CD44

Gene Summary

Gene:CD44; CD44 molecule (Indian blood group)
Aliases: IN, LHR, MC56, MDU2, MDU3, MIC4, Pgp1, CDW44, CSPG8, HCELL, HUTCH-I, ECMR-III
Location:11p13
Summary:The protein encoded by this gene is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. It is a receptor for hyaluronic acid (HA) and can also interact with other ligands, such as osteopontin, collagens, and matrix metalloproteinases (MMPs). This protein participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis. Transcripts for this gene undergo complex alternative splicing that results in many functionally distinct isoforms, however, the full length nature of some of these variants has not been determined. Alternative splicing is the basis for the structural and functional diversity of this protein, and may be related to tumor metastasis. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:CD44 antigen
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD44 (cancer-related)

Candas D, Lu CL, Fan M, et al.
Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells.
Cancer Res. 2014; 74(24):7498-509 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
The MAPK phosphatase MKP1 (DUSP1) is overexpressed in many human cancers, including chemoresistant and radioresistant breast cancer cells, but its functional contributions in these settings are unclear. Here, we report that after cell irradiation, MKP1 translocates into mitochondria, where it prevents apoptotic induction by limiting accumulation of phosphorylated active forms of the stress kinase JNK. Increased levels of mitochondrial MKP1 after irradiation occurred in the mitochondrial inner membrane space. Notably, cell survival regulated by mitochondrial MKP1 was responsible for conferring radioresistance in HER2-overexpressing breast cancer cells, due to the fact that MKP1 serves as a major downstream effector in the HER2-activated RAF-MEK-ERK pathway. Clinically, we documented MKP1 expression exclusively in HER2-positive breast tumors, relative to normal adjacent tissue from the same patients. MKP1 overexpression was also detected in irradiated HER2-positive breast cancer stem-like cells (HER2(+)/CD44(+)/CD24(-/low)) isolated from a radioresistant breast cancer cell population after long-term radiation treatment. MKP1 silencing reduced clonogenic survival and enhanced radiosensitivity in these stem-like cells. Combined inhibition of MKP1 and HER2 enhanced cell killing in breast cancer. Together, our findings identify a new mechanism of resistance in breast tumors and reveal MKP1 as a novel therapeutic target for radiosensitization.

Gil M, Komorowski MP, Seshadri M, et al.
CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells.
J Immunol. 2014; 193(10):5327-37 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Signals mediated by the chemokine CXCL12 and its receptor CXCR4 are involved in the progression of ovarian cancer through enhancement of tumor angiogenesis and immunosuppressive networks that regulate dissemination of peritoneal metastasis and development of cancer-initiating cells (CICs). In this study, we investigated the antitumor efficacy of a CXCR4 antagonist expressed by oncolytic vaccinia virus (OVV) against an invasive variant of the murine epithelial ovarian cancer cell line ID8-T. This variant harbors a high frequency of CICs that form multilayered spheroid cells and express the hyaluronan receptor CD44, as well as stem cell factor receptor CD117 (c-kit). Using an orthotopic ID8-T tumor model, we observed that i.p. delivery of a CXCR4 antagonist-expressing OVV led to reduced metastatic spread of tumors and improved overall survival compared with oncolysis alone. Inhibition of tumor growth with the armed virus was associated with efficient killing of CICs, reduced expression of ascitic CXCL12 and vascular endothelial growth factor, and decreases in i.p. numbers of endothelial and myeloid cells, as well as plasmacytoid dendritic cells. These changes, together with reduced recruitment of T regulatory cells, were associated with higher ratios of IFN-γ(+)/IL-10(+) tumor-infiltrating T lymphocytes, as well as induction of spontaneous humoral and cellular antitumor responses. Similarly, the CXCR4 antagonist released from virally infected human CAOV2 ovarian carcinoma cells inhibited peritoneal dissemination of tumors in SCID mice, leading to improved tumor-free survival in a xenograft model. Our findings demonstrate that OVV armed with a CXCR4 antagonist represents a potent therapy for ovarian CICs with a broad antitumor repertoire.

Volinia S, Nuovo G, Drusco A, et al.
Pluripotent stem cell miRNAs and metastasis in invasive breast cancer.
J Natl Cancer Inst. 2014; 106(12) [PubMed] Related Publications
BACKGROUND: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome.
METHODS: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296). In parallel, using next-generation sequencing data from breast cancer patients (n = 684), we assessed microRNA association with stem cell markers. All statistical tests were two-sided.
RESULTS: In healthy tissues, the MIR302 (high)/MIR203 (low) asymmetry was exclusive for pluripotent stem cells. MIR302 was expressed in a small population of cancer cells within invasive ductal carcinoma, but not in normal breast (P < .001). Furthermore, MIR302 was expressed in the tumor cells together with stem cell markers, such as CD44 and BMI1. Conversely, MIR203 expression in 684 breast tumors negatively correlated with CD44 (Spearman correlation, Rho = -0.08, P = .04) and BMI1 (Rho = -0.11, P = .004), but positively correlated with differentiation marker CD24 (Rho = 0.15, P < .001). Primary tumors with lymph node metastasis had cancer cells showing scattered expression of MIR302 and widespread repression of MIR203. Finally, overall survival was statistically significantly shorter in patients with MIR302-positive cancer cells (P = .03).
CONCLUSIONS: In healthy tissues the MIR302(high)/MIR203(low) asymmetry was characteristic of embryonic and induced pluripotency. In invasive ductal carcinoma, the MIR302/MIR203 asymmetry was associated with stem cell markers, metastasis, and shorter survival.

