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Cancer Stem Cell Plasticity Drives Therapeutic Resistance

Mary Doherty, Jacob Smigiel, Damian Junk and 1 more

Cancers · 2016 · Review · CC BY

doi:10.3390/cancers8010008

Abstract

The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The metastatic spread of cancer cells and tumor recurrence following therapy causes 90% of cancer mortalities. However, despite their importance, our understanding of the molecular pathways involved in generating invasive, metastatic and therapy-resistant cells remains fairly limited. Tumors are complex tissues composed of a hierarchical organization of tumor cell sub-populations as well as numerous tumor-associated stromal cell types. The cancer stem cell (CSC) hypothesis places cells with self-renewal capacity and the ability to differentiate at the top of the tumor cell hierarchy. By definition, CSCs have the ability to form tumors that recapitulate the heterogeneity of the primary tumor from which they were isolated following orthotopic transplantation into mice. As the progeny of CSCs differentiate, they lose their ability to generate tumors, despite their identical genetic landscape. This highlights the importance of the tumor microenvironment (TME), which serves as the CSC niche, to regulate CSC self-renewal and differentiation. Current evidence supports the hypothesis that CSCs harbor properties that promote therapeutic resistance (upregulation of drug efflux pumps, activation of signaling that circumvents drug targets, and deregulation of apoptotic signaling). In essence, CSCs are the “roots” of aggressive tumors for which we currently have no effective treatments. Devising a way to kill CSCs or prevent them from being generated is a significant clinical challenge. Recent evidence suggests that not only do CSCs exist in tumors prior to treatment, but that treatment can also induce the de novo generation of cells harboring CSC properties. The degree to which the cells that acquire CSC properties in response to chemotherapy are similar to those found in untreated tumors is an important question, yet it remains undetermined. Thus, we will refer to non-CSC cells that have acquired CSC properties as “CSC-like”. Here, we review how cells harboring CSC properties contribute to therapeutic resistance and discuss the emerging evidence suggesting that non-CSC cells can acquire these key, CSC properties.

2. Connecting the Dots: CSC Properties and Epithelial-Mesenchymal Transition (EMT)

CSCs have been isolated from nearly every type of human malignancy using a limited (albeit non-overlapping) set of markers. For example, breast CSCs were originally identified as having a CD24LoCD44Hi cell-surface marker profile. Subsequently, elevated Aldehyde Dehydrogenase (ALDH) activity was also shown to correlate with CSC potential, although CD24LoCD44Hi and ALDH+ CSCs identify distinct CSC populations. Thus, rather than using specific markers, functional assays are necessary to truly define a CSC population, including the capacity for anchorage-independent growth (AIG) as tumorspheres and the ability to generate tumors following orthotopic implantation (typically at low cell numbers;). Our studies, along with the studies of others, have determined that transformed human mammary epithelial cells (HMEC) acquire CSC properties when they undergo EMT, in addition to acquiring an invasive, mesenchymal phenotype.

The acquisition of mesenchymal/CSC properties can occur spontaneously during the transformation process, following exogenous expression of EMT-inducing transcription factors, or upon exposure to specific cytokines. For example, the induction of EMT in immortalized and transformed human mammary epithelial cells (HMEC) by ectopic expression of Twist, Snail, or FoxC2 transcription factors induces EMT, concomitant with an increased ability to form tumorspheres in vitro and tumors in vivo. Our laboratory has demonstrated that transformed HMEC harboring a mesenchymal phenotype arose spontaneously during the transformation process. However, the spontaneously generated mesenchymal cells lack plasticity. In contrast, exposure of non-CSCs to Transforming Growth Factor Beta (TGF-β) generated a mesenchymal/CSC-like population, which retained remarkable plasticity. The TGF-β-induced CSC-like cells required the sustained presence of TGF-β, as removal of TGF-β or inhibition of TGF-β signaling (by pharmacologic or genetic means) led to a marked loss in mesenchymal/CSC properties and the re-emergence of an epithelial/non-CSC phenotype (or differentiation). We propose that targeting cytokine signaling emanating from the TME (such as TGF-β) may disrupt E-M plasticity and inhibit the emergence of invasive, drug-resistant CSC-like cells. The link between E-M plasticity and CSC properties has been paradigm-shifting, coupling key concepts that relate metastatic progression with therapeutic resistance resulting in tumor recurrence. We posit that the TME, acting as the CSC niche, serves as the key source of plasticity-inducing cytokines. In fact, beyond TGF-β, many TME cytokines are emerging that can induce EMT and CSC properties. Further characterization of the cytokines present in the TME and defining how they impact E-M and CSC plasticity is of key importance for understanding metastasis and recurrence.

