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1 REVIEW Intest Res 2011;9(2):90-96 소화기암의분자영상 울산대학교의과대학서울아산병원소화기내과학교실, 아산소화기병연구소, 충북대학교의과대학내과학교실 1 김정욱ㆍ윤순만 1 ㆍ명승재 Molecular Imaging of Gastrointestinal Malignancies Jong Wook Kim, M.D., Soon Man Yoon, M.D. 1, Seung-Jae Myung, M.D. Division of Gastroenterology, Asan Digestive Disease Research Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Department of Internal Medicine, Chungbuk National University College of Medicine 1, Cheongju, Korea Endoscopic detection of gastrointestinal cancer currently depends in large part on white light images, which show mucosal surface changes in real time. Molecular imaging is a rapidly growing new field in gastrointestinal endoscopy, which could provide additional information about molecular expression of cells and processes involved in cancer biology. It uses the molecular signature of cells for minimally-invasive, targeted imaging of gastrointestinal pathologies. Exogenous fluorescent agents serve as molecular beacons and include labeled peptides and antibodies, and probes with tumor-specific activation. An advantage of molecular imaging in digestive tract is the opportunity to apply such agents topically, overcoming the hurdles for delivery of these agents to the region of involvement, including immunogenic reaction and potential toxicity. Recently developed molecular targets include proteolytic enzymes, endothelial-specific markers, and apoptosis reporters. Molecular imaging has the potential to greatly impact on future endoscopy in gastroenterology. (Intest Res 2011;9:90-96) Key Words: Molecular Imaging; Gastrointestinal Neoplasms; Biomarkers 서 분자영상은최근급속히발전하고있는분야로서, 특히소화기영역에서내시경을통하여직접병변을관찰하여조기에병변을찾아내거나, 예후에관련된인자의발현을관찰하는데사용될수있을것으로기대되고있다. 형광을발하는제제를투여하여표지자로사용할수있으며, 여기에는종양에특이적인표지항체및펩티드, 종양에서특이적으로활성화를통해발현되는탐색자 (probe) 등이있다. 대부분의분자영 론 상기법은종양의조기발견을위해형광내시경및공초점현미경내시경 (confocal endomicroscopy) 을통해이루어지고있으며, 초기연구들을통해마우스대장종양발생및인간에서의조직모델을통해유망한효과가관찰된바있다. 분자영상은최근의종양치료에서개인의바이오마커발현에따른개별화된치료를결정하는데에도영향을줄수있을것으로기대되고있다. 내시경의기술적인발달에따라조기종양병변을찾는데색소내시경 (chromoendoscopy) 및가상색소내시경 (virtual chromoendoscopy), 고해상도내시경 접수 :2011년 7월 22일승인 :2011년 7월 26일 연락처 : 명승재, 서울시송파구올림픽로 43길 84 ( ) 울산대학교의과대학서울아산병원소화기내과학교실, 아산소화기병연구소 Tel: 02) , Fax: 02) sjmyung@amc.seoul.kr Received July 22, Accepted July 26, Correspondence to:seung-jae Myung, M.D., Division of Gastroenterology, Asan Digestive Disease Research Institute, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul , Korea Tel: , Fax: sjmyung@amc.seoul.kr 90

Jong Wook Kim, et al:molecular Imaging of Gastrointestinal Malignancies 등이이미사용되고있지만, 전체위장관내에서조기병변을놓치는경우도많다.

동물실험을통해얻어진지식들을토대로전임상및임상시험이진행되고있으며, 주로는형광물질을사용하여분자영상을취득함으로써, 조기병변의위험신호를증폭하는방법이사용되고있다. 이러한표지자물질의해당병변으로전달이문제가되는데, 이는물질의독성, 면역반응등의부작용이걸림돌로작용할수있기때문이다.

분자영상에사용되는바이오마커및표지자물질 1) 자가형광자가형광영상 (autofluorescence imaging) 은다른형 론 광영상과마찬가지로짧은파장의광원으로자극 (excitation) 을시켰을때, 더긴파장의빛이방출되는원리로, 종양조직의자가형광이 flavin adenosine dinucleotide, nicotinamide adenine

2) 유도형광유도형광 (induced fluorescence) 은자가형광에비해더강한신호를발한다. 외부로부터투여된표지자는주로질병-특이바이오마커를표적으로한다.