Dauksa A, Gulbinas A, Endzinas Z, et al.
DNA methylation at selected CpG sites in peripheral blood leukocytes is predictive of gastric cancer.
Anticancer Res. 2014; 34(10):5381-8 [PubMed] Related Publications
BACKGROUND/AIM: Recently, a set of studies addressed the question of the prevalence of aberrant methylation in surrogate tissues, such as peripheral blood leukocytes. Toward this aim, we conducted a case-control pilot study to investigate aberrant methylation in leukocytes of gastric cancer patients.
MATERIALS AND METHODS: The SNuPE combined with ion pair reverse phase HPLC (SIRPH method) was used to examine site-specific methylation status at selected CpG sites of the promoter regions of APC, ACIN1, BCL2, CD44, DAPK1, CDKN2A, RARB, TNFRSF10C HS3ST2 and of LINE-1, Alu repeats.
RESULTS: We observed that in the patients, tumor suppressor genes were slightly but significantly higher methylated at several CpG sites, while DNA repetitive elements were slightly less methylated compared to controls. This was found to be significantly associated with higher prevalence for gastric cancer.
CONCLUSION: These results suggest that larger studies must be carried-out to explore the biological significance and clinical usefulness of leukocyte DNA as non-invasive detection tool for gastric cancer.

La Starza R, Borga C, Barba G, et al.
Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations.
Blood. 2014; 124(24):3577-82 [PubMed] Related Publications
MYC translocations represent a genetic subtype of T-lineage acute lymphoblastic leukemia (T-ALL), which occurs at an incidence of ∼6%, assessed within a cohort of 196 T-ALL patients (64 adults and 132 children). The translocations were of 2 types; those rearranged with the T-cell receptor loci and those with other partners. MYC translocations were significantly associated with the TAL/LMO subtype of T-ALL (P = .018) and trisomies 6 (P < .001) and 7 (P < .001). Within the TAL/LMO subtype, gene expression profiling identified 148 differentially expressed genes between patients with and without MYC translocations; specifically, 77 were upregulated and 71 downregulated in those with MYC translocations. The poor prognostic marker, CD44, was among the upregulated genes. MYC translocations occurred as secondary abnormalities, present in subclones in one-half of the cases. Longitudinal studies indicated an association with induction failure and relapse.

Ali A, Shah AS, Ahmad A
Gain-of-function of mutant p53: mutant p53 enhances cancer progression by inhibiting KLF17 expression in invasive breast carcinoma cells.
Cancer Lett. 2014; 354(1):87-96 [PubMed] Related Publications
Kruppel-like-factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal-transition (EMT). However, its expression is downregulated in metastatic breast cancer that contains p53 mutations. Here, we show that mutant-p53 plays a key role to suppress KLF17 and thereby enhances cancer progression, which defines novel gain-of-function (GOF) of mutant-p53. Mutant-p53 interacts with KLF17 and antagonizes KLF17 mediated EMT genes transcription. Depletion of KLF17 promotes cell viability, decreases apoptosis and induces drug resistance in metastatic breast cancer cells. KLF17 suppresses cell migration and invasion by decreasing CD44, PAI-1 and Cyclin-D1 expressions. Taken together, our results show that KLF17 is important for the suppression of metastasis and could be a potential therapeutic target during chemotherapy.

Ma L, Pan Q, Sun F, et al.
Cluster of differentiation 166 (CD166) regulates cluster of differentiation (CD44) via NF-κB in liver cancer cell line Bel-7402.
Biochem Biophys Res Commun. 2014; 451(2):334-8 [PubMed] Related Publications
Cluster of differentiation 166 (CD166) is critical for liver cancer cell survival. Our previously study demonstrated that CD166 exerts its anti-apoptotic role through interaction with YAP in liver cancer. However, the interaction between CD166 and other cell surface molecules remains unclear in liver cancer cells. In the current study, we found that both mRNA and protein of CD44 expression was significantly inhibited by knocking-down CD166. Moreover, CD166 affected-CD44 expression is dependent of transcription via blocking NF-κB pathway. On the contrary, CD44 promoted up-regulation of CD166 mRNA and protein. And it may be through E3 ubiquitin ligases COP1 and UBC3 to regulate CD166 protein degradation. Collectively, these results suggest that CD166 and CD44 play important roles in liver cancer development. Therefore, CD166 may develop as a potential therapeutic molecule target for the treatment of liver cancer.

Marino N, Collins JW, Shen C, et al.
Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines.
Clin Exp Metastasis. 2014; 31(7):771-86 [PubMed] Related Publications
Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

Senturk S, Yao Z, Camiolo M, et al.
p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state.
Proc Natl Acad Sci U S A. 2014; 111(32):E3287-96 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Ψ attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53Ψ encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner.

