Tumor Microenvironment

Authors: Š. Novák 1,2;  V. Bandurová 1,2;  A. Mifková 1,2;  D. Kalfeřt 1;  Z. Fík 1;  P. Lukeš 1;  P. Szabó 2,3;  J. Plzák 1;  K. Smetana Jr. 2,3
Published in: Otorinolaryngol Foniatr, 68, 2019, No. 1, pp. 41-51.
Category: Review Article


Cancer microenvironment plays an essential role in promoting the growth, proliferation and ability of cancer cells to establish metastatic deposits. This microenvironment consists predominantly of cancer-associated fibroblasts and the extracellular matrix produced by them, immune cells (macrophages, granulocytes, mast cells and lymphocytes), blood vessels, adipocytes and mesenchymal stem cells. These cells interact with each other, both via intercellular communication and signal molecules. The signal molecules include, for example, growth factors, chemokines, interleukins or galectins. In the review article, we present the current knowledge about individual cell groups and their interaction. The presented information relates mainly to the already applied or future prospective clinical use.


Stem cells – cancer-associated fibroblasts – extracellular matrix – immune cells – growth factors – chemokines – interleukins – galectin


1. Amano, M., Eriksson, H., Manning, J. C. et al.: Tumour suppressor p16(INK4a) - anoikis-favouring decrease in N/O-glycan/cell surface sialylation by down-regulation of enzymes in sialic acid biosynthesis in tandem in a pancreatic carcinoma model. FEBS J, 279, 2012, 21, s. 4062-4080.

2. Amend, S. R. and Pienta, K. J.: Ecology meets cancer biology: the cancer swamp promotes the lethal cancer phenotype. Oncotarget, 6, 2015, 12, s. 9669-78.

3. Appleby, T. C., Greenstein, A. E., Hung, M. et al.: Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9. J Biol Chem, 292, 2017, 16, s. 6810-6820.

4. Augsten, M., Hagglof, C., Olsson, E. et al.: CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. Proc Natl Acad Sci U S A, 106, 2009, 9, s. 3414-9.

5. Augsten, M., Sjoberg, E., Frings, O. et al.: Cancer-associated fibroblasts expressing CXCL14 rely upon NOS1-derived nitric oxide signaling for their tumor-supporting properties. Cancer Res, 74, 2014, 11, s. 2999-3010.

6. Barrett, D. M., Grupp, S. A. and June, C. H.: Chimeric Antigen Receptor- and TCR-Modified T Cells Enter Main Street and Wall Street. J Immunol, 195, 2015, 3, s. 755-61.

7. Berndt, A., Richter, P., Kosmehl, H. and Franz, M.: Tenascin-C and carcinoma cell invasion in oral and urinary bladder cancer. Cell Adh Migr, 9, 2015, 1-2, s. 105-11.

8. Bierie, B., Stover, D. G., Chytil, A. et al.: Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Research, 68, 2008, 6, s. 1809-1819.

9. Bollag, G., Tsai, J., Zhang, J. et al.: Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov, 11, 2012, 11, s. 873-86.

10. Bonifazi, F., de Vivo, A., Rosti, G. et al.: Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood, 98, 2001, 10, s. 3074-81.

11. Bonnans, C., Chou, J., Werb, Z.: Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol, 15, 2014, 12, s. 786-801.

12. Bromberg, J. and Wang, T. C.: Inflammation and Cancer: IL-6 and STAT3 Complete the Link. Cancer Cell, 15, 2009, 2, s. 79-80.

13. Buglioni, S., Vici, P., Sergi, D. et al.: Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment. Oncoimmunology, 5, 2016, 6, s. e1160187.

14. Burger, J. A., Stewart, D. J., Wald, O., Peled, A.: Potential of CXCR4 antagonists for the treatment of metastatic lung cancer. Expert Rev Anticancer Ther, 11, 2011, 4, s. 621-630.

15. Calvo, F., Ege, N., Grande-Garcia, A. et al.: Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol, 15, 2013, 6, s. 637-646.

16. Cedeno-Laurent, F., Dimitroff, C. J.: Galectins and their ligands: negative regulators of anti-tumor immunity. Glycoconj J, 29, 2012, 8-9, s. 619-625.

