Bedeutung von Stammzellen in der Biologie und Therapie von Kopf-Hals-Karzinomen

Zusammenfassung

Mit den Erkenntnissen der letzten Jahre, wird es immer offensichtlicher, dass Stammzellen eine zentrale Rolle in der Re- und Generation von Geweben einnehmen. Besonders deutlich lässt sich dies an der Entwicklung von Karzinomen zeigen. Primär werden 2 Arten von Stammzellfunktionen unterschieden, beide Stammzellarten sind von entscheidender Bedeutung für die Initiierung und Aufrechterhaltung eines Tumors. Zum einen werden Tumore von einer Vielzahl von Stammzellen infiltriert, die vom Tumor für verschiedene Funktionen genutzt werden, z. B. für den Aufbau von Gefäßen aber auch anderen Gewebeanteilen. Dennoch sind diese Stammzellen per se nicht maligne. Andererseits lassen sich auch die tumorinitiierenden Tumorstammzellen (CSC) nachweisen. Sie sind in der Lage aus jeder einzelnen Zelle einen Tumor entstehen zu lassen, der histologisch dem gleicht, aus dem die originale CSC entstammt. Vieles ist an der CSC- Biologie nicht verstanden. Es fehlen immer noch verlässliche Marker, die eine genaue Charakterisierung einzelner Untergruppen zulässt. Vieles spricht dafür, dass Tumore aus einem kleinen Prozentsatz CSC bestehen, die dann, im Sinne einer Hierarchie, in beliebig viele Zellen weiterdifferenzieren können. Da diese Stammzellen sehr vielen Differenzierungs- und Redifferenzierungsschritten unterworfen sind, geht es eher um die Beschreibung eines Fließgleichgewichtes. Die Definition der einzelnen Stadien ist weitgehend unverstanden, ebenso wie die Faktoren des Mikromilieus, die die einzelnen Differenzierungsschritte auslösen. Dennoch wird gerade in diesen Fähigkeiten der Schlüssel zur Tumorinitiierung, Metastasierung und Therapieresistenz vermutet. Bedeutsam sind die biologischen Funktionen und die damit assoziierten Signalwege innerhalb der Zellen, wie z. B. das Self Renewal. Eine spezifische Beeinflussung eines solchen Weges könnte auch für die Therapie solcher Zellen von hohem Interesse sein. Aktuell gibt es hierzu nur vorläufige Überlegungen und einige in vitro Testungen, die allerdings noch weit von einer translationalen klinischen Umsetzung entfernt sind.

Abstract

Implication of Stem Cells in the Biology and Therapy of Head and Neck Cancer

Stem cells play a central role in re- and generation of tissues. Special importance has been attributed to them in cancer biology. 2 entities can be discriminated: cancer infiltrating stem cells and cancer initiating stem cells. Infiltrating stem cells will be attracted to the tumor in order to be remodelled for tumor expansion, e. g. endothelial cells or other cancerous tissue components, yet these cells are per se benign. Malignant cancer stem cells are capable to generate a new tumor, histologically identical with the cancer they originate from. Many steps in cancer stem cell biology are not understood to date. It is still believed that CSC are only a minor cell fraction in tumor but capable to differentiate in hierarchical manner into any other tissue type. These stem cells are undergoing many steps of differentiation and dedifferentiation in a steady state. The factors of the micromilieu contributing to this are largely not understood. Still these steps are regarded as the key to tumorinitiation, metastases and resistance to therapy. The biological functions and associated signaltransduction pathways, e. g. self renewal pathways will be the key to future therapeutical strategies.

