CD44; CD44 molecule (Indian blood group) (11p13)

Gene Summary

Gene:CD44; CD44 molecule (Indian blood group)
Aliases: IN, LHR, MC56, MDU2, MDU3, MIC4, Pgp1, CDW44, CSPG8, HCELL, HUTCH-I, ECMR-III
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
Updated:14 December, 2014


What does this gene/protein do?
Show (39)


What pathways are this gene/protein implicaed in?
- Adhesion Molecules on Lymphocyte BIOCARTA
- Monocyte and its Surface Molecules BIOCARTA
- Neutrophil and Its Surface Molecules BIOCARTA
- ECM-receptor interaction KEGG
- Hematopoietic cell lineage KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (7)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerCD44 and Breast Cancer View Publications224
Prostate CancerCD44 and Prostate Cancer View Publications85
Stomach CancerCD44 and Stomach Cancer View Publications70
NeuroblastomaCD44 and Neuroblastoma View Publications62
OsteosarcomaCD44 and OsteosarcomaPrognostic View Publications47
Bladder CancerCD44 and Bladder Cancer View Publications33
Eye CancerCD44 and Uveal Neoplasms View Publications3

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

Related Links

Latest Publications: CD44 (cancer-related)

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.

Related: Apoptosis Breast Cancer Cancer Prevention and Risk Reduction TP53 BCL1 Gene (CCND1)

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.

Related: Apoptosis Liver Cancer Signal Transduction

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] Free Access to Full Article 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.

Related: Non-Small Cell Lung Cancer Lung Cancer Mitochondrial Mutations in Cancer TP53

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.

Related: Bone Cancers Angiogenesis and Cancer Signal Transduction

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.

Related: Colorectal (Bowel) Cancer

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 01/02/2015 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.

Related: Breast Cancer Signal Transduction

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.

Related: Breast Cancer

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 01/02/2015 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.

Related: Signal Transduction TGFB1

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.

Related: Breast Cancer TFAP2A TFAP2C

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.

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.

Related: Cancer of the Pancreas Pancreatic Cancer

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.

Related: Bladder Cancer Bladder Cancer - Molecular Biology

Bao B, Azmi AS, Aboukameel A, et al.
Pancreatic cancer stem-like cells display aggressive behavior mediated via activation of FoxQ1.
J Biol Chem. 2014; 289(21):14520-33 [PubMed] Article available free on PMC after 23/05/2015 Related Publications
Subpopulations of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors, including pancreatic cancer (PC), and the existence of these cells is clinically relevant. Emerging evidence suggests that CSLCs participate in cell growth/proliferation, migration/invasion, metastasis, and chemo-radiotherapy resistance, ultimately contributing to poor clinical outcome. However, the pathogenesis and biological significance of CSLCs in PC has not been well characterized. In the present study, we found that isolated triple-marker-positive (CD44(+)/CD133(+)/EpCAM(+)) cells of human PC MiaPaCa-2 and L3.6pl cells behave as CSLCs. These CSLCs exhibit aggressive behavior, such as increased cell growth, migration, clonogenicity, and self-renewal capacity. The mRNA expression profiling analysis showed that CSLCs (CD44(+)/CD133(+)/EpCAM(+)) exhibit differential expression of more than 1,600 mRNAs, including FoxQ1, compared with the triple-marker-negative (CD44(-)/CD133(-)/EpCAM(-)) cells. The knockdown of FoxQ1 by its siRNA in CSLCs resulted in the inhibition of aggressive behavior, consistent with the inhibition of EpCAM and Snail expression. Mouse xenograft tumor studies showed that CSLCs have a 100-fold higher potential for tumor formation and rapid tumor growth, consistent with overexpression of CSC-associated markers/mediators, including FoxQ1, compared with its parental MiaPaCa-2 cells. The inhibition of FoxQ1 attenuated tumor formation and growth, and expression of CSC markers in the xenograft tumor derived from CSLCs of MiaPaCa-2 cells. These data clearly suggest the role of differentially expressed genes in the regulation of CSLC characteristics, further suggesting that targeting some of these genes could be important for the development of novel therapies for achieving better treatment outcome of PC.