17. Cirri, P. and Chiarugi, P.: Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res, 1, 2011, 4, s. 482-497.

18. Civenni, G., Longoni, N., Costales, P. et al.: EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-kappaB. Mol Cancer Ther, 15, 2016, 5, s. 806-818.

19. Clayton, A., Evans, R. A., Pettit, E. et al.: Cellular activation through the ligation of intercellular adhesion molecule-1. J Cell Sci, 111 ( Pt 4), 1998, s. 443-453.

20. Correia, A. L., Bissell, M. J.: The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist Updat, 15, 2012, 1-2, s. 39-49.

21. Curry, J. M., Sprandio, J., Cognetti, D. et al.: Tumor microenvironment in head and neck squamous cell carcinoma. Semin Oncol, 41, 2014, 2, s. 217-234.

22. De Kruijf, E. M., van Nes, J. G., van de Velde, C. J. et al.: Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients. Breast Cancer Res Treat, 125, 2011, 3, s. 687-696.

23. Dhawan, P., Richmond, A.: Role of CXCL1 in tumorigenesis of melanoma. J Leukoc Biol, 72, 2002, 1, s. 9-18.

24. Domanska, U. M., Timmer-Bosscha, H., Nagengast, W. B. et al.: CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia, 14, 2012, 8, s. 709-718.

25. Du, Y. E., Tu, G., Yang, G. et al.: MiR-205/YAP1 in Activated Fibroblasts of Breast Tumor Promotes VEGF-independent Angiogenesis through STAT3 Signaling. Theranostics, 7, 2017, 16, s. 3972-3988.

26. Dumitru, C. A., Gholaman, H., Trellakis, S. et al.: Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation. Int J Cancer, 129, 2011, 4, s. 859-869.

27. Duray, A., Demoulin, S., Hubert, P., Delvenne, P., Saussez, S.: Immune suppression in head and neck cancers: a review. Clin Dev Immunol, 2010, 2010, s. 701657.

28. Dvorak, H. F.: Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med, 315, 1986, 26, s. 1650-1659.

29. Dvorankova, B., Smetana, K., Jr., Rihova, B. et al.: Cancer-associated fibroblasts are not formed from cancer cells by epithelial-to-mesenchymal transition in nu/nu mice. Histochem Cell Biol, 143, 2015, 5, s. 463-469.

30. Dvorankova, B., Szabo, P., Lacina, L. et al.: Human galectins induce conversion of dermal fibroblasts into myofibroblasts and production of extracellular matrix: potential application in tissue engineering and wound repair. Cells Tissues Organs, 194, 2011, 6, s. 469-480.

31. Dvorankova, B., Szabo, P., Lacina, L. et al.: Fibroblasts prepared from different types of malignant tumors stimulate expression of luminal marker keratin 8 in the EM-G3 breast cancer cell line. Histochem Cell Biol, 137, 2012, 5, s. 679-685.

32. El-Rouby, D. H.: Association of macrophages with angiogenesis in oral verrucous and squamous cell carcinomas. J Oral Pathol Med, 39, 2010, 7, s. 559-564.

33. Faivre, S. J., Santoro, A., Gane, E. et al.: A phase 2 study of galunisertib, a novel transforming growth factor-beta (TGF-beta) receptor I kinase inhibitor in patients with advanced hepatocellular carcinoma (HCC) and low serum alpha fetoprotein (AFP). Journal of Clinical Oncology, 34, 2016, 15.

34. Ferrara, N.: Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev, 21, 2010, 1, s. 21-26.

35. Ferris, R. L., Whiteside, T. L. and Ferrone, S.: Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res, 12, 2006, 13, s. 3890-3895.

36. Fidler, I. J.: The pathogenesis of cancer metastasis: the ‚seed and soil‘ hypothesis revisited. Nat Rev Cancer, 3, 2003, 6, s. 453-458.

37. Franz, M., Hansen, T., Richter, P. et al.: Complex formation of the laminin-5 gamma2 chain and large unspliced tenascin-C in oral squamous cell carcinoma in vitro and in situ: implications for sequential modulation of extracellular matrix in the invasive tumor front. Histochem Cell Biol, 126, 2006, 1, s. 125-131.

38. Fujita, H., Ohuchida, K., Mizumoto, K. et al.: Tumor-stromal interactions with direct cell contacts enhance proliferation of human pancreatic carcinoma cells. Cancer Sci, 100, 2009, 12, s. 2309-2317.