Fagan-Solis KD, Reaves DK, Rangel MC, et al.
Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer.
Mol Cancer. 2014; 13:163 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
BACKGROUND: Translational exploration of bacterial toxins has come to the forefront of research given their potential as a chemotherapeutic tool. Studies in select tissues have demonstrated that Clostridium perfringens iota toxin binds to CD44 and lipolysis stimulated lipoprotein receptor (LSR) cell-surface proteins. We recently demonstrated that LSR expression correlates with estrogen receptor positive breast cancers and that LSR signaling directs aggressive, tumor-initiating cell behaviors. Herein, we identify the mechanisms of iota toxin cytotoxicity in a tissue-specific, breast cancer model with the ultimate goal of laying the foundation for using iota toxin as a targeted breast cancer therapy.
METHODS: In vitro model systems were used to determine the cytotoxic effect of iota toxin on breast cancer intrinsic subtypes. The use of overexpression and knockdown technologies confirmed the roles of LSR and CD44 in regulating iota toxin endocytosis and induction of cell death. Lastly, cytotoxicity assays were used to demonstrate the effect of iota toxin on a validated set of tamoxifen resistant breast cancer cell lines.
RESULTS: Treatment of 14 breast cancer cell lines revealed that LSR+/CD44- lines were highly sensitive, LSR+/CD44+ lines were slightly sensitive, and LSR-/CD44+ lines were resistant to iota cytotoxicity. Reduction in LSR expression resulted in a significant decrease in toxin sensitivity; however, overexpression of CD44 conveyed toxin resistance. CD44 overexpression was correlated with decreased toxin-stimulated lysosome formation and decreased cytosolic levels of iota toxin. These findings indicated that expression of CD44 drives iota toxin resistance through inhibition of endocytosis in breast cancer cells, a role not previously defined for CD44. Moreover, tamoxifen-resistant breast cancer cells exhibited robust expression of LSR and were highly sensitive to iota-induced cytotoxicity.
CONCLUSIONS: Collectively, these data are the first to show that iota toxin has the potential to be an effective, targeted therapy for breast cancer.

Mashita N, Yamada S, Nakayama G, et al.
Epithelial to mesenchymal transition might be induced via CD44 isoform switching in colorectal cancer.
J Surg Oncol. 2014; 110(6):745-51 [PubMed] Related Publications
BACKGROUND: Isoform switching of CD44 is associated with epithelial to mesenchymal transition (EMT) in several cancers; however, the clinical implications of this remain unclear for colorectal cancer (CRC).
METHODS: We measured expression levels of E-cadherin, vimentin, CD44 standard (CD44s) and CD44 variant 9 (CD44v9) transcripts in 14 CRC cell lines and 150 CRC patients. We determined EMT and CD44 status by calculating vimentin/E-cadherin and CD44s/CD44v9 expression ratios, respectively. Associations between EMT status and CD44 isoform switching, and between clinicopathological factors and prognosis were analyzed.
RESULTS: CD44s was highly expressed in mesenchymal-type cell lines, while CD44v9 was highly expressed in epithelial-type cell lines. CD44 knockdown resulted in decreased levels of vimentin expression, and significantly reduced proliferation, migration and invasion of cells. In CRC patients, the mesenchymal group and the high CD44 status group exhibited significantly poorer survival than that for the epithelial group (5-year survival; 62.1% vs. 85.5%, P = 0.0085) and the low CD44 status group (5-year survival; 66.1% vs. 85.0%, P = 0.0251). On multivariate analysis, CD44 status was an independent prognostic factor.
CONCLUSIONS: The status of EMT and CD44 is a critical prognostic factor, with CD44 isoform switching a possible trigger for EMT in CRC.

Chen R, Dong Y, Xie X, et al.
Screening candidate metastasis-associated genes in three-dimensional HCC spheroids with different metastasis potential.
Int J Clin Exp Pathol. 2014; 7(5):2527-35 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
PURPOSE: Previously, we have established a tissue-like HCC spheroid which better mirrors the biological features of tumorigenesis and metastasis. This study was to find out metastasis-associated genes between two 3D HCC spheroids with different metastasis potential using comparative PCR arrays.
MATERIALS AND METHODS: Two HCC spheroids derived from high-metastatic MHCC97H cells and low-metastatic Hep3B cells were formed respectively in a rotating wall vessel bioreactor after 3D culture for 15 days. The candidate metastasis-associated genes related to cell adhesion, matrix secretion and invasion in HCC spheroids were screened by RT² profiler PCR arrays. The expression patterns of several differentially-expressed genes were further confirmed by real-time RT-PCR.
RESULTS: Total of 123 differential expression genes (fold-change>2) were found between two HCC spheroids, including 70 up-regulated genes (VCAM-1, IL-1β, CD44, tenascin C, SPP1, fibronectin, MMP-2, MMP-7, etc) and 53 down-regulated genes (E-cadherin, CTNND2, etc) in the high-metastatic spheroid. Function classification showed that the number of up-regulated genes related to adhesion molecules mediating cell-matrix interactions and matrix secretion was significantly higher in high-metastatic spheroid than that in low-metastatic spheroid. In contrast, the expressions of adhesion molecules maintaining homotypic tumor cell adhesion were decreased in metastatic spheroid as compared with that in low-metastatic spheroid. In addition, the expression pattern of seven selected genes associated with tumor metastasis measured by real-time RT-PCR were consistent with results of PCR arrays.
CONCLUSIONS: Obvious differences between two HCC spheroids in gene expression patterns of adhesion molecules, matrix secretion, invasion and other molecules may determine the different metastatic characteristics and malignant phenotype of HCC spheroid.

