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Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis

      Abstract

      Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.

      Graphical abstract

      Keywords

      Abbreviations:

      CAFs (Cancer-associated fibroblasts), DHh (Desert hedgehog), EpCAM (Epithelial cell adhesion molecules), FOXM1 (Forkhead Box M1), GLI1 (Glioma-associated oncogene), IHh (Indian hedgehog), IL6Rβ (Interleukin 6R beta), KRAS (Kirsten rat sarcoma virus), LATS2 (Large tumor suppressor kinase 2), MDSC (Myeloid-derived suppressor cell), NK cell (Natural killer cell), NPs (Nanoparticles), OTUB2 (Ubiquitin thioesterase), PAR1 (Protease-activated receptor 1), PTCH1 (Protein-patched homolog 1), SDF-1 (Stromal cell-derived factor), SMO (Smoothened), TAZ (Transcriptional activator with a PDZ binding motif), TLR (Toll-like receptor), TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand), YAP1 (Yes-associated protein 1), ZEB1 (Zinc finger e-box 1)
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      References

        • Hapach L.A.
        • Carey S.P.
        • Schwager S.C.
        • et al.
        Phenotypic heterogeneity and metastasis of breast cancer cells.
        Cancer Research. 2021; 81: 3649-3663
        • Malla R.R.
        • Farran B.
        • Nagaraju G.P.
        Understanding the function of the tumor microenvironment, and compounds from marine organisms for breast cancer therapy.
        World J Biol Chem. 2021; 12: 15-37
        • Al-thoubaity F.K.
        Molecular classification of breast cancer: A retrospective cohort study.
        Ann Med Surg. 2020; 49: 44-48
        • Bareche Y.
        • Buisseret L.
        • Gruosso T.
        • et al.
        Unraveling triple-negative breast cancer tumor microenvironment heterogeneity:towards an optimized treatment approach.
        J Natl Cancer Inst. 2020; 112: 708-719
        • Jia Y.
        • Chen Y.
        • Wang Q.
        • et al.
        Exosome: emerging biomarker in breast cancer.
        Oncotarget. 2017; 8: 41717-41733
        • Toss A.
        • Mu Z.
        • Fernandez S.
        • Cristofanilli M.
        CTC enumeration and characterization: moving toward personalized medicine.
        Ann Transl Med. 2014; 2: 108
        • Yang M.H.
        • Imrali A.
        • Heeschen C.
        Circulating cancer stem cells: the importance to select.
        Chin J Cancer Res. 2015; 27: 437-449
        • Marrinucci D.
        • Bethel K.
        • Kolatkar A.
        • et al.
        Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers.
        Phys Biol. 2012; 9016003
        • Clara J.A.
        • Monge C.
        • Yang Y.
        • Takebe N.
        Targeting signalling pathways and the immune microenvironment of cancer stem cells - a clinical update.
        Nat Rev Clin Oncol. 2020; 17: 204-232
        • Bezdenezhnykh N.
        • Semesiuk N.
        • Lykhova O.
        • Zhylchuk V.
        • Kudryavets Y.
        Impact of stromal cell components of tumor microenvironment on epithelial-mesenchymal transition in breast cancer cells.
        Exp Oncol. 2014; 36: 72-78
        • Strauch U.G.
        • Mueller R.C.
        • Li X.Y.
        • et al.
        Integrin αE (CD103) β7 mediates adhesion to intestinal microvascular endothelial cell lines via an E-cadherin-independent interaction.
        The Journal of Immunology. 2001; 166: 3506-3514
        • Alkatout I.
        • Hübner F.
        • Wenners A.
        • et al.
        In situ localization of tumor cells associated with the epithelial-mesenchymal transition marker Snail and the prognostic impact of lymphocytes in the tumor microenvironment in invasive ductal breast cancer.
        Exp Mol Pathol. 2017; 102: 268-275
        • Ribeiro Franco P.I.
        • Rodrigues A.P.
        • de Menezes L.B.
        • Pacheco Miguel M.
        Tumor microenvironment components: Allies of cancer progression.
        Pathol Res Pract. 2020; 216152729
        • Weng Y.S.
        • Tseng H.Y.
        • Chen Y.A.
        • et al.
        MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer.
        Mol. Cancer. 2019; 18: 42
        • Gao T.
        • Li J.Z.
        • Lu Y.
        • et al.
        The mechanism between epithelial mesenchymal transition in breast cancer and hypoxia microenvironment.
        Biomed Pharmacother. 2016; 80: 393-405
        • Boulding T.