39. Fukui, H., Zhang, X., Sun, C. et al.: IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling. Br J Cancer, 111, 2014, 4, s. 763-771.

40. Galdiero, M. R., Garlanda, C., Jaillon, S., Marone, G., Mantovani, A.: Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol, 228, 2013, 7, s. 1404-1412.

41. Gao, S. P., Mark, K. G., Leslie, K. et al.: Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest, 117, 2007, 12, s. 3846-3856.

42. Gettinger, S., Horn, L., Jackman, D. et al.: Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: Results from the CA209-003 study. J Clin Oncol, 36, 2018, 17, s. 1675-1684.

43. Gialeli, C., Nikitovic, D., Kletsas, D. et al.: PDGF/PDGFR signaling and targeting in cancer growth and progression: Focus on tumor microenvironment and cancer-associated fibroblasts. Curr Pharm Des, 20, 2014, 17, s. 2843-2848.

44. Glas, J., Toeroek, H. P., Schneider, A. et al.: Allele 2 of the interleukin-1 receptor antagonist gene: An independent genetic risk factor in early gastric cancer. Gastroenterology, 126, 2004, 4, s. A453-A453.

45. Gomes, A. M., Stelling, M. P., Pavao, M. S.: Heparan sulfate and heparanase as modulators of breast cancer progression. Biomed Res Int, 2013, 2013, s. 852093.

46. Gore, J., Korc, M.: Pancreatic cancer stroma: friend or foe? Cancer Cell, 25, 2014, 6, s. 711-712.

47. Gudleviciene, Z., Didziapetriene, J., Mackeviciene, I. et al.: Prevalence of human papillomaviruses in patients with head and neck squamous cell carcinoma in Lithuania and Belarus. J Med Virol, 86, 2014, 3, s. 531-535.

48. Hamburger, A. W., Salmon, S. E.: Primary bioassay of human tumor stem cells. Science, 197, 1977, 4302, s. 461-463.

49. Hammarstedt, L., Lindquist, D., Dahlstrand, H. et al.: Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer, 119, 2006, 11, s. 2620-2623.

50. Hawiger, D., Inaba, K., Dorsett, Y. et al.: Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med, 194, 2001, 6, s. 769-779.

51. He, J., Baum, L. G.: Presentation of galectin-1 by extracellular matrix triggers T cell death. J Biol Chem, 279, 2004, 6, s. 4705-4712.

52. Heckmann, D., Maier, P., Laufs, S. et al.: CXCR4 Expression and treatment with SDF-1alpha or plerixafor nodulate proliferation and chemosensitivity of colon cancer cells. Transl Oncol, 6, 2013, 2, s. 124-232.

53. Honjo, Y., Inohara, H., Akahani, S. et al.: Expression of cytoplasmic galectin-3 as a prognostic marker in tongue carcinoma. Clin Cancer Res, 6, 2000, 12, s. 4635-4640.

54. Hoos, A., Ibrahim, R., Korman, A. et al.: Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol, 37, 2010, 5, s. 533-46.

55. Charalambous, A., Oks, M., Nchinda, G., Yamazaki, S. and Steinman, R. M.: Dendritic cell targeting of survivin protein in a xenogeneic form elicits strong CD4+ T cell immunity to mouse survivin. J Immunol, 177, 2006, 12, s. 8410-8421.

56. Chatzistamou, I., Dioufa, N., Trimis, G. et al.: p21/waf1 and smooth-muscle actin alpha expression in stromal fibroblasts of oral cancers. Cell Oncol (Dordr), 34, 2011, 5, s. 483-488.

57. Cho, Y. A., Yoon, H. J., Lee, J. I., Hong, S. P., Hong, S. D.: Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncol, 47, 2011, 12, s. 1148-1153.

58. Jansson, S., Aaltonen, K., Bendahl, P. O. et al.: The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence. Breast Cancer Res Treat, 169, 2018, 2, s. 231-241.

59. Jayatilaka, H., Tyle, P., Chen, J. J. et al.: Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration. Nat Commun, 8, 2017, s. 15584.

60. Kareva, I.: What can ecology teach us about cancer? Transl Oncol, 4, 2011, 5, s. 266-270.

61. Kerbel, R. S.: A cancer therapy resistant to resistance. Nature, 390, 1997, 6658, s. 335-336.

62. Kilvaer, T. K., Rakaee, M., Hellevik, T. et al.: Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer. PLoS One, 13, 2018, 2, s. e0192157.

