Tumor initiating cells

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Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma

Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma

Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPα. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/ CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.
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Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer

Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer

BTICs in human breast tumors [14] or breast tumor cell lines [15]. We recently reported that various transgenic mouse models of breast cancer, including those shown to follow the CSC model, comprise a high fraction of BTIC [6], as determined by limiting dilution tumor cell transplantation experiments, the “gold standard” assay for tumor-initiating cells [14]. BTIC frequencies in the tumors of 3 different models averaged 30%; indeed, single tumor cells induced tumors at high frequency [6]. Moreover, we also showed that tumor cells isolated from mouse mammary tumors maintain a high BTIC frequency [6] when propagated in serum-free, chemically-defined medium first developed to culture mouse neuronal stem and progenitor cells [16]. By contrast, propagating the tumor cells in serum-containing medium reduced BTIC frequencies by 4–5 orders of magnitude [6]. We reasoned that these models would enable us to complete high- throughput screens with BTIC-enriched mouse mammary tumor cells and thereby identify agents targeting BTIC, which could be subsequently tested for their capacity to abrogate the tumorigenicity of their human counterparts. Here we report that SSRI, antagonists of the serotonin (5-hydroxytryptamine; 5-HT) transporter, targeted BTIC in tumors of the MMTV-Neu (N202) model [17] of breast cancer. Interestingly, 5-HT signalling has previously been implicated in postnatal mammary gland development [18, 19] and linked to breast cancer [20].
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Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133 tumor initiating cells

Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133 tumor initiating cells

Pancreatic tumors are notoriously chemo-resistant. Further, the recurrence of these tumors results in a dismal survival statistics. Tumor initiating cells are reported to be responsible for both recurrence and chemo-resistance in this disease. Thus successful therapeutic intervention in this disease is only possible once we understand the underlying mechanisms of chemo-resistance. Our study shows that understanding the metabolic pathways in TIC and non-TIC populations in pancreatic cancer may hold the key to developing therapies that can completely abrogate the TIC population by overriding their chemo- resistant mechanisms.
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LncGPR107 drives the self-renewal of liver tumor initiating cells and liver tumorigenesis through GPR107-dependent manner

LncGPR107 drives the self-renewal of liver tumor initiating cells and liver tumorigenesis through GPR107-dependent manner

Liver tumor initiating cells (TICs), also termed as liver cancer stem cells (CSCs), are the reason of liver tumorigenesis, metastasis, drug resistance and relapse [1]. Because these cells are in quiescent state and highly express many drug pumps (including ABCG2), liver TICs can survive during drug treatment, and ini- tiate new tumors once drugs are removed [2]. Liver TICs have self-renewal and differentiate capacities, and can form many cell types along with tumorigen- esis [3]. Based these specific characteristics, several functional systems have been developed for liver TICs, including sphere formation, side population, colony formation, transwell assay and tumor initiation assay [4–6]. Recent years, various surface markers of liver TICs were found, including CD13, CD133, EPCAM, CD24 and CD90 [7–10]. Some transcription factors were also found to participate in the self-renewal regulation of liver TICs, including Sox4, Zic2 and Oct4 [6, 11]. Although the importance of liver TICs is well-known, the self-renewal regulation of liver TICs are still unclear.
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The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells

The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells

The evolving theory of cancer stem cells (CSCs) postu- lates that the capacity to drive tumor formation and growth resides in a subpopulation of tumor cells, namely CSCs or tumor-initiating cells (TICs) [4]. CSCs are able to self-renew, differentiate into heterogeneous nontumori- genic cancer cells forming the bulk of tumor mass, and develop tumors in murine models. These cells also possess intrinsic chemoresistance and radioresistance and act as a reservoir of cancer cells responsible for relapse after surgery, radiation, or chemotherapy [5]. CSCs, identified in many human solid cancers including MPM, are mech- anistically responsible for treatment failure, tumor relapse, and metastasis development [5]. Thus, the identification of CSC-targeting drugs represents a translationally rele- vant approach to improve cancer therapy [6], in particular to overcome refractoriness to conventional anticancer agents.
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RBPJ maintains brain tumor–initiating cells through CDK9 mediated transcriptional elongation