        • McCuaig R.D.
        • Tan A.
        • et al.
        LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer.
        Sci Rep. 2018; 8: 73
        • Khoshbakht S.
        • Azimzadeh Jamalkandi S.
        • Masudi-Nejad A.
        Involvement of immune system and Epithelial–Mesenchymal-Transition in increased invasiveness of clustered circulatory tumor cells in breast cancer.
        BMC medical genomics. 2021; 14: 1-12
        • Huang T.X.
        • Guan X.Y.
        • Fu L.
        Therapeutic targeting of the crosstalk between cancer-associated fibroblasts and cancer stem cells.
        Am.J .Cancer Res. 2019; 9: 1889-1904
        • Duan H.
        • Liu Y.
        • Gao Z.
        • Huang W.
        Recent advances in drug delivery systems for targeting cancer stem cells.
        Acta Pharm Sin B. 2021; 11: 55-70
        • Deepak K.G.K.
        • Vempati R.
        • Nagaraju G.P.
        • et al.
        Tumor microenvironment: Challenges and opportunities in targeting metastasis of triple negative breast cancer.
        Pharmacol . Res. 2020; 153104683
        • Grover P.K.
        • Cummins A.G.
        • Price T.J.
        • Roberts-Thomson I.C.
        • Hardingham J.E.
        Circulating tumor cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research.
        Ann Oncol. 2014; 25: 1506-1516
        • Balkwill F.R.
        • Capasso M.
        • Hagemann T.
        The Tumor Microenvironment At A Glance.
        The Company of Biologists Ltd, 2012
        • Bian X.
        • Xiao Y.-T.
        • Wu T.
        • et al.
        Microvesicles and chemokines in tumor microenvironment: mediators of intercellular communications in tumor progression.
        Mol. Cancer. 2019; 18: 50
        • Dasgupta A.
        • Lim A.R.
        • Ghajar C.M.
        Circulating and disseminated tumor cells: harbingers or initiators of metastasis?.
        Mol Oncol. 2017; 11: 40-61
        • Fu Q.
        • Zhang Q.
        • Lou Y.
        • et al.
        Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer.
        Oncogene. 2018; 37: 6105-6118
        • Masuda T.
        • Hayashi N.
        • Iguchi T.
        • Ito S.
        • Eguchi H.
        • Mimori K.
        Clinical and biological significance of circulating tumor cells in cancer.
        Mol Oncol. 2016; 10: 408-417
        • Theodoropoulos P.A.
        • Polioudaki H.
        • Agelaki S.
        • et al.
        Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer.
        Cancer Lett. 2010; 288: 99-106
        • Wang J.
        • Cao M.
        • You C.
        • et al.
        A preliminary investigation of the relationship between circulating tumor cells and cancer stem cells in patients with breast cancer.
        Cell Mol Biol. 2012; 58: 1641-1645
        • Książkiewicz M.
        • Markiewicz A.
        • Żaczek A.J.
        Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells.
        Pathobiology. 2012; 79: 195-208
        • Scatena R.
        • Bottoni P.
        • Giardina B.
        Circulating tumour cells and cancer stem cells: A role for proteomics in defining the interrelationships between function, phenotype and differentiation with potential clinical applications.
        Biochim Biophys Acta - Reviews on Cancer. 2013; 1835: 129-143
        • Ivanova E.
        • Ward A.
        • Wiegmans A.P.
        • Richard D.J.
        Circulating tumorcells in metastatic breast cancer: from genome instability to metastasis.
        Front Mol Biosci. 2020; 7: 134
        • Raskov H.
        • Orhan A.
        • Salanti A.
        • Gögenur I.
        Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery.
        Int J Cancer. 2020; 146: 3244-3255
        • Sprouse M.L.
        • Welte T.
        • Boral D.
        • et al.
        PMN-MDSCs enhance CTC metastatic properties through reciprocal interactions via ROS/Notch/Nodal signaling.
        Int.J. Mol. Sci. 2019; 20: 1916
        • Szczerba B.M.
        • Castro-Giner F.
        • Vetter M.
        • et al.
        neutrophils escort circulating tumour cells to enable cell cycle progression.
        Nature. 2019; 566: 553-557
        • Mego M.
        • Gao H.
        • Cohen E.N.
        • et al.
        Circulating tumor cells (CTCs) are associated with abnormalities in peripheral blood dendritic cells in patients with inflammatory breast cancer.
        Oncotarget. 2017; 8: 35656-35668
        • Papadaki M.A.
