix metalloproteinase 9 at the tumor-bone interface promotes transforming growth factor-beta signaling and bone destruction. Pelletier, L. Gamma-secretase-dependent proteolysis of CD44 promotes neoplastic transformation of rat fibroblastic cells.
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Itano, N. Altered hyaluronan biosynthesis in cancer progression. Klingbeil, P. CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance. Adamia, S. Hyaluronan and hyaluronan synthases: potential therapeutic targets in cancer. Drug Targets.
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Kim, M. Weber, G. Molecular mechanisms of metastasis. Kollet, O. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Absence of the CD44 gene prevents sarcoma metastasis. Kaplan, R. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Barnhart, B. Metastasis and stem cell pathways. Ponta, H. CD from adhesion molecules to signalling regulators. CD44 in cancer progression: adhesion, migration and growth regulation.
Mani, S. The epithelial-mesenchymal transition generates cells with properties of stem cells. Ahmed, N. Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Cancer Drug Targets. Wong, N. Beta-catenin--a linchpin in colorectal carcinogenesis? Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells. Yoshihara, S. A hyaluronan synthase suppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells.
FEBS Lett. Uchino, M. Nuclear beta-catenin and CD44 upregulation characterize invasive cell populations in non-aggressive MCF-7 breast cancer cells. Takahashi, E. Tumor necrosis factor-alpha regulates transforming growth factor-beta-dependent epithelial-mesenchymal transition by promoting hyaluronan-CDmoesin interaction. Acharya, P. Allouche, M. Ligation of the CD44 adhesion molecule inhibits drug-induced apoptosis in human myeloid leukemia cells.
Blood 96 , — Bates, R. Fujita, Y. CD44 signaling through focal adhesion kinase and its anti-apoptotic effect. Induction of apoptosis of metastatic mammary carcinoma cells in vivo by disruption of tumor cell surface CD44 function. Wang, S. In the present work, we studied how IL-1beta turns on the monocyte adhesion of the hyaluronan coat on human keratinocytes.
IL-1beta did not influence hyaluronan synthesis or increase the amount of pericellular hyaluronan in these cells. Instead, we found that the increase in the hyaluronan-dependent monocyte binding was associated with the CD44 of the keratinocytes. Although IL-1beta caused a small increase in the total amount of CD44, a more marked impact was the decrease of CD44 phosphorylation at serine Treatment of keratinocyte cultures with KN93, an inhibitor of calmodulin kinase 2, known to phosphorylate Ser in CD44, caused similar effects as IL-1beta i.
Overexpression of wild type CD44 standard form, but not a corresponding CD44 mutant mimicking the Serphosphorylated form, was able to induce monocyte binding to keratinocytes. In conclusion, treatment of human keratinocytes with IL-1beta changes the structure of their hyaluronan coat by influencing the amount, post-translational modification, and cytoskeletal association of CD44, thus enhancing monocyte retention on keratinocytes. The high-molecular-weight glycosaminoglycan, hyaluronic acid HA , makes up a significant portion of the brain extracellular matrix.
CD44 suppression in culture reduces cell adhesion to HA on short time scales 0. Moreover, time-lapse imaging demonstrates that cell adhesive structures formed during migration on bare HA matrices are more short lived than cellular protrusions formed on surfaces containing RGD.
Interestingly, adhesion and migration speed were dependent on HA hydrogel stiffness, implying that CDbased signaling is intrinsically mechanosensitive. Finally, CD44 expression paired with an HA-rich microenvironment maximized three-dimensional invasion, whereas CD44 suppression or abundant integrin-based adhesion limited it.
These findings demonstrate that CD44 transduces HA-based stiffness cues, temporally precedes integrin-based adhesion maturation, and facilitates invasion.
A striking feature of microvascular endothelial cells is their capacity to fuse and differentiate into tubular structures when grown in three-dimensional 3D extracellular matrices, in collagen or Matrigel, mimicking the in vivo blood vessel formation. In this study we demonstrate that human telomerase-immortalised foreskin microvascular endothelial TIME cells express high levels of the hyaluronan receptor CD44 and the hyaluronidase HYAL2. This was accompanied by a defect maturation of the tubular structure network and increased phosphorylation of the inhibitor of NFkappaB kinase IKK complex and thus translocation of NFkappaB into the nucleus and activation of chemokine targed genes.