Related: Apoptosis Cancer of the Pancreas Pancreatic Cancer EPCAM

Tilghman J, Wu H, Sang Y, et al.
HMMR maintains the stemness and tumorigenicity of glioblastoma stem-like cells.
Cancer Res. 2014; 74(11):3168-79 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Glioblastoma (GBM) stem cells (GSC) are a subpopulation of tumor cells that display stem-like characteristics (stemness) and play unique roles in tumor propagation, therapeutic resistance, and tumor recurrence. Therapeutic targets in GSCs are a focus of increasing interest to improve GBM therapy. Here we report that the hyaluronan-mediated motility receptor (HMMR) is highly expressed in GBM tumors, where it supports the self-renewal and tumorigenic potential of GSCs. HMMR silencing impairs GSC self-renewal and inhibits the expression of GSC markers and regulators. Furthermore, HMMR silencing suppresses GSC-derived tumor growth and extends the survival of mice bearing GSC xenografts. Conversely, HMMR overexpression promotes GSC self-renewal and intracranial tumor propagation. In human GBM tumor specimens, HMMR expression is correlated positively with the expression of stemness-associated markers and regulators. Our findings identify HMMR as a candidate therapeutic target to GSCs as a GBM treatment strategy.

Chen X, Iliopoulos D, Zhang Q, et al.
XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.
Nature. 2014; 508(7494):103-7 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.

Related: HIF1A

Goksel G, Bilir A, Uslu R, et al.
WNT1 gene expression alters in heterogeneous population of prostate cancer cells; decreased expression pattern observed in CD133+/CD44+ prostate cancer stem cell spheroids.
J BUON. 2014 Jan-Mar; 19(1):207-14 [PubMed] Related Publications
PURPOSE: Established cancer cell lines contain cancer stem cells (CSCs) which can propagate to form three dimensional (3D) tumor spheroids in vitro. Aberrant activation of WNT signaling is strongly implicated in the progression of cancer and controls CSCs properties. In this study we hypothesized that when cells were maintained as spheroids, the structure of CSCs could show differentiation between CSCs and non- CSCs.
METHODS: CD133+/CD44+ cancer-initiating cells were isolated from DU-145 human prostate cancer cell line monolayer cultures, propagated as tumor spheroids and compared with the remaining heterogeneous cancer cells bulk population. The expression levels of WNT1, FZD1, ADAR, APC, AXIN, BTRC, FRAT1 and PPARD genes were measured by polymerase chain reaction (PCR) array assay and the protein expression levels of WNT1, FZD and AXIN by immunohistochemistry.
RESULTS: The expression levels of WNT pathway-related molecules were found to increase in both CSCs and non- CSCs when CSCs were maintained as spheroids. However, different expression profiles were observed when CSCs and non-CSCs were compared. In spheroids, the expression levels of FZD1, APC, ADAR, WNT1, PPARD genes in CSCs decreased when compared to non-CSCs. Interestingly, when CSCs from spheroids were compared with CSCs from monolayers the most significant decrease was observed in FZD1 and increase in APC genes.
CONCLUSION: It is possible to assume that intracellular signaling of WNT-related molecules in the nucleus and/or cytoplasm might play an important role but it is independent from increased ligand expression and this expression strongly differentiate CSCs and non-CSCs population. This unexpected expression could be important for CSCs behavior and targeting this pathway could have therapeutic implications in cancer.