63. Kim, H., Hong, S. H., Kim, J. Y. et al.: Preclinical development of a humanized neutralizing antibody targeting HGF. Exp Mol Med, 49, 2017, 3, s. e309.

64. Kim, H. M., Jung, W. H. and Koo, J. S.: Expression of cancer-associated fibroblast related proteins in metastatic breast cancer: an immunohistochemical analysis. J Transl Med, 13, 2015, s. 222.

65. Kolar, M., Szabo, P., Dvorankova, B. et al.: Upregulation of IL-6, IL-8 and CXCL-1 production in dermal fibroblasts by normal/malignant epithelial cells in vitro: Immunohistochemical and transcriptomic analyses. Biology of the Cell, 104, 2012, 12, s. 738-751.

66. Kolar, M., Szabo, P., Dvorankova, B. et al.: Upregulation of IL-6, IL-8 and CXCL-1 production in dermal fibroblasts by normal/malignant epithelial cells in vitro: Immunohistochemical and transcriptomic analyses. Biol Cell, 104, 2012, 12, s. 738-751.

67. Kubota, Y., Takubo, K., Shimizu, T. et al.: M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med, 206, 2009, 5, s. 1089-1102.

68. Lacina, L., Dvorankova, B., Smetana, K., Jr. et al.: Marker profiling of normal keratinocytes identifies the stroma from squamous cell carcinoma of the oral cavity as a modulatory microenvironment in co-culture. Int J Radiat Biol, 83, 2007, 11-12, s. 837-848.

69. Lee, H. J., Kim, Y. A., Sim, C. K. et al.: Expansion of tumor-infiltrating lymphocytes and their potential for application as adoptive cell transfer therapy in human breast cancer. Oncotarget, 8, 2017, 69, s. 113345-113359.

70. Li, C., Shintani, S., Terakado, N., Nakashiro, K., Hamakawa, H.: Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma. Oncol Rep, 9, 2002, 6, s. 1219-1223.

71. Li, H., Fan, X., Houghton, J.: Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem, 101, 2007, 4, s. 805-815.

72. Liu, S. Y., Chang, L. C., Pan, L. F. et al.: Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma. Oral Oncol, 44, 2008, 3, s. 277-285.

73. Liu, Y., Chen, X., Han, W., Zhang, Y.: Tisagenlecleucel, an approved anti-CD19 chimeric antigen receptor T-cell therapy for the treatment of leukemia. Drugs Today (Barc), 53, 2017, 11, s. 597-608.

74. Lohr, M., Lensch, M., Andre, S. et al.: Murine homodimeric adhesion/growth-regulatory galectins-1, -2 and -7: comparative profiling of gene/ promoter sequences by database mining, of expression by RT-PCR/immunohistochemistry and of contact sites for carbohydrate ligands by computational chemistry. Folia Biol (Praha), 53, 2007, 4, s. 109-128.

75. Lorusso, G., Ruegg, C.: The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol, 130, 2008, 6, s. 1091-1103.

76. Luker, K. E., Lewin, S. A., Mihalko, L. A. et al.: Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells. Oncogene, 31, 2012, 45, s. 4750-4758.

77. Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S., Ruco, L.: The origin and function of tumor-associated macrophages. Immunol Today, 13, 1992, 7, s. 265-270.

78. Marcus, B., Arenberg, D., Lee, J. et al.: Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma. Cancer, 101, 2004, 12, s. 2779-2787.

79. Marsh, T., Pietras, K., McAllister, S. S.: Fibroblasts as architects of cancer pathogenesis. Biochim Biophys Acta, 1832, 2013, 7, s. 1070-1078.

80. Martin, F. T., Dwyer, R. M., Kelly, J. et al.: Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res Treat, 124, 2010, 2, s. 317-326.

81. Melaku, Y. A., Appleton, S. L., Gill, T. K. et al.: Incidence, prevalence, mortality, disability-adjusted life years and risk factors of cancer in Australia and comparison with OECD countries, 1990-2015: findings from the Global Burden of Disease Study 2015. Cancer Epidemiol, 52, 2018, s. 43-54.

