Mesenchymale Stammzellen: Tumorfördernde oder -hemmende Eigenschaften – Ein aktueller Überblick

Zusammenfassung

Eine multimodale Tumortherapie richtet sich nicht nur gegen die Tumorzellen, sondern beeinflusst auch das tumorumgebende Stroma. Das Tumorstroma beherbergt verschiedene nicht-maligne Zellen, unter anderem Fibroblasten, Immunzellen, aber auch mesenchymalen Stammzellen (MSC). MSC haben die Fähigkeit der Migration in Richtung Tumorgewebe. Welche Einflüsse MSC auf Tumorzellen ausüben wird in der gängigen Literatur kontrovers diskutiert. Die meisten Publikationen berichten von tumorfördernden Eigenschaften der MSC, welche über vier Hauptmechanismen ermöglicht werden: Die Sekretion löslicher Mediatoren verbunden mit Zell-Zell-Kontakten, die Transdifferenzierung der MSC in tumorassoziierte Fibroblasten, die Verbesserung der Neoangiogenese und zuletzt die Einleitung einer Immunsuppression durch MSC. In dieser Übersicht wird über den aktuellen Stand der Literatur referiert.

Abstract

The multimodal treatment of cancer deals with cancer cells as well as with the cancer surrounding stroma. This stroma contains non-malignant cells like fibroblasts, immune cells as well as mesenchymal stem cells (MSC). MSC have the ability to migrate towards cancer tissue. In the current literature the impact of MSC on cancer cells is discussed divergently. The majority of the current publications reveal an induction of cancer progression by MSC. Four main processes namely the secretion of soluble factors and cell-cell contact, the transdifferentiation of MSC into carcinoma associated fibroblasts, the improvement of neoangiogenesis and the induction of immune suppression are responsible for cancer progression. This publication gives an overview on the current literature.

Schlüsselwörter

Mesenchymale Stammzellen - lösliche Mediatoren - Immunsuppression - Neoangiogenese - Tumorstroma

Key words

mesenchymal stem cells - soluble mediators - immune suppression - neoangiogenesis - cancer stroma

