Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma

Dambrauskas,Zilvinas; Svensson,Helena; Joshi,Meghnad; Hyltander,Anders; Naredi,Peter; Iresjö,Britt-Marie

doi:10.3892/ijo.2013.2156

Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma

Authors:
- Zilvinas Dambrauskas
- Helena Svensson
- Meghnad Joshi
- Anders Hyltander
- Peter Naredi
- Britt-Marie Iresjö
View Affiliations

Affiliations: Department of Surgery and Institute for Research of Digestive System, Lithuanian University of Health Sciences, Kaunas, Lithuania, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden
Published online on: October 31, 2013 https://doi.org/10.3892/ijo.2013.2156
Pages: 99-104

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind to the immunoreceptor NKG2D and play an important role in mediating cytotoxicity of NK and T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells and thus could be associated with more aggressive course of tumor growth. In this study, we investigated the expression of MICA/B in ductal pancreatic carcinoma and serum in relation to tumor stage, differentiation and survival. MICA/B expression in tumor tissues and sera from patients with pancreatic cancer were analyzed by immunohistochemical staining (IHC), western blotting and ELISA, respectively. MICA/B expression was present in 17 of 22 (77%) of the tumors but not in normal pancreatic ductal epithelial cells. Poorly differentiated tumors showed more pronounced MICA/B expression compared to differentiated tumors, but did not correlate significantly to other tumor characteristics. MICA/B-negative tumors displayed significantly lower incidence of lymph node metastases (p<0.01), and less mortality within 3 years following resection (p<0.02). In conclusion, tissue levels of MICA/B expression were elevated in pancreatic cancer cells without elevated levels in serum, despite well-recognized acute phase reactants in serum. Poorly differentiated tumors showed high MICA/B expression, which was related to extended tumor lymph node metastases and less frequent long-term survival.