82. Mesker, W. E., Junggeburt, J. M., Szuhai, K. et al.: The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Cell Oncol, 29, 2007, 5, s. 387-398.

83. Metwaly, H., Maruyama, S., Yamazaki, M. et al.: Parenchymal-stromal switching for extracellular matrix production on invasion of oral squamous cell carcinoma. Hum Pathol, 43, 2012, 11, s. 1973-1981.

84. Mhawech, P., Dulguerov, P., Assaly, M., Ares, C., Allal, A. S.: EB-D fibronectin expression in squamous cell carcinoma of the head and neck. Oral Oncol, 41, 2005, 1, s. 82-88.

85. Micke, P., Kappert, K., Ohshima, M. et al.: In situ identification of genes regulated specifically in fibroblasts of human basal cell carcinoma. J Invest Dermatol, 127, 2007, 6, s. 1516-1523.

86. Mishra, P. J., Mishra, P. J., Glod, J. W., Banerjee, D.: Mesenchymal stem cells: flip side of the coin. Cancer Res, 69, 2009, 4, s. 1255-1258.

87. Mitra, A. K., Zillhardt, M., Hua, Y. et al.: MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov, 2, 2012, 12, s. 1100-1118.

88. Moisan, F., Francisco, E. B., Brozovic, A. et al.: Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers. Mol Oncol, 8, 2014, 7, s. 1231-1239.

89. Motlik, J., Klima, J., Dvorankova, B., Smetana, K., Jr.: Porcine epidermal stem cells as a biomedical model for wound healing and normal/malignant epithelial cell propagation. Theriogenology, 67, 2007, 1, s. 105-111.

90. Nagasaki, T., Hara, M., Nakanishi, H. et al.: Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer, 110, 2014, 2, s. 469-478.

91. Nasman, A., Attner, P., Hammarstedt, L. et al.: Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer, 125, 2009, 2, s. 362-366.

92. Ogino, T., Shigyo, H., Ishii, H. et al.: HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res, 66, 2006, 18, s. 9281-9289.

93. Orimo, A., Gupta, P. B., Sgroi, D. C. et al.: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121, 2005, 3, s. 335-348.

94. Ostermann, E., Garin-Chesa, P., Heider, K. H. et al.: Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res, 14, 2008, 14, s. 4584-4592.

95. Papaspyridonos, M., McNeill, E., de Bono, J. P. et al.: Galectin-3 is an amplifier of inflammation in atherosclerotic plaque progression through macrophage activation and monocyte chemoattraction. Arterioscler Thromb Vasc Biol, 28, 2008, 3, s. 433-440.

96. Perez-Losada, J. and Balmain, A.: Stem-cell hierarchy in skin cancer. Nat Rev Cancer, 3, 2003, 6, s. 434-443.

97. Perillo, N. L., Pace, K. E., Seilhamer, J. J., Baum, L. G.: Apoptosis of T cells mediated by galectin-1. Nature, 378, 1995, 6558, s. 736-739.

98. Plzak, J., Lacina, L., Chovanec, M. et al.: Epithelial-stromal interaction in squamous cell epithelium-derived tumors: an important new player in the control of tumor biological properties. Anticancer Res, 30, 2010, 2, s. 455-462.

99. Plzak, J., Smetana, K., Jr., Hrdlickova, E. et al.: Expression of galectin-3-reactive ligands in squamous cancer and normal epithelial cells as a marker of differentiation. Int J Oncol, 19, 2001, 1, s. 59-64.

100. Polyak, K., Haviv, I., Campbell, I. G.: Co-evolution of tumor cells and their microenvironment. Trends Genet, 25, 2009, 1, s. 30-8.

101. Rakesh, K., Agrawal, D. K.: Controlling cytokine signaling by constitutive inhibitors. Biochemical Pharmacology, 70, 2005, 5, s. 649-657.

102. Rasanen, K., Vaheri, A.: Activation of fibroblasts in cancer stroma. Exp Cell Res, 316, 2010, 17, s. 2713-22.

103. Ritzenthaler, J. D., Han, S. and Roman, J.: Stimulation of lung carcinoma cell growth by fibronectin-integrin signalling. Mol Biosyst, 4, 2008, 12, s. 1160-9.