3. Mirroring Metastasis: Trends in Tumor Recurrence

Metastasis is the overwhelming cause of cancer mortality. Despite recent studies linking CSC properties with metastatic progression, our understanding of this complex problem remains limited. Metastasis is most often thought to be initiated by epithelial cancer cells undergoing EMT, resulting in the dissolution of tight cell-cell interaction by downregulation of junctional/epithelial proteins (claudin, occludin, ZO1, E-cadherin, cytokeratins;). EMT is regulated by transcription factors that include Snail, Twist, and ZEB1/2, which initiate the repression of the epithelial phenotype and activation of mesenchymal markers (N-cadherin, Vimentin). The loss of important cell-cell interactions is an important step in allowing escape from the primary tumor and entrance into the lymphatics or bloodstream, but additional characteristics that facilitate the metastatic cascade are also acquired during EMT. These include: (1) the induction of matrix metalloproteinases (MMPs) responsible for the degradation of the extracellular matrix (ECM) and tumor cell intravasation; (2) survival in the bloodstream (by creating multi-cell aggregates); and (3) extravasation (by enhanced membrane protrusions and blood vessel contacts).

EMT in primary Triple Negative Breast Cancer (TNBC), as evidenced by loss of epithelial markers (E-cadherin) or gain of mesenchymal markers (Vimentin, N-Cadherin, Snail expression) typically at the tumor’s edge, correlates with poor clinical outcome in TNBC. Likewise, the presence and abundance of circulating tumor cells (CTC) that express mesenchymal markers can be used to track a patient’s response to therapy. For example, patients that respond positively to therapy have a decrease in mesenchymal CTC while patients with progressive disease have an increase in mesenchymal CTC following treatment. Moreover, the re-emergence of mesenchymal CTC in initial responders is accompanied by tumor recurrence. Further evidence linking E-M plasticity and a CSC phenotype is provided by the observation that a sub-set of CTC responsible for initiating metastasis (termed the metastasis-initiating cells) express high levels of the CSC marker CD44 or ALDH1. Moreover, single-cell analysis recently identified distinct EMT and CSC gene expression patterns in early-stage breast cancer micro-metastases. Importantly, larger, late-state metastases were more heterogeneous, more proliferative, expressed higher levels of differentiation markers, and displayed similarity to the primary tumors. Since these micro- and macro-metastases were identified from the same patient-derived xenografts, the findings are consistent with the idea that mesenchymal/CSCs initiate metastatic outgrowth at a secondary site, followed later by increased proliferation and differentiation. Likewise, evidence has suggested that epithelial cancer cells, which undergo EMT to initiate metastases, must undergo a reciprocal mesenchymal-epithelial transition (MET) at secondary sites, as macro-metastases have long been noted to have a largely epithelial phenotype. The conditions regulating E-M and CSC plasticity at secondary sites are currently unclear, but may be due to the significant change in microenvironmental factors, including the availability of microenvironmental cytokines.

The idea that tumor cells capable of seeding metastasis must retain (or regain) the ability to proliferate and differentiate mirrors what happens during tumor recurrence following chemotherapy (Figure 1). Differentiated, non-CSCs, which make up the bulk of a tumor, are more sensitive to conventional chemotherapies than CSCs are. The efficient killing of large numbers of non-CSCs explains the initial responses often observed following treatment with first-line therapy. In contrast, CSCs are more refractory to genotoxic therapies, allowing them to survive, proliferate, and differentiate in order to fuel tumor recurrence. Indeed, analysis of paired breast cancer core biopsies before and after chemotherapy demonstrates that a higher percentage of CD24LoCD44Hi CSCs capable of forming mammospheres exist in post-treatment biopsies. In addition, gene expression analyses of paired breast cancer biopsies before and after endocrine therapy or chemotherapy demonstrate that residual, surviving cells harbor elevated CSC gene expression signatures. CSCs avoid therapy-induced apoptotic signaling through more effective DNA damage responses evolved to protect genomic integrity. CSCs also express lower levels of pro-apoptotic proteins, such as caspase-8, and elevated levels of drug efflux pumps, such as MDR-1 and the p-glycoproteins, which transport chemotherapeutics out of the cell, rendering them ineffective.