• Literatur

• 1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians 2016; 66: 7-30
• 2 Fitzmaurice C, Allen C, Barber RM. et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA oncology 2017; 3: 524-548
• 3 Turley EA, Veiseh M, Radisky DC. et al. Mechanisms of disease: epithelial-mesenchymal transition--does cellular plasticity fuel neoplastic progression?. Nature clinical practice Oncology 2008; 5: 280-290
• 4 Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell 1997; 88: 287-298
• 5 Pittenger MF, Mackay AM, Beck SC. et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-147
• 6 Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Experimental hematology 1976; 4: 267-274
• 7 Caplan AI. Mesenchymal stem cells. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 1991; 9: 641-650
• 8 Horwitz EM, Le Blanc K, Dominici M. et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 2005; 7: 393-395
• 9 Dominici M, Le Blanc K, Mueller I. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315-317
• 10 Civin CI, Trischmann T, Kadan NS. et al. Highly purified CD34-positive cells reconstitute hematopoiesis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1996; 14: 2224-2233
• 11 Covas DT, Panepucci RA, Fontes AM. et al. Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts. Experimental hematology 2008; 36: 642-654
• 12 Tang W, Zeve D, Suh JM. et al. White fat progenitor cells reside in the adipose vasculature. Science 2008; 322: 583-586
• 13 Tavian M, Zheng B, Oberlin E. et al. The vascular wall as a source of stem cells. Annals of the New York Academy of Sciences 2005; 1044: 41-50
• 14 Chen CW, Corselli M, Peault B. et al. Human blood-vessel-derived stem cells for tissue repair and regeneration. Journal of biomedicine & biotechnology 2012; 2012: 597439
• 15 Sacchetti B, Funari A, Michienzi S. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 2007; 131: 324-336
• 16 Crisan M, Chen CW, Corselli M. et al. Perivascular multipotent progenitor cells in human organs. Annals of the New York Academy of Sciences 2009; 1176: 118-123
• 17 Crisan M, Yap S, Casteilla L. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell stem cell 2008; 3: 301-313
• 18 Horwitz EM, Gordon PL, Koo WK. et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proceedings of the National Academy of Sciences of the United States of America 2002; 99: 8932-8937
• 19 Ortiz LA, Dutreil M, Fattman C. et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proceedings of the National Academy of Sciences of the United States of America 2007; 104: 11002-11007
• 20 Lin BL, Chen JF, Qiu WH. et al. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial. Hepatology 2017; 66: 209-219
• 21 Lee RH, Pulin AA, Seo MJ. et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell stem cell 2009; 5: 54-63
• 22 Malliaras K, Kreke M, Marban E. The stuttering progress of cell therapy for heart disease. Clinical pharmacology and therapeutics 2011; 90: 532-541
• 23 Pacini S. Deterministic and stochastic approaches in the clinical application of mesenchymal stromal cells (MSCs). Frontiers in cell and developmental biology 2014; 2: 50
• 24 Hall B, Andreeff M, Marini F. The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. Handbook of experimental pharmacology. 2007 DOI: 10.1007/978–3–540–68976–8_12 263-283
• 25 Hong IS, Lee HY, Kang KS. Mesenchymal stem cells and cancer: friends or enemies?. Mutation research 2014; 768: 98-106
• 26 Kidd S, Spaeth E, Dembinski JL. et al. Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells 2009; 27: 2614-2623
• 27 Kolluri KK, Laurent GJ, Janes SM. Mesenchymal stem cells as vectors for lung cancer therapy. Respiration; international review of thoracic diseases 2013; 85: 443-451
• 28 Zhang TY, Huang B, Yuan ZY. et al. Gene recombinant bone marrow mesenchymal stem cells as a tumor-targeted suicide gene delivery vehicle in pulmonary metastasis therapy using non-viral transfection. Nanomedicine : nanotechnology, biology, and medicine 2014; 10: 257-267
• 29 Spaeth E, Klopp A, Dembinski J. et al. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene therapy 2008; 15: 730-738
• 30 Ji JF, He BP, Dheen ST. et al. Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells 2004; 22: 415-427
• 31 Heil M, Mitnacht-Krauss R, Issbrucker K. et al. An engineered heparin-binding form of VEGF-E (hbVEGF-E). Biological effects in vitro and mobilizatiion of precursor cells. Angiogenesis 2003; 6: 201-211
• 32 Wang L, Li Y, Chen X. et al. MCP-1, MIP-1, IL-8 and ischemic cerebral tissue enhance human bone marrow stromal cell migration in interface culture. Hematology 2002; 7: 113-117
• 33 Ponte AL, Marais E, Gallay N. et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells 2007; 25: 1737-1745
• 34 Hata N, Shinojima N, Gumin J. et al. Platelet-derived growth factor BB mediates the tropism of human mesenchymal stem cells for malignant gliomas. Neurosurgery 2010; 66: 144-156 discussion 156–147
• 35 Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell stem cell 2009; 4: 206-216
• 36 Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. The New England journal of medicine 1986; 315: 1650-1659
• 37 Antsiferova M, Werner S. The bright and the dark sides of activin in wound healing and cancer. Journal of cell science 2012; 125: 3929-3937
• 38 Karnoub AE, Dash AB, Vo AP. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557-U554
• 39 Zhang Y, Yang PY, Sun T. et al. miR-126 and miR-126*repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol 2013; 15: 284-294
• 40 Gutova M, Najbauer J, Frank RT. et al. Urokinase plasminogen activator and urokinase plasminogen activator receptor mediate human stem cell tropism to malignant solid tumors. Stem Cells 2008; 26: 1406-1413
• 41 Beckermann BM, Kallifatidis G, Groth A. et al. VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. British journal of cancer 2008; 99: 622-631
• 42 Shinagawa K, Kitadai Y, Tanaka M. et al. Mesenchymal stem cells enhance growth and metastasis of colon cancer. International Journal of Cancer 2010; 127: 2323-2333
• 43 Barcellos-de-Souza P, Gori V, Bambi F. et al. Tumor microenvironment: bone marrow-mesenchymal stem cells as key players. Biochimica et biophysica acta 2013; 1836: 321-335
• 44 Henschler R, Deak E, Seifried E. Homing of Mesenchymal Stem Cells. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 2008; 35: 306-312