Villegas-Ruíz V, Salcedo M, Zentella-Dehesa A, et al.
A case of cervical cancer expressed three mRNA variant of Hyaluronan-mediated motility receptor.
Int J Clin Exp Pathol. 2014; 7(5):2256-64 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Cervical cancer is the second malignancy in Mexico, little is known about the prognostic factors associated with this disease. Several cellular components are important in their transformation and progression. Alternative mRNA splice is an important mechanism for generating protein diversity, nevertheless, in cancer unknown mRNA diversity is expressed. Hyaluronan-mediated motility receptor (HMMR, RHAMM, CD168) is a family member of proteins, hyaluronan acid dependent, and has been associated with different malignant processes such as: angiogenesis, cell invasiveness, proliferation, metastasis and poor outcome in some tumors. In the present study we identified expression of HMMR in cervical cancer by means of RT-PCR and sequencing. Our results indicate co-expression of two HMMR variants in all samples, and one case expressed three alternative HMMR splice transcripts. These results showed the heterogeneity of mRNA transcripts of HMMR that could express in cancer and the expression of HMMR could be marker of malignancy in CC.

Xiong B, Ma L, Hu X, et al.
Characterization of side population cells isolated from the colon cancer cell line SW480.
Int J Oncol. 2014; 45(3):1175-83 [PubMed] Related Publications
Side population (SP) cells may play a crucial role in tumorigenesis and the recurrence of cancer. Many types of cell lines and tissues have demonstrated the presence of SP cells, including colon cancer cell lines. This study aimed to identify cancer stem cells (CSCs) in the SP of the colon cancer cell line SW480. SP cells were isolated by fluorescence-activated cell sorting (FACS), followed by serum-free medium (SFM) culture. The self-renewal, differentiated progeny, clone formation, proliferation, invasion ability, cell cycle, chemosensitivity and tumorigenic properties in SP and non-SP (NSP) cells were investigated through in vitro culture and in vivo serial transplantation. The expression profiles of ATP-binding cassette (ABC) protein transporters and stem cell-related genes were examined by RT-PCR and western blot analysis. The human colon cancer cell lines SW480, Lovo and HCT116 contain 1.1 ± 0.10, 0.93 ± 0.11 and 1.33 ± 0.05% SP cells, respectively. Flow cytometry analysis revealed that SP cells could differentiate into SP and NSP cells. SP cells had a higher proliferation potency and CFE than NSP cells. Compared to NSP cells, SP cells were also more resistant to CDDP and 5-FU, and were more invasive and displayed increased tumorigenic ability. Moreover, SP cells showed higher mRNA and protein expression of ABCG2, MDR1, OCT-4, NANOG, SOX-2, CD44 and CD133. SP cells isolated from human colon cancer cell lines harbor CSC properties that may be related to the invasive potential and therapeutic resistance of colon cancer.

McManus MM, Weiss KR, Hughes DP
Understanding the role of Notch in osteosarcoma.
Adv Exp Med Biol. 2014; 804:67-92 [PubMed] Related Publications
The Notch pathway has been described as an oncogene in osteosarcoma, but the myriad functions of all the members of this complex signaling pathway, both in malignant cells and nonmalignant components of tumors, make it more difficult to define Notch as simply an oncogene or a tumor suppressor. The cell-autonomous behaviors caused by Notch pathway manipulation may vary between cell lines but can include changes in proliferation, migration, invasiveness, oxidative stress resistance, and expression of markers associated with stemness or tumor-initiating cells. Beyond these roles, Notch signaling also plays a vital role in regulating tumor angiogenesis and vasculogenesis, which are vital aspects of osteosarcoma growth and behavior in vivo. Further, osteosarcoma cells themselves express relatively low levels of Notch ligand, making it likely that nonmalignant cells, especially endothelial cells and pericytes, are the major source of Notch activation in osteosarcoma tumors in vivo and in patients. As a result, Notch pathway expression is not expected to be uniform across a tumor but likely to be highest in those areas immediately adjacent to blood vessels. Therapeutic targeting of the Notch pathway is likewise expected to be complicated. Most pharmacologic approaches thus far have focused on inhibition of gamma secretase, a protease of the presenilin complex. This enzyme, however, has numerous other target proteins that would be expected to affect osteosarcoma behavior, including CD44, the WNT/β-catenin pathway, and Her-4. In addition, Notch plays a vital role in tissue and organ homeostasis in numerous systems, and toxicities, especially GI intolerance, have limited the effectiveness of gamma secretase inhibitors. New approaches are in development, and the downstream targets of Notch pathway signaling also may turn out to be good targets for therapy. In summary, a full understanding of the complex functions of Notch in osteosarcoma is only now unfolding, and this deeper knowledge will help position the field to better utilize novel therapies as they are developed.