4. De Novo Generation of CSC from non-CSC

The enrichment of cells with a CSC phenotype following therapy has been interpreted in two significantly different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, accumulating evidence supports the idea that non-CSCs can be induced into a drug-tolerant, CSC-like state by chemotherapy (Figure 1;). For example, drug-sensitive Non-Small Cell Lung Carcinoma Cells (NSCLC), which lacked CSC properties prior to therapy, acquired CSC properties following acute exposure to either conventional chemotherapy (paclitaxel) or targeted therapies (Erlotinib). Importantly, this drug-induced CSC-like phenotype was transient, as drug removal resulted in loss of CSC properties as cells differentiated into non-CSCs and regained drug sensitivity. Overall, this observation suggests that CSC plasticity, in response to cancer therapy, can be a transient event engaged during the stress of drug exposure. Interestingly, drug-induced CSC plasticity was dependent on increased expression of epigenetic modifiers such as histone deacetylases (HDAC) as well as growth factor signaling through the Insulin Growth Factor Receptor (IGFR), as pharmacological inhibition of either HDAC or IGFR disrupted CSC plasticity and restored drug sensitivity. The effectiveness of IGFR and HDAC inhibitors was dependent on the timing of their administration, and was only effective in suppressing CSC plasticity when given as an adjuvant therapy. Simply pre-treating with these pharmacological inhibitors prior to conventional therapy was ineffective, demonstrating that the pathways which induced CSC properties were not engaged prior to therapy and thus were not a function of a pre-existing CSC state.

Similarly, emerging evidence in breast cancer suggests that conventional cancer therapy can directly induce de novo generation of transient CSC-like cells from non-CSCs and that this CSC plasticity drives acquired therapeutic resistance. In these studies, high-dose exposure of tumor explants and cancer cell lines to taxanes or anthracyclines not only induced cell death in the majority of cells but also induced a phenotypic cell state transition in which some non-CSCs acquired CSC properties. These CSC properties included induction of breast CSC cell surface marker expression, enhanced tumor growth and decreased survival of patient-derived xenograft (PDX) mouse models. Importantly the drug-resistant, CSC-like state was not simply the result of a selective enrichment of pre-existing CSCs, as acute low dose exposure to chemotherapy resulted in a dose-dependent increase in breast CSC-like cells in the absence of cell death. Interestingly, this finding was not exclusive to breast cancer alone, as melanoma, ovarian, and prostate cancer cell lines also responded to conventional cancer therapy with the induction of a chemo-refractory CSC-like population. In the case of breast cancer, however, the de novo generation of chemo-refractory CSC-like cells was dependent on SRC kinase signaling, as treatment with the SRC kinase inhibitor Dasatinib re-sensitized the resistant cells to chemotherapy, resulting in decreased cell viability and decreased tumor volume. Importantly, the ability to re-sensitize these resistant cells was again temporally dependent, and only effective following chemotherapy, not as a pre- or co-treatment. Finally, carboplatin and ionizing radiation can also induce the emergence of CSC properties from non-CSCs, which is dependent on stem cell markers Sox2 and Oct3/4. The ability of cancer cells to transition between distinct cell states has prompted deeper thought beyond the paradigm that treatment induces the selection for a pre-existing sub-population. If the induction of CSC properties by cancer therapy is critical for the survival of tumor cells, then targeting the plasticity needed to acquire CSC properties will be an important therapeutic target rather than simply only targeting the CSC state.

5. The TME; Supporting E-M and CSC Plasticity

Progeny emanating from CSCs depend not only on the genetic profile of the cell, but also, perhaps more importantly, on the TME surrounding the cell, which serves as the CSC niche. As a tumor develops, changes occur not only in the tumor cells, but also in nearby tumor-associated stromal cells. Studies of breast tumor interstitial fluid have identified over 1000 distinct proteins present only in the TME. Many of these proteins are secreted from the 20 or more different cell types that are present within the TME. Cytokines top the list of tumor-associated secreted factors, and are likely to have important effects on the pathways that govern CSC and E-M plasticity. In addition to TGFβ, additional cytokines and growth factors (IL4, IL6, OSM, IL10, TNFα, ILEI, IFNγ, and VEGF) have also been implicated in inducing EMT (and by extension, CSC properties;). The ability of these cytokines and growth factors to induce CSC properties concomitant with EMT may explain why their presence in the TME correlates with poor patient outcomes.

For example, our laboratory has studied how Oncostatin M (OSM) induces aggressive cancer cell properties implicated in poor patient outcomes. Elevated levels of OSM in the TME are associated with highly aggressive metastatic cancers and an increased risk of tumor recurrence (chemotherapy resistance) in a variety of tumor types. OSM in the TME may originate from immune cells, adipose tissue, as well as cancer cells. Immune cells (especially macrophages) localized at the advancing, infiltrative margins of carcinomas secrete elevated levels of OSM. Moreover, DNA damaging chemotherapy induces additional OSM secretion from macrophages, potentially exacerbating the aggressive properties associated with mesenchymal and CSC properties following treatment with genotoxic therapies. At the same time, cancer cells from more aggressive tumor types express markedly higher levels of OSM Receptor (OSMR). Expression of OSMR correlates with the increased expression of the CSC marker CD44 and mesenchymal markers, most frequently at the invasive edge of the tumor near the OSM-secreting macrophages. Moreover, exposure of cancer cells or pre-malignant HMEC to OSM is sufficient to induce EMT, acquisition of CSC properties, and an invasive and transformed phenotype. OSM serves as but one example of how TME cytokines might contribute to tumor cell survival following therapy, and ultimately, therapeutic resistance and tumor recurrence.

