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RAGE, inflammation and oral cancer: Recreating the connexion
Oral Oncology 50 (2014) e58–e59
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Letter to the Editor RAGE, inflammation and oral cancer: Recreating the connexion
Introduction Tumors in a hypoxic microenvironment are primarily dependent on anaerobic metabolism, demonstrating an increase in glycolysis which in turn directs to the formation of advanced glycation end products (AGEs) [1]. Various human cancer tissues
have expressed the presence of AGEs with substantial variation between different types of tumor [2]. There are definite receptors for AGE products known as receptor for advanced glycation endproducts (RAGE). Quite a number of clinical studies have established that RAGE expression correlates with the malignant potential in an array of cancers, such as gastric, colon, common bile duct, pancreatic, prostate and even in oral squamous cell carcinoma [3]. RAGE from the superfamily of immunglobulins was first recognized in 1992 [1]. Other than AGEs, it also binds to proteins of the S100/calgranulin family, including S100-A12/extracellular
Fig. 1. RAGE, inflammation and oral cancer: recreating the connexion. http://dx.doi.org/10.1016/j.oraloncology.2014.07.016 1368-8375/Ó 2014 Elsevier Ltd. All rights reserved.
Letter to the Editor / Oral Oncology 50 (2014) e58–e59
newly identified RAGE-binding protein (ENRAGE), and S100B. Another signal-transducing ligand of RAGE is amphoterin/highmobility group box 1(HMGB1), one of the HMGB DNA-binding proteins [4]. The chief task of RAGE is to be involved in the signal transduction from pathogen substrates to cell activation during the onset and perpetuation of inflammation [5]. It was Rudolph Virchow, who first pitched the theory that inflammation and cancer have a connexion [6] and Feller et al., in their review evidently detailed that inflammation in context to oral cancer played a predictable role in tumor progression [7]. Inevitably, instigation of RAGE, induces nuclear factor kappa B (NF-jB) and mitogen-activated protein kinase (MAPK) pathways, which are confirmed pathways for cancer prgression also (Fig. 1) [4]. In tumor biology, S100/calgranulins and HMGB1 have been identified as ligands of this receptor playing an important role in maintenance of this link between RAGE, inflammation and cancer [3]. Encoded on human chromosome 1q21, S100/calgranulin via RAGE, leads to activation of signaling cascades and production of cytokines and proinflammatory adhesion molecules [8]. Similarly, another member of this family, S100P has been confirmed to stimulate cell proliferation and survival via RAGE [9].HMGB1, encoded on human chromosome 13q12-13, a nuclear protein, belongs to damage-associated molecular pattern molecules group, are known to stimulate cellular migration, proliferation, invasion and metastasis when RAGE is engaged in tumor cells [10]. A Medline/Pubmed search with terms ‘RAGE and Oral Cancer’ and ‘RAGE and oral squamous cell carcinoma’ yielded a total of 9 articles ranging from 2005 to 2013. Bhawal et al. were the first ones to associate expression of RAGE with invasive activity of oral squamous cell carcinoma(OSCC) [11].Others like Sasahira et al., associated it with angiogenesis in 2007 [12] and later its importance in the prediction of recurrence in OSCC [13]. In 2008, they associated HMGB1 activity with nodal metastasis and lymphangiogenesis via RAGE [14]. Landesberg et al., demonstrated that RAGE is positively expressed in well-differentiated OSCCs compared to moderately and poorly differentiated OSCCs and the expression decreases in OSCCs as they become less differentiated [15]. In the most recent study by Clarissa et al., the first evidence of interaction between HMGB1 with regulatory T cells (Treg), which express the HMGB1-recognizing receptors, toll like receptors (TLR4) and RAGE in patients with HNSCC was reported establishing their role in antitumor immune responses [16]. These studies and literature review from a decade confirm that RAGE is an important contributor to inflammation-related oral tumorigenesis through different signalling mechanisms such as promoting resistance to apoptotic insults and hypoxia, interfering with antitumor immunity, stimulating angiogenesis and supporting invasiveness. It indeed makes itself an important regulator of hallmarks of cancer, making it an evitable target for cancer therapy unswervingly. Modulating RAGE or understanding its mechanisms that result in TLR versus RAGE signalling or RAGE–TLR cross-talk in response to their shared ligands should be stressed on as a primacy in future research perspectives. Conflict of interest None.