104. Rupp, C., Scherzer, M., Rudisch, A. et al.: IGFBP7, a novel tumor stroma marker, with growth-promoting effects in colon cancer through a paracrine tumor-stroma interaction. Oncogene, 34, 2015, 7, s. 815-25.

105. Ruvolo, P. P.: Galectin 3 as a guardian of the tumor microenvironment. Biochim Biophys Acta, 1863, 2016, 3, s. 427-437.

106. Sakurai, T., He, G., Matsuzawa, A. et al.: Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell, 14, 2008, 2, s. 156-165.

107. Schott, A. F., Goldstein, L. J., Cristofanilli, M. et al.: Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer. Clin Cancer Res, 23, 2017, 18, s. 5358-5365.

108. Sica, A., Schioppa, T., Mantovani, A., Allavena, P.: Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer, 42, 2006, 6, s. 717-27.

109. Slany, A., Bileck, A., Muqaku, B., Gerner, C.: Targeting breast cancer-associated fibroblasts to improve anti-cancer therapy. Breast, 24, 2015, 5, s. 532-8.

110. Smetana, K., Jr., Andre, S., Kaltner, H., Kopitz, J., Gabius, H. J.: Context-dependent multifunctionality of galectin-1: a challenge for defining the lectin as therapeutic target. Expert Opin Ther Targets, 17, 2013, 4, s. 379-92.

111. Smetana, K., Jr., Lacina, L., Szabo, P. et al.: Ageing as an Important Risk Factor for Cancer. Anticancer Res, 36, 2016, 10, s. 5009-5017.

112. Smith, E. M., Ritchie, J. M., Summersgill, K. F. et al.: Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer, 108, 2004, 5, s. 766-72.

113. Solis, D., Bovin, N. V., Davis, A. P. et al.: A guide into glycosciences: How chemistry, biochemistry and biology cooperate to crack the sugar code. Biochim Biophys Acta, 1850, 2015, 1, s. 186-235.

114. Song, I. Y., Balmain, A.: Cellular reprogramming in skin cancer. Semin Cancer Biol, 32, 2015, s. 32-9.

115. Straussman, R., Morikawa, T., Shee, K. et al.: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature, 487, 2012, 7408, s. 500-4.

116. Strnad, H., Lacina, L., Kolar, M. et al.: Head and neck squamous cancer stromal fibroblasts produce growth factors influencing phenotype of normal human keratinocytes. Histochemistry and Cell Biology, 133, 2010, 2, s. 201-211.

117. Strnad, H., Lacina, L., Kolar, M. et al.: Head and neck squamous cancer stromal fibroblasts produce growth factors influencing phenotype of normal human keratinocytes. Histochem Cell Biol, 133, 2010, 2, s. 201-11.

118. Strome, S. E., Dong, H., Tamura, H. et al.: B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res, 63, 2003, 19, s. 6501-5.

119. Sulic, S., Panic, L., Dikic, I., Volarevic, S.: Deregulation of cell growth and malignant transformation. Croat Med J, 46, 2005, 4, s. 622-38.

120. Sun, X., Mao, Y., Wang, J. et al.: IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer. Oncogene, 2014, s.

121. Sun, Y.: Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures. Med Res Rev, 35, 2015, 2, s. 408-436.

122. Sun, Y., Campisi, J., Higano, C. et al.: Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med, 18, 2012, 9, s. 1359-1368.

123. Szabo, P., Kolar, M., Dvorankova, B. et al.: Mouse 3T3 fibroblasts under the influence of fibroblasts isolated from stroma of human basal cell carcinoma acquire properties of multipotent stem cells. Biol Cell, 103, 2011, 5, s. 233-48.

124. Szabo, P., Valach, J., Smetana, K., Jr., Dvorankova, B.: Comparative analysis of IL-8 and CXCL-1 production by normal and cancer stromal fibroblasts. Folia Biol (Praha), 59, 2013, 3, s. 134-7.

125. Tewari, K. S., Sill, M. W., Penson, R. T. et al.: Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet, 390, 2017, 10103, s. 1654-1663.

126. Thiery, J. P., Acloque, H., Huang, R. Y. and Nieto, M. A.: Epithelial-mesenchymal transitions in development and disease. Cell, 139, 2009, 5, s. 871-90.

127. Tilman, G., Mattiussi, M., Brasseur, F., van Baren, N. and Decottignies, A.: Human periostin gene expression in normal tissues, tumors and melanoma: evidences for periostin production by both stromal and melanoma cells. Mol Cancer, 6, 2007, s. 80.

