Immunohistochemical Expression of TGF-Î’1, SMAD4, SMAD7, TGFÎ²RII and CD68-Positive TAM Densities in Papillary Thyroid Cancer

Koni Ivanova; Irena Manolova; Maria-Magdalena Ignatova; Maya Gulubova

doi:10.3889/oamjms.2018.105

Authors

Koni Ivanova Trakia University, Medical Faculty, Department of General and Clinical Pathology, Stara Zagora
Irena Manolova Trakia University, Medical Faculty, Department Molecular Biology, Immunology and Medical Genetics, Stara Zagora
Maria-Magdalena Ignatova Trakia University, Medical Faculty, Department of General and Clinical Pathology, Stara Zagora
Maya Gulubova Trakia University, Medical Faculty, Department of General and Clinical Pathology, Stara Zagora

DOI:

https://doi.org/10.3889/oamjms.2018.105

Keywords:

Thyroid cancer, TGF-Î² pathway, Immunohistochemical expression, Macrophages, Tumorigenesis

Abstract

BACKGROUND: Papillary thyroid carcinoma (PTC) accounts for 80% of the thyroid malignancies that are characterised by slow growth and an excellent prognosis. Over-expression of SMAD4 protein restores TGF-Î² signalling, determines a strong increase in anti-proliferative effect and reduces invasive potential of tumour cells expressing it.

AIM: The study aimed to analyse the immunohistochemical expression of TGF-Î²1 and its downstream phosphorylated SMAD4, element and of the inhibitory SMAD7 PTC variants and their association with the localisation of TAMs within the tumour microenvironment.

METHODS: For this retrospective study we investigated 69 patients immunohistochemistry with antibodies against TGF-Î², TGF â€“ Î²-RII, SMAD4, SMAD7, CD68+ macrophages.

RESULTS: Patients with low infiltration with CD68+ cells in tumour stroma has significantly shorter survival (median of 129.267 months) compared to those with high CD68+ cells infiltration (p = 0.034). From the analysis of CD68+ cells in tumour border and tumour stroma correlated with expression of TGF-Î²1 / SMAD proteins, we observed that the positive expression of TGF-Î²1 in tumour cytoplasm, significantly correlated with increased number of CD68+ cells in tumour border (X² = 5,945; Ñ€ = 0.015).

CONCLUSION: TGF-Î² enhances motility and stimulates recruitment of monocytes, macrophages and other immune cells while directly inhibiting their anti-tumour effector functions.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Bierie B, Moses HL. Transforming growth factor beta (TGF-Î²) and inflammation in cancer cytokine. Growth Factor Rev. 2010; 21(1):4959.

Eloy C, Santos J, Cameselle-Teiyeiro C, Soares P, Simoes-Sobrinho M. TGF-beta/Smad pathway and BRAF mutation play different roles in circumscribed and infiltrative papillary thyroid carcinoma. Virchows Arch. 2012; 460:587-600. https://doi.org/10.1007/s00428-012-1234-y PMid:22527019

Cunha LL, Marcello MA, Ward LS. The role of inflammatory microenvironment in thyroid carcinogenesis. Endocrineâ€“Related Cancer. 2014; 21:R85-R103. https://doi.org/10.1530/ERC-13-0431 PMid:24302667

Miyazono K, Ehata S, Koinuma D. Tumor-promoting function of transforming growth factor Î² in progression of cancer. Upsala J of Medical Sci. 2012; 117:143-152. https://doi.org/10.3109/03009734.2011.638729 PMid:22111550 PMCid:PMC3339546

Zhang YE. Non-Smad pathway in TGF-Î² signaling. Cell Res. 2009; 19(1):128-139. https://doi.org/10.1038/cr.2008.328 PMid:19114990 PMCid:PMC2635127

Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin alpha v beta 6 binds and activates latent TGF beta1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999; 96(3):319-328. https://doi.org/10.1016/S0092-8674(00)80545-0

Taipale J, Lohi J, Saarinen J, et al. Human mast cell chymase and leukocyte elastase release latent transforming growth factor-beta 1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem. 1995; 270:4689â€“4696. https://doi.org/10.1074/jbc.270.9.4689 PMid:7876240

Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-Î² and promotes tumor invasion and angiogenesis. Genes Dev. 2000; 14(2):163-176. PMid:10652271 PMCid:PMC316345

Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, Smith SM, Derynck R. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. Embo J. 2007; 26(17):3957-3967. https://doi.org/10.1038/sj.emboj.7601818 PMid:17673906 PMCid:PMC1994119

Elliot RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol. 2005; 23:2078-2093. https://doi.org/10.1200/JCO.2005.02.047 PMid:15774796

Matsuo SE, Fiore AP, Siguematu SM, Ebina KN, Friguglietti CU, Ferro MC, Kulcsar MA, Kimura ET. Expression of SMAD proteins, TGF-beta/active in signaling mediators, in human thyroid tissues. Arq Bras Endocrinol Metab. 2010; 54: 405-412. https://doi.org/10.1590/S0004-27302010000400010

Vendramini-Costa DB and Carvalho JE. Molecular link mechanisms between inflammation and cancer. Current Pharmaceutical Design. 2012; 18:3831-3852. https://doi.org/10.2174/138161212802083707 PMid:22632748

Fabregat I, Fernando J, Mainez J, Sancho P. TGF-Î² signaling in cancer treatment. Current Pharmaceutical Design. 2013; 287(4):755â€“63.

Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Gorman CA, Maurer MS, McIver B, Mullan BP. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940â€“1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg. 2002; 26:879-885. https://doi.org/10.1007/s00268-002-6612-1 PMid:12016468

Wang NI, Jiang R, Yang J-Y, Tang C, Yang L, Xu M, Jiang Q-F, Lin Z-M. Expression of TGF-Î²1, SNAI1 and MMP-9 is associated with lymph node metastasis in papillary thyroid carcinoma. J Mol Histol. 2014; 45:391-399. https://doi.org/10.1007/s10735-013-9557-9 PMid:24276590

Colleta G, Cirafici AM, Di Carlo A. Dual effect of transforming growth factor beta on rat thyroid cells: inhibition of thyrotropin-induced proliferation and reduction of thyroid-specific differentiation markers. Cancer Res. 1989; 49(13):3457-62.

Mincione G, Tarantelli C, Vianale G, Di Marcantonio MC, Cotellese R, Francomano F, Di Nicola M, Constantini E, Cichella A, Muraro R. Mutual regulation of TGF-Î²1, TÎ²RII and ErbB receptors expression in human thyroid carcinomas. Exp. Cell Res. 2014; 327:24-36. https://doi.org/10.1016/j.yexcr.2014.06.012 PMid:24973511

Kimura ET, Kopp P, Zbaren J, Asmis LM, Ruchti C, Maciel RM, Studer H. Expression of Transforming Growth Factor Î²1, Î²2, and Î²3 in Multinodular Goiters and Differentiated Thyroid Carcinomas: A Comparative Study. Thyroid. 1999; 9:119-125. https://doi.org/10.1089/thy.1999.9.119 PMid:10090310

D'Inzeo S, Nicolussi A, Ricci A, Mancini P, Porcellini A, Nardi F, Coppa A. Role of reduced expression of SMAD4 in papillary thyroid carcinoma. J Mol Endocrinol. 2010; 45:229-244. https://doi.org/10.1677/JME-10-0044 PMid:20685810

Cerutti JM, Ebina KN, Matusio SE, Martins R, Maciel RM, Kimura ET. Expression of Smad4 and Smad7 in human thyroid follicular carcinoma cell lines. J Endocrinol Invest. 2003; 26:516-521. https://doi.org/10.1007/BF03345213 PMid:12952364

Lazzereschi D, Ranieri A, Mincione G, Taccogna S, Nardi F, Colletta G. Human malignant thyroid tumors displayed reduced levels of transforming growth factor beta receptor type II messenger RNA and protein. Cancer Res. 1997; 57(10):2071-2076. PMid:9158007

Gong D, Shi W, Yi S-J, Chen H, Groffen J, Heisterkamp N. TGFÎ² signaling plays a critical role in promoting alternative macrophage activation. BMC Immunology. 2012; 13:31-41. https://doi.org/10.1186/1471-2172-13-31 PMid:22703233 PMCid:PMC3406960

Li MO, Yisong Y, Wan SS et al. Transforming-growth factor- beta regulation of immune responses. Annu Rev Immunol. 2006; 24:99-146. https://doi.org/10.1146/annurev.immunol.24.021605.090737 PMid:16551245

Lang BH, Lo CY, Chan WF, Lam KY, Wan KY. Staging systems for papillary thyroid carcinoma: a review and comparison. Ann Surg. 2007; 245:366-378. https://doi.org/10.1097/01.sla.0000250445.92336.2a PMid:17435543 PMCid:PMC1877011

DeLellis RA, Lloyd RV, Heitz PU, et al. Pathology and genetics of tumors of endocrine organs World Held Organization Clasifications of tumors. Lyon: IARC press, 2004.

Gulubova MV, Ananiev J, Yovchev Y, Julianov A, Karashmalakov A, Vlaykova T. The density of macrophages in colorectal cancer is inversely correlated to TGF- Î² expression and patients' survival. J Mol Histol. 2013; 44:679-692. https://doi.org/10.1007/s10735-013-9520-9 PMid:23801404

Lazzereschi D, Nardi F, Turco A, Ottini L, D'Amico C, Mariani-Costantini R, Gulino A, Coppa A. A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumors. Oncogene. 2005; 24:5344-5354. https://doi.org/10.1038/sj.onc.1208603 PMid:15940269

Rosenwald IB. The role of translation in neoplastic transformation from a pathologists point of view. Oncogene. 2004; 23:3230-3247. https://doi.org/10.1038/sj.onc.1207552 PMid:15094773

Hill CS. Nucleocytoplasmic shuttling of Smad proteins. Cell Research. 2009; 19:36-46. https://doi.org/10.1038/cr.2008.325 PMid:19114992

Jung KY, Cho SW, Kim YA, Kim D et al. Cancers with higher density of tumor-associated macrophages was associated with poor survival rates. J Pathol Translat Med. 2015; 49:318-324. https://doi.org/10.4132/jptm.2015.06.01 PMid:26081823 PMCid:PMC4508569

Li Mo et al. Transforming growth factor beta and the immune responses. Annu Rev Immunol. 2006; 24; 99-146. https://doi.org/10.1146/annurev.immunol.24.021605.090737 PMid:16551245