Furthermore, the interaction between CD44 and hyaluronan determines the adhesion of breast cancer cells. In summary, our observations support the notion that the interaction between CD44 and hyaluronan regulates microvascular endothelial cell tubulogenesis by affecting the expression of cytokines and their receptors, as well as breast cancer dissemination.
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Immunity 17 , — Download references. Ramarini 32, , Monterotondo, Italy. Valentine Svensson, Kedar N. You can also search for this author in PubMed Google Scholar. Correspondence to Christophe Lancrin.
Peer review information Nature Communications thanks the anonymous reviewer s for their contribution to the peer review of this work. Peer reviewer reports are available. Reprints and Permissions. Oatley, M. Single-cell transcriptomics identifies CD44 as a marker and regulator of endothelial to haematopoietic transition.
Nat Commun 11, Download citation. Received : 27 July Accepted : 18 December Published : 29 January Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Acta Pharmacologica Sinica Scientific Reports Cell Research By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Advanced search. Skip to main content Thank you for visiting nature. CD44 isoforms switching was reported to contribute to cancer metastasis associated with variant isoforms [ 15 , 68 , 70 , 54 ].
Epithelial splicing regulatory protein ESRP 1 was essential for promoting exon inclusion of CD44 isoforms and was required for expression of CD44v isoforms [ ]. CD44 mediates multiple signaling pathways including protein kinases, cytoskeletal changes, intracellular pathways, proteinases, and transcriptional factors to contribute cancer cell division, proliferation, invasion, and angiogenesis as well as metabolic shift Fig.
CDmediated downstream signaling pathways. CD44s and CD44v6 are shown as representative CD44 isoforms that mediate specific downstream signaling pathways. CD44v can act as a coreceptor for the receptor tyrosine kinase c-Met to promote cancer cell invasion.
CD44 activation was attributed to the activation of protein kinase pathways. The activation of these pathways played a role in promoting drug resistance, tumor invasiveness, and other oncogenic properties. Although CD44 lacks kinase activity, there are several mechanisms by which CD44 can activate protein kinases.
CD44 acts as a co-receptor by binding and sequestering growth factors at the cell surface and helps to stabilize tyrosine kinase receptor RTK complexes [ ]. This binding motif is coded by exon v6 of the CD44 gene. Neutralizing antibodies to CD44v6 inhibit c-Met activation. Silencing of CD44v6 decreased phosphorylated ErbB2 in colon cancer cells suggesting that CD44v6 may play a role in the activation of this oncogenic pathway [ ].
CD44 also contributes to the activation of Kras-mediated signaling through MAPK pathway in lung cancer cell line models. In these cell line models, CD44 promotes tumor cell proliferation and cell survival. Moreover, deletion of CD44 conferred a survival advantage to mice expressing oncogenic Kras G12D in the lung. Transient knock-down of CD44 in human colon cancer cells resulted in upregulation of AKT, whereas overexpression of variant isoforms of CD44 such as v or v caused deactivation of AKT.
Inhibition of phosphorylation of AKT downregulated cofillin expression and transient knock-down of CD44 decreased cofillin expression [ ]. The expression and activity of cell migration-related proteins, including c-Src, paxillin, and FAK, were decreased by CD44 silencing [ ].
CD44 may contribute to both the expression and the activation of non-receptor kinases such as the Src family, c-Abl, and Jak that control eukaryotic cell growth and differentiation. Retroviral-mediated CD44 knock-down decreased cell proliferation, migration, and invasion of breast cancer cells [ ]. HA activation of CD44 caused an activation of c-Src in breast cancer cells [ ]. CDmediated cell spreading and induced tyrosine phosphorylation were prevented by the Src kinase inhibitor, PP2 in murine BW T lymphoma cells [ ].
Collectively, these studies suggest that CD44 may act indirectly in regulating the expression of protein kinases and their ligands. ERM activation as a result of CD44 interaction initiates cross-talk with multiple pathways.
