BMC Cancer | |
Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes – an immunohistochemical study | |
Falk Wehrhan3  Maike Büttner-Herold2  Peter Hyckel1  Patrick Moebius3  Raimund Preidl3  Luitpold Distel4  Jutta Ries3  Kerstin Amann2  Christian Schmitt3  Friedrich W Neukam3  Manuel Weber3  | |
[1] Department of Oral and Maxillofacial Surgery, University of Jena, Erlanger Allee 101, 07749 Jena, Germany | |
[2] Institute of Pathology, Department of Nephropathology, Friedrich-Alexander University Erlangen-Nürnberg, Krankenhausstraße 12, 91054 Erlangen, Germany | |
[3] Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Glueckstrasse 11, 91054 Erlangen, Germany | |
[4] Department of Radiation Oncology, Friedrich-Alexander University Erlangen-Nürnberg, Universitätsstraße 27, 91054 Erlangen, Germany | |
关键词: M2; M1; oscc; Peripheral tolerance; Macrophage polarization; Lymph node; Oral cancer; Oral squamous cell carcinoma; | |
Others : 1125326 DOI : 10.1186/1471-2407-14-522 |
|
received in 2014-03-05, accepted in 2014-07-09, 发布年份 2014 | |
【 摘 要 】
Background
It is largely accepted that specific immunological parameters in solid malignancies are associated with patient’s prognosis. Recently a correlation of macrophage polarization with histomorphological parameters could also be shown in oral squamous cell carcinoma (oscc). The observed tumor derived peripheral immune tolerance could be associated with the macrophage polarization in regional tumor draining lymph nodes.
So far there are no studies analyzing the macrophage polarization in cervical lymph nodes of oscc patients. In the present study we aimed to correlate macrophage polarization in different anatomical lymph node compartments of patients diagnosed with oscc with histopathologic parameters of the primary tumor (T-, N-, L-, V-, Pn-status, grading).
Methods
Tumor free (n = 37) and metastatic (n = 17) lymph nodes of T1 and T2 oscc patients were processed for immunohistochemistry to detect CD68, CD11c, CD163 and MRC1 positive cells. Samples were digitized using whole slide imaging and the number of cells expressing the aforementioned markers in the region of interest quantitatively analyzed.
Results
The malignancy of the primary tumor (defined by T-, L-, Pn-status, grading) correlated with the lymph node macrophage polarization. L1 and Pn1 tumor cases displayed a significantly (p < 0.05) decreased M1 and increased M2 polarization in the sinus of the lymph nodes. G3 cases presented a significantly (p < 0.05) increased M2 polarization in the sinus compared to G2 cases. T2 tumors had significantly (p < 0.05) increased M2 polarization in the interfollicular zone of regional lymph nodes compared to T1 tumors. Metastatic and non-metastatic lymph nodes did not differ regarding their macrophage polarization.
Conclusions
The current study revealed for the first time an influence of oscc on the macrophage polarization in regional lymph nodes. Markers of malignant behavior in the primary tumor were associated with a shift of macrophage polarization in lymph nodes from the anti-tumoral M1 type to the tumor-promoting M2 type. As tumor free and metastatic lymph nodes did not differ in terms of their macrophage polarization pattern, there must be other factors influencing the location for lymph node metastasis formation.
【 授权许可】
2014 Wehrhan et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20150217015130631.pdf | 2433KB | download | |
Figure 7. | 54KB | Image | download |
Figure 6. | 65KB | Image | download |
Figure 5. | 35KB | Image | download |
Figure 4. | 102KB | Image | download |
Figure 3. | 101KB | Image | download |
Figure 2. | 194KB | Image | download |
Figure 1. | 71KB | Image | download |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
Figure 7.
【 参考文献 】
- [1]Shaw RJ, Pace-Balzan A, Butterworth C: Contemporary clinical management of oral squamous cell carcinoma. Periodontol 2011, 57(1):89-101.
- [2]Scully C, Bagan J: Oral squamous cell carcinoma: overview of current understanding of aetiopathogenesis and clinical implications. Oral Dis 2009, 15(6):388-399.
- [3]Warnakulasuriya S: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 2009, 45(4–5):309-316.
- [4]Kumagai K, Hamada Y, Gotoh A, Kobayashi H, Kawaguchi K, Horie A, Yamada H, Suzuki S, Suzuki R: Evidence for the changes of antitumor immune response during lymph node metastasis in head and neck squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010, 110(3):341-350.
- [5]Weber W, Reuther J, Muhling J, Ordung R, Michel C: [Statistical results in patients with squamous cell cancer of the mouth, 1981–1990 patient sample]. Fortschr Kiefer Gesichtschir 1992, 37:33-36.
- [6]Fan S, Tang QL, Lin YJ, Chen WL, Li JS, Huang ZQ, Yang ZH, Wang YY, Zhang DM, Wang HJ, Dias-Ribeiro E, Cai Q, Wang L: A review of clinical and histological parameters associated with contralateral neck metastases in oral squamous cell carcinoma. Int J Oral Sci 2011, 3(4):180-191.