RBPJ maintains brain tumor–initiating cells through CDK9 mediated transcriptional elongation

early development, and neural stem cells (NSCs) are quiescent (5), both of which are important distinctions from brain tumors. In most organs, the NOTCH pathway serves multiple roles in cell fate and lineage commitment, as it mediates interactions between heterolo- gous cell types (6). Upon engagement of NOTCH receptors to their ligands, the extracellular NOTCH region is cleaved by a disintegrin and metalloproteinase (ADAM) family of metalloproteases followed by the rate-limiting step of liberation of the NOTCH intracellular domain (NICD) by the γ-secretase complex. The NICD translocates to the nucleus and binds to transcriptional regulators to direct gene regulation, including target genes that, in turn, have strong tran- scriptional regulatory function (e.g., the HES and HEY transcrip- tion factors). NOTCH signaling is complex due to the differential expression of 4 receptors and 5 ligands, but NOTCH converges on a limited repertoire of transcriptional regulators, prominently RBPJ (recombining binding protein suppressor of hairless or recombina- tion signal-binding protein for immunoglobulin kappa j region; also known as CBF1 [mammalian C promoter–binding factor 1]) or CSL (for CBF1, suppressor of hairless [fly], Lag2 [worm]). In the absence of NOTCH activation, RBPJ recruits histone deacetylases and core- pressor components. Nuclear localization of NICD leads to binding to and displacement of an RBPJ transcriptional corepressor com- plex to act as a transcriptional activator by the recruitment of his- tone acetylases to activate transcription of NOTCH target genes (7). NOTCH signaling is highly context dependent with strong dif- ferences in the biologic outcome of NOTCH activation or disrup- tion based on developmental stage, tissue type, and cell type (6). Glioblastomas co-opt stem cell regulatory pathways to maintain brain tumorinitiating cells (BTICs), also known as cancer
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Senescence evasion by MCF 7 human breast tumor initiating cells

Senescence evasion by MCF 7 human breast tumor initiating cells

For cancer stem cells, mutation avoidance may be less crucial, but cell survival should be a dominant character- istic and may result in enhanced resistance to radiation and chemotherapeutic agents [4,16]. Thus, there is a clear need to identify the mechanisms that are involved in the maintenance of genome stability and cell survival in can- cer stem cells. It has proven extremely difficult to culture sufficient numbers of stem cells from fresh solid tumor material for such studies. However, many established tumor cell lines possess a small fraction of self-renewing tumor-initiating (stem) cells that can form tumors from very few cells [5,17-19]. Studies with such glioma [20] and breast tumor-initiating cells [16,21,22], cultured as neu- rospheres and mammospheres, respectively, have pro- vided some insights. In both cases the stem cells were observed to have elevated resistance to ionizing radiation, and additional data indicated enhanced DNA damage checkpoint activation [20] and repair capacity, as well as a marked reduction in the measured level of ROS following exposure to ionizing radiation [21], in comparison to the monolayer cell populations from which the stem cells were isolated.
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The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells

The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells

Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation (n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/ STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC.
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Proteolysis–a characteristic of tumor-initiating cells in murine metastatic breast cancer

Proteolysis–a characteristic of tumor-initiating cells in murine metastatic breast cancer

cancers, such as colon, prostate, breast, and pancreatic carcinomas [3, 6–9]. Essentially, cancer stem cells have the ability to asymmetrically divide, which results in self- renewal of the tumorigenic stem cell population and a large mass of cancer cells that have no, or only a limited, ability to establish new tumors [10, 11]. In addition, malignant stem cells from carcinomas are thought to be motile and, therefore, able to establish metastases in distant organs [12]. Due to their cancer-forming ability, and in order to distinguish them from physiological stem cells in tissues, these cells are often referred to as tumor initiating cells (TICs); a term which we will use hereafter. Based on a variety of specific cell surface markers, TICs can be isolated from solid tumors via fluorescence- activated cell sorting (FACS) and subsequently functionally characterized in vitro and in vivo [13–15]. The first TICs in human breast cancers were identified based on the cell surface makers CD44 + CD24 -/low [13].
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Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

Cancer stem cells (CSCs, also called tumor-initiating cells, TICs, due to their in vivo tumorigenic activity) derive their denomination from several phenotypical and functional characteristics shared with normal stem cells [40] and were identified over a decade ago in glioblastoma (GBM), the most common and aggressive CNS tumor [41]. GBM CSCs are resistant to conventional chemo- radiotherapy due to high activity of DNA repairing enzyme and drug efflux pumps, and their persistence after cytotoxic therapy is believed to determine tumor recurrence [42, 43]. In virtue of these proprieties, GBM CSCs represent the focus for novel targeted therapies [44, 45]; moreover, the identification of specific signaling pathways responsible for the retention of stemness, might have a significant translational relevance, contributing to the eradication of this cell subpopulation.
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Epithelial mesenchymal transition can suppress major attributes of
                    human epithelial tumor initiating cells

Epithelial mesenchymal transition can suppress major attributes of human epithelial tumor initiating cells

Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial- mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and
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The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor initiating cells