The binding of ERMs and adaptor proteins to the cytoplasmic portion of CD44 initiates changes in tumor cell cytoskeletal architecture and in cell signaling. CD44 extracellular domain was required for c-Met activation, whereas its cytoplasmic domain recruits ERM proteins that bind the cytoskeleton and promotes Ras activation [ ].
In non-migrating cells, CD44 mainly localizes in rafts and Ezrin in nonraft compartments. During migration, CD44 interaction with threonine-phosphorylated ERM proteins in the nonraft compartments was increased. Pharmacological raft disruption increases colocalization of CDezrin as determined by co-IP and colocalization studies [ ].
CD44 expression and isoform type is thought to modulate the activities of multiple cellular signaling components. Some examples of how CD44 influences the activities of cell signaling were listed and briefly discussed below.
The immunoglobulin superfamily glycoprotein emmprin CD is a multifunctional glycoprotein that can modify the tumor microenvironment by activating proteinases, inducing angiogenic factors in tumor and stromal cells. CD was originally identified as a factor on the surface of tumor cells that induces MMP production in fibroblasts [ ]. Perturbation of hyaluronan-CD44 interaction or downregulation of CD suppressed lactate efflux in the plasma membrane.
Interactions among hyaluronan, CD44, and CD also contributed to the glycolytic phenotype of breast cancer cells [ ]. Thus, these studies support a role of CD44 in regulating the activities of matrix metalloproteinases MMPs linked to tumor cell invasion. Several studies in different cancer types link CD44 with activation of signal transducer and activator of transcription 3 STAT3.
Tumor microenvironment plays an active role in promoting tumor progression since the growth factor or ligand secreted by CAF may interact with CD44 causing malignant phenotype or triggering tumor promoting downstream signaling. Cell survival and drug resistance analysis showed CDpositive CAFs promoted breast cancer cell survival and paclitaxel resistance and inhibited paclitaxel-induced apoptosis [ ].
CD44 activating and modulating a number of cell signaling networks that play an important role in mediating tumorigenic properties of tumor cells leading to tumor progression, metastasis and chemoresistance. CD44 is thought to play a role in the adaptive plasticity of cancer cells [ 12 ]. Adaptive plasticity of cancer cells is a term used to explain how a phenotypic change in response to the microenvironment that provides cancer cells a selective growth and survival capabilities. EMT is a form of adaptive plasticity and it is exemplified by a change from an epithelial to a mesenchymal-like phenotype and these cells show increase in motility, are more invasive, and are generally more resistant to apoptosis [ 11 ].
However, the development of metastatic lesions likely requires these cells to re-establish their epithelial state through the reverse mesenchymal to epithelial transition MET , which is believed to favor tumor engraftment and growth of cancer cells at metastatic sites [ ].
This results in a change in cell shape and apico-basal polarity. In colon cancer cells, a mesenchymal phenotype was associated with an increase in CD44 and knock-down of CD44 showed a decrease in EMT phenotype.
CD44 knock-down cells show a marked decreased migration and invasion, CD44 overexpressing cells showed significantly increased cell migratory and invasive capacity [ ]. Breast cancer cells with ectopic expression of ATF3 displayed more elongated and scattered phenotype and the percentage of CD24 Low CD44 High cell populations was increased [ ]. These studies suggest CD44 isoforms expression positively correlates with mesenchymal phenotype and metastasis in variety cancers.
CD44 alternative splicing was differentially regulated during EMT, resulting in a switch in expression from CD44v to CD44s in human immortalized epithelial mammary cells and in a murine model of breast cancer progression [ 54 ]. CD44s re-expression fully rescued the impaired EMT phenotype in the CDknock-down cells with decreased expression of epithelial markers E-cadherin and occludin and increased expression of mesenchymal markers N-cadherin and vimentin.
ESRP1 is expressed highly in cells with an epithelial phenotype. We were recently able to separate cancer cells on the bases of CD44 expression level using flow cytometry [ 12 ].
This study showed that cells possessing an EMT phenotype expressed high levels of CD44s with lower levels of CD44 single exon variants. Mice with orthotopic implants of CD44s high cells formed tumors more rapidly and gradually developed resistance to gemcitabine, whereas tumors from CD44 low expressing cells took longer to grow and maintained sensitivity to gemcitabine over an extended period of time.