Related: Prostate Cancer

Nilubol N, Boufraqech M, Zhang L, Kebebew E
Loss of CPSF2 expression is associated with increased thyroid cancer cellular invasion and cancer stem cell population, and more aggressive disease.
J Clin Endocrinol Metab. 2014; 99(7):E1173-82 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: Identification of molecular factors that promote thyroid cancer progression have important clinical implications for therapy and prognostication in patients with papillary thyroid cancer (PTC). The aim of this study was to validate and determine the function of dysregulated genes that were associated increased mortality in patients with PTC. Experiemental Design: We selected the cleavage and polyadenylation specificity factor subunit 2 (CPSF2) gene from the top 5 significantly dysregulated genes associated with PTC-associated mortality from our previous study. We used 86 PTC samples enriched for aggressive disease (recurrence and mortality) by quantitative RT-PCR (qRT-PCR). In vitro functional studies of the validated gene were performed.
RESULTS: Decreased CPSF2 gene expression was associated with shorter disease-free survival (P = .03), large tumor size (T3 and T4) (P = .03), tumor recurrence (P < .01), and mortality (P < .01), independent of BRAF V600E mutation status. CPSF2 knockdown increased cellular invasion by 1.8- to 3.2-fold (P < .01) and increased markers of thyroid cancer stem cells (CD44 and CD133 expression). Immunohistochemistry showed an inverse correlation between CD44 protein expression in PTC samples and CPSF2 expression.
CONCLUSION: Decreased CPSF2 expression is associated with increased cellular invasion and cancer stem cell population, and more aggressive disease in PTC.

Related: Thyroid Cancer

Cao Z, Ding BS, Guo P, et al.
Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.
Cancer Cell. 2014; 25(3):350-65 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.

Related: FGFR1 gene IGF1R CSF1R NOTCH2 gene Signal Transduction

Hu S, Wu X, Zhou B, et al.
IMP3 combined with CD44s, a novel predictor for prognosis of patients with hepatocellular carcinoma.
J Cancer Res Clin Oncol. 2014; 140(6):883-93 [PubMed] Related Publications
PURPOSE: Insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) is reported to be re-expressed in malignant tumors and can regulate the expression of multiple genes related to tumor invasion. CD44 standard isoform (CD44s) has been reported to play an important role in facilitating tumor invasion. In this text, we investigate the regulatory function of IMP3 on CD44s and the role of IMP3 and CD44s in predicting the outcomes of patients with hepatocellular carcinoma.
METHODS: IMP3 and CD44s were measured in hepatocellular carcinoma (HCC) tissues by immunohistochemical assay, and survival analysis was conducted among 128 patients. Moreover, we studied the effect of IMP3 on the expression of CD44s and the biological functions of tumor cells in HCC cell lines.
RESULTS: Our results showed that the expression of IMP3 was significantly correlated with CD44s expression (r = 0.505, P < 0.001), and both of them correlated with high AFP level, advanced tumor stage and grade, portal vein tumor thrombus, and early tumor recurrence or metastasis. The results of survival analysis exhibited that the 1-, 3-, 5-year disease-free and overall survival rates significantly reduced in IMP3- and CD44s-positive patients, and IMP3 combined with CD44s was an independent prognostic risk factor for HCC. In vitro assay, our results showed that IMP3 promoted HepG2 and MHCC97H cells invading and migrating via regulating CD44s expression.
CONCLUSIONS: Our findings suggest that IMP3 facilitates HCC aggressiveness through regulating CD44s expression, and IMP3 combined with CD44s can be as a new predictor for unfavorable prognosis in HCC patients.

Related: Liver Cancer

Ni J, Cozzi PJ, Hao JL, et al.
CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance.
Prostate. 2014; 74(6):602-17 [PubMed] Related Publications
INTRODUCTION: Prostate cancer (CaP) is the second leading malignancy in older men in Western countries. The role of CD44 variant 6 (CD44v6) in CaP progression and therapeutic resistance is still uncertain. Here, we investigated the roles of CD44v6 in CaP metastasis and chemo/radioresistance. Expression of CD44v6 in metastatic CaP cell lines, human primary CaP tissues and lymph node metastases was assessed using immunofluorescence and immunohistochemistry, respectively.
METHODS: Knock down (KD) of CD44v6 was performed in PC-3M, DU145, and LNCaP cells using small interfering RNA (siRNA), and confirmed by confocal microscope, Western blot and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The adhesive ability and invasive potential were assessed using a hyaluronic acid (HA) adhesion and a matrigel chamber assay, respectively. Tumorigenesis potential and chemo-/radiosensitivity were measured by a sphere formation assay and a colony assay, respectively.
RESULTS: Over-expression of CD44v6 was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of CD44v6 suppressed CaP proliferative, invasive and adhesive abilities, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated epithelial-mesenchymal transition (EMT), PI3K/Akt/mTOR, and Wnt/β-catenin signaling pathway proteins in vitro.
CONCLUSIONS: Our findings demonstrate that CD44v6 is an important cancer stem cell-like marker associated with CaP proliferation, invasion, adhesion, metastasis, chemo-/radioresistance, and the induction of EMT as well as the activation PI3K/Akt/mTOR and Wnt signaling pathways, suggesting that CD44v6 is a novel therapeutic target to sensitize CaP cells to chemo/radiotherapy.