Recent comparison of matched patient-derived colorectal cancer samples before and after chemotherapy identified a significant increase in the secretion of IL-17A cytokine from Cancer Associated Fibroblasts (CAFs), which induced CSC properties, resulting in therapeutic resistance. Importantly, pharmacological suppression of IL-17A signaling impaired self-renewal and tumor growth and thus demonstrated that aberrant TME signaling induced by conventional cancer therapy plays an important role in influencing the acquisition of CSC. In addition, paclitaxel treatment was recently shown to induce the expression of a TGFβ gene signature and CSCs in primary patient-derived Triple Negative Breast Cancer (TNBC) tumor biopsies. The expression of the TGFβ signature correlated with increased tumor relapse in treated patients. Importantly, pharmacological suppression of TGFβ signaling with small molecule inhibitors suppressed the acquisition of CSC properties and prevented therapeutic resistance and tumor relapse in TNBC PDX mouse models. Finally, in glioblastoma (GBM), there is often an induction of aberrant TME signaling following conventional cancer therapy such as ionizing radiation and chemotherapy. For example, the pro-inflammatory cytokines IL-6 and OSM, along with their major transcription factor Signal Transducer of Activated Transcription 3 (STAT3), drive the acquisition of CSC properties resulting in therapeutic resistance. Despite the ability to target and successfully kill rapidly proliferating non-CSCs, these aggressive brain tumors relapse and effectively resist DNA damage-induced apoptosis. Interestingly, suppression of IL-6 or OSM induced STAT3 signaling in GBM following conventional therapy suppressed tumor growth and stemness-related factors, respectively. Similarly, inhibiting STAT3-mediated signaling with a small molecule inhibitor (BBI608) resulted in suppressed stemness-related genes including Nanog, Sox2 and OCT4 which are often upregulated following conventional cancer therapy. Importantly, inhibition of these STAT3 targets suppressed tumor growth and metastasis in a variety of cancers including pancreatic, head and neck and colorectal. Taken together, these data suggest that TME factors, induced by chemotherapy, may drive the TME to promote CSC plasticity and therapeutic resistance (Figure 2).

6. Conclusion: Targeting CSC Plasticity to Suppress Therapeutic Resistance

Following chemotherapy, the presence of residual disease at the time of surgery is associated with poor survival and early recurrence. Unfortunately, even second-line therapies do not significantly improve outcomes for these patients, and limited data exists regarding which pathways should be targeted in patients with residual disease. There is significant support for the role of CSCs in therapeutic resistance and tumor recurrence. However, while invasive CSCs are established drivers of metastasis and recurrence, our understanding of the molecular forces that regulate the generation and sustainability of CSCs remains limited. Novel therapeutic strategies have been proposed which combine conventional cancer therapies with specific inhibitors targeting CSCs. However, this strategy may only be effective at killing pre-existing CSCs, failing to prevent non-CSCs from acquiring CSC-like properties in response to the TME and genotoxic therapy. The increasing recognition of the importance of E-M and CSC plasticity in therapeutic resistance and tumor recurrence makes the pathways governing plasticity highly attractive. Of course, targeting plasticity presents new challenges, such as the identity of which pathways should be targeted in individual tumors and the timing of the plasticity-targeting therapy. As described above, several important signaling cascades activated by TME cytokines have been identified that can promote CSC plasticity and tumor survival following chemotherapy (Figure 2). Each of these may be targetable as an adjuvant therapy to help suppress the emergence of CSC properties during conventional cancer therapy. Cytokine receptors are engaged by extracellular ligands, and, therefore, prevention of the cytokine/receptor interaction using antibodies or soluble decoy receptors is both rational and justified. Studies to determine which cytokines support CSC generation and their maintenance and how they can be targeted will provide important information about preventing CSC plasticity, which can be translated into clinical interventions to suppress metastatic progression and recurrence.

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    Creighton C.J., Li X., Landis M., Dixon J.M., Neumeister V.M., Sjolund A., Rimm D.L., Wong H., Rodriguez A., Herschkowitz J.I., et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl. Acad. Sci. USA. 2009;106:13820-13825.

    Not in our library10.1073/pnas.0905718106

  42. 42.