The emergence of chemoresistant cancer cells may result from the expansion of a subpopulation of cancer cells that are inherently resistant or by reprograming or phenotypic changes of initially sensitive cancer cells induced by the stress of chemotherapy. We found that treating a pancreatic cancer cell line BxPC-3 with gemcitabine induces cells to undergo an EMT, to become more invasive, and to show a switch from expressing mainly low levels of CD44v to expressing high levels of CD44s [ ].
Chemotherapy or other environmental stresses may induce a CD44s high expressing phenotype that promotes survival and that are more invasive.
Inhibiting or reversing the switch toward a mesenchymal phenotype may prove to be an important strategy for increasing the response to chemotherapy. Clinical evidence showed a positive correlation between CD44 expression and breast cancer bone metastasis [ ].
In vitro, knock-down of CD44s expression in breast cancer cell lines leads to markedly decreased number of tumor sphere formation in suspension cultures. Cell migration and invasion were suppressed by CD44s knock-down.
Overexpression of CD44s increased tumor sphere formation and cell migration. In vivo, tumor formation was inhibited in mice orthotopically inoculated with CD44s knock-down cells. The number of osteoclasts decreased in the bone metastases of CD44s knock-down tumors [ ].
These studies suggest cancer cells gaining acquired drug resistance tend to be accompanied with relatively higher expression of CD44s isoform. P-glycoprotein either reduces drug uptake or causes efflux of the drug out of cancer cells. MDR1 has also been linked to an increase in hyaluronan production in drug-sensitive tumor cells [ ]. HA and CD44 interaction activated an ErbB2-containing signaling complex, stimulating PI3K activity in multidrug-resistant human breast carcinoma cells.
Transient knock-down CD44 from placenta-derived human mesenchymal stem cells suppressed the hyaluronan-substratum-induced drug resistance and resulted in fewer MDR1-positive cells [ ].
The resistant cells form greater numbers of colonies; they were also able to form more tumor spheres in serum-free medium than their counterpart parental cells. Those gemcitabine-resistant cells were more tumorigenic in vivo confirmed by subcutaneous xenografts. FACS analysis had shown that most of the repopulated cells after surviving high-dose gemcitabine were CD44 positive.
These studies suggested that CD44 plays a role in chemoresistance although the mechanisms are still under the investigation [ ]. CD44 plays an indispensable role in activating survival pathways that protect cancer cells from apoptosis. The role of CD44 in cell survival involves alteration of multiple molecules that regulate pre or anti-apoptotic processes. CD44s, CD44v3-v10, and CD44v8-v10 transfected human colon cancer cell line promoted resistance to etoposide-induced apoptosis.
Bcl-2and caspase-3 expression was elevated in both CD44s- and CD44v-transfected cells [ ]. AKT phosphorylation, p21, and pRb were downregulated in CDtransfected cancer cells after anticancer reagent etoposide treatment. This suggests that expression of CD44 modulates cell cycle regulators pRb and p21, and the pro-survival protein AKT [ ]. CD44 also contributes to cell survival via regulating Fas in lung cancer cells. CD44 expression was found enriched in CLL patients.
Targeted deletion of CD44 in murine leukemogenesis model decreased the tumor burden in peripheral blood and spleen, resulting in a prolonged overall survival. CD44 expressing cells were significantly resistant to etoposide-induced apoptosis. Therefore, CD44 may provide a protection mechanism for cancer cells from apoptosis.
Targeted therapies are designed to block aberrantly activated signaling pathways in tumor cells specifically and are often tolerated better than conventional chemotherapies. CD44 may serve as a therapeutic target due to its role in regulating multiple survival signaling pathways and overexpressing CD44 is considered as a CSC marker. The major categories of CDtargeted therapies include neutralizing antibodies, peptide mimetics, aptamers, pharmacological inhibitors, CD44 decoys, and HA oligomers.