Related: Prostate Cancer AKT1

Chen L, Bourguignon LY
Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells.
Mol Cancer. 2014; 13:52 [PubMed] Article available free on PMC after 17/03/2015 Related Publications
MicroRNA-21 (miR-21) is associated with the development of solid tumors progression including breast cancer. In this study we investigated matrix hyaluronan (HA)-CD44 (a primary HA receptor) interaction with c-Jun N-Terminal Kinase (JNK)/c-Jun signaling in MDA-MB-468 breast cancer cells [a triple-negative (estrogen receptor-negative/progesterone receptor-negative/HER2-negative) breast cancer cell line]. Our results indicated that HA binding to CD44 promotes c-Jun nuclear translocation and transcriptional activation. Further analyses revealed that miR-21 is regulated by an upstream promoter containing AP1 binding site(s), and chromatin immunoprecipitation (CHIP) assays demonstrated that stimulation of miR-21 expression by HA/CD44 interaction is c-Jun-dependent in these breast cancer cells. This process results in an increase of the anti-apoptosis protein Bcl-2 and upregulation of inhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in MDA-MB-468 cells. Treatment with c-Jun specific small interfering RNAs effectively blocks HA-mediated c-Jun signaling and abrogates miR-21 production as well as causes downregulation of survival proteins (Bcl-2 and IAPs) and enhancement of chemosensitivity. In addition, our results demonstrated that anti-miR-21 inhibitor not only downregulates Bcl-2/IAP expression but also increases chemosensitivity in HA-treated breast cancer cells. Together, these findings suggest that the HA/CD44-induced c-Jun signaling plays a pivotal role in miR-21 production leading to survival protein (Bcl-2/IAP) upregulation and chemoresistance in triple negative breast cancer cells such as MDA-MB-468 cell line. This novel HA/CD44-mediated c-Jun signaling pathway and miR-21 production provide a new drug target for the future intervention strategies to treat breast cancer.

Related: Breast Cancer Signal Transduction miR-21

Slaoui M, Razine R, Ibrahimi A, et al.
Breast cancer in Morocco: a literature review.
Asian Pac J Cancer Prev. 2014; 15(3):1067-74 [PubMed] Related Publications
In Morocco, breast cancer is the most prevalent cancer in women and a major public health problem. Several Moroccan studies have focused on studying this disease, but more are needed, especially at the genetic and molecular levels. It is therefore interesting to establish the genetic and molecular profile of Moroccan patients with breast cancer. In this paper, we will highlight some pertinent hypotheses that may enhance breast cancer care in Moroccan patients. This review will give a precise description of breast cancer in Morocco and propose some new markers for detection and prediction of breast cancer prognosis.