Ozawa M, Ichikawa Y, Zheng YW, et al.
Prognostic significance of CD44 variant 2 upregulation in colorectal cancer.
Br J Cancer. 2014; 111(2):365-74 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
BACKGROUND: CD133 and CD44 are putative cancer stem cell (CSC) markers in colorectal cancer (CRC). However, their clinical significance is currently unclear. Here, we evaluated primary CRC cell isolates to determine the significance of several CSC markers, including CD133 and CD44, as predictors of tumourigenesis and prognosis.
METHODS: CD133- and CD44-positive cells from fresh clinical samples of 77 CRCs were selected by flow cytometric sorting and evaluated for tumourigenicity following subcutaneous transplantation into NOD/SCID mice. Cancer stem cell marker expression was examined in both xenografts and a complementary DNA library compiled from 167 CRC patient samples.
RESULTS: CD44(+), CD133(+) and CD133(+)CD44(+) sub-populations were significantly more tumourigenic than the total cell population. The clinical samples expressed several transcript variants of CD44. Variant 2 was specifically overexpressed in both primary tumours and xenografts in comparison with the normal mucosa. A prognostic assay using qRT-PCR showed that the CD44v2(high) group (n=84, 5-year survival rate (5-OS): 0.74) had a significantly worse prognosis (P=0.041) than the CD44v2(low) group (n=83, 5-OS: 0.88).
CONCLUSIONS: CD44 is an important CSC marker in CRC patients. Furthermore, CRC patients with high expression of CD44v2 have a poorer prognosis than patients with other CD44 variants.

Sulpice L, Rayar M, Turlin B, et al.
Epithelial cell adhesion molecule is a prognosis marker for intrahepatic cholangiocarcinoma.
J Surg Res. 2014; 192(1):117-23 [PubMed] Related Publications
BACKGROUND: Recently, we identified a gene signature of intrahepatic cholangiocarcinoma (ICC) stroma and demonstrated its clinical relevance for prognosis. The most upregulated genes included epithelial cell adhesion molecule (EpCAM), a biomarker of cancer stem cells (CSC). We hypothesized that CSC biomarkers could predict recurrence of resected ICC.
METHODS: Both functional analysis of the stroma signature previously obtained and immunohistochemistry of 40 resected ICC were performed. The relationships between the expression of CSC markers and clinicopathologic factors including survival were assessed by univariate and multivariable analyzes.
RESULTS: Gene expression profile of the stroma of ICC highlighted embryonic stem cells signature. Immunohistochemistry on tissue microarray showed at a protein level the increased expression of CSC biomarkers in the stroma of ICC compared with nontumor fibrous liver tissue. The overexpression of EpCAM in the stroma of ICC is an independent risk factor for overall (hazard ratio = 2.6; 95% confidence interval, 1.3-5.1; P = 0.005) and disease-free survival (hazard ratio = 2.2; 95% confidence interval, 1.2-4.2; P = 0.012). In addition, the overexpression of EpCAM in nontumor fibrous liver tissue is closely correlated with a worst disease-free survival (P = 0.035).
CONCLUSIONS: Our findings provide new arguments for a potential role of CSC on ICC progression supporting the idea that targeting CSC biomarkers might represent a promise personalized treatment.

Zafar A, Wu F, Hardy K, et al.
Chromatinized protein kinase C-θ directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells.
Mol Cell Biol. 2014; 34(16):2961-80 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. Signal transduction kinases play a pivotal role as chromatin-anchored proteins in eukaryotes. Here we report for the first time that protein kinase C-theta (PKC-θ) promotes EMT by acting as a critical chromatin-anchored switch for inducible genes via transforming growth factor β (TGF-β) and the key inflammatory regulatory protein NF-κB. Chromatinized PKC-θ exists as an active transcription complex and is required to establish a permissive chromatin state at signature EMT genes. Genome-wide analysis identifies a unique cohort of inducible PKC-θ-sensitive genes that are directly tethered to PKC-θ in the mesenchymal state. Collectively, we show that cross talk between signaling kinases and chromatin is critical for eliciting inducible transcriptional programs that drive mesenchymal differentiation and CSC formation, providing novel mechanisms to target using epigenetic therapy in breast cancer.

Cortes-Dericks L, Froment L, Boesch R, et al.
Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity.
BMC Cancer. 2014; 14:304 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
BACKGROUND: Conventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs). We sought to identify a sub-population of chemoresistant cells by using putative CSC markers, aldehyde dehydrogenase (ALDH) and CD44 in three MPM cell lines; H28, H2052 and Meso4.
METHODS: The Aldefluor assay was used to measure ALDH activity and sort ALDH(high) and ALDH(low) cells. Drug-resistance was evaluated by cell viability, anchorage-independent sphere formation, flow-cytometry and qRT-PCR analyses.
RESULTS: The ALDH(high) - and ALDH(low) -sorted fractions were able to demonstrate phenotypic heterogeneity and generate spheres, the latter being less efficient, and both showed an association with CD44. Cis- diamminedichloroplatinum (II) (cisplatin) treatment failed to reduce ALDH activity and conferred only a short-term inhibition of sphere generation in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation. At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines.
CONCLUSIONS: Our study shows that ALDH(high) CD44(+) cells are implicated in conveying tolerance to cisplatin in the three MPM cell lines. The combined use of CD44 and ALDH widens the window for identification and targeting of a drug-resistant population which may improve the current treatment modalities in mesothelioma.