- [7]Lingen MW, Kalmar JR, Karrison T, Speight PM: Critical evaluation of diagnostic aids for the detection of oral cancer. Oral Oncol 2008, 44(1):10-22.
- [8]Hyckel P, Metzner G, Muller P, Haroske D, Quade R: [The significance of immunologic parameters for preoperative prognostication in carcinoma of the mouth]. Dtsch Z Mund Kiefer Gesichtschir 1985, 9(6):461-468.
- [9]Bier J, Nicklisch U: [Cellular and humoral immune reactivity in patients with squamous cell carcinoma of the oral cavity]. Dtsch Zahnarztl Z 1977, 32(10):804-807.
- [10]Metelmann HR, Hyckel P, Podmelle F: Oral cancer treatment and immune targets - a role for dendritic cells? J Craniomaxillofac Surg 2012, 40(2):103-104.
- [11]Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F, Sakoda M, Ueno S, Natsugoe S, Takao S: Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 2011, 167(2):e211-219.
- [12]Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation. Nature 2008, 454(7203):436-444.
- [13]Rauser S, Langer R, Tschernitz S, Gais P, Jutting U, Feith M, Hofler H, Walch A: High number of CD45RO + tumor infiltrating lymphocytes is an independent prognostic factor in non-metastasized (stage I-IIA) esophageal adenocarcinoma. BMC Cancer 2010, 10:608.
- [14]Grotz TE, Mansfield AS, Jakub JW, Markovic SN: Regional lymphatic immunity in melanoma. Melanoma Res 2012, 22(1):9-18.
- [15]Mao Y, Poschke I, Wennerberg E, de Pico Coana Y, Egyhazi Brage S, Schultz I, Hansson J, Masucci G, Lundqvist A, Kiessling R: Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res 2013, 73(13):3877-3887.
- [16]Swartz MA, Lund AW: Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat Rev Cancer 2012, 12(3):210-219.
- [17]Watanabe Y, Katou F, Ohtani H, Nakayama T, Yoshie O, Hashimoto K: Tumor-infiltrating lymphocytes, particularly the balance between CD8(+) T cells and CCR4(+) regulatory T cells, affect the survival of patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010, 109(5):744-752.
- [18]Shah W, Yan X, Jing L, Zhou Y, Chen H, Wang Y: A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4 (+) FOXP3 (+) regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix. Cell Mol Immunol 2011, 8(1):59-66.
- [19]Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, Hiraoka N: Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 2013, 108(4):914-923.
- [20]Balermpas P, Michel Y, Wagenblast J, Seitz O, Weiss C, Rodel F, Rodel C, Fokas E: Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer. Br J Cancer 2014, 110(2):501-509.
- [21]Costa NL, Valadares MC, Souza PP, Mendonca EF, Oliveira JC, Silva TA, Batista AC: Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol 2012.
- [22]El-Rouby DH: Association of macrophages with angiogenesis in oral verrucous and squamous cell carcinomas. J Oral Pathol Med 2010, 39(7):559-564.
- [23]Fujii N, Shomori K, Shiomi T, Nakabayashi M, Takeda C, Ryoke K, Ito H: Cancer-associated fibroblasts and CD163-positive macrophages in oral squamous cell carcinoma: their clinicopathological and prognostic significance. J Oral Pathol Med 2012, 41(6):444-451.
- [24]Lu CF, Huang CS, Tjiu JW, Chiang CP: Infiltrating macrophage count: a significant predictor for the progression and prognosis of oral squamous cell carcinomas in Taiwan. Head Neck 2010, 32(1):18-25.
- [25]Tong CC, Kao J, Sikora AG: Recognizing and reversing the immunosuppressive tumor microenvironment of head and neck cancer. Immunol Res 2012, 54(1–3):266-274.
- [26]Weber M, Buttner-Herold M, Hyckel P, Moebius P, Distel L, Ries J, Amann K, Neukam FW, Wehrhan F: Small oral squamous cell carcinomas with nodal lymphogenic metastasis show increased infiltration of M2 polarized macrophages - An immunohistochemical analysis. J Craniomaxillofac Surg 2014.
- [27]Vu HL, Sikora AG, Fu S, Kao J: HPV-induced oropharyngeal cancer, immune response and response to therapy. Cancer Lett 2010, 288(2):149-155.
- [28]Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, Suchak K, Webb A, Hampton C, Patel NN, Randall CJ, Cox HJ, Jogai S, Primrose J, Piper K, Ottensmeier CH, King EV, Thomas GJ: Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer 2014, 110(2):489-500.
- [29]Mantovani A, Sica A, Locati M: New vistas on macrophage differentiation and activation. Eur J Immunol 2007, 37(1):14-16.
- [30]Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M: Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 2013, 229(2):176-185.
- [31]Sica A, Mantovani A: Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012, 122(3):787-795.