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References [1] Schmidt AM, Stern DM. Receptor for AGE (RAGE) is a gene within the major histocompatibility class III region: implications for host response mechanisms in homeostasis and chronic disease. Front Biosci 2001;6:D1151–60. [2] van Heijst JW, Niessen HW, Hoekman K, Schalkwijk CG. Advanced glycation end products in human cancer tissues: detection of Nepsilon(carboxymethyl)lysine and argpyrimidine. Ann NY Acad Sci 2005; 1043:725–33. [3] Rojas A, Figueroa H, Morales E. Fueling inflammation at tumor microenvironment: the role of multiligand/rage axis. Carcinogenesis 2010; 31(3):334–41. [4] Bopp C, Bierhaus A, Hofer S, Bouchon A, Nawroth PP, Martin E, et al. Bench-tobedside review: the inflammation-perpetuating pattern recognition receptor RAGE as a therapeutic target in sepsis. Critical Care 2008;12:201. [5] Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 2005;83:876–86. [6] Kundu JK et al. Inflammation: gearing the journey to cancer. Mutat Res 2008;659:15–30. [7] Feller L, Altini M, Lemmer J. Inflammation in the context of oral cancer. Oral Oncol 2013;49(9):887–92. [8] Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/ calgranulin polypeptides. Cell 1999;97:889–901. [9] Arumugam T, Simeone DM, Schmidt AM, Logsdon CD. S100P stimulates cell proliferation and survival via receptor for activated glycation end products (RAGE). J Biol Chem 2004;279:5059–65. [10] Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005;5:331–42. [11] Bhawal UK, Ozaki Y, Nishimura M, Sugiyama M, Sasahira T, Nomura Y, et al. Association of expression of receptor for advanced glycation end products and invasive activity of oral squamous cell carcinoma. Oncology 2005;69(3): 246–55. [12] Sasahira T, Kirita T, Bhawal UK, Ikeda M, Nagasawa A, Yamamoto K, et al. The expression of receptor for advanced glycation end products is associated with angiogenesis in human oral squamous cell carcinoma. Virchows Arch 2007; 450(3):287–95. [13] Sasahira T, Kirita T, Bhawal UK, Yamamoto K, Ohmori H, Fujii K, et al. Receptor for advanced glycation end products (RAGE) is important in the prediction of recurrence in human oral squamous cell carcinoma. Histopathology 2007; 51(2):166–72. [14] Sasahira T, Kirita T, Oue N, Bhawal UK, Yamamoto K, Fujii K, et al. High mobility group box-1-inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma. Cancer Sci 2008;99(9):1806–12. [15] Landesberg R, Woo V, Huang L, Cozin M, Lu Y, Bailey C, et al. The expression of the receptor for glycation endproducts (RAGE) in oral squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105(5):617–24. [16] Wild CA, Brandau S, Lotfi R, Mattheis S, Gu X, Lang S, et al. HMGB1 is overexpressed in tumor cells and promotes activity of regulatory T cells in patients with head and neck cancer. Oral Oncol 2012;48(5):409–16.
Samapika Routray Department of Oral Pathology & Microbiology, Institute of Dental Sciences, ‘SOA’ University, Bhubaneswar, Odisha 751003, India Tel.: +91 9937149690. E-mail address: [email protected] Available online 12 August 2014
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Letter to the Editor RAGE, inflammation and oral cancer: Recreating the connexion
Introduction Tumors in a hypoxic microenvironment are primarily dependent on anaerobic metabolism, demonstrating an increase in glycolysis which in turn directs to the formation of advanced glycation end products (AGEs) [1]. Various human cancer tissues
have expressed the presence of AGEs with substantial variation between different types of tumor [2]. There are definite receptors for AGE products known as receptor for advanced glycation endproducts (RAGE). Quite a number of clinical studies have established that RAGE expression correlates with the malignant potential in an array of cancers, such as gastric, colon, common bile duct, pancreatic, prostate and even in oral squamous cell carcinoma [3]. RAGE from the superfamily of immunglobulins was first recognized in 1992 [1]. Other than AGEs, it also binds to proteins of the S100/calgranulin family, including S100-A12/extracellular
Fig. 1. RAGE, inflammation and oral cancer: recreating the connexion. http://dx.doi.org/10.1016/j.oraloncology.2014.07.016 1368-8375/Ó 2014 Elsevier Ltd. All rights reserved.
