Cancer stem cells: A new paradigm for understanding tumor progression and therapeutic resistance

Huang, Emina H.; Heidt, David G.; Li, Chen Wei; Simeone, Diane M.

doi:10.1016/j.surg.2006.12.015

Cited by 60 publications

(39 citation statements)

References 16 publications

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“…Cancer stem cells found in solid tumors (including breast and ovarian cancers) have been implicated in both the initiation/ development of malignancy and multidrug resistance (60,61). Tumor cells derived from cancer stem cells display heterogeneous phenotypes of the parental cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, CD44 is thought to be one of the important cell surface markers for both normal stem cells and cancer stem cells (58,59). Furthermore, cancer stem cells have been clearly implicated in the phenomenon of chemoresistance (60,61). During our search for HA-CD44-induced transcriptional factor(s) that correlate(s) with stem cell functions and possible chemoresistance, we have identified the Nanog family of proteins as a prime candidate.…”

Section: Acid and N-acetyl-d-glucosaminementioning

confidence: 99%

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Hyaluronan-CD44 Interaction Activates Stem Cell Marker Nanog, Stat-3-mediated MDR1 Gene Expression, and Ankyrin-regulated Multidrug Efflux in Breast and Ovarian Tumor Cells

Bourguignon¹,

Peyrollier²,

Xia³

et al. 2008

Journal of Biological Chemistry

405

390

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Hyaluronan (HA) is a major glycosaminoglycan in the extracellular matrix whose expression is tightly linked to multidrug resistance and tumor progression. In this study we investigated HA-induced interaction between CD44 (a HA receptor) and Nanog (an embryonic stem cell transcription factor) in both human breast tumor cells (MCF-7 cells) and human ovarian tumor cells (SK-OV-3.ipl cells). Using a specific primer pair to amplify Nanog by reverse transcriptase-PCR, we detected the expression of Nanog transcript in both tumor cell lines. In addition, our results reveal that HA binding to these tumor cells promotes Nanog protein association with CD44 followed by Nanog activation and the expression of pluripotent stem cell regulators (e.g. Rex1 and Sox2). Nanog also forms a complex with the "signal transducer and activator of transcription protein 3" (Stat-3) in the nucleus leading to Stat-3-specific transcriptional activation and multidrug transporter, MDR1 (P-glycoprotein) gene expression. Furthermore, we observed that HA-CD44 interaction induces ankyrin (a cytoskeletal protein) binding to MDR1 resulting in the efflux of chemotherapeutic drugs (e.g. doxorubicin and paclitaxel (Taxol)) and chemoresistance in these tumor cells. Overexpression of Nanog by transfecting tumor cells with Nanog cDNA stimulates Stat-3 transcriptional activation, MDR1 overexpression, and multidrug resistance. Down regulation of Nanog signaling or ankyrin function (by transfecting tumor cells with Nanog small interfering RNA or ankyrin repeat domain cDNA) not only blocks HA/CD44-mediated tumor cell behaviors but also enhances chemosensitivity. Taken together, these findings suggest that targeting HA/CD44-mediated Nanog-Stat-3 signaling pathways and ankyrin/cytoskeleton function may represent a novel approach to overcome chemotherapy resistance in some breast and ovarian tumor cells displaying stem cell marker properties during tumor progression.Multidrug resistance frequently contributes to the failure of chemotherapeutic drug treatments in patients diagnosed with solid tumors such as breast and ovarian cancers (1). It is now certain that oncogenic signaling and cytoskeleton function are directly involved in chemotherapeutic drug resistance and tumor progression (2-4). A number of studies have aimed at identifying those molecules that are expressed specifically by epithelial tumor cells and correlate with metastatic behavior and chemoresistance. Among such molecules is hyaluronan (HA), 2 a major component in the extracellular matrix (ECM) of most mammalian tissues (5, 6). HA is a nonsulfated, unbranched glycosaminoglycan consisting of the repeating disaccharide units, D-glucuronic acid and N-acetyl-D-glucosamine (5, 6). HA is synthesized by specific HA synthases (6, 7) and digested into various smaller sized molecules by various hyaluronidases (8). It is well known that HA is enriched in many types of tumors (9, 10). In cancer patients, HA concentrations are usually higher in malignant tumors than in corresponding benign or normal tissues. Ac...

