Destructive impact of t-lymphocytes, NK and mast cells on basal cell layers: implications for tumor invasion

BMC Cancer

Hongyan Yuan²  Yi-Hsuan Hsiao³  Yiyu Zhang⁵  Jinlian Wang¹  Chao Yin⁴  Rong Shen²  Yiping Su² 

[1] Department of Oncology, Georgetown University, Washington, DC, USA

[2] Department of Oncology, the Affiliated Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China

[3] Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan

[4] Georgetown University School of Medicine, Washington, DC, USA

[5] Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

关键词: Invasion;    Immune cells;    Destruction;    Infiltration;    Tumor;   

Others  :  1127569
DOI  :  10.1186/1471-2407-13-258

 received in 2012-12-27, accepted in 2013-05-14,  发布年份 2013

【 摘 要 】

Background

Our previous studies have suggested that the primary impact of immune cell infiltration into the normal or pre-invasive tissue component is associated with the physical destruction of epithelial capsules, which may promote tumor progression and invasion. Our current study attempted to further verify our previous observations and determine the primary type(s) of infiltrating immune cells and the possible mechanism associated with physical destructions of the epithelial capsules.

Methods

In total, the study was conducted with 250 primary breast and prostate tumors, the primary immune cell of cytotoxic T-lymphocytes (CTL), Natural killer cells (NK) and Mast cells were analyzed by immunohistochemistry, fluorescent labeling and apoptosis assay. qRT-PCR was used for gene expression analysis. Our current study assessed the physical disruption of these immune cells and potential impact on the epithelial capsule of human breast and prostate tumors.

Results

Our study yield several clinically-relevant findings that have not been studied before. (1) A vast majority of these infiltrating immune cells are distributed in the normal-appearing or pre-invasive tissue components rather than in invasive cancer tissues. (2) These cells often form rings or semilunar structures that either surround focally-disrupted basal cell layers or physically attach to the basal cells. (3) Basal cells physically associated with these immune cells generally displayed distinct signs of degeneration, including substantially elevated apoptosis, necrosis, and reduced tumor suppressor p63 expression. In contrast, luminal cells overlying focally disrupted basal cell layers had a substantially increased proliferation rate and elevated expression of stem cell markers compared to their adjacent morphologically similar counterparts that overlie a non-disrupted capsule.

Conclusion

Our findings suggest that at the early stage of tumor invasion, CTL, NK and Mast cells are the main types of tumor infiltrating immune cells involved in focal degenerative products in the tumor capsules. The primary impact of these infiltrating immune cells is that they are associated with focal disruptions of the tumor capsule, which selectively favor tumor stem cells proliferation and invasion.