Letter to the Editor / Oral Oncology 50 (2014) e58–e59
newly identified RAGE-binding protein (ENRAGE), and S100B. Another signal-transducing ligand of RAGE is amphoterin/highmobility group box 1(HMGB1), one of the HMGB DNA-binding proteins [4]. The chief task of RAGE is to be involved in the signal transduction from pathogen substrates to cell activation during the onset and perpetuation of inflammation [5]. It was Rudolph Virchow, who first pitched the theory that inflammation and cancer have a connexion [6] and Feller et al., in their review evidently detailed that inflammation in context to oral cancer played a predictable role in tumor progression [7]. Inevitably, instigation of RAGE, induces nuclear factor kappa B (NF-jB) and mitogen-activated protein kinase (MAPK) pathways, which are confirmed pathways for cancer prgression also (Fig. 1) [4]. In tumor biology, S100/calgranulins and HMGB1 have been identified as ligands of this receptor playing an important role in maintenance of this link between RAGE, inflammation and cancer [3]. Encoded on human chromosome 1q21, S100/calgranulin via RAGE, leads to activation of signaling cascades and production of cytokines and proinflammatory adhesion molecules [8]. Similarly, another member of this family, S100P has been confirmed to stimulate cell proliferation and survival via RAGE [9].HMGB1, encoded on human chromosome 13q12-13, a nuclear protein, belongs to damage-associated molecular pattern molecules group, are known to stimulate cellular migration, proliferation, invasion and metastasis when RAGE is engaged in tumor cells [10]. A Medline/Pubmed search with terms ‘RAGE and Oral Cancer’ and ‘RAGE and oral squamous cell carcinoma’ yielded a total of 9 articles ranging from 2005 to 2013. Bhawal et al. were the first ones to associate expression of RAGE with invasive activity of oral squamous cell carcinoma(OSCC) [11].Others like Sasahira et al., associated it with angiogenesis in 2007 [12] and later its importance in the prediction of recurrence in OSCC [13]. In 2008, they associated HMGB1 activity with nodal metastasis and lymphangiogenesis via RAGE [14]. Landesberg et al., demonstrated that RAGE is positively expressed in well-differentiated OSCCs compared to moderately and poorly differentiated OSCCs and the expression decreases in OSCCs as they become less differentiated [15]. In the most recent study by Clarissa et al., the first evidence of interaction between HMGB1 with regulatory T cells (Treg), which express the HMGB1-recognizing receptors, toll like receptors (TLR4) and RAGE in patients with HNSCC was reported establishing their role in antitumor immune responses [16]. These studies and literature review from a decade confirm that RAGE is an important contributor to inflammation-related oral tumorigenesis through different signalling mechanisms such as promoting resistance to apoptotic insults and hypoxia, interfering with antitumor immunity, stimulating angiogenesis and supporting invasiveness. It indeed makes itself an important regulator of hallmarks of cancer, making it an evitable target for cancer therapy unswervingly. Modulating RAGE or understanding its mechanisms that result in TLR versus RAGE signalling or RAGE–TLR cross-talk in response to their shared ligands should be stressed on as a primacy in future research perspectives. Conflict of interest None.
e59
References [1] Schmidt AM, Stern DM. Receptor for AGE (RAGE) is a gene within the major histocompatibility class III region: implications for host response mechanisms in homeostasis and chronic disease. Front Biosci 2001;6:D1151–60. [2] van Heijst JW, Niessen HW, Hoekman K, Schalkwijk CG. Advanced glycation end products in human cancer tissues: detection of Nepsilon(carboxymethyl)lysine and argpyrimidine. Ann NY Acad Sci 2005; 1043:725–33. [3] Rojas A, Figueroa H, Morales E. Fueling inflammation at tumor microenvironment: the role of multiligand/rage axis. Carcinogenesis 2010; 31(3):334–41. [4] Bopp C, Bierhaus A, Hofer S, Bouchon A, Nawroth PP, Martin E, et al. Bench-tobedside review: the inflammation-perpetuating pattern recognition receptor RAGE as a therapeutic target in sepsis. Critical Care 2008;12:201. [5] Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 2005;83:876–86. [6] Kundu JK et al. Inflammation: gearing the journey to cancer. Mutat Res 2008;659:15–30. [7] Feller L, Altini M, Lemmer J. Inflammation in the context of oral cancer. Oral Oncol 2013;49(9):887–92. [8] Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/ calgranulin polypeptides. Cell 1999;97:889–901. [9] Arumugam T, Simeone DM, Schmidt AM, Logsdon CD. S100P stimulates cell proliferation and survival via receptor for activated glycation end products (RAGE). J Biol Chem 2004;279:5059–65. [10] Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005;5:331–42. [11] Bhawal UK, Ozaki Y, Nishimura M, Sugiyama M, Sasahira T, Nomura Y, et al. Association of expression of receptor for advanced glycation end products and invasive activity of oral squamous cell carcinoma. Oncology 2005;69(3): 246–55. [12] Sasahira T, Kirita T, Bhawal UK, Ikeda M, Nagasawa A, Yamamoto K, et al. The expression of receptor for advanced glycation end products is associated with angiogenesis in human oral squamous cell carcinoma. Virchows Arch 2007; 450(3):287–95. [13] Sasahira T, Kirita T, Bhawal UK, Yamamoto K, Ohmori H, Fujii K, et al. Receptor for advanced glycation end products (RAGE) is important in the prediction of recurrence in human oral squamous cell carcinoma. Histopathology 2007; 51(2):166–72. [14] Sasahira T, Kirita T, Oue N, Bhawal UK, Yamamoto K, Fujii K, et al. High mobility group box-1-inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma. Cancer Sci 2008;99(9):1806–12. [15] Landesberg R, Woo V, Huang L, Cozin M, Lu Y, Bailey C, et al. The expression of the receptor for glycation endproducts (RAGE) in oral squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105(5):617–24. [16] Wild CA, Brandau S, Lotfi R, Mattheis S, Gu X, Lang S, et al. HMGB1 is overexpressed in tumor cells and promotes activity of regulatory T cells in patients with head and neck cancer. Oral Oncol 2012;48(5):409–16.
Samapika Routray Department of Oral Pathology & Microbiology, Institute of Dental Sciences, ‘SOA’ University, Bhubaneswar, Odisha 751003, India Tel.: +91 9937149690. E-mail address: [email protected] Available online 12 August 2014