Related: Male Breast Cancer Cancer Screening and Early Detection MUC1 gene RHOC

Xiao S, Zhou Y, Jiang J, et al.
CD44 affects the expression level of FOS‑like antigen 1 in cervical cancer tissues.
Mol Med Rep. 2014; 9(5):1667-74 [PubMed] Related Publications
Cervical carcinoma is the second most prevalent type of malignancy in females worldwide. The crucial etiological factors involved in the development of cervical carcinoma include infection with the papillomavirus, and the structural or functional mutation of oncogenes and tumor suppressor genes. CD44 refers to a multifunctional family of type I transmembrane proteins. These proteins have been implicated in numerous biological processes, including cell adhesion, cell migration and metastasis. The present study examined the differences in the expression levels of ATP-binding cassette sub-family G member 2, CD24, CD44, CD133, cytokeratin (CK) 14 and CK19 between cervical cancer tissues and corresponding normal non-tumor tissues by flow cytometry. Then, the CD44+ or CD44‑ cells from cervical cancer tissues were sorted for identification and confirmation of differential expression by flow cytometry. The results demonstrated that the expression level of CD44 in cervical cancer tissues was higher than in the corresponding non-tumor normal tissues (t=3.12; P=0.0102). Compared with the CD44‑ cells, the FOS-like antigen 1 (Fra-1), nestin, nuclear receptor subfamily 4, group A, member 2, OCT4 and p63 genes were highly expressed in CD44+ cells. The fold changes were 3.55, 3.55, 2.46, 2.87 and 2.56, respectively (P<0.05). However, BMI1 polycomb ring finger oncogene, ck5, tumor protein p53 and lactotransferrin genes exhibited low expression levels in CD44+ cells. It was verified by western blot analysis and flow cytometry that Fra-1 was highly expressed in CD44+ cells. Fra-1 was a potential target of miR-19a and miR-19b. The expression of miR-19a and miR-19b was downregulated by ~50% in CD44+ cells compared with CD44‑ cells. These findings suggested that CD44 dysregulated the activation of the Fra‑1 gene. The interaction of Fra-1 and CD44 may therefore be important in cervical carcinoma.

Related: Cervical Cancer

Zhu B, Zhang P, Zeng P, et al.
Tissue factor pathway inhibitor-2 silencing promotes hepatocellular carcinoma cell invasion in vitro.
Anat Rec (Hoboken). 2013; 296(11):1708-16 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the world and metastasis is an essential aspect of HCC progression. Tissue factor pathway inhibitor-2 (TFPI-2) has been implicated as a potential suppressor gene to regulate tumor invasion and metastasis. In this study, we silenced TFPI-2 in the HCC cell line MHCC97-L and evaluated the role of TFPI-2 in cell invasion and its impact on gene expression. We showed in this study that stable TFPI-2 downregulation in MHCC97-L cells resulted in increased cell adhesion and invasion. We also showed that mRNA and protein expression levels of MMP-1/3, CD44, and ICAM-1 were increased, while those of MMP-2/9 were not changed by TFPI-2 silencing. Furthermore, silencing of TFPI-2 caused increased Akt phosphorylation level and NF-κB transcription in MHCC97-L cells. In conclusion, this study confirms that TFPI-2 downregulation can contribute to tumor invasion of HCC cells through alteration in the expression of metastasis-related genes.

Related: Liver Cancer AKT1

Liu Y, Nenutil R, Appleyard MV, et al.
Lack of correlation of stem cell markers in breast cancer stem cells.
Br J Cancer. 2014; 110(8):2063-71 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: Various markers are used to identify the unique sub-population of breast cancer cells with stem cell properties. Whether these markers are expressed in all breast cancers, identify the same population of cells, or equate to therapeutic response is controversial.
METHODS: We investigated the expression of multiple cancer stem cell markers in human breast cancer samples and cell lines in vitro and in vivo, comparing across and within samples and relating expression with growth and therapeutic response to doxorubicin, docetaxol and radiotherapy.
RESULTS: CD24, CD44, ALDH and SOX2 expression, the ability to form mammospheres and side-population cells are variably present in human cancers and cell lines. Each marker identifies a unique rather than common population of cancer cells. In vivo, cells expressing these markers are not specifically localized to the presumptive stem cell niche at the tumour/stroma interface. Repeated therapy does not consistently enrich cells expressing these markers, although ER-negative cells accumulate.
CONCLUSIONS: Commonly employed methods identify different cancer cell sub-populations with no consistent therapeutic implications, rather than a single population of cells. The relationships of breast cancer stem cells to clinical parameters will require identification of specific markers or panels for the individual cancer.