【 授权许可】

   
2013 Yuan et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Baxevanis CN, Dedoussis GV, Papadopoulos NG, Missitzis I, Stathopoulos GP, Papamichail M: Tumor specific cytolysis by tumor infiltrating lymphocytes in breast cancer. Cancer 1994, 74(4):1275-1282.
• [2]Boon T, Coulie PG, Van den Eynde B: Tumor antigens recognized by T cells. Immunol Today 1997, 18(6):267-268.
• [3]Van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T: A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991, 254(5038):1643-1647.
• [4]Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, Giovannucci E, Dranoff G, Fuchs CS, Ogino S: Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010, 222(4):350-366.
• [5]Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, et al.: Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005, 353(25):2654-2666.
• [6]Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, Sozaki M, Tanaka M, Onishi H, Morisaki T, et al.: Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 2010, 59(5):653-661.
• [7]Gannot G, Gannot I, Vered H, Buchner A, Keisari Y: Increase in immune cell infiltration with progression of oral epithelium from hyperkeratosis to dysplasia and carcinoma. Br J Cancer 2002, 86(9):1444-1448.
• [8]MacLennan GT, Eisenberg R, Fleshman RL, Taylor JM, Fu P, Resnick MI, Gupta S: The influence of chronic inflammation in prostatic carcinogenesis: a 5-year followup study. J Urol 2006, 176(3):1012-1016.
• [9]Smith CJ, Gardner WA Jr: Inflammation-proliferation: possible relationships in the prostate. Prog Clin Biol Res 1987, 239:317-325.
• [10]Pollard JW: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004, 4(1):71-78.
• [11]Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J: A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 2004, 64(19):7022-7029.
• [12]Pawelek JM, Chakraborty AK: The cancer cell–leukocyte fusion theory of metastasis. Adv Cancer Res 2008, 101:397-444.
• [13]DeNardo DG, Johansson M, Coussens LM: Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev 2008, 27(1):11-18.
• [14]Hunter KW, Crawford NP, Alsarraj J: Mechanisms of metastasis. Breast Cancer Res 2008, 10 Suppl(1):S2.
• [15]Nauseef JT, Henry MD: Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle? Nat Rev Urol 2011, 8(8):428-439.
• [16]Kuppen PJ, Gorter A, Hagenaars M, Jonges LE, Giezeman-Smits KM, Nagelkerke JF, Fleuren G, Van de Velde CJ: Role of NK cells in adoptive immunotherapy of metastatic colorectal cancer in a syngeneic rat model. Immunol Rev 2001, 184:236-243.
• [17]Liu KJ, Wang CJ, Chang CJ, Hu HI, Hsu PJ, Wu YC, Bai CH, Sytwu HK, Yen BL: Surface expression of HLA-G is involved in mediating immunomodulatory effects of placenta-derived multipotent cells (PDMCs) towards natural killer lymphocytes. Cell Transplant 2011, 20(11–12):1721-1730.
• [18]Fishman M, Gunther G: Induction of tumor cell resistance to macrophagemediated lysis by preexposure to non-activated macrophages. Cell Immunol 1986, 99(1):241-256.
• [19]Kovacs EJ, Palmer JL, Fortin CF, Fulop T Jr, Goldstein DR, Linton PJ: Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol 2009, 30(7):319-324.
• [20]Padgett EL, Pruett SB: Rat, mouse and human neutrophils stimulated by a variety of activating agents produce much less nitrite than rodent macrophages. Immunology 1995, 84(1):135-141.
• [21]Man YG, Shen T, Zhao Y, Amy Sang QX: Focal prostate basal cell layer disruptions and leukocyte infiltration are correlated events: A potential mechanism for basal cell layer disruptions and tumor invasion. Cancer Detect Prev 2005, 29(2):161-169.
• [22]Yousefi M, Mattu R, Gao C, Man YG: Mammary ducts with and without focal myoepithelial cell layer disruptions show a different frequency of white blood cell infiltration and growth pattern: implications for tumor progression and invasion. Appl Immunohistochem Mol Morphol 2005, 13(1):30-37.
• [23]Man YG, Tai L, Barner R, Vang R, Saenger JS, Shekitka KM, Bratthauer GL, Wheeler DT, Liang CY, Vinh TN, et al.: Cell clusters overlying focally disrupted mammary myoepithelial cell layers and adjacent cells within the same duct display different immunohistochemical and genetic features: implications for tumor progression and invasion. Breast Cancer Res 2003, 5(6):R231-R241. BioMed Central Full Text
• [24]Man YG, Zhang Y, Shen T, Zeng X, Tauler J, Mulshine JL, Strauss BL: cDNA expression profiling reveals elevated gene expression in cell clusters overlying focally disrupted myoepithelial cell layers: implications for breast tumor invasion. Breast Cancer Res Treat 2005, 89(2):199-208.
• [25]Man YGZC, Wang J: Breast tumor cell clusters and their budding derivatives show different immunohistochemical profiles during stromal invasion: implications for hormonal and drug therapies. Cancer Therapy 2006, 4:193-204.
• [26]Man YG: Focal degeneration of aged or injured myoepithelial cells and the resultant auto-immunoreactions are trigger factors for breast tumor invasion. Med Hypotheses 2007, 69(6):1340-1357.