The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor initiating cells

Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persistence and massive expansion of hepatic progenitor cells. Upon induction of differentiation, Cul3-deficient progenitor cells underwent sub- stantial DNA damage in vivo and in vitro, thereby triggering the activation of a cellular senescence response that selectively blocked the expansion of the differentiated offspring. Positive selection of undifferentiated progenitor cells required the expression of the tumor suppressor protein p53. Simultaneous loss of Cul3 and p53 in hepatic progenitors turned these cells into highly malignant tumor-initiating cells that formed largely undifferentiated tumors in nude mice. In addition, loss of Cul3 and p53 led to the formation of primary hepatocellular carcinomas. Importantly, loss of Cul3 expression was also detected in a large series of human liver cancers and correlated directly with tumor de-differentiation. The expression of Cul3 during hepatic differentiation therefore safeguards against the formation of progenitor cells that carry a great potential for transformation into tumor-initiating cells.
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Characterization and Inhibition of Canine Osteosarcoma Tumor-Initiating Cells

Characterization and Inhibition of Canine Osteosarcoma Tumor-Initiating Cells

Controlling metastatic and invasive tumors is the challenging part of treating cancer. The overall aim of this dissertation was to target these aggressive cells, called tumor-initiating cells (TICs). They exploit embryonic stem cell genes that should not otherwise be activated, allowing them their aggressive capabilities. Osteosarcoma is the most common bone cancer of children. Canine osteosarcoma was selected as the type of cancer to study because of its predictable and similar behavior to human osteosarcoma. Human osteosarcoma has an analogous gene signature to canine osteosarcoma, but a slightly prolonged length of remission due to more aggressive therapy. The goals accomplished in this dissertation were: 1) Optimized a method using epirubicin to enrich for TICs; 2) Used molecular techniques to determine the phenotypic differences in canine osteosarcoma TICs compared to typical cancer cells; 3) Evaluated two classes of drugs that specifically target the unique
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ERN1 and ALPK1 inhibit differentiation of bi-potential tumor- initiating cells in human breast cancer

ERN1 and ALPK1 inhibit differentiation of bi-potential tumor- initiating cells in human breast cancer

11 kinases that inhibit the differentiation of MDA- MB-468 cells. We present evidence for a role of ERN1 (endoplasmic reticulum to nucleus signaling 1), also known as IRE1 alpha (inositol-requiring 1), and ALPK1 (alpha-kinase 1) in inhibiting the spontaneous differentiation of mammary bi-lineage tumor-initiating cells. The knockdown of either kinase elicits a cytostatic response, shifts marker patterns and phenotype, impairs in vitro colony forming ability and dramatically inhibits tumorigenicity. We show that inhibition of ERN1 and ALPK1 restricts anchorage-independent spheroid formation of an additional TNBC cell line and two luminal breast cancer cell lines. Finally, we identify a chemical kinase inhibitor capable of mimicking the effect of knocking down ERN1 in several breast cancer cell lines. This study validates the phenotypic screening strategy and opens the way to re-evaluate kinase inhibitors that may not have been effective in inducing cell death but might still be effective chemotherapeutic agents.
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CDC20 maintains tumor initiating cells

CDC20 maintains tumor initiating cells

Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor. Glioblastoma displays hierarchical arrangement with a population of self-renewing and tumorigenic glioma tumor initiating cells (TICs), or cancer stem cells. While non-neoplastic neural stem cells are generally quiescent, glioblastoma TICs are often proliferative with mitotic control offering a potential point of fragility. Here, we interrogate the role of cell-division cycle protein 20 (CDC20), an essential activator of anaphase-promoting complex (APC) E3 ubiquitination ligase, in the maintenance of TICs. By chromatin analysis and immunoblotting, CDC20 was preferentially expressed in TICs relative to matched non-TICs. Targeting CDC20 expression by RNA interference attenuated TIC proliferation, self-renewal and in vivo tumor growth. CDC20 disruption mediated its effects through induction of apoptosis and inhibition of cell cycle progression. CDC20 maintains TICs through degradation of p21 CIP1/WAF1 , a
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The inhibition of FGF receptor 1 activity mediates sorafenib induced antiproliferative effects in human mesothelioma tumor initiating cells

The inhibition of FGF receptor 1 activity mediates sorafenib induced antiproliferative effects in human mesothelioma tumor initiating cells