Related: Breast Cancer SOX2 gene

Yang Y, Wang Y, Yin C, Li X
Clinical significance of the stem cell gene Oct-4 in cervical cancer.
Tumour Biol. 2014; 35(6):5339-45 [PubMed] Related Publications
This study aims to investigate the association between the expression of Oct-4 and the biological behavior or prognosis of cervical cancer. Serum-free suspension culture technology was used to select a suspension of microspheres that can stabilize clones. The tumorigenicity of the microsphere suspension was analyzed in NOD/SCID mice. Microarray analysis was used to detect the specific expression of genes in the microsphere suspension. The expression of Oct-4 was detected by immunohistochemistry, and the correlation between Oct-4 expression and clinical pathological prognostic indicators was analyzed in cervical cancer. The expression of the following genes was significantly different between the experimental and control groups: stem cell differentiation (CD44 and Oct-4), markers cell cycle regulators (APC), cell cycle regulators (MYC), and self-renewal markers (MYST2, NEUROG2, and SOX1). The expression of Oct-4 was significantly higher in cervical cancer tissues than in adjacent normal tissues and was significantly related to differentiation, clinical stage, and lymph node metastasis. The 5-year survival rate of patients with Oct-4-positive expression was lower than that of patients with Oct-4-negative expression (36.7 vs. 67.7 %, respectively; P=0.001). Cox regression analysis revealed that clinical stage, lymph node metastasis, and Oct-4 were independent prognostic factors in cervical cancer (P=0.031, 0.012, and 0.001, respectively). Our results showed that Oct-4 was highly expressed in cervical cancer stem cells; Oct-4 expression was associated with biological behavior and was an independent prognostic factor in cervical cancer. Therefore, it may represent a potential target for cervical cancer treatment.

Related: Cervical Cancer

Moon BS, Jeong WJ, Park J, et al.
Role of oncogenic K-Ras in cancer stem cell activation by aberrant Wnt/β-catenin signaling.
J Natl Cancer Inst. 2014; 106(2):djt373 [PubMed] Related Publications
BACKGROUND: Adenomatous polyposis coli (APC) loss-of-function mutations and K-Ras gain-of-function mutations are common abnormalities that occur during the initiation and intermediate adenoma stages of colorectal tumorigenesis, respectively. However, little is known about the role these mutations play in cancer stem cells (CSCs) associated with colorectal cancer (CRC) tumorigenesis.
METHODS: We analyzed tissue from CRC patients (n = 49) to determine whether K-Ras mutations contributed to CSC activation during colorectal tumorigenesis. DLD-1-K-Ras-WT and DLD-1-K-Ras-MT cells were cultured and evaluated for their ability to differentiate, form spheroids in vitro, and form tumors in vivo. Interaction between APC and K-Ras mutations in colorectal tumorigenesis was evaluated using APC (Min/+)/K-Ras (LA2) mice and DLD-1-K-Ras-WT and DLD-1-K-Ras-MT cell xenografts. (n = 4) Group differences were determined by Student t test. All statistical tests were two-sided.
RESULTS: The sphere-forming capability of DLD-1-K-Ras-MT cells was statistically significantly higher than that of DLD-1-K-Ras-WT cells (DLD-1-K-Ras-MT mean = 86.661 pixel, 95% confidence interval [CI] = 81.701 to 91.621 pixel; DLD-1-K-Ras-WT mean = 42.367 pixel, 95% CI = 36.467 to 48.267 pixel; P = .003). Moreover, both the size and weight of tumors from DLD-1-K-Ras-MT xenografts were markedly increased compared with tumors from DLD-1-K-Ras-WT cells. Expression of the CSC markers CD44, CD133, and CD166 was induced in intestinal tumors from APC (Min/+)/K-Ras (LA2)mice, but not K-Ras (LA2) mice, indicating that APC mutation is required for CSC activation by oncogenic K-Ras mutation.
CONCLUSIONS: K-Ras mutation activates CSCs, contributing to colorectal tumorigenesis and metastasis in CRC cells harboring APC mutations. Initial activation of β-catenin by APC loss and further enhancement through K-Ras mutation induces CD44, CD133, and CD166 expression.