    Bao S., Wu Q., McLendon R.E., Hao Y., Shi Q., Hjelmeland A.B., Dewhirst M.W., Bigner D.D., Rich J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756-760.

    Not in our library10.1038/nature05236

  43. 43.

    Signore M., Ricci-Vitiani L., De Maria R. Targeting apoptosis pathways in cancer stem cells. Cancer Lett. 2013;332:374-382.

    Not in our library10.1016/j.canlet.2011.01.013

  44. 44.

    Moitra K., Lou H., Dean M. Multidrug efflux pumps and cancer stem cells: Insights into multidrug resistance and therapeutic development. Clin. Pharmacol. Ther. 2011;89:491-502.

    Not in our library10.1038/clpt.2011.14

  45. 45.

    Gottesman M.M. Mechanisms of cancer drug resistance. Annu Rev. Med. 2002;53:615-627.

    Not in our library10.1146/annurev.med.53.082901.103929

  46. 46.

    Holohan C., van Schaeybroeck S., Longley D.B., Johnston P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer. 2013;13:714-726.

    Not in our library10.1038/nrc3599

  47. 47.
    Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition · 2015
    No notice
  48. 48.

    Biddle A., Liang X., Gammon L., Fazil B., Harper L.J., Emich H., Costea D.E., Mackenzie I.C. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res. 2011;71:5317-5326.

    Not in our library10.1158/0008-5472.can-11-1059

  49. 49.

    Li Q.Q., Xu J.D., Wang W.J., Cao X.X., Chen Q., Tang F., Chen Z.Q., Liu X.P., Xu Z.D. Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin. Cancer Res. 2009;15:2657-2665.

    Not in our library10.1158/1078-0432.ccr-08-2372

  50. 50.

    Sun L., Yao Y., Liu B., Lin Z., Lin L., Yang M., Zhang W., Chen W., Pan C., Liu Q., et al. MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1. Oncogene. 2012;31:432-445.

    Not in our library10.1038/onc.2011.263

  51. 51.

    Sharma S.V., Lee D.Y., Li B., Quinlan M.P., Takahashi F., Maheswaran S., McDermott U., Azizian N., Zou L., Fischbach M.A., et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69-80.

    Not in our library10.1016/j.cell.2010.02.027

  52. 52.

    Pisco A.O., Huang S. Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: “What does not kill me strengthens me”. Br. J. Cancer. 2015;112:1725-1732.

    Not in our library10.1038/bjc.2015.146

  53. 53.

    Hu X., Ghisolfi L., Keates A.C., Zhang J., Xiang S., Lee D.K., Li C.J. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11:2691-2698.

    Not in our library10.4161/cc.21021

  54. 54.
    Ionizing Radiation Induces Stemness in Cancer Cells · 2012
    Corrected
  55. 55.

    Liu S., Ginestier C., Ou S.J., Clouthier S.G., Patel S.H., Monville F., Korkaya H., Heath A., Dutcher J., Kleer C.G., et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res. 2011;71:614-624.

    Not in our library10.1158/0008-5472.can-10-0538

  56. 56.

    Celis J.E., Gromov P., Cabezon T., Moreira J.M., Ambartsumian N., Sandelin K., Rank F., Gromova I. Proteomic characterization of the interstitial fluid perfusing the breast tumor microenvironment: A novel resource for biomarker and therapeutic target discovery. Mol. Cell. Proteom. 2004;3:327-344.

    Not in our library10.1074/mcp.m400009-mcp200

  57. 57.

    Gonzalez-Moreno O., Lecanda J., Green J.E., Segura V., Catena R., Serrano D., Calvo A. Vegf elicits epithelial-mesenchymal transition (EMT) in prostate intraepithelial neoplasia (pin)-like cells via an autocrine loop. Exp. Cell Res. 2010;316:554-567.

    Not in our library10.1016/j.yexcr.2009.11.020

  58. 58.

    Sullivan N.J., Sasser A.K., Axel A.E., Vesuna F., Raman V., Ramirez N., Oberyszyn T.M., Hall B.M. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 2009;28:2940-2947.

    Not in our library10.1038/onc.2009.180

  59. 59.

    Liu X. Inflammatory cytokines augments TGF-β1-induced epithelial-mesenchymal transition in A549 cells by up-regulating TβR-I. Cell Motil. Cytoskelet. 2008;65:935-944.

    Not in our library10.1002/cm.20315

  60. 60.

    Waerner T., Alacakaptan M., Tamir I., Oberauer R., Gal A., Brabletz T., Schreiber M., Jechlinger M., Beug H. ILEI: A cytokine essential for emt, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell. 2006;10:227-239.

    Not in our library10.1016/j.ccr.2006.07.020

  61. 61.