Some of the current approaches used to target CD44 are discussed below. Antibodies to CD44 are being studied in preclinical and clinical trials for cancer therapy. CD44 antibodies conjugated to anti-tumor agents can be used to target CDexpressing cancer cells or netballing antibodies that block CDmediated signaling were being developed for cancer therapy. However, these clinical trials were discontinued because of severe skin toxicities with one fatal outcome attributed to mertansine conjugates [ , ].
Peptide sequencing and screening data revealed that U36 antigen was identical to the squamous cell specific CD44v6 [ ]. The mAb U36 had significantly higher uptake in tumors [ ]. Moreover, the murine monoclonal IgG1 antibody VFF18, specific for human CD44v6, showed fast and selective tumor uptake of the radioimmunoconjugate in nude mice bearing human epidermoid carcinoma xenograft [ ].
In addition, a humanized mAb specific for CD44 RG was found to be cytotoxic to leukemia B cells without affecting the viability of normal B cells in chronic lymphocytic leukemia cells. Interestingly, the effects of RG were not neutralized in the presence of HA [ ]. Invasive potential of breast cancer cells with a mesenchymal phenotype can be inhibited by rat anti-human CDspecific antibodies IM7 [ ].
Treatment of mice harboring orthotopically implanted pancreas tumors with a CD44 neutralizing antibody H4C4 reduced tumor growth, metastasis, and postradiation recurrence [ 13 ]. Roche has developed a novel functional mAb RO which targets a glycosylated, conformation-dependent epitope of CD Based on preclinical investigations, RO and its radioimmunoconjugates were approved and used in several clinical trials.
First cohorts of patients received RO intravenously at escalating doses. In , a dose-escalation clinical trial study in patients with advanced gastric cancer was conducted. CD44 variant was shown to interact with xCT, a subunit of cystine-glutamate transporter, which maintains high levels of intracellular-reduced glutathione GSH which defend the cell against oxidative stress. Sulfasalazine, an inhibitor of xCT, was shown to suppress the proliferation of CD44v-positive cancer cells both in vitro and in vivo [ ].
Another ongoing clinical trial study ClinicalTrials. Those studies support the continued development of therapeutic strategies to target CD44 expression in patients. Other than antibodies, another strategy is to utilize the synthetic peptides that block CDHA interactions or to reduce CD44 expression in cancer cells. Treating CD44 double knockout mice with PEP-1 did not further reduce the rate of proliferation suggesting that CD44 may play an indispensable role in maintaining normal stem cell turnover.
PEP-1 can reduce CD44 expression in gastric cancer cells [ ]. A novel CDbinding peptide from the pro-matrix metalloproteinase-9 hemopexin domain impairs adhesion and migration of CLL cells [ ]. Aptamers have high binding affinity and specificity for target proteins to inhibit their functions. CD44v10 proteins formed complexes with the surface protein EphA2, which contributes to the invasiveness of cancer cells.
DNA aptamers that specifically bound to CD44 exon v10 inhibited the migration of breast cancer cells [ 18 ]. The bispecific CDEpCAM aptamer was significantly more effective than either single CD44 or EpCAM aptamer for inhibiting the cells growth or inducing apoptosis in ovarian cancer cells both in vitro and in vivo studies [ ].
In addition to directly targeting CD44, several natural compounds or chemotherapeutic drugs were shown to indirectly inhibit CSC which express CD44 isoforms [ ]. Silibinin, a major bioactive component of the plant Silybum marianum , has been studied extensively for its efficacy in prostate cancer and in phase II clinical trials.
Silibinin also caused a dose- and time-dependent cell growth inhibition in pancreatic cancer cell lines BxPC3 and Panc1 both in vitro and in vivo [ , , ].
Zerumbone, a monocyclic sesquiterpene derived from a Southeast Asian ginger, is often used as an anti-inflammatory and antioxidant agent. Zerumbone downregulated the basal level of CD44 expression in breast cancer cells. Gemini, a family of vitamin D analogs, is active in gene transcription with enhanced anti-tumor activity.
Gemini vitamin D decreased CD44 protein level, inhibited the invasion of the basal-like human breast cancer cells, and reduced tumor size in an orthotopic mice model [ , ]. This suggested these two phytochemicals may inhibit CD44 expression [ ]. The flavonoid apigenin also inhibited CDpositive CSC and prostate cancer cell survival in a dose-dependent manner and the mechanism might be due to a significant increase in expression of p21 and p27 [ ].