He KF, Zhang L, Huang CF, et al.
CD163+ tumor-associated macrophages correlated with poor prognosis and cancer stem cells in oral squamous cell carcinoma.
Biomed Res Int. 2014; 2014:838632 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Tumor-associated macrophages (TAMs) play an important role in the progression and prognostication of numerous cancers. However, the role and clinical significance of TAM markers in oral squamous cell carcinoma (OSCC) has not been elucidated. The present study was designed to investigate the correlation between the expression of TAM markers and pathological features in OSCC by tissue microarray. Tissue microarrays containing 16 normal oral mucosa, 6 oral epithelial dysplasia, and 43 OSCC specimens were studied by immunohistochemistry. We observed that the protein expression of the TAM markers CD68 and CD163 as well as the cancer stem cell (CSC) markers ALDH1, CD44, and SOX2 increased successively from the normal oral mucosa to OSCC. The expressions of CD68 and CD163 were significantly associated with lymph node status, and SOX2 was significantly correlated with pathological grade and lymph node status, whereas ALDH1 was correlated with tumor stage. Furthermore, CD68 was significantly correlated with CD163, SOX2, and ALDH1 (P < 0.05). Kaplan-Meier analysis revealed that OSCC patients overexpressing CD163 had significantly worse overall survival (P < 0.05). TAM markers are associated with cancer stem cell marker and OSCC overall survival, suggesting their potential prognostic value in OSCC.

Cui FB, Liu Q, Li RT, et al.
Enhancement of radiotherapy efficacy by miR-200c-loaded gelatinase-stimuli PEG-Pep-PCL nanoparticles in gastric cancer cells.
Int J Nanomedicine. 2014; 9:2345-58 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Radiotherapy is the main locoregional control modality for many types of unresectable tumors, including gastric cancer. However, many patients fail radiotherapy due to intrinsic radioresistance of cancer cells, which has been found to be strongly associated with cancer stem cell (CSC)-like properties. In this study, we developed a nanoparticle formulation to deliver miR-200c, which is reported to inhibit CSC-like properties, and then evaluated its potential activity as a radiosensitizer. miR-200c nanoparticles significantly augmented radiosensitivity in three gastric cancer cell lines (sensitization enhancement ratio 1.13-1.25), but only slightly in GES-1 cells (1.06). In addition to radioenhancement, miR-200c nanoparticles reduced the expression of CD44, a putative CSC marker, and the percentage of CD44(+) BGC823 cells. Meanwhile, other CSC-like properties, including invasiveness and resistance to apoptosis, could be suppressed by miR-200c nanoparticles. CSC-associated radioresistance mechanisms, involving reactive oxygen species levels and DNA repair capacity, were also attenuated. We have demonstrated that miR-200c nanoparticles are an effective radiosensitizer in gastric cancer cells and induce little radiosensitization in normal cells, which suggests that they are as a promising candidate for further preclinical and clinical evaluation.

Yu G, Li H, Wang J, et al.
miRNA-34a suppresses cell proliferation and metastasis by targeting CD44 in human renal carcinoma cells.
J Urol. 2014; 192(4):1229-37 [PubMed] Related Publications
PURPOSE: We investigated the potential functions of miR-34a in CD44 transcriptional complexes in renal cell carcinoma.
MATERIALS AND METHODS: We detected miR-34a expression by quantitative real-time polymerase chain reaction. Oligonucleotides were used to over express miR-34a. Cell proliferation and xenograft assays, colony formation and flow cytometry were done to examine effects on cancer cell proliferation in vitro and in vivo. Luciferase assay was performed to verify the precise target of miR-34a.
RESULTS: Promoter methylation contributed to miR-34a loss in the ACHN, 786-O and SN12PM6 renal carcinoma cell lines. Ectopic over expression of miR-34a restrained cell growth, tube formation and migration/invasion, and significantly suppressed the growth of renal carcinoma xenografts and metastasis in nude mice. Dual luciferase assay revealed that CD44 was a direct target of miR-34a in renal cancer cells and CD44 knockdown by RNAi in renal cancer cells suppressed tumor progression. In contrast, CD44 ectopic expression partially reversed the antitumor effects of miR-34a in renal cancer cells.
CONCLUSIONS: Our findings indicate that miR-34a targets CD44 in renal cancer cells and suppresses renal cancer cell growth, tube formation and metastasis in vitro and in vivo. Thus, miR-34a may be a potential molecular target for novel therapeutic strategies for clear cell renal carcinoma.

Kottakis F, Foltopoulou P, Sanidas I, et al.
NDY1/KDM2B functions as a master regulator of polycomb complexes and controls self-renewal of breast cancer stem cells.
Cancer Res. 2014; 74(14):3935-46 [PubMed] Related Publications
The JmjC domain histone H3K36me2/me1 demethylase NDY1/KDM2B is overexpressed in various types of cancer. Here we show that knocking down NDY1 in a set of 10 cell lines derived from a broad range of human tumors inhibited their anchorage-dependent and anchorage-independent growth by inducing senescence and/or apoptosis in some and by inhibiting G1 progression in all. We further show that the knockdown of NDY1 in mammary adenocarcinoma cell lines decreased the number, size, and replating efficiency of mammospheres and downregulated the stem cell markers ALDH and CD44, while upregulating CD24. Together, these findings suggest that NDY1 is required for the self-renewal of cancer stem cells and are in agreement with additional findings showing that tumor cells in which NDY1 was knocked down undergo differentiation and a higher number of them is required to induce mammary adenocarcinomas, upon orthotopic injection in animals. Mechanistically, NDY1 functions as a master regulator of a set of miRNAs that target several members of the polycomb complexes PRC1 and PRC2, and its knockdown results in the de-repression of these miRNAs and the downregulation of their polycomb targets. Consistent with these observations, NDY1/KDM2B is expressed at higher levels in basal-like triple-negative breast cancers, and its overexpression is associated with higher rates of relapse after treatment. In addition, NDY1-regulated miRNAs are downregulated in both normal and cancer mammary stem cells. Finally, in primary human breast cancer, NDY1/KDM2B expression correlates negatively with the expression of the NDY1-regulated miRNAs and positively with the expression of their PRC targets.

