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1 Kor J Oral Maxillofac Pathol 2013;37(4): 염증성사이토카인과구강편평세포암종 김도경 1), 배정윤 1), 박영진 1), 손화경 2), 이재훈 3), 김진 1) * 연세대학교치과대학구강병리학교실, 구강종양연구소 1), 백석대학교치위생학과 2), 연세대학교치과대학보철학교실 3) <Abstract> Inflammatory Cytokines and Oral Squamous Cell Carcinoma Do Kyeong Kim 1), Jung Yoon Bae 1), Young Jin Park 1), Hwa Kyung Son 2), Jae Hoon Lee 3), Jin Kim 1) * Department of Oral pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry 1), Department of Dental hygiene, Baekseok University 2), Department of Prosthodontics, Yonsei University College of Dentistry 3) Inflammation functions as a double-edged sword against external stimulus. For instance, inflammation can have anti-cancer effect and simultaneously can play cancer-promoting factors. Recent studies have shown that cytokine plays an important role in tumor biology by influencing tumor growth, invasion and metastasis. We classify these cytokines by cancer type and review current knowledge of cytokines in terms of carcinogenesis. Here, we also focus on whether cytokines can act as biomarkers for early detection of oral squamous cell carcinoma (OSCC). This review will provide basis for further approach to study the role of cytokines in carcinogenesis and evaluating the possibilities of cytokines as biomarkers for cancer detection. Key words:cytokines, Biomarkers, Inflammation, Oral squamous cell carcinoma Ⅰ. 서론 염증 (Inflammation) 은외부의여러유해한자극에대한방어기전으로서조직손상의회복을돕는반면, 과도한염증반응은질병을유발할수도있기때문에양날의칼과같은기능을갖는다 1). 이러한염증은주요매개자인염증성사이토카인 (Inflammatory cytokine) 을분비하여염증반응의증폭과지속을조절한다 2). 특히, 암세포에서발현되는염증성사이토카인은암세포의성장과전이, 신생혈관형성등과같은암발달과정을촉진시킨다 3,4). * Correspondence: Jin Kim, Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry,134 Shinchon-Dong, Seoul , Republic of Korea. Tel: , Fax: , jink@yuhs.ac * 본논문은교육부의재원으로한국연구재단의지원을받아수행된기초연구사업중중점연구소사업 ( 과제번호 : ) 으로이루어졌음. Received: Jul 16, 2013; Revised: Jul 19, 2013; Accepted: Jul 29, 2013 암에서발현되는사이토카인은종류가무척다양하고, 조직손상의회복을유도하는사이토카인과양성 (Benign tumor) 및악성종양 (Malignant tumor) 에서발현되는사이토카인이특별히구분되지않기때문에 5), 암에서사이토카인의발현이보이더라도암특이적으로나타내는바이오마커 (Biomarker) 라기보다는단순히염증반응에서나타나는비특이적인표지자 (non-specific indicator) 로여겨왔다. 그러나, 최근에암세포에서발현되는일부사이토카인은암에대한단순한숙주의면역반응이외에신생혈관형성, 악성종양의전이등생물학적악성도와관련이있는것으로알려지면서염증성사이토카인의중요성이대두되었다 2,3,6). 현재까지일부사이토카인이각종암에서세포의성장및진행에관여한다고보고되어있으나세포및조직에따라발현되는사이토카인의종류및발현정도가다르기때문에임상적으로암진단바이오마커적용에대해논란의여지가있다. 더구나외부자극으로부터숙주를보호하는면역반응에서의사이토카인과대조적으로암의발생과진행

과정에서이들인자들의변화에대한연구는잘알려져있지않다. 그렇기때문에암에서발현되는사이토카인의특이적인특성을규명한다면암진단을위한새로운바이오마커의독자적인확보가가능할것이다. 따라서본논문은암에서많이발현되는염증성사이토카인을검토하고, 구강편평세포암종관련검토를통하여암조기진단표지자로서염증성사이토카인의가능성을확인하기위한기초자료로삼고자한다. 1.

