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. Torchinsky M, Blander J. T helper cells: discovery, function, and physiological trigger. Cell Mol Life Sci 2010;67:1407-1421. 45. Quyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in infl ammation. Immunity 2008;28(4):454-467. 46. Su X, Ye J, Hsueh EC, Zhang , Hoft DF, Peng G. Tumor microenvironments direct the recruitment and expansion of human Th17 cells. The Journal of Immunology 2010;184:1630-1641. 47. Laurence A, O’Shea JJ. T(H)-17 differentiation: of mice and men. Nat Immunol 2007;8:903-905. 48. Wilson NJ, Boniface K, Chan

concepts. Cell Adh Migr. 2012;6(3):220-30. 7. Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316(8):1324-31. 8. Koontongkaew S. The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas. J Cancer. 2013;4(1):66-83. 9. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007;67(21):10123-8. 10. D’souza N, Burns JS, Grisendi G, Candini O

1/TP53 (in MES) and epidermal growth factor receptor EGFR abnormalities i.e . amplification of the epidermal growth factor (EGF) (in N) and mutation in EGFRvIII/PTEN (in CL). These GB subtypes differ significantly in survival rate, being shorter in MES subtype. However, mixed subtypes are observed in the single tumour, giving rise to intra-tumour heterogeneity. 11 Tumour microenvironment Solid tumour progression is not only relaying on the genetic and epigenetic variations of cancerous cells acquired during their evolution, but also on how their homotypic and

matrix and the basal membranes of blood vessels. 5 , 6 The recently recognized important role of the tumor microenvironment in cancer cell invasion 7 has become an important topic and the subject of intensive research. 8 - 10 The effects of the microenvironment also include the impact of the different types of cells comprising the stroma within a tumor mass. Infiltrating and tumor-associated mesenchymal stem cells (MSCs) may significantly affect tumor progression and resistance to treatment, as reviewed in. 8 , 11 MSCs are known to be recruited by tumor

endoscopic biopsy in gastric lesions with a special reference to the significance of mast cell density. Indian Journal of Pathology and Microbiology. 2009; 52(1): 20-4. 5. DALTON DK, RANDOLPH JN. The roles of mast cells in anticancer immunity. Cancer Immunology, Immunotherapy 2012; 61(9): 1511-20. 6. MA Y, HWANG RF, LOGSDON CD, ULLRICH SE. Dynamic Mast Cell–Stromal Cell Interactions Promote Growth of Pancreatic Cancer . Cancer Research, 2013, 73: 3927. 7. WHITESIDE TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008, 27: 5904-12. 8

lymphoproliferative syndrome associated with FAS gene mutations, 2014, Blood 123:1989–1999 22. McClain KL - Why do T cells cause so much trouble?, 2014, Blood 123:1978 23. Sanchez-Aguilera A, Montalban C, de la Cueva P, et al.- Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma, 2006, Blood 108:662–668 24. Chetaille B, Bertucci F, Finetti P, et al. - Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome, 2009, Blood 113

a guide for cancer immunotherapy. Clin Cancer Res 2015, 21, doi: 10.1158/1078-0432. 4. Beyer M., Schultze J.L.: Regulatory T cells: major players in the tumor microenvironment. Curr Pharm Des 2009, 15, 1879-1892. 5. Biller B.J., Elmslie R.E., Burnett R.C., Avery A.C., Dow S.W.: Use of FoxP3 expression to identify regulatory T cells in healthy dogs and dogs with cancer. Vet Immunol Immunopathol 2007, 116, 69-78. 6. Biswas S.K., Lewis C.E.: NF-κB as a central regulator of macrophage function in tumors. J Leukoc Biol 2010, 88, 877-884. 7. Candolfi M., Curtin J

: 221-228. [4] Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 2014; 4: doi: 10.3389/fonc.2014.00062. [5] Ausprunk DH, Folkman J. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res 1977; 14: 53-65. [6] Baeten C, Hillen F., Pauwels P, de Bruine A., Baeten C. Prognostic role of vasculogenic mimicry in colorectal cancer. Dis Colon Rectum 2009; 52: 2028-2035. [7] Brana I, Calles A, LoRusso PM, Yee LK, Puchalski TA

., Houghton J.M.: Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem 2007, 101, 805–815. 13. Maffini M.V., Soto A.M., Calabro J.M., Ucci A.A., Sonnenschein C.: The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 2004, 15, 1495–1502. 14. Molin D., Edström A., Glimelius I., Glimelius B., Nilsson G., Sundström C., Enblad G.: Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. Br J Haematol 2002, 119, 122–124. 15. Pichler M., Hutterer G.C., Chromecki T.F., Jesche J., Kampel-Kettner K., Rehak P

small lesions, unclear lesions on CT, and lesions after locoregional therapies. Considering the multiple sequences included on MRI, there is a huge potential to extract several imaging biomarkers that reflect the tumor microenvironment and which, in the future, may add decision-making value in the management of patients with HCC. Acknowledgments The authors would like to thank Joanne Chin for her editorial support on this manuscript. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. The work by Romina Grazia Giancipoli was