- [32]Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C, Higashida M, Mikasa H, Nakaya Y, Takanashi S, Igarashi T, Kitagawa T, Sata M: Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 2011, 58(3):248-255.
- [33]Cao X, Shen D, Patel MM, Tuo J, Johnson TM, Olsen TW, Chan CC: Macrophage polarization in the maculae of age-related macular degeneration: A pilot study. Pathol Int 2011, 61(9):528-535.
- [34]Murray PJ, Wynn TA: Obstacles and opportunities for understanding macrophage polarization. J Leukoc Biol 2011, 89(4):557-563.
- [35]Cho KY, Miyoshi H, Kuroda S, Yasuda H, Kamiyama K, Nakagawara J, Takigami M, Kondo T, Atsumi T: The Phenotype of Infiltrating Macrophages Influences Arteriosclerotic Plaque Vulnerability in the Carotid Artery. J Stroke Cerebrovasc Dis 2012.
- [36]Kawamura K, Komohara Y, Takaishi K, Katabuchi H, Takeya M: Detection of M2 macrophages and colony-stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors. Pathol Int 2009, 59(5):300-305.
- [37]Pejnovic N, Pantic J, Jovanovic I, Radosavljevic G, Milovanovic M, Nikolic I, Zdravkovic N, Djukic A, Arsenijevic N, Lukic M: Galectin-3 Deficiency Accelerates High-Fat Diet Induced Obesity and Amplifies Inflammation in Adipose Tissue and Pancreatic Islets. Diabetes 2013, 62:1932-1944.
- [38]Fischer-Posovszky P, Wang QA, Asterholm IW, Rutkowski JM, Scherer PE: Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages. Endocrinology 2011, 152(8):3074-3081.
- [39]Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, Aissat A, Guerre-Millo M, Clement K: Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab 2009, 94(11):4619-4623.
- [40]Hasan D, Chalouhi N, Jabbour P, Hashimoto T: Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results. J Neuroinflammation 2012, 9:222.
- [41]van Putten SM, Ploeger DT, Popa ER, Bank RA: Macrophage phenotypes in the collagen-induced foreign body reaction in rats. Acta Biomater 2013, 6502:10.
- [42]Lan C, Huang X, Lin S, Huang H, Cai Q, Wan T, Lu J, Liu J: Expression of M2-Polarized Macrophages is Associated with Poor Prognosis for Advanced Epithelial Ovarian Cancer. Technol Cancer Res Treat 2012.
- [43]Herwig MC, Bergstrom C, Wells JR, Holler T, Grossniklaus HE: M2/M1 ratio of tumor associated macrophages and PPAR-gamma expression in uveal melanomas with class 1 and class 2 molecular profiles. Exp Eye Res 2013, 107:52-58.
- [44]O'Brien CJ, Lauer CS, Fredricks S, Clifford AR, McNeil EB, Bagia JS, Koulmandas C: Tumor thickness influences prognosis of T1 and T2 oral cavity cancer–but what thickness? Head Neck 2003, 25(11):937-945.
- [45]Lanzer M, Gander T, Kruse A, Luebbers HT, Reinisch S: Influence of histopathologic factors on pattern of metastasis in squamous cell carcinoma of the head and neck. Laryngoscope 2013.
- [46]Fagan JJ, Collins B, Barnes L, D'Amico F, Myers EN, Johnson JT: Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1998, 124(6):637-640.
- [47]Fortin A, Couture C, Doucet R, Albert M, Allard J, Tetu B: Does histologic grade have a role in the management of head and neck cancers? J Clin Oncol 2001, 19(21):4107-4116.
- [48]Carinci F, Pelucchi S, Farina A, De Franciscis G, Calearo C: Extension as a prognostic factor in oropharyngeal cancer: largest mucosal dimension compared with number of (sub) sites involved. Br J Oral Maxillofac Surg 1998, 36(6):440-445.
- [49]Mansfield AS, Holtan SG, Grotz TE, Allred JB, Jakub JW, Erickson LA, Markovic SN: Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis. Mod Pathol 2011, 24(4):487-494.
- [50]Beranek JT: CD68 is not a macrophage-specific antigen. Ann Rheum Dis 2005, 64(2):342-343. author reply 343–344
- [51]Coleman R, Gnant M, Morgan G, Clezardin P: Effects of bone-targeted agents on cancer progression and mortality. J Natl Cancer Inst 2012, 104(14):1059-1067.
- [52]Ben-Aharon I, Vidal L, Rizel S, Yerushalmi R, Shpilberg O, Sulkes A, Stemmer SM: Bisphosphonates in the adjuvant setting of breast cancer therapy–effect on survival: a systematic review and meta-analysis. PLoS One 2013, 8(8):e70044.
- [53]Rogers TL, Holen I: Tumour macrophages as potential targets of bisphosphonates. J Transl Med 2011, 9:177.
- [54]Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Monkkonen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M: Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med 2010, 14(12):2803-2815.