Xu Y, Gao XD, Lee JH, et al.
Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing.
Genes Dev. 2014; 28(11):1191-203 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFβ signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFβ-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.

Bogachek MV, Chen Y, Kulak MV, et al.
Sumoylation pathway is required to maintain the basal breast cancer subtype.
Cancer Cell. 2014; 25(6):748-61 [PubMed] Article available free on PMC after 16/06/2015 Related Publications
The TFAP2C/AP-2γ transcription factor regulates luminal breast cancer genes, and loss of TFAP2C induces epithelial-mesenchymal transition. By contrast, the highly homologous family member, TFAP2A, lacks transcriptional activity at luminal gene promoters. A detailed structure-function analysis identified that sumoylation of TFAP2A blocks its ability to induce the expression of luminal genes. Disruption of the sumoylation pathway by knockdown of sumoylation enzymes, mutation of the SUMO-target lysine of TFAP2A, or treatment with sumoylation inhibitors induced a basal-to-luminal transition, which was dependent on TFAP2A. Sumoylation inhibitors cleared the CD44(+/hi)/CD24(-/low) cell population characterizing basal cancers and inhibited tumor outgrowth of basal cancer xenografts. These findings establish a critical role for sumoylation in regulating the transcriptional mechanisms that maintain the basal cancer phenotype.

Owen JH, Hauff SJ, Tang AL, et al.
UM-SCC-103: a unique tongue cancer cell line that recapitulates the tumorigenic stem cell population of the primary tumor.
Ann Otol Rhinol Laryngol. 2014; 123(9):662-72 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
OBJECTIVE: A new head and neck cancer cell line was developed from a highly aggressive HNSCC of the oral cavity diagnosed in a 26-year-old pregnant woman.
METHODS: Cells from the primary tumor were passaged in culture and genotyped as a unique cell line. The resultant cell line was assessed for its ability to replicate the primary tumor.
RESULTS: The primary tumor and cell line contained 19.03% and 19.62% CD44(high) cells, respectively. CD44(high) cancer stem cells from UM-SCC-103 formed tumors after flank injections in mice that reconstituted the heterogeneity of the primary tumor. CD44 staining and histology in the primary tumor and tumors grown in vivo from the cell line were similar. CD44(high) cells from the primary tumor resulted in lung colony formation in 2 out of 2 tail vein injections in mice, whereas CD44(low) cells did not. Similarly, CD44(high) cells from UM-SCC-103 formed lung tumors in 2 out of 4 mice, whereas CD44(low) cells did not.
CONCLUSION: The similarity in marker expression and tumorigenic behavior between the primary tumor and the resulting cell line strongly suggests that the cell line resembles the primary tumor that it was derived from and provides an important new research tool for the study of head and neck carcinomas in young patients.

Okada T, Nakamura T, Watanabe T, et al.
Coexpression of EpCAM, CD44 variant isoforms and claudin-7 in anaplastic thyroid carcinoma.
PLoS One. 2014; 9(4):e94487 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Anaplastic thyroid cancer is considered to be one of the most aggressive human malignancies, and the mean survival time after diagnosis is approximately six months, regardless of treatments. This study aimed to examine how EpCAM and its related molecules are involved in the characteristics of anaplastic thyroid carcinoma.
METHODOLOGY/PRINCIPAL FINDINGS: Two differentiated thyroid cancer cell lines (TPC-1 and FTC-133), and two anaplastic thyroid cancer cell lines (FRO, ACT-1) were analyzed for expression of CD44 standard isoform (CD44s), CD44 variant isoforms, and EpCAM, and human aldehyde dehydrogenase-1 (ALDH1) enzymatic activity using flow cytometry. CD44s expression was higher in TPC-1 and FTC-133 than in the FRO and ACT-1, whereas ALDH1 activities were higher in FRO and ACT-1 than in TPC-1 and FTC-133. An inverse correlation between CD44s expression and ALDH1 activity was observed in all thyroid cancer cell lines. As for the expressions of CD44 variant isoforms, ACT-1 showed higher and FRO showed moderate CD44v6 expressions, whereas either TPC-1 or FTC-133 showed negative CD44v6 expression. EpCAM expressions in FRO and ACT-1 were higher than those in TPC-1 and FTC-133, and EpCAM expressions inversely correlated with those of CD44s. A positive correlation was observed between EpCAM expression and ALDH1 activity in thyroid cancer cell lines. In the RT-PCR analysis, the expression levels of EpCAM, caludin-7 and ALDH1 in FRO and ATC-1 cells were significantly higher than those in TPC-1 and FTC-133 cells. In clinical specimens of thyroid cancers, nuclear expression of EpCAM and high expression of CD44v6 were detected significantly more frequently in anaplastic carcinomas.
CONCLUSIONS/SIGNIFICANCE: Our study suggests the possibility that EpCAM, together with CD44v6 and claudin-7 as well as ALDH1, may be involved in the development of the aggressive phenotype of anaplastic thyroid carcinoma. Our findings may suggest a novel therapeutic strategy for treatment of anaplastic thyroid carcinoma.