    West N.R., Murray J.I., Watson P.H. Oncostatin-m promotes phenotypic changes associated with mesenchymal and stem cell-like differentiation in breast cancer. Oncogene. 2014;33:1485-1494.

    Not in our library10.1038/onc.2013.105

  62. 62.

    Techasen A., Loilome W., Namwat N., Dokduang H., Jongthawin J., Yongvanit P. Cytokines released from activated human macrophages induce epithelial mesenchymal transition markers of cholangiocarcinoma cells. Asian Pac. J. Cancer Prev. 2012;13:115-118.

    Not in our library

  63. 63.

    Kan C.E., Cipriano R., Jackson M.W. C-myc functions as a molecular switch to alter the response of human mammary epithelial cells to oncostatin M. Cancer Res. 2011.

    Not in our library10.1158/0008-5472.can-10-3860

  64. 64.

    Ng G., Winder D., Muralidhar B., Gooding E., Roberts I., Pett M., Mukherjee G., Huang J., Coleman N. Gain and overexpression of the oncostatin M receptor occur frequently in cervical squamous cell carcinoma and are associated with adverse clinical outcome. J. Pathol. 2007;212:325-334.

    Not in our library10.1002/path.2184

  65. 65.

    Smith D.A., Kiba A., Zong Y., Witte O.N. Interleukin-6 and oncostatin-M synergize with the PI3K/AKT pathway to promote aggressive prostate malignancy in mouse and human tissues. Mol. Cancer Res. 2013;11:1159-1165.

    Not in our library10.1158/1541-7786.mcr-13-0238

  66. 66.
    Macrophages are recruited to hypoxic tumor areas and acquire a Pro-Angiogenic M2-Polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin · 2014
    No notice
  67. 67.

    Lauber S., Wong S., Cutz J.C., Tanaka M., Barra N., Lhotak S., Ashkar A., Richards C.D. Novel function of oncostatin m as a potent tumour-promoting agent in lung. Int. J. Cancer. 2015;136:831-843.

    Not in our library10.1002/ijc.29055

  68. 68.

    Wong S., Botelho F.M., Rodrigues R.M., Richards C.D. Oncostatin M overexpression induces matrix deposition, STAT3 activation, and SMAD1 dysregulation in lungs of fibrosis-resistant BALB/c mice. Lab. Investig. 2014;94:1003-1016.

    Not in our library10.1038/labinvest.2014.81

  69. 69.

    Atkinson R.L., Yang W.T., Rosen D.G., Landis M.D., Wong H., Lewis M.T., Creighton C.J., Sexton K.R., Hilsenbeck S.G., Sahin A.A., et al. Cancer stem cell markers are enriched in normal tissue adjacent to triple negative breast cancer and inversely correlated with DNA repair deficiency. Breast cancer Res. 2013;15:R77.

    Not in our library10.1186/bcr3471

  70. 70.

    Li Q., Zhu J., Sun F., Liu L., Liu X., Yue Y. Oncostatin m promotes proliferation of ovarian cancer cells through signal transducer and activator of transcription 3. Int. J. Mol. Med. 2011;28:101-108.

    Not in our library10.3892/ijmm.2011.647

  71. 71.

    Zhu M., Che Q., Liao Y., Wang H., Wang J., Chen Z., Wang F., Dai C., Wan X. Oncostatin m activates STAT3 to promote endometrial cancer invasion and angiogenesis. Oncol. Rep. 2015;34:129-138.

    Not in our library10.3892/or.2015.3951

  72. 72.

    Bolin C., Tawara K., Sutherland C., Redshaw J., Aranda P., Moselhy J., Anderson R., Jorcyk C.L. Oncostatin m promotes mammary tumor metastasis to bone and osteolytic bone degradation. Genes Cancer. 2012;3:117-130.

    Not in our library10.1177/1947601912458284

  73. 73.

    Holzer R.G., Ryan R.E., Tommack M., Schlekeway E., Jorcyk C.L. Oncostatin M stimulates the detachment of a reservoir of invasive mammary carcinoma cells: Role of cyclooxygenase-2. Clin. Exp. Metastasis. 2004;21:167-176.

    Not in our library10.1023/b:clin.0000024760.02667.db

  74. 74.

    Jorcyk C.L., Holzer R.G., Ryan R.E. Oncostatin m induces cell detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells. Cytokine. 2006;33:323-336.

    Not in our library10.1016/j.cyto.2006.03.004

  75. 75.

    Queen M.M., Ryan R.E., Holzer R.G., Keller-Peck C.R., Jorcyk C.L. Breast cancer cells stimulate neutrophils to produce oncostatin m: Potential implications for tumor progression. Cancer Res. 2005;65:8896-8904.