128. Timoshenko, A. V., Kaltner, H., Andre, S., Gabius, H. J., Lala, P. K.: Differential stimulation of VEGF-C production by adhesion/growth-regulatory galectins and plant lectins in human breast cancer cells. Anticancer Res, 30, 2010, 12, s. 4829-33.

129. Tommelein, J., Verset, L., Boterberg, T. et al.: Cancer-associated fibroblasts connect metastasis-promoting communication in colorectal cancer. Front Oncol, 5, 2015, s. 63.

130. Toscano, M. A., Bianco, G. A., Ilarregui, J. M. et al.: Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat Immunol, 8, 2007, 8, s. 825-34.

131. Valach, J., Fik, Z., Strnad, H. et al.: Smooth muscle actin-expressing stromal fibroblasts in head and neck squamous cell carcinoma: increased expression of galectin-1 and induction of poor prognosis factors. Int J Cancer, 131, 2012, 11, s. 2499-508.

132. Van Obberghen-Schilling, E., Tucker, R. P., Saupe, F. et al.: Fibronectin and tenascin-C: accomplices in vascular morphogenesis during development and tumor growth. Int J Dev Biol, 55, 2011, 4-5, s. 511-25.

133. Wagner, A. J., Kindler, H., Gelderblom, H. et al.: A phase II study of a human anti-PDGFRalpha monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors. Ann Oncol, 28, 2017, 3, s. 541-546.

134. Walker, M. R., Patel, K. K. and Stappenbeck, T. S.: The stem cell niche. J Pathol, 217, 2009, 2, s. 169-80.

135. Wang, K., Ma, W., Wang, J. et al.: Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma. J Thorac Oncol, 7, 2012, 9, s. 1457-61.

136. Wang, Z., Liu, H., Zhao, R. et al.: Tumor-stroma ratio is an independent prognostic factor of non-small cell lung cancer. Zhongguo Fei Ai Za Zhi, 16, 2013, 4, s. 191-6.

137. Warnakulasuriya, S.: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol, 45, 2009, 4-5, s. 309-16.

138. Whiteside, T. L.: Immunobiology of head and neck cancer. Cancer Metastasis Rev, 24, 2005, 1, s. 95-105.

139. Wiest, I., Alexiou, C., Kuhn, C. et al.: Expression of different carbohydrate tumour markers and galectins 1 and 3 in normal squamous and malignant epithelia of the upper aaerodigestive tract. Anticancer Res, 32, 2012, 5, s. 2023-9.

140. Wilson, T. R., Fridlyand, J., Yan, Y. et al.: Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature, 487, 2012, 7408, s. 505-9.

141. Wolchok, J. D., Rollin, L. and Larkin, J.: Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med, 377, 2017, 25, s. 2503-2504.

142. Wong, S. F.: Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther, 27, 2005, 6, s. 684-94.

143. Wu, M. H., Hong, H. C., Hong, T. M. et al.: Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression. Clin Cancer Res, 17, 2011, 6, s. 1306-16.

144. Wu, X., Ruan, L., Yang, Y. and Mei, Q.: Analysis of gene expression changes associated with human carcinoma-associated fibroblasts in non-small cell lung carcinoma. Biol Res, 50, 2017, 1, s. 6.

145. Yao, Z., Fenoglio, S., Gao, D. C. et al.: TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl. Acad. Sci U S A, 107, 2010, 35, s. 15535-40.

146. Yeh, C. R., Slavin, S., Da, J. et al.: Estrogen receptor alpha in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment. Mol Cancer, 15, 2016, s. 7.

147. Young, M. R.: Protective mechanisms of head and neck squamous cell carcinomas from immune assault. Head Neck, 28, 2006, 5, s. 462-70.

148. Yurkovetsky, Z. R., Kirkwood, J. M., Edington, H. D. et al.: Multiplex analysis of serum cytokines in melanoma patients treated with interferon-alpha2b. Clin. Cancer Res., 13, 2007, 8, s. 2422-8.

149. Zhang, X. H., Jin, X., Malladi, S. et al.: Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell, 154, 2013, 5, s. 1060-1073.

Audiology Paediatric ENT ENT (Otorhinolaryngology)
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account