View Figures

View References

1.	Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H and Buchler MW: Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 91:586–594. 2004. View Article : Google Scholar : PubMed/NCBI
2.	Bramhall SR, Allum WH, Jones AG, Allwood A, Cummins C and Neoptolemos JP: Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study. Br J Surg. 82:111–115. 1995. View Article : Google Scholar : PubMed/NCBI
3.	Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar
4.	McCracken M, Olsen M, Chen MS Jr, et al: Cancer incidence, mortality, and associated risk factors among Asian Americans of Chinese, Filipino, Vietnamese, Korean, and Japanese ethnicities. CA Cancer J Clin. 57:190–205. 2007. View Article : Google Scholar : PubMed/NCBI
5.	Buchler MW, Wagner M, Schmied BM, Uhl W, Friess H and Z’Graggen K: Changes in morbidity after pancreatic resection: toward the end of completion pancreatectomy. Arch Surg. 138:1310–1315. 2003. View Article : Google Scholar : PubMed/NCBI
6.	Diener MK, Heukaufer C, Schwarzer G, et al: Pancreaticoduodenectomy (classic Whipple) versus pylorus-preserving pancreaticoduodenectomy (pp Whipple) for surgical treatment of periampullary and pancreatic carcinoma. Cochrane Database Syst Re. 16:CD0060532008.
7.	Jaffee EM, Hruban RH, Biedrzycki B, et al: Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol. 19:145–156. 2001.
8.	Picozzi VJ, Kozarek RA and Traverso LW: Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg. 185:476–480. 2003. View Article : Google Scholar : PubMed/NCBI
9.	Dranoff G: Coordinated tumor immunity. J Clin Invest. 111:1116–1118. 2003. View Article : Google Scholar : PubMed/NCBI
10.	Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH and Spies T: Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci USA. 96:6879–6884. 1999. View Article : Google Scholar : PubMed/NCBI
11.	Groh V, Wu J, Yee C and Spies T: Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 419:734–738. 2002. View Article : Google Scholar : PubMed/NCBI
12.	Pende D, Rivera P, Marcenaro S, et al: Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res. 62:6178–6186. 2002.
13.	Liu G, Atteridge CL, Wang X, Lundgren AD and Wu JD: The membrane type matrix metalloproteinase MMP14 mediates constitutive shedding of MHC class I chain-related molecule A independent of A disintegrin and metalloproteinases. J Immunol. 184:3346–3350. 2010. View Article : Google Scholar : PubMed/NCBI
14.	Salih HR, Rammensee HG and Steinle A: Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol. 169:4098–4102. 2002. View Article : Google Scholar : PubMed/NCBI
15.	Waldhauer I, Goehlsdorf D, Gieseke F, et al: Tumor-associated MICA is shed by ADAM proteases. Cancer Res. 68:6368–6376. 2008. View Article : Google Scholar : PubMed/NCBI
16.	Doubrovina ES, Doubrovin MM, Vider E, et al: Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol. 171:6891–6899. 2003. View Article : Google Scholar : PubMed/NCBI
17.	Xu X, Rao G, Gaffud MJ, et al: Clinicopathological significance of major histocompatibility complex class I-related chain a and B expression in thyroid cancer. J Clin Endocrinol Metab. 91:2704–2712. 2006. View Article : Google Scholar : PubMed/NCBI
18.	Xu X, Rao GS, Groh V, et al: Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: role of uric acid accumulation in gemcitabine-induced MICA/B expression. BMC Cancer. 11:1942011. View Article : Google Scholar : PubMed/NCBI
19.	Duan X, Deng L, Chen X, et al: Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer. Med Oncol. 28:466–474. 2011. View Article : Google Scholar : PubMed/NCBI
20.	Groh V, Bahram S, Bauer S, Herman A, Beauchamp M and Spies T: Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci USA. 93:12445–12450. 1996. View Article : Google Scholar : PubMed/NCBI
21.	Bauer S, Groh V, Wu J, et al: Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 285:727–729. 1999. View Article : Google Scholar : PubMed/NCBI
22.	Diefenbach A, Jensen ER, Jamieson AM and Raulet DH: Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature. 413:165–171. 2001. View Article : Google Scholar : PubMed/NCBI
23.	Hayakawa Y, Kelly JM, Westwood JA, et al: Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin. J Immunol. 169:5377–5381. 2002. View Article : Google Scholar : PubMed/NCBI
24.	Raulet DH: Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 3:781–790. 2003. View Article : Google Scholar : PubMed/NCBI
25.	Watson NF, Spendlove I, Madjd Z, et al: Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int J Cancer. 118:1445–1452. 2006. View Article : Google Scholar : PubMed/NCBI
26.	Marten A, von Lilienfeld-Toal M, Buchler MW and Schmidt J: Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing gammadelta T cell cytotoxicity. Int J Cancer. 119:2359–2365. 2006. View Article : Google Scholar : PubMed/NCBI
27.	Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A and Salih HR: Soluble MICA in malignant diseases. Int J Cancer. 118:684–687. 2006. View Article : Google Scholar : PubMed/NCBI
28.	Chung HW and Lim JB: Clinical significance of serum levels of immune-associated molecules, uric acid and soluble MHC class I chain-related molecules A and B, as diagnostic tumor markers for pancreatic ductal adenocarcinoma. Cancer Sci. 102:1673–1679. 2011. View Article : Google Scholar
29.	Bahram S: MIC genes: from genetics to biology. Adv Immunol. 76:1–60. 2000. View Article : Google Scholar : PubMed/NCBI
30.	Collins RW, Stephens HA, Clare MA and Vaughan RW: High resolution molecular phototyping of MICA and MICB alleles using sequence specific primers. Hum Immunol. 63:783–794. 2002. View Article : Google Scholar : PubMed/NCBI
31.	Stephens HA: MICA and MICB genes: can the enigma of their polymorphism be resolved? Trends Immunol. 22:378–385. 2001. View Article : Google Scholar : PubMed/NCBI
32.	Arreygue-Garcia NA, Daneri-Navarro A, del Toro-Arreola A, et al: Augmented serum level of major histocompatibility complex class I-related chain A (MICA) protein and reduced NKG2D expression on NK and T cells in patients with cervical cancer and precursor lesions. BMC Cancer. 8:162008. View Article : Google Scholar
33.	Chitadze G, Lettau M, Bhat J, et al: Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the ‘a disintegrin and metalloproteases’ 10 and 17. Int J Cancer. 133:1557–1566. 2013.PubMed/NCBI
34.	Ashiru O, Boutet P, Fernandez-Messina L, et al: Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA^*008 that is shed by tumor cells in exosomes. Cancer Res. 70:481–489. 2010. View Article : Google Scholar : PubMed/NCBI
35.	Collins RW: Human MHC class I chain related (MIC) genes: their biological function and relevance to disease and transplantation. Eur J Immunogenet. 31:105–114. 2004. View Article : Google Scholar : PubMed/NCBI
36.	Bedel R, Thiery-Vuillemin A, Grandclement C, et al: Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. Cancer Res. 71:1615–1626. 2011. View Article : Google Scholar : PubMed/NCBI