    Not in our library10.1158/0008-5472.can-05-1734

  76. 76.

    Ryan R.E., Martin B., Mellor L., Jacob R.B., Tawara K., McDougal O.M., Oxford J.T., Jorcyk C.L. Oncostatin M binds to extracellular matrix in a bioactive conformation: Implications for inflammation and metastasis. Cytokine. 2015;72:71-85.

    Not in our library10.1016/j.cyto.2014.11.007

  77. 77.

    Caffarel M.M., Coleman N. Oncostatin m receptor is a novel therapeutic target in cervical squamous cell carcinoma. J. Pathol. 2014;232:386-390.

    Not in our library10.1002/path.4305

  78. 78.

    Winder D.M., Chattopadhyay A., Muralidhar B., Bauer J., English W.R., Zhang X., Karagavriilidou K., Roberts I., Pett M.R., Murphy G., et al. Overexpression of the oncostatin m receptor in cervical squamous cell carcinoma cells is associated with a pro-angiogenic phenotype and increased cell motility and invasiveness. J. Pathol. 2011;225:448-462.

    Not in our library10.1002/path.2968

  79. 79.

    West N.R., Murphy L.C., Watson P.H. Oncostatin m suppresses oestrogen receptor-alpha expression and is associated with poor outcome in human breast cancer. Endocr.-Relat. Cancer. 2012;19:181-195.

    Not in our library10.1530/erc-11-0326

  80. 80.

    Gurluler E., Tumay L.V., Guner O.S., Kucukmetin N.T., Hizli B., Zorluoglu A. Oncostatin-M as a novel biomarker in colon cancer patients and its association with clinicopathologic variables. Eur. Rev. Med. Pharmacol. Sci. 2014;18:2042-2047.

    Not in our library

  81. 81.

    Garcia-Tunon I., Ricote M., Ruiz A., Fraile B., Paniagua R., Royuela M. Osm, lif, its receptors, and its relationship with the malignance in human breast carcinoma (in situ and in infiltrative). Cancer Investig. 2008;26:222-229.

    Not in our library10.1080/07357900701638491

  82. 82.

    Royuela M., Ricote M., Parsons M.S., Garcia-Tunon I., Paniagua R., de Miguel M.P. Immunohistochemical analysis of the IL-6 family of cytokines and their receptors in benign, hyperplasic, and malignant human prostate. J. Pathol. 2004;202:41-49.

    Not in our library10.1002/path.1476

  83. 83.

    Torres C., Perales S., Alejandre M.J., Iglesias J., Palomino R.J., Martin M., Caba O., Prados J.C., Aranega A., Delgado J.R., et al. Serum cytokine profile in patients with pancreatic cancer. Pancreas. 2014;43:1042-1049.

    Not in our library10.1097/mpa.0000000000000155

  84. 84.

    Vlaicu P., Mertins P., Mayr T., Widschwendter P., Ataseven B., Hogel B., Eiermann W., Knyazev P., Ullrich A. Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator. BMC Cancer. 2013;13:197.

    Not in our library10.1186/1471-2407-13-197

  85. 85.

    Grenier A., Combaux D., Chastre J., Gougerot-Pocidalo M.A., Gibert C., Dehoux M., Chollet-Martin S. Oncostatin m production by blood and alveolar neutrophils during acute lung injury. Lab. Investig. 2001;81:133-141.

    Not in our library10.1038/labinvest.3780220

  86. 86.

    Grenier A., Dehoux M., Boutten A., Arce-Vicioso M., Durand G., Gougerot-Pocidalo M.A., Chollet-Martin S. Oncostatin M production and regulation by human polymorphonuclear neutrophils. Blood. 1999;93:1413-1421.

    Not in our library

  87. 87.

    Zhu Q., Zhang X., Zhang L., Li W., Wu H., Yuan X., Mao F., Wang M., Zhu W., Qian H., et al. The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. Cell. Death Dis. 2014;5:8.

    Not in our library10.1038/cddis.2014.263

  88. 88.

    Guo S., Li Z.Z., Gong J., Xiang M., Zhang P., Zhao G.N., Li M., Zheng A., Zhu X., Lei H., et al. Oncostatin m confers neuroprotection against ischemic stroke. J. Neurosci. 2015;35:12047-12062.

    Not in our library10.1523/jneurosci.1800-15.2015

  89. 89.

    Levano K.S., Jung E.H., Kenny P.A. Breast cancer subtypes express distinct receptor repertoires for tumor-associated macrophage derived cytokines. Biochem. Biophys. Res. Commun. 2011;411:107-110.

    Not in our library10.1016/j.bbrc.2011.06.102

  90. 90.