Related: Colorectal (Bowel) Cancer Signal Transduction CTNNB1 gene KRAS gene

Mirkina I, Hadzijusufovic E, Krepler C, et al.
Phenotyping of human melanoma cells reveals a unique composition of receptor targets and a subpopulation co-expressing ErbB4, EPO-R and NGF-R.
PLoS One. 2014; 9(1):e84417 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Malignant melanoma is a life-threatening skin cancer increasingly diagnosed in the western world. In advanced disease the prognosis is grave. Growth and metastasis formation in melanomas are regulated by a network of cytokines, cytokine-receptors, and adhesion molecules. However, little is known about surface antigens and target expression profiles in human melanomas. We examined the cell surface antigen profile of human skin melanoma cells by multicolor flow cytometry, and compared their phenotype with 4 melanoma cell lines (A375, 607B, Mel-Juso, SK-Mel28). Melanoma cells were defined as CD45-/CD31- cells co-expressing one or more melanoma-related antigens (CD63, CD146, CD166). In most patients, melanoma cells exhibited ErbB3/Her3, CD44/Pgp-1, ICAM-1/CD54 and IGF-1-R/CD221, but did not express CD20, ErbB2/Her2, KIT/CD117, AC133/CD133 or MDR-1/CD243. Melanoma cell lines were found to display a similar phenotype. In most patients, a distinct subpopulation of melanoma cells (4-40%) expressed the erythropoietin receptor (EPO-R) and ErbB4 together with PD-1 and NGF-R/CD271. Both the EPO-R+ and EPO-R- subpopulations produced melanoma lesions in NOD/SCID IL-2Rgamma(null) (NSG) mice in first and secondary recipients. Normal skin melanocytes did not express ErbB4 or EPO-R, but expressed a functional KIT receptor (CD117) as well as NGF-R, ErbB3/Her3, IGF-1-R and CD44. In conclusion, melanoma cells display a unique composition of surface target antigens and cytokine receptors. Malignant transformation of melanomas is accompanied by loss of KIT and acquisition of EPO-R and ErbB4, both of which are co-expressed with NGF-R and PD-1 in distinct subfractions of melanoma cells. However, expression of EPO-R/ErbB4/PD-1 is not indicative of a selective melanoma-initiating potential.

Related: Melanoma Skin Cancer PDCD1 ERBB4 (HER4)

Mao J, Fan S, Ma W, et al.
Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment.
Cell Death Dis. 2014; 5:e1039 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells' proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo. This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and β-catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy.

Related: Signal Transduction Stomach Cancer Gastric Cancer CTNNB1 gene

Parent R, Plissonnier ML, Bancel B, et al.
Diversity of hepatocellular carcinoma clones bearing hematopoietic malignancies-related chromosomal translocation.
J Cell Biochem. 2014; 115(4):666-77 [PubMed] Related Publications
Interpatient heterogeneity of hepatocellular carcinoma has been in-depth addressed. Intrapatient heterogeneity is less known. Four clones were freshly isolated from an Edmondson grade I HCV-associated hepatocellular carcinoma. Biochemical approaches, functional assays and cytogenetics were used. Albumin inducibility was uncoupled from canonical cytokeratin profiles, suggesting pathological combinations of hepatospecific and biliary markers. Poor differentiation and TGFβ's proproliferative effect on all clones were observed. TGFβ, Interferon α and doxorubicin sensitivity levels were found highly heterogeneous. Progenitor and stem cells markers OV6 and EpCAM were mutually exclusively expressed. All clones were CD44+, while none expressed CD90, CD133, or CD117. Three clones displayed a liver progenitor OV6+ phenotype, and were susceptible to hepatocytic differentiation, among which one fibroblastoid clone displayed intrahepatic parenchymal engraftment capability. A fourth clone, the less motile, displayed a cancer stem cell EpCAM+ phenotype, was essentially β-catenin negative, and was as expected devoid of hepatocytic differentiation capability, yet the most sensitive to doxorubicin treatment. Cytogenetics evidenced in all clones a t(12;22)(p11;q11) translocation found in several myelodysplastic syndromes. All clones, that probably derive from EpCAM+ tumor cells, display aberrant E-cadherin cytosolic localization. Because of their diverse pathophysiolocal features, these freshly isolated, low population doubling-defined, HCC clones may provide novel opportunities to tackle HCC heterogeneity in a single patient background for therapy improvement purposes, especially regarding recently developed targeted strategies.

Related: Haematological Malignancies & Realted Disorders Liver Cancer CTNNB1 gene EPCAM


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Cite this page: Cotterill SJ. CD44, Cancer Genetics Web: http://www.cancerindex.org/geneweb/CD44.htm Accessed: date

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