        • Koutsopoulos A.V.
        • Tsoulfas P.G.
        • et al.
        Clinical relevance of immune checkpoints on circulating tumor cells in breast cancer.
        Cancers (Basel). 2020; 12: 376
        • Green T.L.
        • Cruse J.M.
        • Lewis R.E.
        • Craft B.S.
        Circulating tumor cells (CTCs) from metastatic breast cancer patients linked to decreased immune function and response to treatment.
        Exp Mol Pathol. 2013; 95: 174-179
        • Santos M.F.
        • Mannam V.K.
        • Craft B.S.
        • et al.
        Comparative analysis of innate immune system function in metastatic breast, colorectal, and prostate cancer patients with circulating tumor cells.
        Exp Mol Pathol. 2014; 96: 367-374
        • Hurtado P.
        • Martínez-Pena I.
        • Piñeiro R.
        Dangerous liaisons: circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs).
        Cancers (Basel). 2020; 12: 2861
        • Matsumura Y.
        • Ito Y.
        • Mezawa Y.
        • et al.
        Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity.
        Life Science Alliance. 2019; 2e201900425
        • Banys-Paluchowski M.
        • Krawczyk N.
        • Meier-Stiegen F.
        • Fehm T.
        Circulating tumor cells in breast cancer–current status and perspectives.
        Crit Rev Oncol Hematol. 2016; 97: 22-29
        • Li D.
        • Wang Y.
        • Li C.
        • et al.
        Cancer-specific calcium nanoregulator suppressing the generation and circulation of circulating tumor cell clusters for enhanced anti-metastasis combinational chemotherapy.
        Acta Pharmaceutica Sinica B. 2021; 11: 3262-3271
        • Gener P.
        • Montero S.
        • Xandri-Monje H.
        • et al.
        Zileuton loaded in polymer micelles effectively reduce breast cancer circulating tumor cells and intratumoral cancer stem cells.
        Nanomedicine. 2020; 24102106
        • Li J.
        • Ai Y.
        • Wang L.
        • et al.
        Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles.
        Biomaterials. 2016; 76: 52-65
        • Smit D.J.
        • Cayrefourcq L.
        • Haider M.T.
        • et al.
        High sensitivity of circulating tumor cells derived from a colorectal cancer patient for dual inhibition with AKT and mTOR inhibitors.
        Cells. 2020; 9: 2129
        • Backhus L.M.
        • Sievers E.
        • Lin G.Y.
        • et al.
        Perioperative cyclooxygenase 2 inhibition to reduce tumor cell adhesion and metastatic potential of circulating tumor cells in non-small cell lung cancer.
        J Thorac Cardiovasc Surg. 2006; 132: 297-303
        • Huang X.
        • Yang Y.
        • Zhao Y.
        • et al.
        RhoA-stimulated intra-capillary morphology switch facilitates the arrest of individual circulating tumor cells.
        Int J Cancer. 2018; 142: 2094-2105
        • Rostami P.
        • Kashaninejad N.
        • Moshksayan K.
        • Saidi M.S.
        • Firoozabadi B.
        • Nguyen N.-T.
        Novel approaches in cancer management with circulating tumor cell clusters.
        Journal of Science: Adv Mater Devices. 2019; 4: 1-18
        • Andree K.C.
        • van Dalum G.
        • Terstappen L.W.
        Challenges in circulating tumor cell detection by the CellSearch system.
        Mol Oncol. 2016; 10: 395-407
        • Miller M.C.
        • Robinson P.S.
        • Wagner C.
        • O'Shannessy D.J.
        The Parsortix cell separation system-a versatile liquid biopsy platform.
        Cytometry A. 2018; 93: 1234-1239
        • Pachmann K.
        Current and potential use of MAINTRAC method for cancer diagnosis and prediction of metastasis.
        Expert Rev Mol Diagn. 2015; 15: 597-605
        • Liu Q.
        • Peng F.
        • Chen J.
        The role of exosomal microRNAs in the tumor microenvironment of breast cancer.
        Int.J. Mol. Sci. 2019; 20: 3884
        • Baig M.S.
        • Roy A.
        • Rajpoot S.
        • et al.
        Tumor-derived exosomes in the regulation of macrophage polarization.
        Inflamm Res. 2020; 69: 435-451
        • Ham S.
        • Lima L.G.
        • Chai E.P.Z.
        • et al.
        Breast cancer-derived exosomes alter macrophage polarization via gp130/STAT3 signaling.
        Front Immunol. 2018; 9: 871
        • Luga V.
        • Zhang L.
        • Viloria-Petit A.M.
        • et al.
        Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration.
        Cell. 2012; 151: 1542-1556
        • Wang H.
        • Wei H.
        • Wang J.
        • Li L.
        • Chen A.
        • Li Z.
        MicroRNA-181d-5p-containing exosomes derived from CAFs Promote EMT by regulating CDX2/HOXA5 in breast cancer.
        Mol Ther Nucleic Acids. 2020; 19: 654-667
        • Wen S.W.
        • Sceneay J.
        • Lima L.G.
        • et al.
        The biodistribution and immune suppressive effects of breast cancer-derivedexosomes.
        Cancer Res. 2016; 76: 6816-6827
        • Dou D.
        • Ren X.
        • Han M.
        • et al.
        Cancer-associated fibroblasts-derived exosomes suppress immune cell function in breast cancer via the miR-92/PD-L1 pathway.
        Front Immunol. 2020; 11: 2026
        • Ni C.
        • Fang Q.Q.
        • Chen W.Z.
        • et al.
        Breast cancer-derived exosomes transmit lncRNA SNHG16 to induce CD73+γδ1 Treg cells.
        Signal Transduct Target Ther. 2020; 5: 41
        • Syn N.
        • Wang L.
        • Sethi G.
        • Thiery J.P.
        • Goh B.C.
        Exosome-mediated metastasis: from epithelial-mesenchymal transition to escape from immunosurveillance.
        Trends Pharmacol Sci. 2016; 37: 606-617
        • Najafi M.
        • Farhood B.
        • Mortezaee K.
        Cancer stem cells (CSCs) in cancer progression and therapy.
        J Cell Physiol. 2019; 234: 8381-8395
        • Singhal U.
        • Wang Y.
        • Henderson J.
        • et al.
        Multigene profiling of CTCs in mCRPC identifies a clinicallyrelevant prognostic signature.
        Mol Cancer Res. 2018; 16: 643-654
        • Ding J.
        • Li H.Y.
        • Zhang L.
        • Zhou Y.
        • Wu J.
        Hedgehog signaling, a critical pathway governing the development and progression of hepatocellular carcinoma.
        Cells. 2021; 10: 123
        • Benjamin D.C.
        • Kang J.H.
        • Hamza B.
        • et al.
        YAP Enhances tumor cell dissemination by promoting intravascular motility and reentry into systemic circulation.
        Cancer Res. 2020; 80: 3867-3879
        • Kameda C.
        • Tanaka H.
        • Yamasaki A.
        • et al.
        The Hedgehog pathway is a possible therapeutic target for patients with estrogen receptor-negative breast cancer.
        Anticancer Res. 2009; 29: 871-879
        • Colavito S.A.
        • Zou M.R.
        • Yan Q.
        • Nguyen D.X.
        • Stern D.F.
        Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway.
        Breast Cancer Res. 2014; 16: 444
        • Pietrobono S.
        • Gagliardi S.
        • Stecca B.
        Non-canonical hedgehog signaling pathway in cancer: activation of GLI transcription factors beyond smoothened.
        Front Genet. 2019; 10: 556
        • Bhateja P.
        • Cherian M.
        • Majumder S.
        • Ramaswamy B.
        The hedgehog signaling pathway: A viable target in breast cancer?.
        Cancers (Basel). 2019; 11: 1126
        • Arnold K.M.
        • Flynn N.J.
        • Sims-Mourtada J.
        Activation of inflammatory responses correlate with hedgehog activation and precede expansion of cancer stem-like cells in an animal model of residual triple negative breast cancer after neoadjuvant chemotherapy.
        Cancer Stud Mol Med. 2015; 2: 80-86
        • Yan Y.
        • Liu F.
        • Han L.
        • et al.
        HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways.
        J. Exp. Clin. Cancer Res. 2018; 37: 256
        • Castagnoli L.
        • Cancila V.
        • Cordoba-Romero S.L.
        • et al.
        WNT signaling modulates PD-L1 expression in the stem cell compartment of triple-negative breast cancer.
        Oncogene. 2019; 38: 4047-4060
        • Zhuang X.
        • Zhang H.
        • Li X.
        • et al.
        Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1.
        Nat Cell Biol. 2017; 19: 1274-1285
        • Eyre R.
        • Alférez D.G.
        • Santiago-Gómez A.
        • et al.
        Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling.
        Nat Commun. 2019; 10: 5016
        • Kar S.
        • Jasuja H.
        • Katti D.R.
        • Katti K.S.
        Wnt/β-Catenin signaling pathway regulates osteogenesis for breast cancer bone metastasis: experiments in an in vitro nanoclay scaffold cancer testbed.
        ACS Biomater Sci Eng. 2020; 6: 2600-2611
        • Li X.
        • Xiang Y.
        • Li F.
        • Yin C.
        • Li B.
        • Ke X.
        WNT/β-Catenin signaling pathway regulating T cell-inflammation in the tumor microenvironment.
        Front Immunol. 2019; 10: 2293
        • Luke J.J.
        • Bao R.
        • Sweis R.F.
        • Spranger S.
        • Gajewski T.F.
        WNT/β-catenin pathway activation correlates with immune exclusion across human cancers.
        Clin.Cancer Res. 2019; 25: 3074-3083
        • Hong A.W.
        • Meng Z.
        • Guan K.L.
        The Hippo pathway in intestinal regeneration and disease.
        Nat Rev Gastroenterol Hepatol. 2016; 13: 324-337
        • Shi P.
        • Feng J.
        • Chen C.
        Hippo pathway in mammary gland development and breast cancer.
        Acta Biochim. Biophys. Sin. 2015; 47: 53-59
        • Maugeri-Saccà M.
        • De Maria R.
        Hippo pathway and breast cancer stem cells.
        Crit Rev Oncol Hematol. 2016; 99: 115-122
        • Zhang Z.
        • Du J.
        • Wang S.
        • et al.
        OTUB2 Promotes cancer metastasis via Hippo-independent activation of YAP and TAZ.
        Mol. Cell. 2019; 73: 7-21
        • Park J.H.
        • Shin J.E.
        • Park H.W.
        The role of Hippo pathway in cancer stem cell biology.
        Mol Cells. 2018; 41: 83-92
        • Cordenonsi M.
        • Zanconato F.
        • Azzolin L.
        • et al.
        The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells.
        Cell. 2011; 147: 759-772
        • Zhang H.
        • Lang T.Y.
        • Zou D.L.
        • et al.
        miR-520b Promotes breast cancer stemness through Hippo/YAP signaling pathway.
        Onco Targets Ther. 2019; 12: 11691-11700
        • Wang Y.
        • Liao R.
        • Chen X.
        • et al.
        Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway.
        Cell Death Dis. 2020; 11: 520
        • He L.
        • Yuan L.
        • Sun Y.
        • et al.
        Glucocorticoid receptor signaling activates TEAD4 to promote breast cancer progression.
        Cancer Res. 2019; 79: 4399-4411
        • Sun H.L.
        • Men J.R.
        • Liu H.Y.
        • Liu M.Y.
        • Zhang H.S.
        FOXM1 facilitates breast cancer cell stemness and migration in YAP1-dependent manner.
        Arch Biochem Biophys. 2020; 685108349
        • Britschgi A.
        • Duss S.
        • Kim S.
        • et al.
        The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα.
        Nature. 2017; 541: 541-545
        • Khan T.
        • Scott K.F.
        • Becker T.M.
        • et al.
        The prospect of identifying resistance mechanisms for castrateresistant prostate cancer using circulating tumor cells: Is epithelial-to-mesenchymal transition a key player?.
        Prostate Cancer. 2020; 20207938280
        • Li W.J.
        • Xie X.X.
        • Bai J.
        • Wang C.
        • Zhao L.
        • Jiang D.Q.
        Increased expression of miR-1179 inhibits breast cancer cell metastasis by modulating Notch signaling pathway and correlates with favorable prognosis.
        Eur Rev Med Pharmacol Sci. 2018; 22: 8374-8382
        • Jiang H.
        • Li X.
        • Wang W.
        • Dong H.
        Long non-coding RNA SNHG3 promotes breast cancer cell proliferation and metastasis by binding to microRNA-154-3p and activating the notch signaling pathway.
        BMC Cancer. 2020; 20: 838
        • Chen J.
        • Imanaka N.
        • Chen J.
        • Griffin J.D.
        Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion.
        Br. J. Cancer. 2010; 102: 351-360
        • Malla R.R.
        • Kiran P.
        Tumor microenvironment pathways: Cross regulation in breast cancer metastasis.
        Genes Dis. 2020; 9: 310-324
        • Wendler F.
        • Bota-Rabassedas N.
        • Franch-Marro X.
        Cancer becomes wasteful: emerging roles of exosomes(†) in cell-fate determination.
        J Extracell Vesicles. 2013; 2: 22390