    Singh R.A., Sodhi A. Cisplatin-treated macrophages produce oncostatin m: Regulation by serine/threonine and protein tyrosine kinases/phosphatases and Ca2+/calmodulin. Immunol. Lett. 1998;62:159-164.

    Not in our library10.1016/s0165-2478(98)00040-6

  91. 91.

    Sodhi A., Shishodia S., Shrivastava A. Cisplatin-stimulated murine bone marrow-derived macrophages secrete oncostatin m. Immunol. Cell. Biol. 1997;75:492-496.

    Not in our library10.1038/icb.1997.76

  92. 92.
    The Enigmatic Cytokine Oncostatin M and Roles in Disease · 2013
    No notice
  93. 93.

    Lotti F., Jarrar A.M., Pai R.K., Hitomi M., Lathia J., Mace A., Gantt G.A., Sukhdeo K., DeVecchio J., Vasanji A., et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 2013;210:2851-2872.

    Not in our library10.1084/jem.20131195

  94. 94.

    Bhola N.E., Balko J.M., Dugger T.C., Kuba M.G., Sanchez V., Sanders M., Stanford J., Cook R.S., Arteaga C.L. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J. Clin. Investig. 2013;123:1348-1358.

    Not in our library10.1172/jci65416

  95. 95.

    Liu W.-H., Chen M.-T., Wang M.-L., Lee Y.-Y., Chiou G.-Y., Chien C.-S., Huang P.-I., Chen Y.-W., Huang M.-C., Chiou S.-H., et al. Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/snail axis in atypical teratoid/rhabdoid tumor cells. Oncotarget. 2015;6:1750-1768.

    Not in our library10.18632/oncotarget.2737

  96. 96.

    Repovic P., Fears C.Y., Gladson C.L., Benveniste E.N. Oncostatin-M induction of vascular endothelial expression in astroglioma cells. Oncogene. 2003;22:8117-8124.

    Not in our library10.1038/sj.onc.1206922

  97. 97.

    Li Y., Rogoff H.A., Keates S., Gao Y., Murikipudi S., Mikule K., Leggett D., Li W., Pardee A.B., Li C.J. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc. Natl. Acad. Sci. USA. 2015;112:1839-1844.

    Not in our library10.1073/pnas.1424171112

  98. 98.
    Current treatment of early breast cancer: adjuvant and neoadjuvant therapy [v1; ref status: indexed, http://f1000r.es/3l2] · 2014
    Not checked
  99. 99.

    Pan Q., Li Q., Liu S., Ning N., Zhang X., Xu Y., Chang A.E., Wicha M.S. Concise review: Targeting cancer stem cells using immunologic approaches. Stem Cells. 2015;33:2085-2092.

    Not in our library10.1002/stem.2039

  100. 100.

    Gangopadhyay S., Nandy A., Hor P., Mukhopadhyay A. Breast cancer stem cells: A novel therapeutic target. Clin. Breast Cancer. 2013;13:7-15.

    Not in our library10.1016/j.clbc.2012.09.017

  101. 101.

    Frank N.Y., Schatton T., Frank M.H. The therapeutic promise of the cancer stem cell concept. J. Clin. Investig. 2010;120:41-50.

    Not in our library10.1172/jci41004

  102. 102.

    Kolev V.N., Wright Q.G., Vidal C.M., Ring J.E., Shapiro I.M., Ricono J., Weaver D.T., Padval M.V., Pachter J.A., Xu Q. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res. 2015;75:446-455.

    Not in our library10.1158/0008-5472.can-14-1223

  103. 103.

    Kemper K., Prasetyanti P.R., de Lau W., Rodermond H., Clevers H., Medema J.P. Monoclonal antibodies against LGR5 identify human colorectal cancer stem cells. Stem Cells. 2012;30:2378-2386.

    Not in our library10.1002/stem.1233

  104. 104.

    Sachlos E., Risueno R.M., Laronde S., Shapovalova Z., Lee J.H., Russell J., Malig M., McNicol J.D., Fiebig-Comyn A., Graham M., et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell. 2012;149:1284-1297.

    Not in our library10.1016/j.cell.2012.03.049

  105. 105.

    Gupta P.B., Onder T.T., Jiang G., Tao K., Kuperwasser C., Weinberg R.A., Lander E.S. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645-659.

    Not in our library10.1016/j.cell.2009.06.034

  106. 106.

    Takebe N., Harris P.J., Warren R.Q., Ivy S.P. Targeting cancer stem cells by inhibiting wnt, notch, and hedgehog pathways. Nat. Rev. Clin. Oncol. 2011;8:97-106.

    Not in our library10.1038/nrclinonc.2010.196

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