• 45 Ley K, Laudanna C, Cybulsky MI. et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature reviews Immunology 2007; 7: 678-689
• 46 Ruster B, Gottig S, Ludwig RJ. et al. Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells. Blood 2006; 108: 3938-3944
• 47 Segers VF, Van RietI, Andries LJ. et al. Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms. American journal of physiology Heart and circulatory physiology 2006; 290: H1370-1377
• 48 Lu ZY, Chen WC, Li YH. et al. TNF-alpha enhances vascular cell adhesion molecule-1 expression in human bone marrow mesenchymal stem cells via the NF-kappaB, ERK and JNK signaling pathways. Molecular medicine reports 2016; 14: 643-648
• 49 Cuiffo BG, Karnoub AE. Mesenchymal stem cells in tumor development: emerging roles and concepts. Cell adhesion & migration 2012; 6: 220-230
• 50 Ciuculescu F, Giesen M, Deak E. et al. Variability in chemokine-induced adhesion of human mesenchymal stromal cells. Cytotherapy 2011; 13: 1172-1179
• 51 Di GH, Liu Y, Lu Y. et al. IL-6 secreted from senescent mesenchymal stem cells promotes proliferation and migration of breast cancer cells. PloS one 2014; 9: e113572
• 52 Scherzad A, Steber M, Gehrke T. et al. Human mesenchymal stem cells enhance cancer cell proliferation via IL-6 secretion and activation of ERK1/2. International journal of oncology 2015; 47: 391-397
• 53 Liu C, Feng X, Wang B. et al. Bone marrow mesenchymal stem cells promote head and neck cancer progression through Periostin-mediated phosphoinositide 3-kinase/Akt/mammalian target of rapamycin. Cancer science 2018; 109: 688-698
• 54 Rafii A, Mirshahi P, Poupot M. et al. Oncologic trogocytosis of an original stromal cells induces chemoresistance of ovarian tumours. PloS one 2008; 3: e3894
• 55 Chen X, Armstrong MA, Li G. Mesenchymal stem cells in immunoregulation. Immunol Cell Biol 2006; 84: 413-421
• 56 Norozi F, Ahmadzadeh A, Shahrabi S. et al. Mesenchymal stem cells as a double-edged sword in suppression or progression of solid tumor cells. Tumor Biol 2016; 37: 11679-11689
• 57 Patel SA, Meyer JR, Greco SJ. et al. Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-beta. J Immunol 2010; 184: 5885-5894
• 58 Djouad F, Plence P, Bony C. et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003; 102: 3837-3844
• 59 Liotta F, Querci V, Mannelli G. et al. Mesenchymal stem cells are enriched in head neck squamous cell carcinoma, correlates with tumour size and inhibit T-cell proliferation. British journal of cancer 2015; 112: 745-754
• 60 Luger D, Lipinski MJ, Westman PC. et al. Intravenously Delivered Mesenchymal Stem Cells: Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy. Circulation research 2017; 120: 1598-1613
• 61 Mathew B, Poston JN, Dreixler JC. et al. Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats. Graefe‘s archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2017 DOI: 10.1007/s00417–017–3690–1
• 62 Wang DG, Zhang FX, Chen ML. et al. Cx43 in mesenchymal stem cells promotes angiogenesis of the infarcted heart independent of gap junctions. Molecular medicine reports 2014; 9: 1095-1102
• 63 Al-Khaldi A, Eliopoulos N, Martineau D. et al. Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivo. Gene therapy 2003; 10: 621-629
• 64 Roorda BD, ter Elst A, Kamps WA. et al. Bone marrow-derived cells and tumor growth: contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells. Critical reviews in oncology/hematology 2009; 69: 187-198
• 65 Burns JS, Kristiansen M, Kristensen LP. et al. Decellularized matrix from tumorigenic human mesenchymal stem cells promotes neovascularization with galectin-1 dependent endothelial interaction. PloS one 2011; 6: e21888
• 66 Ho IA, Toh HC, Ng WH. et al. Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis. Stem Cells 2013; 31: 146-155
• 67 De Boeck A, Narine K, De Neve W. et al. Resident and bone marrow-derived mesenchymal stem cells in head and neck squamous cell carcinoma. Oral oncology 2010; 46: 336-342
• 68 Direkze NC, Hodivala-Dilke K, Jeffery R. et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer research 2004; 64: 8492-8495
• 69 Hall B, Dembinski J, Sasser AK. et al. Mesenchymal stem cells in cancer: Tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007; 86: 8-16
• 70 Ishii G, Sangai T, Oda T. et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochemical and biophysical research communications 2003; 309: 232-240
• 71 Mishra PJ, Mishra PJ, Humeniuk R. et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer research 2008; 68: 4331-4339
• 72 De Veirman K, Rao L, De Bruyne E. et al. Cancer associated fibroblasts and tumor growth: focus on multiple myeloma. Cancers 2014; 6: 1363-1381
• 73 Chiquet-Ehrismann R, Chiquet M. Tenascins: regulation and putative functions during pathological stress. The Journal of pathology 2003; 200: 488-499
• 74 Johansson AC, Ansell A, Jerhammar F. et al. Cancer-associated fibroblasts induce matrix metalloproteinase-mediated cetuximab resistance in head and neck squamous cell carcinoma cells. Molecular cancer research : MCR 2012; 10: 1158-1168
• 75 Ohlsson LB, Varas L, Kjellman C. et al. Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and in vitro in gelatin matrix. Experimental and molecular pathology 2003; 75: 248-255
• 76 Secchiero P, Zorzet S, Tripodo C. et al. Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin’s lymphoma xenografts. PloS one 2010; 5: e11140
• 77 Wang ML, Pan CM, Chiou SH. et al. Oncostatin m modulates the mesenchymal-epithelial transition of lung adenocarcinoma cells by a mesenchymal stem cell-mediated paracrine effect. Cancer research 2012; 72: 6051-6064
• 78 Maestroni GJ, Hertens E, Galli P. Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. Cellular and molecular life sciences : CMLS 1999; 55: 663-667
• 79 Khakoo AY, Pati S, Anderson SA. et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. The Journal of experimental medicine 2006; 203: 1235-1247
• 80 Ji X, Zhang Z, Han Y. et al. Mesenchymal stem cells derived from normal gingival tissue inhibit the proliferation of oral cancer cells in vitro and in vivo. International journal of oncology 2016; 49: 2011-2022
• 81 Waterman RS, Henkle SL, Betancourt AM. Mesenchymal stem cell 1 (MSC1)-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis. PloS one 2012; 7: e45590
• 82 Waterman RS, Tomchuck SL, Henkle SL. et al. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PloS one 2010; 5: e10088