2 과정에서이들인자들의변화에대한연구는잘알려져있지않다. 그렇기때문에암에서발현되는사이토카인의특이적인특성을규명한다면암진단을위한새로운바이오마커의독자적인확보가가능할것이다. 따라서본논문은암에서많이발현되는염증성사이토카인을검토하고, 구강편평세포암종관련검토를통하여암조기진단표지자로서염증성사이토카인의가능성을확인하기위한기초자료로삼고자한다. 1. 암에서발현되는염증성사이토카인 (Inflammatory cytokine) 염증성사이토카인은암에서발현되어염증성네트워크를형성하면서암생성및발달을매개하는데중요한역할을한다고알려져있으며, 이러한염증성사이토카인중 IL-1α, IL-1β, IL-6, IL-8, TNF-α 는여러암에서가장많이발현하는사이토카인으로염증관련전사인자인 NF-κB, STAT3에의해조절되는중요한암촉진매개자이다 7-10) (Fig. 1). IL-1 은 IL-1α 와 IL-1β 로나뉘며, 많은암및암미세환경에서생성되어전이및혈관생성유전자 (MMP 등 ) 와성장인자 (VEGF, IL-8,, TGF-β) 의발현을유도하면서암의 다단계과정을조절하는주요인자이다 8). IL-6 는다양한암에서세포사멸 (Apoptosis) 을억제하고암의성장을촉진시키며, 최근에는상피세포의간엽세포로의변이 (Epithelial-mesenchymal transition, EMT) 를매개하는것으로보고되어암세포의침윤및전이에중요한역할을한다고알려져있다 11,12). 또다른염증성사이토카인인 IL-8은비만세포, 중성구등에서생성되어염증반응에서백혈구에대한화학주성인자로작용하며다양한암에서암세포의성장과전이에관여하는것으로알려져있으며 13), TNF-α는병원성자극에의해유도되는염증반응에관여하는주요인자이다. TNF-α 는세포를변형, 증식하며암을촉진시킨다고보고되어있고, 또한암미세환경 (Tumor microenvironment) 에서다른염증성사이토카인을함께유도하며염증성반응을조절한다 14). 최근 10년내에등록된논문을대상으로암에서가장많이발현되는다섯가지사이토카인, IL-1α, IL-1β, IL-6, IL-8, TNF-α 의연구현황을살펴보았다. 발생부위별로암을분류하였으며 6), 각암과염증성사이토카인을함께 ( 예를들어, Bladder cancer and IL-1α) 검색어로지정하였다. 그결과총 13,775편의논문이검색되었으며, 이중 IL-1α와관련된논문은 166편, IL-1β는 853편, IL-6는 3736편, IL-8는 1,910편, TNF-α는 7,110 편으로분류되었다. IL-1α는각각 19편씩 Breast cancer (11.4 %) 와 Lung cancer (11.4 %) 에서가장많은연구보고가있음을확인하였고, IL-1β는 199편의 Gastric cancer (23.3 %), IL-6 는 526편의 Breast cancer (14.1 %), IL-8은 278편의 lung cancer (14.6 %), TNF-α는 1,102편의 Breast cancer (15.5 %) 에서가장많은연구가진행됨을확인하였다 (Fig. 2). 2. 자가및측분비인자 (/ growth effector) 로서의사이토카인 Fig. 1. The cytokine that links inflammation and cancer 암미세환경 (Tumor microenvironment) 은섬유모세포 (Fibroblast), 내피세포 (Endothelial cell), 염증세포 (Inflammatory cell) 등으로구성되어있으며, 이러한세포들은사이토카인의자가및측분비 ( / manner) 를통해자기자신또는주변세포들을재구성 (Reprogramming) 하면서암의개시와진행에중요한역할을한다 14,15). 134