Schlüsselwörter

Stammzellen - Tumorstammzellen - EMT - WNT - Self Renewal

Key words

stem cells - cancer stem cells - WNT - EMT - self renewal

Literatur

• 1 Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001.  CA Cancer J Clin. 2001;  51 (1) 15-36
• 2 Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor.  Cancer. 1994;  73 (1) 187-190
• 3 Young MR. Tumor skewing of CD34+ progenitor cell differentiation into endothelial cells.  Int J Cancer. 2004;  109 (4) 516-524
• 4 Young MR, Kolesiak K, Wright MA, Gabrilovich DI. Chemoattraction of femoral CD34+ progenitor cells by tumor-derived vascular endothelial cell growth factor.  Clin Exp Metastasis. 1999;  17 (10) 881-888
• 5 Reers S, Hagge AC, Pries R, Wollenberg B. Profiling of potential stem cell marker proteins in HNSCC submitted.  2011; 
• 6 Gorjup E, Danner S, Rotter N, Habermann J, Brassat U, Brummendorf TH, Wien S, Meyerhans A, Wollenberg B, Kruse C, von Briesen H. Glandular tissue from human pancreas and salivary gland yields similar stem cell populations.  Eur J Cell Biol. 2009;  88 (7) 409-421
• 7 Rotter N, Oder J, Schlenke P, Lindner U, Bohrnsen F, Kramer J, Rohwedel J, Huss R, Brandau S, Wollenberg B, Lang S. Isolation and characterization of adult stem cells from human salivary glands.  Stem Cells Dev. 2008;  17 (3) 509-518
• 8 Reers S, Hagge AC, Pries R, Wollenberg B. Oct-4 expressing subpopulation with chemoresistance properties in head and neck cancer submitted.  2011; 
• 9 Caplan A. Mesenchymal stem cells: building blocks for molecular medicine in the 21^st century.  Trends in Molecular Medicine. 2001;  7 (6) 259-264
• 10 Garrity T, Pandit R, Wright MA, Benefield J, Keni S, Young MR. Increased presence of CD34+ cells in the peripheral blood of head and neck cancer patients and their differentiation into dendritic cells.  Int J Cancer. 1997;  73 (5) 663-669
• 11 Pandit R, Lathers DM, Beal NM, Garrity T, Young MR. CD34+ immune suppressive cells in the peripheral blood of patients with head and neck cancer.  Ann Otol Rhinol Laryngol. 2000;  109 (8 Pt 1) 749-754
• 12 Young MR, Petruzzelli GJ, Kolesiak K, Achille N, Lathers DM, Gabrilovich DI. Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34(+) progenitor cells.  Hum Immunol. 2001;  62 (4) 332-341
• 13 Benefield J, Petruzzelli GJ, Fowler S, Taitz A, Kalkanis J, Young MR. Regulation of the steps of angiogenesis by human head and neck squamous cell carcinomas.  Invasion Metastasis. 1996;  16 (6) 291-301
• 14 Studeny MMF, Champlin RE, Zompetta C, Fidler IJ, Andreeff M. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors.  Cancer Res. 2002;  62 (13) 3603-3608
• 15 Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?.  Nat Rev Cancer. 2002;  2 (11) 826-835
• 16 De Palma M, Venneri MA, Roca C, Naldini L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells.  Nat Med. 2003;  9 (6) 789-795
• 17 Stoll BR, Migliorini C, Kadambi A, Munn LL, Jain RK. A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for antiangiogenic therapy.  Blood. 2003;  102 (7) 2555-2561
• 18 Blumenthal RD, Reising A, Leon E, Goldenberg DM. Modulation of marrow proliferation and chemosensitivity by tumor-produced cytokines from syngeneic pancreatic tumor lines.  Clin Cancer Res. 2002;  8 (5) 1301-1309
• 19 Lathers DM, Achille N, Kolesiak K, Hulett K, Sparano A, Petruzzelli GJ, Young MR. Increased levels of immune inhibitory CD34+ progenitor cells in the peripheral blood of patients with node positive head and neck squamous cell carcinomas and the ability of these CD34+ cells to differentiate into immune stimulatory dendritic cells.  Otolaryngol Head Neck Surg. 2001;  125 (3) 205-212