Zhu Y, Karakhanova S, Huang X, et al.
Influence of interferon-α on the expression of the cancer stem cell markers in pancreatic carcinoma cells.
Exp Cell Res. 2014; 324(2):146-56 [PubMed] Related Publications
The cytokine interferon-α (IFNα) belongs to the group of type I interferons already used in cancer therapy. This drug possesses radio- and chemo-sensitizing, and shows anti-angiogenic properties. Cancer stem cells (CSC) are a unique population of tumor cells that initiate secondary tumors, and are responsible for metastasis formation. Patients with pancreatic ductal adenocarcinoma (PDAC) have an especially poor prognosis, with 5-year survival rates of only ~1% and median survival of 4-6 months. PDAC is characterized by the presence of CSC. In this work we demonstrate for the first time that IFNα up-regulates the expression of the CSC markers CD24, CD44 and CD133 in in vitro and in vivo models of PDAC. We showed the IFNα effects on the migration and invasion of PDAC cells, which is associated with the level of the CSC marker expression. In vivo, this drug inhibits tumor growth but promotes metastasis formation in the early stage of tumor growth. We propose that IFNα may enhance the enrichment of CSC in PDAC tumors. Additionally we also suggest that in combination therapy of solid tumors with IFNα, this drug should be given to patients prior to chemotherapy to achieve the CSC activation.

Hattori S, Kojima K, Minoshima K, et al.
Detection of bladder cancer by measuring CD44v6 expression in urine with real-time quantitative reverse transcription polymerase chain reaction.
Urology. 2014; 83(6):1443.e9-15 [PubMed] Related Publications
OBJECTIVE: To examine urinary CD44v6 total ribonucleic acid (RNA) expression in patients with bladder cancer using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and evaluate its potential as a novel marker of bladder cancer.
METHODS: We used the bladder cancer cell line T24 and determined CD44v6 expression in cancer cells using in situ hybridization and immunohistochemistry. Subsequently, we obtained urine samples from 21 patients with bladder cancer and 25 patients without bladder cancer (controls). We extracted total RNA from the urine samples, measured CD44v6 total RNA expression in both groups using qRT-PCR, and compared the expression between groups. We also compared the sensitivity, specificity, and concordance rate between CD44v6 total RNA expression analysis by qRT-PCR and cytologic analysis, UroVysion fluorescent in situ hybridization, bladder tumor antigen identification, and nuclear matrix protein 22 measurements.
RESULTS: We observed increased CD44v6 expression in bladder cancer cells using in situ hybridization and immunohistochemistry. CD44v6 total RNA expression was significantly higher in the urine samples of patients with bladder cancer than in those of controls. We calculated the cutoff value from the receiver operating characteristic curve and obtained sensitivity and specificity values of 85.7% and 72.0%, respectively, for qRT-PCR analysis.
CONCLUSION: Our results suggest that CD44v6 total RNA levels in urine can serve as a potential noninvasive biomarker of bladder cancer.

Weng M, Gong W, Ma M, et al.
Targeting gallbladder cancer: oncolytic virotherapy with myxoma virus is enhanced by rapamycin in vitro and further improved by hyaluronan in vivo.
Mol Cancer. 2014; 13:82 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Gallbladder carcinoma (GBC) is highly lethal, and effective treatment will require synergistic anti-tumor management. The study is aimed at investigating the oncolytic value of myxoma virus (MYXV) infection against GBC and optimizing MYXV oncolytic efficiency.
METHODS: We examined the permissiveness of GBC cell lines to MYXV infection and compared the effects of MYXV on cell viability among GBC and control permissive glioma cells in vitro and in vivo after MYXV + rapamycin (Rap) treatment, which is known to enhance cell permissiveness to MYXV by upregulating p-Akt levels. We also assessed MYXV + hyaluronan (HA) therapy efficiency by examinating Akt activation status, MMP-9 expression, cell viability, and collagen distribution. We further compared hydraulic conductivity, tumor area, and survival of tumor-bearing mice between the MYXV + Rap and MYXV + HA therapeutic regimens.
RESULTS: MYXV + Rap treatment could considerably increase the oncolytic ability of MYXV against GBC cell lines in vitro but not against GBC xenografts in vivo. We found higher levels of collagen IV in GBC tumors than in glioma tumors. Diffusion analysis demonstrated that collagen IV could physically hinder MYXV intratumoral distribution. HA-CD44 interplay was found to activate the Akt signaling pathway, which increases oncolytic rates. HA was also found to enhance the MMP-9 secretion, which contributes to collagen IV degradation.
CONCLUSIONS: Unlike MYXV + Rap, MYXV + HA therapy significantly enhanced the anti-tumor effects of MYXV in vivo and prolonged survival of GBC tumor-bearing mice. HA may optimize the oncolytic effects of MYXV on GBC via the HA-CD44 interaction which can promote viral infection and diffusion.

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