3 Fig. 2. Inflammatory cytokine-associated articles reported by cancer type 135

4 즉, 동일한사이토카인의경우에도세포에따라자가분비인자또는측분비인자로다른기능을수행한다. 따라서암세포에작용하는대표적인사이토카인을자가및측분비기능으로나누어분류하였다 (Table 1). IL-1α는췌장암 (Pancreatic cancer) 등의암세포에서는자가분비인자로서작용하여세포증식에관여하고 16), 측분비인자로서는대식세포 (Macrophage), 수지상세포 (Dendritic cell) 등에서생성되어암의침윤을촉진시키며, 암의성장에있어서충분한혈액공급을유지하는데에기여한다 3). IL-6는자가분비인자로서암세포에서분비되어 EMT와같은암미세환경의변화를통해악성종양의표현형을유도하여암의악성도를증가시키며암세포의성장을촉진하며, 측분비인자로서는 T림프구, B림프구, 대식세포, 섬유모세포등여러세포에서생성되며류마티스관절염 (Rheumatoid arthritis), 건선 (Psoriasis), 암등에서의염증반응을증가시킨다 6,11,17). 그밖에사이토카인은많은암에서자가분비 ( manner) 를통해암세포의증식 (proliferation) 을촉진하여직접적으로암세포의성장을조절한다. 또한, 대식세포등을포함한면역세포와섬유모세포등에생성된사이토카인은측분비 ( manner) 를통해서면역체계를억제하여암미세환경을암이촉진되는환경으로유도하고, 신생혈관생성, 전이등을촉진하는성장인자및사이토카인의생성을증가시켜 주변세포가암세포의성장을간접적으로조절하는데기여한다 18). 3. 암세포에서발현되는염증성사이토카인의수용체 (Receptor) 및신호전달 (Signaling pathway) 사이토카인의자가및측분비 ( / manner) 에의한타깃세포의신호전달체계 (Signaling pathway) 에서는세포표면에존재하는수용체 (Receptor) 가외부로부터오는신호를감지하여받아들이고이러한신호의증폭을통해이후대사, 분비, 세포성장과같은활동을가능하게한다. 많은암세포는세포표면의사이토카인수용체를발현한다고알려져있으며, 수용체의하향신호전달체계가암세포의발달및생존을조절하는데에중요한역할을한다 (Table 2). IL-1과결합하는수용체는 Immunoglobulin superfamily receptor 의종류로서, type1과 type2로나뉘는데, 수용체와결합한 IL-1는침윤촉진인자및혈관성장인자를유도하며발암과정에관여한다 8,19). Type 1 cytokine receptor family 중하나인 IL-6 수용체는 IL-6와그수용체의발현정도에따라서암환자의예후에영향을미친다는보고가있으며 20) 또한, IL-6 수용체의하향신호전달체계인 JAK-STAT 신호전달체계는다양한신호전달체계 (MAP kinase, EGFR, PI3K/AKT 등 ) 와상호 Table 1. Inflammatory cytokine as an autocrine and paracrine effector Cytokine Forms of Secretion Cellular sources IL-1α IL-1β IL- 6 IL- 8 TNF-α Breast cancer cells, Cervix cancer cells, Skin cancer cells, Pancreatic cancer cells Macrophage, Dendritic cells, B cells, Natural killer cells, Keratinocytes Breast cancer cells, Skin cancer cells, Pancreatic cancer cells, Prostate cancer cells Macrophage, Dendritic cells, B cells, Natural killer cells, Keratinocytes Bladder cancer cells, Breast cancer cells, Cervix cancer cells, Esophageal cancer cells, Gastric cancer cells, Head and neck cancer cells, Lung cancer cells, Ovarian cancer cells, Skin cancer cells, Pancreatic cancer cells, Prostate cancer cells, Renal cancer cells, Liver cancer cells Macrophages, T cells, B cells, Endothelial cells, Fibroblasts Colon cancer cells, Gastric cancer cells, Head and neck cancer cells, Lung cancer cells, Skin cancer cells, Pancreatic cancer cells Macrophages, Mast cell, Neutrophil, T cells, Endothelial cells, Fibroblasts Glioblastroma, Ovarian cancer cells, Prostate cancer cells, Renal cancer cells, Liver cancer cells Macrophages, Natural killer cells, B cells, T cells, Neutrophils, Fibroblasts, Keratinocytes 136

5 Table 2. Receptor family of cytokine and its function Receptor family Immunoglobulin Superfamily Receptors Receptor- IL-1R1 IL-1R2 Cytokine (Ligand) IL-1α IL-1β Type I Cytokine receptors IL-6R IL-6 Chemokine receptor (G Protein-Coupled Receptors) Tumor Necrosis Factor Receptors (TNFR) CXCR1 CXCR2 TNFR TNF-α Function Associated with cancer progression and a metastatic phenotype,) Signals through JAK-STAT pathway ) Associated with aggressiveness and a poor prognosis in cancer ) IL-8 Increases survival, proliferation and tumor cell migration ) Signals through NF-κB pathway) Functions as co-stimulatory and co-inhibitory receptors,) 작용하며암성장과진행을촉진하는역할을한다 20,21). IL-8은케모카인수용체 (G protein-coupled receptor) 인 CXCR1과 CXCR2 수용체와결합하며이러한수용체는많은암조직에서빈번히발견된다. 22) 암미세환경에의해변형된세포에서발현되는케모카인수용체는암세포의침윤및전이에영향을미친다고보고되고있다 15,23). TNF-α의수용체와 TNF-α는암발달과관련해서실험동물모델및유전적결실등을이용하여연구되고있으며 6), TNF receptor 에의해매개되는신호전달은염증 Table 3. Cytokine in serum of patients with cancer Cancer Secreted cytokine in serum Bladder IL-6 Breast IL-1β, IL-6, IL-8, TNF-α Cervix IL-6 Colon IL-6, IL-8 Esophageal IL-6 Gastric Head and neck IL-1β, IL-6, IL-8, TNF-α Lung Ovarian IL-6, IL-8 Skin IL-6, IL-8, TNF-α Pancreatic IL-6, IL-8 Prostate Renal Liver 관련전사인자인 NF-κB와 MAP kinase 신호전달과관련하여암의성장을촉진한다고보고되어있다 24,25). 4. 암조기진단표지자로서염증성사이토카인의임상적용가능성 임상영역의암진단에서바이오마커 (Biomarker) 를이용하여 serum 내의특정단백질을검출 (detection) 할수있는방법은암의조기진단을가능하게하고암치료및예방효과를높일수있다. 따라서암진단바이오마커 (Biomarker) 로서염증성사이토카인의임상적용가능성을확인하기위해암환자의 Serum내사이토카인의발현확인이필요가있다. 각암환자의 serum 내에서검출된사이토카인을나타내었다 (Table 3). 암에서많이발현되어진다고알려진 IL-1α, IL-β, IL-6, IL-8, TNF-α 의사이토카인들을확인한결과 IL-6는모든암환자의 serum 내에서검출되었으나 IL-1α는검출이되지않았다 26-29). 즉, IL-6 는모든암환자의 serum 내에서검출됨에따라염증반응에서나타나는비특이적인표지자임을확인하였고, 이와같은조사결과를토대로향후암과염증의차이를규명하는연구에후보타깃으로서 IL-6의단면적가능성을확인할수있었다. 137