• 20 Gabri MR, Menna PL, Scursoni AM, Gomez DE, Alonso DF. Role of tumor-derived granulocyte-macrophage colony-stimulating factor in mice bearing a highly invasive and metastatic mammary carcinoma.  Pathobiology. 1999;  67 (4) 180-185
• 21 Young MR, Wright MA, Lozano Y, Matthews JP, Benefield J, Prechel MM. Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer.  Int J Cancer. 1996;  67 (3) 333-338
• 22 Young MR, Wright MA, Lozano Y, Prechel MM, Benefield J, Leonetti JP, Collins SL, Petruzzelli GJ. Increased recurrence and metastasis in patients whose primary head and neck squamous cell carcinomas secreted granulocyte-macrophage colony-stimulating factor and contained CD34+ natural suppressor cells.  Int J Cancer. 1997;  74 (1) 69-74
• 23 Pak AS, Wright MA, Matthews JP, Collins SL, Petruzzelli GJ, Young MR. Mechanisms of immune suppression in patients with head and neck cancer: presence of CD34(+) cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor.  Clin Cancer Res. 1995;  1 (1) 95-103
• 24 Wright MA, Wiers K, Vellody K, Djordjevic D, Young MR. Stimulation of immune suppressive CD34+ cells from normal bone marrow by Lewis lung carcinoma tumors.  Cancer Immunol Immunother. 1998;  46 (5) 253-260
• 25 Young MR, Wright MA, Coogan M, Young ME, Bagash J. Tumor-derived cytokines induce bone marrow suppressor cells that mediate immunosuppression through transforming growth factor beta.  Cancer Immunol Immunother. 1992;  35 (1) 14-18
• 26 Hirashima M, Kataoka H, Nishikawa S, Matsuyoshi N. Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis.  Blood. 1999;  93 (4) 1253-1263
• 27 Banich JC, Kolesiak K, Young MR. Chemoattraction of CD34+ progenitor cells and dendritic cells to the site of tumor excision as the first step of an immunotherapeutic approach to target residual tumor cells.  J Immunother. 2003;  26 (1) 31-40
• 28 Dutt P, Wang JF, Groopman JE. Stromal cell-derived factor-1 alpha and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis.  J Immunol. 1998;  161 (7) 3652-3658
• 29 Kim CH, Broxmeyer HE. In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment.  Blood. 1998;  91 (1) 100-110
• 30 Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood.  J Exp Med. 1997;  185 (1) 111-120
• 31 Young MR, Wright MA, Pandit R. Myeloid differentiation treatment to diminish the presence of immune-suppressive CD34+ cells within human head and neck squamous cell carcinomas.  J Immunol. 1997;  159 (2) 990-996
• 32 Nitsch SM, Pries R, Wollenberg B. Head and neck cancer triggers increased IL-6 production of CD34+ stem cells from human cord blood.  In Vivo. 2007;  21 (3) 493-498
• 33 Pries R, Nitsch S, Wollenberg B. Role of cytokines in head and neck squamous cell carcinoma.  Expert Rev Anticancer Ther. 2006;  6 (9) 1195-1203
• 34 Young MR, Lathers DM. Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers.  Int J Immunopharmacol. 1999;  21 (4) 241-252
• 35 Lathers DM, Achille N, Young MR. Dendritic cell development from mobilized peripheral blood CD34+ cells.  Methods Mol Biol. 2003;  215 409-415
• 36 Lathers DM, Lubbers E, Wright MA, Young MR. Dendritic cell differentiation pathways of CD34+ cells from the peripheral blood of head and neck cancer patients.  J Leukoc Biol. 1999;  65 (5) 623-628
• 37 Lathers DM, Lubbers E, Beal NM, Wright MA, Young MR. Cultures derived from peripheral blood CD34+ progenitor cells of head and neck cancer patients and from cord blood are functionally different.  Hum Immunol. 1999;  60 (12) 1207-1215
• 38 Tjoa B, Erickson S, Barren 3rd R, Ragde H, Kenny G, Boynton A, Murphy G. In vitro propagated dendritic cells from prostate cancer patients as a component of prostate cancer immunotherapy.  Prostate. 1995;  27 (2) 63-69
• 39 Bernhard H, Disis ML, Heimfeld S, Hand S, Gralow JR, Cheever MA. Generation of immunostimulatory dendritic cells from human CD34+ hematopoietic progenitor cells of the bone marrow and peripheral blood.  Cancer Res. 1995;  55 (5) 1099-1104
• 40 Kanangat S, Nair S, Babu JS, Rouse BT. Expression of cytokine mRNA in murine splenic dendritic cells and better induction of T cell-derived cytokines by dendritic cells than by macrophages during in vitro costimulation assay using specific antigens.  J Leukoc Biol. 1995;  57 (2) 310-316
• 41 Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions.  Nat Rev Cancer. 2008;  8 (10) 755-768
• 42 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells.  Nature. 2001;  414 (6859) 105-111
• 43 Dick JE. Stem cell concepts renew cancer research.  Blood. 2008;  112 (13) 4793-4807
• 44 Maenhaut C, Dumont JE, Roger PP, van Staveren WC. Cancer stem cells: a reality, a myth, a fuzzy concept or a misnomer? An analysis.  Carcinogenesis. 2010;  31 (2) 149-158
• 45 Braakhuis BJ, Leemans CR, Brakenhoff RH. Expanding fields of genetically altered cells in head and neck squamous carcinogenesis.  Semin Cancer Biol. 2005;  15 (2) 113-120
• 46 Braakhuis BJ, Tabor MP, Leemans CR, van der Waal I, Snow GB, Brakenhoff RH. Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions.  Head Neck. 2002;  24 (2) 198-206
• 47 Regenbrecht CR, Lehrach H, Adjaye J. Stemming cancer: functional genomics of cancer stem cells in solid tumors.  Stem Cell Rev. 2008;  4 (4) 319-328
• 48 Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts.  Annu Rev Med. 2007;  58 267-284
• 49 Dalerba P, Clarke MF. Cancer stem cells and tumor metastasis: first steps into uncharted territory.  Cell Stem Cell. 2007;  1 (3) 241-242
• 50 Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman, Clarke MF, Ailles LE. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma.  Proc Natl Acad Sci U S A. 2007;  104 (3) 973-978
• 51 Prince ME, Ailles LE. Cancer stem cells in head and neck squamous cell cancer.  J Clin Oncol. 2008;  26 (17) 2871-2875
• 52 Mack B, Gires O. CD44s and CD44v6 expression in head and neck epithelia.  PLoS One. 2008;  3 (10) e3360
• 53 Pries R, Witrkopf N, Trenkle T, Nitsch SM, Wollenberg B. Potential stem cell marker CD44 is constitutively expressed in permanent cell lines of head and neck cancer.  In Vivo. 2008;  22 (1) 89-92
• 54 Hough MR, Rosten PM, Sexton TL, Kay R, Humphries RK. Mapping of CD24 and homologous sequences to multiple chromosomal loci.  Genomics. 1994;  22 (1) 154-161
• 55 Deng S, Yang X, Lassus H, Liang S, Kaur S, Ye Q, Li C, Wang LP, Roby KF, Orsulic S, Connolly DC, Zhang Y, Montone K, Butzow R, Coukos G, Zhang L. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers.  PLoS One. 2010;  5 (4) e10277
• 56 Chen YC, Chen YW, Hsu HS, Tseng LM, Huang PI, Lu KH, Chen DT, Tai LK, Yung MC, Chang SC, Ku HH, Chiou SH, Lo WL. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer.  Biochem Biophys Res Commun. 2009;  385 (3) 307-313
• 57 Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.  Cell Stem Cell. 2007;  1 (5) 555-567
• 58 Chen YC, Chang CJ, Hsu HS, Chen YW, Tai LK, Tseng LM, Chiou GY, Chang SC, Kao SY, Chiou SH, Lo WL. Inhibition of tumorigenicity and enhancement of radiochemosensitivity in head and neck squamous cell cancer-derived ALDH1-positive cells by knockdown of Bmi-1.  Oral Oncol. 2010;  46 (3) 158-165
• 59 Visus C, Ito D, Amoscato A, Maciejewska-Franczak M, Abdelsalem A, Dhir R, Shin DM, Donnenberg VS, Whiteside TL, DeLeo AB. Identification of human aldehyde dehydrogenase 1 family member A1 as a novel CD8+ T-cell-defined tumor antigen in squamous cell carcinoma of the head and neck.  Cancer Res. 2007;  67 (21) 10538-10545
• 60 Yu CC, Lo WL, Chen YW, Huang PI, Hsu HS, Tseng LM, Hung SC, Kao SY, Chang CJ, Chiou SH. Bmi-1 Regulates Snail Expression and Promotes Metastasis Ability in Head and Neck Squamous Cancer-Derived ALDH1 Positive Cells.  J Oncol. 2011;  Epub 2010 Sep 27
• 61 Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB. The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions.  J Biol Chem. 2000;  275 (8) 5512-5520
• 62 Wu X, Spitz M, Lee J. Novel susceptibility loci for second primary tumors/recurrence in head and neck cancer patients: large-scale evaluation of genetic variants.  Cancer Prev Res (Phila Pa). 2009;  2 (7) 617-624
• 63 Harper LJ, Piper K, Common J, Fortune F, Mackenzie IC. Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma.  J Oral Pathol Med. 2007;  36 (10) 594-603
• 64 Okamoto A, Chikamatsu K, Sakakura K, Hatsushika K, Takahashi G, Masuyama K. Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck.  Oral Oncol. 2009;  45 (7) 633-639
• 65 Wei XD, Zhou L, Cheng L, Tian J, Jiang JJ, Maccallum J. In vivo investigation of CD133 as a putative marker of cancer stem cells in Hep-2 cell line.  Head Neck. 2009;  31 (1) 94-101
• 66 Zhou L, Wei X, Cheng L, Tian J, Jiang JJ. CD133, one of the markers of cancer stem cells in Hep-2 cell line.  Laryngoscope. 2007;  117 (3) 455-460
• 67 Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior.  Curr Opin Cell Biol. 2007;  19 (2) 150-158
• 68 Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome.  Cell. 1982;  31 (1) 99-109
• 69 Rijsewijk F, Schuermann M, Wagenaar E, Parren P, Weigel D, Nusse R. The Drosophila Homolog of the Mouse Mammary Oncogene Int-1 Is Identical to the Segment Polarity Gene Wingless.  Cell. 1987;  50 (4) 649-657
• 70 Angers S, Moon RT. Proximal events in Wnt signal transduction.  Nat Rev Mol Cell Biol. 2009;  10 (7) 468-477
• 71 Rhee CS, Sen M, Lu D, Wu C, Leoni L, Rubin J, Corr M, Carson DA. Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas.  Oncogene;. 2002;  21 (43) 6598-6605
• 72 Yang F, Zeng Q, Yu G, Li S, Wang CY. Wnt/beta-catenin signaling inhibits death receptor-mediated apoptosis and promotes invasive growth of HNSCC.  Cell Signal. 2006;  18 (5) 679-687
• 73 Song J, Chang I, Chen Z, Kang M, Wang CY. Characterization of side populations in HNSCC: highly invasive, chemoresistant and abnormal Wnt signaling.  PLoS One. 2010;  5 (7) e11456
• 74 Diaz Prado SM, Medina Villaamil V, Aparicio Gallego G, Blanco Calvo M, Lopez Cedrun JL, Sironvalle Soliva S, Valladares Ayerbes M, Garcia Campelo R, Anton Aparicio LM. Expression of Wnt gene family and frizzled receptors in head and neck squamous cell carcinomas.  Virchows Arch. 2009;  455 (1) 67-75
• 75 Goto M, Mitra RS, Liu M, Lee J, Henson BS, Carey T, Bradford C, Prince M, Wang CY, Fearon ER, D’Silva NJ. Rap1 stabilizes beta-catenin and enhances beta-catenin-dependent transcription and invasion in squamous cell carcinoma of the head and neck.  Clin Cancer Res. 2010;  16 (1) 65-76
• 76 Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells.  J Cell Biol. 1982;  95 (1) 333-339
• 77 Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?.  Cancer Res. 2005;  65 (14) 5991-5995 ; discussion 5995
• 78 Christofori G. New signals from the invasive front.  Nature. 2006;  441 (7092) 444-450
• 79 Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression.  Curr Opin Cell Biol. 2005;  17 (5) 548-558
• 80 Grunert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis.  Nat Rev Mol Cell Biol. 2003;  4 (8) 657-665
• 81 Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions.  Nat Rev Mol Cell Biol. 2006;  7 (2) 131-142
• 82 Klymkowsky MW, Savagner P. Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe.  Am J Pathol. 2009;  174 (5) 1588-1593
• 83 Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions.  J Clin Invest. 2009;  119 (6) 1429-1437
• 84 Chung CH, Parker J, Levy S, Slebos RJ, Dicker AP, Rodeck U. Gene expression profiles as markers of aggressive disease-EGFR as a factor.  Int J Radiat Oncol Biol Phys. 2007;  69 (2 Suppl) S102-S105
• 85 Boyer B, Roche S, Denoyelle M, Thiery JP. Src and Ras are involved in separate pathways in epithelial cell scattering.  Embo J. 1997;  16 (19) 5904-5913
• 86 De Craene B, Gilbert B, Stove C, Bruyneel E, van Roy F, Berx G. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program.  Cancer Res. 2005;  65 (14) 6237-6244
• 87 Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD, Chodosh LA. The transcriptional repressor Snail promotes mammary tumor recurrence.  Cancer Cell. 2005;  8 (3) 197-209
• 88 Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers.  Proc Natl Acad Sci U S A. 2007;  104 (24) 10069-10074
• 89 Masuda M, Wakasaki T, Suzui M, Toh S, Joe AK, Weinstein IB. Stat3 orchestrates tumor development and progression: the Achilles’ heel of head and neck cancers?.  Curr Cancer Drug Targets. 2010;  10 (1) 117-126
• 90 Kupferman ME, Jiffar T, El-Naggar A, Yilmaz T, Zhou G, Xie T, Feng L, Wang J, Holsinger FC, Yu D, Myers JN. TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma.  Oncogene. 2010;  29 (14) 2047-2059
• 91 Dohadwala M, Wang G, Heinrich E, Luo J, Lau O, Shih H, Munaim Q, Lee G, Hong L, Lai C, Abemayor E, Fishbein MC, Elashoff DA, Dubinett SM, St John MA. The role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC.  Otolaryngol Head Neck Surg. 2000;  142 (5) 753-759
• 92 Yang MH, Chang SY, Chiou SH, Liu CJ, Chi CW, Chen PM, Teng SC, Wu KJ. Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer.  Oncogene. 2007;  26 (10) 1459-1467
• 93 Clarke MF, Fuller M. Stem cells and cancer: two faces of eve.  Cell. 2006;  124 (6) 1111-1115
• 94 LaBarge MA, Petersen OW, Bissell MJ. Of microenvironments and mammary stem cells.  Stem Cell Rev. 2007;  3 (2) 137-146
• 95 Bissell MJ, Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment?.  Cancer Cell. 2005;  7 (1) 17-23
• 96 Sagar J, Chaib B, Sales K, Winslet M, Seifalian A. Role of stem cells in cancer therapy and cancer stem cells: a review.  Cancer Cell Int. 2007;  7 9
• 97 Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters.  Cancer Res. 2006;  66 (9) 4553-4557
• 98 Zhang B, Bowerman NA, Salama JK, Schmidt H, Spiotto MT, Schietinger A, Yu P, FuY X, Weichselbaum RR, Rowley DA, Kranz DM, Schreiber H. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells.  JEM. 2007;  204 49-55
• 99 Hamzah J. Vascular normalization in Rgs5-deficient tumours promotes immune destruction.  Nature. 2008;  453 (7193) 410-414

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