• [27]Man YG, Gardner WA: Focal degeneration of basal cells and the resultant auto-immunoreactions: a novel mechanism for prostate tumor progression and invasion. Med Hypotheses 2008, 70(2):387-408.
• [28]Cullen SP, Brunet M, Martin SJ: Granzymes in cancer and immunity. Cell Death Differ 2010, 17(4):616-623.
• [29]Topham NJ, Hewitt EW: Natural killer cell cytotoxicity: how do they pull the trigger? Immunology 2009, 128(1):7-15.
• [30]Waterhouse NJ, Clarke CJ, Sedelies KA, Teng MW, Trapani JA: Cytotoxic lymphocytes; instigators of dramatic target cell death. Biochem Pharmacol 2004, 68(6):1033-1040.
• [31]De Saint BG, Menasche G, Fischer A: Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 2010, 10(8):568-579.
• [32]Man YG, Burgar A: An antigen unmasking protocol that satisfies both immunohistochemistry and subsequent PCR amplification. Pathol Res Pract 2003, 199:815-825.
• [33]Hsiao YH, Su YA, Tsai HD, Mason JT, Chou MC, Man YG: Increased invasiveness and aggressiveness in breast epithelia with cytoplasmic p63 expression. Int J Biol Sci 2010, 6(5):428-442.
• [34]O'Brien J, Lyons T, Monks J, Lucia MS, Wilson RS, Hines L, Man YG, Borges V, Schedin P: Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. Am J Pathol 2010, 176(3):1241-1255.
• [35]Man YG: A seemingly most effective target for early detection and intervention of prostate tumor invasion. J Cancer 2010, 24(1):63-69.
• [36]Pires MM, Hopkins BD, Saal LH, Parsons RE: Alterations of EGFR, p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of human mammary epithelial cells. Cancer Biol Ther 2013, 14(3):246-253.
• [37]Brimo F, Epstein JI: Immunohistochemical pitfalls in prostate pathology. Hum Pathol 2012, 43(3):313-324.
• [38]Man YG, Stojadinovic A, Mason J, Avital I, Bilchik A, Bruecher B, Protic M, Nissan A, Izadjoo M, Zhang X, Jewett A: Tumor-infiltrating immune cells promoting tumor invasion and metastasis: existing theories. J Cancer 2013, 4(1):84-95.
• [39]Ogino S, Galon J, Fuchs CS, Dranoff G: Cancer immunology-analysis of host and tumor factors for personalized medicine. Nat Rev Clin Oncol 2011, 8(12):711-719.
• [40]Ilunga K, Nishiura R, Inada H, El-Karef A, Imanaka-Yoshida K, Sakakura T, Yoshida T: Co-stimulation of human breast cancer cells with transforming growth factor-beta and tenasicin-c enhances matrix metalloproteinase-9 expression and cancer cell invasion. Int J Exp Pathol 2004, 85:373-379.
• [41]Kryczka J, Stasiak M, Dziki L, Mik M, Dziki A, Cierniewski C: Matrix metalloproteinase-2 cleavage of the β1 integrin ectodomain facilitates colon cancer cell motility. J Biol Chem 2012, 287(43):36556-36566.
• [42]Yoshimura A: Signal transduction of inflammatory cytokines and tumor development. Cancer Sci 2006, 97(6):439-447.
• [43]Midwood KS, Orend G: The role of tenascin-C in tissue injury and tumorigenesis. J Cell Commun Signal 2009, 3(3–4):287-310.
• [44]Verstraeten AA, Mackie EJ, Hageman PC, Hilgers J, Schol DJ, De Jongh GJ, Schalkwijk J: Tenascin expression in basal cell carcinoma. Brit J Dermt 1992, 127:571-574.
• [45]Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012, 487(7408):500-504.
• [46]Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski LJ: Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res 2008, 10(1):R10. BioMed Central Full Text
• [47]Gou S, Liu T, Wang C, Yin T, Li K, Yang M, Zhou J: Establishment of clonal colony-forming assay for propagation of pancreatic cancer cells with stem cell properties. Pancreas 2007, 34:429-435.
• [48]Ben-Porath I, Thomson MW, Carey VJ, Gxxe R, Bell GW, Regev A, Weinberg RA: An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008, 40:499-507.
• [49]Moinfar F, Man YG, Bratthauer GL, Ratschek M, Tavassoli FA: Genetic abnormalities in mammary ductal intraepithelial neoplasia-flat type (“clinging ductal carcinoma in situ”): a simulator of normal mammary epithelium. Cancer 2000, 88(9):2072-2081.
• [50]Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS: Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 1997, 274(5295):2057-2059.
• [51]Malins DC, Gilman NK, Green VM, Wheeler TM, Barker EA, Vinson MA, Sayeeduddin M, Hellström KE, Anderson KM: Metastatic cancer DNA phenotype identified in normal tissues surrounding metastasizing prostate carcinomas. Proc Natl Acad Sci 2004, 101:11428-11431.
• [52]Malins DC, Anderson KM, Gilman NK, Green VM, Barker EA, Hellström KE: Development of a cancer DNA phenotype prior to tumor formation. Proc Natl Acad Sci 2004, 101:10721-10725.
• [53]Malins DC, Gilman NK, Green VM, Wheeler TM, Barker EA, Anderson KM: A cancer DNA phenotype in healthy prostates, conserved in tumors and adjacent normal cells, implies a relationship to carcinogenesis. Proc Natl Acad Sci 2005, 102:19093-19096.
• [54]Galon J, Pagès F, Marincola FM, Thurin M, Trinchieri G, Fox BA, Gajewski TF, Ascierto PA: The immune score as a new possible approachfor the classification of cancer. J Transl Med 2012, 3(10):1.