6 5. 구강편평세포암종조기진단표지자로서염증성사이토카인의임상적용가능성 연구를통해구강암의조기진단및예후결정인자로서 IL-1α 의검토가필요하다고사료된다. 구강암의약 90% 이상을차지하는구강편평세포암종은대 부분 stage III 와 IV의진행된단계에서발견되고 30), 따라서병의예후를결정하는 5년생존율이약 60% 인낮은생존율의암종이다 31). 그러나구강암은조기발견될경우기능유지등의예후가우수하기때문에구강암의조기발견은환자의생존율향상에매우중요하다. 현재까지구강암의진단은조직검사를통한의사의주관적판단이일반적이기때문에객관적인표지자및조기진단에서의사이토카인의가능성을확인하고자한다. 구강암을포함한두경부암 (Head and neck squamous cell carcinoma, HNSCC) 환자의 serum 을대상으로한연구보고에서는 26-29) IL-1β, IL-6, IL-8, TNF-α가통계적으로유의성이있으며그발현을확인할수있는반면, IL-1α 는 secretion level은확인할수없었다 (Table 3). 하지만 In vitro 실험을진행한 IL-1α 관련연구보고들에따르면 32,33), 두경부암에서발현된 IL-1α 은 IL-6와 IL-8 과같은사이토카인을유도하며세포의증식 (proliferation) 과생존 (survival) 을촉진시키고, NF-κB와 AP-1과같은전사인자를활성화시켜, 악성표현형 (malignant phenotype) 을유지하는데에주요역할을한다고제시하고있다. 또한, 본실험실의선행연구에서는, 구강편평세포암종 (Oral squamous cell carcinoma, OSCC) 에서분비되는 IL-1α가암주위섬유모세포 (Cancer-associated fibroblasts, CAF) 와의상호작용에관여하는주요인자로서, 암미세환경내의상호작용을촉진하여암세포의침윤을증가시켜암세포의악성도를증가시키는것을확인하였다 34). 즉, IL-1β, IL-6, IL-8, TNF-α 등의사이토카인은많은암에서도높은발현을보이기때문에구강암진단에서특이적표지자로서의가능성이낮을것으로예상된다. 그에반해 IL-1α 은많은암에서높은발현을보이지는않지만, 발현이확인된다면구강암에서강한악성표현형을나타내는특이적인표지자로서가능성이매우높을것으로예상된다. 따라서향후추가적인 Ⅱ. 결론사이토카인은종류가매우방대하고, 염증반응에서발현되는비특이적인표지자로서인식되어암진단표지자로서의가능성이배제되어있었다. 하지만, 암에서발현되는염증성사이토카인은암의진행과정에서염증의중요성을제시하였으며최근활발히진행되고있는염증과암관련성에대한연구에서도암에서발현되는사이토카인의신호전달이암세포와암미세환경의상호작용을촉진하여암세포의성장, 침윤, 이동에영향을줄것이라고제기되고있다. 이를토대로본연구에서는객관적인암표지자로서의염증성사이토카인의가능성을검토하였다. 이러한조사결과는향후발암과정에서염증성사이토카인연구에매우도움이될것으로생각한다. 또한, 본연구는향후사이토카인을이용한구강편평세포암종의조기진단및예후판정을위해서암진단표지자연구에유용한자료로활용될것이다. Ⅲ. 참고문헌 1. Coussens LM, Werb Z: Inflammation and cancer. Nature 2002;420: Multhoff G, Molls M, Radons J: Chronic inflammation in cancer development. Front Immunol 2011;2: Dranoff G: Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 2004;4: Grivennikov SI, Greten FR, Karin M: Immunity, inflammation, and cancer. Cell 2010;140: Punnonen R, Teisala K, Kuoppala T, Bennett B, Punnonen J: Cytokine production profiles in the peritoneal fluids of patients with malignant or benign 138

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract