Implications of NOVA1 suppression within the microenvironment of gastric cancer: association with immune cell dysregulation
Tóm tắt
The neuronal splicing factor neuro-oncological ventral antigen 1 (NOVA1) is enriched in normal fibroblasts. Stromal spindle cells such as fibroblasts are major components of tissue inflammation and tertiary lymphoid structures within the microenvironment that contribute to the survival and growth of cancer cells. In the present study, we investigated changes of NOVA1 expression in tertiary lymphoid structures in early and advanced gastric cancer microenvironments in terms of tumor progression and immune regulation. Using immunohistochemistry, we analyzed NOVA1 expression in tumor cells, T cells, and stromal spindle cells as well as infiltrating densities of CD3+ T cells, forkhead box P3 positive (FOXP3+) regulatory T cells, CD68+ macrophages, CD163+ M2 macrophages, and myeloperoxidase-positive neutrophils in 396 surgically resected gastric cancer tissues. Suppressed NOVA1 expression in tumor cells, T cells, and stromal spindle cells was closely related to decreased infiltration of FOXP3+ regulatory T cells, increased infiltration of CD68+ macrophages and CD163+ M2 macrophages, more advanced tumor stage, and inferior overall survival rate. In addition, low infiltration of CD3+ T cells and FOXP3+ regulatory T cells and high infiltration of CD68+ macrophages were associated with inferior overall survival. Specifically, weak NOVA1 expression in tumor cells was independently related to more advanced tumor stage and inferior overall survival. NOVA1 suppression was frequently noted in the gastric cancer microenvironment, and attenuated NOVA1 expression in tumor cells was associated with tumor progression and poor prognosis. This finding seems to be related to immune dysfunction through changes in the immune cell composition of T cells and macrophages.
Tài liệu tham khảo
Buckley CD, Barone F, Nayar S, Benezech C, Caamano J. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu Rev Immunol. 2015;33:715–45.
Dieu-Nosjean MC, Goc J, Giraldo NA, Sautes-Fridman C, Fridman WH. Tertiary lymphoid structures in cancer and beyond. Trends Immunol. 2014;35(11):571–80.
Di Caro G, Castino GF, Bergomas F, Cortese N, Chiriva-Internati M, Grizzi F, et al. Tertiary lymphoid tissue in the tumor microenvironment: from its occurrence to immunotherapeutic implications. Int Rev Immunol. 2015;34(2):123–33.
Drayton DL, Liao S, Mounzer RH, Ruddle NH. Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol. 2006;7(4):344–53.
Ruddle NH, Akirav EM. Secondary lymphoid organs: responding to genetic and environmental cues in ontogeny and the immune response. J Immunol. 2009;183(4):2205–12.
Barash Y, Calarco JA, Gao W, Pan Q, Wang X, Shai O, et al. Deciphering the splicing code. Nature. 2010;465(7294):53–9.
de la Grange P, Gratadou L, Delord M, Dutertre M, Auboeuf D. Splicing factor and exon profiling across human tissues. Nucleic Acids Res. 2010;38(9):2825–38.
Merkin J, Russell C, Chen P, Burge CB. Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science. 2012;338(6114):1593–9.
Kalsotra A, Cooper TA. Functional consequences of developmentally regulated alternative splicing. Nat Rev Genet. 2011;12(10):715–29.
Mallinjoud P, Villemin JP, Mortada H, Polay Espinoza M, Desmet FO, Samaan S, et al. Endothelial, epithelial, and fibroblast cells exhibit specific splicing programs independently of their tissue of origin. Genome Res. 2014;24(3):511–21.
Yoon SO, Kim EK, Lee M, Jung WY, Lee H, Kang Y et al. NOVA1 inhibition by miR-146b-5p in the remnant tissue microenvironment defines occult residual disease after gastric cancer removal. Oncotarget. 2016;7(3):2475–95.
Edge SB, Byrd DR., Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York; London: Springer; 2010.
Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. 4th ed. Lyon: International Agency for Research on Cancer; 2010.
Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101–12.
Kim H, Yoo SB, Sun P, Jin Y, Jheon S, Lee CT, et al. Alteration of the E-cadherin/β-catenin complex is an independent poor prognostic factor in lung adenocarcinoma. Korean J Pathol. 2013;47(1):44–51.
Kim BH, Jung WY, Lee H, Kang Y, Jang YJ, Hong SW, et al. Lysyl-tRNA synthetase (KRS) expression in gastric carcinoma and tumor-associated inflammation. Ann Surg Oncol. 2014;21(6):2020–7.
deLeeuw RJ, Kost SE, Kakal JA, Nelson BH. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res. 2012;18(11):3022–9.
Lanca T, Silva-Santos B. The split nature of tumor-infiltrating leukocytes: implications for cancer surveillance and immunotherapy. Oncoimmunology. 2012;1(5):717–25.
Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27(4):462–72.
Qiu W, Hu M, Sridhar A, Opeskin K, Fox S, Shipitsin M, et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat Genet. 2008;40(5):650–5.
Kohlhapp FJ, Mitra AK, Lengyel E, Peter ME. MicroRNAs as mediators and communicators between cancer cells and the tumor microenvironment. Oncogene. 2015;34(48):5857–68.