The evolving theory of cancer stem cells (CSCs) postu- lates that the capacity to drive tumor formation and growth resides in a subpopulation of tumor cells, namely CSCs or tumor-initiating cells (TICs) [4]. CSCs are able to self-renew, differentiate into heterogeneous nontumori- genic cancer cells forming the bulk of tumor mass, and develop tumors in murine models. These cells also possess intrinsic chemoresistance and radioresistance and act as a reservoir of cancer cells responsible for relapse after surgery, radiation, or chemotherapy [5]. CSCs, identified in many human solid cancers including MPM, are mech- anistically responsible for treatment failure, tumor relapse, and metastasis development [5]. Thus, the identification of CSC-targeting drugs represents a translationally rele- vant approach to improve cancer therapy [6], in particular to overcome refractoriness to conventional anticancer agents.
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MRI of Breast Tumor Initiating Cells Using the Extra Domain-B of Fibronectin Targeting Nanoparticles

MRI of Breast Tumor Initiating Cells Using the Extra Domain-B of Fibronectin Targeting Nanoparticles

Current therapies such as a combination of sur- gery, chemotherapy, hormone therapy, and radiation therapy can eliminate the bulk of a breast tumor, but they fail to completely eradicate the BTICs responsible for the recurrence and metastasis of the cancers [28]. Therefore, screening and identifying characteristic BTIC biomarkers is important for distinguishing BTICs from differentiated tumor cells within the tu- mor mass. It has been shown that the BTICs found in breast cancer express characteristic biomarkers (CD44+/CD24-/ALDH1+) that are distinct from dif- ferentiated breast cancer cells [1, 4]. In this study, we found that NDY-1 cells, which are derived from the cancerous tissue of a breast cancer patient, highly ex- pressed the self-renewal genes Oct-4, Nanog, and KLF4 in addition to the characteristic biomarkers of BTICs. We examined EDB-FN expression in various human breast cancer cells with different molecular subtypes and metastatic potentials and found that only NDY-1 cells specifically expressed abundant
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Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Several mechanisms have been proposed to explain the increased resistance of TICs to clinical treatments. Firstly, both radiotherapy and the majority of chemotherapeutic treatments target rapidly dividing cells and it has been proposed that the resistance of TICs was due to them having a quiescent slow-cycling phenotype [10]. However, it has since been demonstrated that CSCs (at least in breast cancer) do cycle and their resistance to stress is not simply a function of quiescence [11, 12]. Furthermore, CSCs have a greater capacity to efflux chemotoxins due to an increased expression of ABC transporters possibly explaining their additional resistance to chemotoxins but obviously these cannot account radio-resistance [13]. CSCs have been shown to be resistance to apoptotic stimuli compared to their non- stem cell counter parts and to have an increased capacity
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Original Article EGCG inhibits the growth and tumorigenicity of nasopharyngeal tumor-initiating cells through attenuation of STAT3 activation

Original Article EGCG inhibits the growth and tumorigenicity of nasopharyngeal tumor-initiating cells through attenuation of STAT3 activation

inhibited the numbers of colony formation (Figure 2D). To examine the influence of EGCG on the chemo-resistance of NPC sphere cells, cell viability and apoptosis analysis was per- formed. We observed a marked decrease in the viability of TW01 and TW06 sphere cells after incubation with cisplatin and 20 μM EGCG, as determined by MTT assay (Figure 2E). The che- mo-induced apoptosis effect detected using flow cytometry with Annexin V and PI double staining showed increased apoptotic activity in both TW01 and TW06 sphere cells with 20 μM EGCG added for 48 hours (Figure 2F). Although the sphere cells showed relatively higher anti- apoptosis than the parental cells, their apop- totic change had increased markedly after combination with EGCG. In consistence with these findings, the mRNA levels of several stemness genes were reduced after EGCG treatment examined by qRT-PCR (Figure 2G). These results suggest that EGCG has the poten- tial to suppress stem-like properties, reduce drug resistance and downregulate the aggres- siveness of NPC.
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Lung cancer tumorigenicity and drug resistance are enhanced through ALDH hi CD44 hi tumor initiating cells

Lung cancer tumorigenicity and drug resistance are enhanced through ALDH hi CD44 hi tumor initiating cells

aldehydes, alkylating drugs, oxidative stress, etc. On the other hand, through the retinoid signaling pathway, it is involved in self-renewal and tissue differentiation [30, 31]. For CD44, binding to hyaluronan increases NANOG phosphorylation and nuclear translocation, subsequently leading to the upregulation and stabilization of multidrug- resistant protein 1 (MDR1) for drug export [32]. CD44 interaction with POU5F1-SOX2-NANOG signaling also plays a pivotal role in CSC maintenance from head and neck cancers [33]. Together, these date suggest ALDH and CD44 could mediate drug-resistance directly or through stem cell regulatory programs. Indeed, in our study, concomitant CD44 depletion and ALDH inhibition led to sensitization of resistant cells to gefitinib and cisplatin, as well as down-regulation of pluripotency genes NANOG, SOX2 and POU5F1.
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