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Section: Discussionmentioning

confidence: 99%

Section: Acid and N-acetyl-d-glucosaminementioning

confidence: 99%

Hyaluronan-CD44 Interaction Activates Stem Cell Marker Nanog, Stat-3-mediated MDR1 Gene Expression, and Ankyrin-regulated Multidrug Efflux in Breast and Ovarian Tumor Cells

Bourguignon¹,

Peyrollier²,

Xia³

et al. 2008

Journal of Biological Chemistry

405

390

View full text Add to dashboard Cite

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“…Therefore, these authors considered that the HiWi gene could be used as a marker of tumor proliferation and as an evaluation index of cancer prognosis (11). Huang et al (12) revealed that tumor growth and proliferation in the body depended on cancer stem cells. Moreover, the ability of self-renewal, differentiation and proliferation of TSCs was correlated with the HiWi gene.…”

Section: Discussionmentioning

confidence: 99%

Effect of RNA interference-related HiWi gene expression on the proliferation and apoptosis of lung cancer stem cells

et al. 2012

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“…Cancer stem cells are generally considered resistant to chemotherapeutic drugs [59]. It is hypothesized that conventional anticancer agents only kill differentiated cancer cells, which form the majority of the tumor, and are unable to kill cancer stem cells.…”

Section: A Possible Targeted Therapy For Cholangiocarcinoma Stem Cellsmentioning

confidence: 99%

Recent advances in cancer stem cell research for cholangiocarcinoma

Kokuryo

Yokoyama

Nagino

2012

J Hepato Biliary Pancreat

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Cancer stem cells have been identified as cells with the capacity to self‐renew and differentiate into multiple lineages of human malignancies. Cholangiocarcinoma is one of the most difficult intra‐abdominal malignancies that can be treated using a surgical approach. Chemotherapy in addition to surgery is necessary to improve patient survival. However, its clinical benefit is limited, and, to date, no other effective anticancer drug is available for this disease. Several reports have shown the existence of cholangiocarcinoma stem cells. Cell surface antigens such as CD133, CD24, EpCAM, CD44, and others have been used to isolate cholangiocarcinoma stem cells. In general, enhanced expression of these markers in resected specimens of cholangiocarcinoma was associated with malignant potential. Distinct and specific pathways are expected to be present in cancer stem cells compared to other cancer cells that have no stem cell properties. To date, reports showing possible signaling pathways in cholangiocarcinoma stem cells are limited. More research is anticipated. Targeting therapies for surface molecular markers or specific signaling pathways of cholangiocarcinoma stem cells may be important in order to change the clinical outcome of patients with this disease. However, no clinical trial has been performed so far. This review will focus on the markers and signaling pathways used to define cholangiocarcinoma stem cells. A novel therapeutic approach of targeting cholangiocarcinoma stem cells will also be discussed.

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Cancer stem cells: A new paradigm for understanding tumor progression and therapeutic resistance

Cited by 60 publications

References 16 publications

Hyaluronan-CD44 Interaction Activates Stem Cell Marker Nanog, Stat-3-mediated MDR1 Gene Expression, and Ankyrin-regulated Multidrug Efflux in Breast and Ovarian Tumor Cells

Hyaluronan-CD44 Interaction Activates Stem Cell Marker Nanog, Stat-3-mediated MDR1 Gene Expression, and Ankyrin-regulated Multidrug Efflux in Breast and Ovarian Tumor Cells

Effect of RNA interference-related HiWi gene expression on the proliferation and apoptosis of lung cancer stem cells

Recent advances in cancer stem cell research for cholangiocarcinoma

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