To maximize the drug effect on CD44 overexpressing cells, CD44 major ligand HA was used as a carrier to deliver chemotherapy agents.
HA-drug bioconjugates, such as HA-Taxol, HA-CPT11, HA-Paclitaxel PTX , and HA-polymer conjugates, can efficiently bind to CD44 overexpressing cancer cells and exert strong anti-proliferative activity on CD44 overexpressing cancer cells including human breast, colon, ovarian, gastric, breast, esophageal, and lung cancer cells as well as rat colon adenocarcinoma and colorectal cancer cells [ , , ].
Of note, the lower molecular weight oligomers of HA had better drug delivery effect by targeting CD44 overexpressing ovarian cancer cells [ ]. CD44 possessing cells have been targeted by HA-containing nanoparticles. Mice inoculated with hepatocellular carcinoma cells were orally administered with HA-selenium nanoparticles at different doses. The HA-selenium nanoparticles showed less toxicity and significantly reduced tumor weights compared to a 5-fluorouracil positive group [ ].
Similarly, the efficacy of doxorubicin loaded hyaluronan-coated superparamagnetic iron oxide nanoparticles has been evaluated in subcutaneous nude mice which intraperitoneal injection of human SKOV-3 ovarian cancer cells. HA-doxorubicin nanoparticles distributed wider in the tumor tissue than intravenously injected free doxorubicin, leading to significant reduction of tumor growth and increased the lifespan of those mice [ ].
HA-encapsulated siRNA nanoparticles have been investigated. In vivo studies showed that these nanoparticles specifically bound CD44 receptors and increased apoptosis of cancer cells, leading to significant decreases in prostate tumor growth [ ]. Chemotherapeutic agent-encapsulated liposomes, or covalently bound HA-bioconjugates, were selectively taken up by tumors in systemic delivery, and reduced specific gene expression in several xenograft models [ ].
In vivo, the tumors from mice in the HA-Lipid-PTX treatment group were significantly smaller compared with the control group [ ]. Nano-sized self-assemblies based on amphiphilic iodinated HA were developed for use in cancer diagnosis and therapy.
Several strategies have been used to block HA-CD44 binding. The soluble CD44 ectodomain was used as a competitor of CD44 on tumor cells to compete out HA ligand as a potential therapeutic approach to inhibit tumor growth and metastasis [ ]. Human melanoma cells transfected with an expression construct for the CD44 ectodomain showed retarded tumor growth [ ].
Several fusion proteins composed of the constant region of human IgG1 fused to the extracellular domain of human CD44v3-v10, CD44v8-v10, or CD44s have been developed. Expression of these fusion proteins reduced binding of HA to glioblastoma cells. Those fusion proteins markedly inhibit subcutaneous and intracranial cell growth and significantly extended the survival of mice-bearing intracranial tumors [ ].
The augmentation of CXCR4 contributed to increased vessel sprouting and angiogenesis. CD44 is upregulated in a variety of cancers and can be expressed in its standard isoform, CD44s, or as a number of alternatively spliced variant isoforms, CD44v.
CD44 isoforms are overexpressed in many cancer types. Here, we discussed the current understanding of the structure and function role of CD44 in the pathogenesis of cancer. CD44 mediates its effects on the cancer cell by activating signaling pathways including protein kinases, by activating transcription factors and by modulating the cytoskeletal architecture.
The functional role of CD44 is pleiotropic, includes inducing EMT, altering the cellular cytoskeleton, by promoting drug resistance and through anti-apoptosis mechanisms. Proteomic and genomic approaches can identify the mechanisms by which CD44 promotes tumorigenicity. Multiple CD44v tends to play a role in epithelial phenotype, tumor initiation, growth, and are often associated with metastatic lesions.
The functional roles of various CD44 isoforms on cancer development and progression remain an active area of investigation. CD44 expression is regulated by multiple levels including transcription factors, epigenetic mechanism, microRNAs, and by post-translational modifications.
The switch of CD44 isoforms as how this relates to their functional roles in adaptive plasticity of tumor cells is becoming more clearly delineated.
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