2 Jong Wook Kim, et al:molecular Imaging of Gastrointestinal Malignancies 등이이미사용되고있지만, 전체위장관내에서조기병변을놓치는경우도많다. 이러한방법들은주로조기병변에서발생하는형태학적인변화에기반을두고있으며, 따라서내시경검사의조기병변발견율을획기적으로높이기위해서는형태변화보다는세포수준의변화를실시간으로탐색하는방법이강구되고있다. 이와동시에인간에서도적용가능한방법이필요한상태이다. 동물실험을통해얻어진지식들을토대로전임상및임상시험이진행되고있으며, 주로는형광물질을사용하여분자영상을취득함으로써, 조기병변의위험신호를증폭하는방법이사용되고있다. 이러한표지자물질의해당병변으로전달이문제가되는데, 이는물질의독성, 면역반응등의부작용이걸림돌로작용할수있기때문이다. 이에반해소화기암에서는내시경등을통해표지자물질을국소적으로전달하는것이가능하기때문에, 다른분야에비해분자영상을적용하기용이한이점이있을것으로생각되며, 추후분자영상이차세대소화기내시경개발에큰영향을미칠것으로기대된다. 이번원고에서는최근소화기분야에서연구되고있는분자영상에대한내용과, 이의한계점, 추후필요한연구내용에대하여고찰해보고자하였다. 본 1. 분자영상에사용되는바이오마커및표지자물질 1) 자가형광자가형광영상 (autofluorescence imaging) 은다른형 론 광영상과마찬가지로짧은파장의광원으로자극 (excitation) 을시켰을때, 더긴파장의빛이방출되는원리로, 종양조직의자가형광이 flavin adenosine dinucleotide, nicotinamide adenine dinucleotide, porphyrin 등의대사의변화및혈색소양의변화, 콜라젠섬유교차결합의분해등으로인해정상조직의자가형광양상과다르다는점을사용하고있다. 1 이방법의이점은특별한외부로부터의표지자물질의주입이없이도영상의취득이가능하다는점이다. 그러나, 이러한양상은종양에서만특이한것이아니고, 위음성률이매우높기때문에잘사용되지않고있으며여기서는주로유도형광에관하여언급하기로한다. 2) 유도형광유도형광 (induced fluorescence) 은자가형광에비해더강한신호를발한다. 외부로부터투여된표지자는주로질병-특이바이오마커를표적으로한다. 2 이러한바이오마커에는 cathepsin, matrix metalloproteinase (MMP) 와같은단백분해효소 (protease), 3,4 혈관내피특이마커 5 및 apoptosis reporter 6,7 등이있다. 또한위장관상피조직이암으로진행함에따라서, 조기이형성에관여하는분자의변화 (p53 및 p16) 와, 후기이형성에관여하는변화 (loss of heterozygosity) 가다르다고알려져있는데, 8 이러한원리를이용하여바렛식도, 위축성위염, 궤양성대장염에서종양발생의위험도를계층화할수도있을것으로생각된다. 이러한바이오마커들을영상화할수있도록하는표지자에는항체, 펩티드, 나노입자및스마트활성화능프로브 (smart activatable probe) 가사용된다 (Fig. 1). 1 보통이 Fig. 1. Comparison of different molecular probe classes (From Goetz M and Wang T. Molecular imaging in gastrointestinal endoscopy. Gastroenterology 2010;138: ; with permission). 1 91

파장대의근적외선 (near-infrared) 영역에서반응을일으키는형광물질을이용하고있다.

epitope를표적으로하는항체에형광물질을결합시켜서분자형광영상을얻는방법은종양특이도가높아서 signal-to-background ratio가높다.

bevacizumab에근적외형광표지자를부착시킴으로써, 분자영상을얻음과동시에치료적인목적도기대해볼가능성도있을것으로생각된다.

Australia) 를사용하여, 형광표지자가부착된항 EGFR 항체를마우스에정주한후, 공초점현미경영 상을취득하였다.

분간배양한후영상을취득한결과, 종양조직의형광발현이정상또는염증에비해유의하게높음을보였다.

12 높은종양특이성을갖는펩티드를개발하는것은쉽지않지만, 최근 Wang 그룹에서는 13 in vivo phage display

3 Intest Res : Vol. 9, No. 2, 2011 러한표지자에형광물질을부착시켜서영상을얻게되는데, 형광물질들중활성후방출되는광선의파장이적외선에가까울수록생체투과율이높기때문에, 주로 nm 파장대의근적외선 (near-infrared) 영역에서반응을일으키는형광물질을이용하고있다. 3) 표적및표지자물질 Epidermal growth factor receptor (EGFR) 와같은대부분의소화기암에서발현되는 epitope를표적으로하는항체에형광물질을결합시켜서분자형광영상을얻는방법은종양특이도가높아서 signal-to-background ratio가높다. 9,10 또한, EGFR 억제제인 cetuximab이나 vascular endothelial growth factor (VEGF) 억제제인 bevacizumab에근적외형광표지자를부착시킴으로써, 분자영상을얻음과동시에치료적인목적도기대해볼가능성도있을것으로생각된다. Goetz 등 10 은공초점현미경내시경으로개발된 Fluorescence In Vivo Endomicroscopy (FIVE1, Optiscan, Notting Hill, Australia) 를사용하여, 형광표지자가부착된항 EGFR 항체를마우스에정주한후, 공초점현미경영 상을취득하였다. 그결과여러종양세포주에따른 EGFR 의발현정도를구분할수있었으며, 인간의조직을형광물질인 full name 표기 (FITC) 로표지된항 EGFR 항체에 30 분간배양한후영상을취득한결과, 종양조직의형광발현이정상또는염증에비해유의하게높음을보였다. 비슷한방법으로형광표지된항 VEGFR 항체를주입한후에형광영상을취득한결과, 11 VEGFR 이종양세포내에서주로세포질에분포하는것까지확인할수있었고, 인간종양조직에서도높은강도의형광을발하는것을보고하였다. 그러나, 이와같이항체를사용하는방법은항체의투여이후과민반응이있을수있고, 높은분자량때문에혈관내에서대상부위까지의전달이어려운단점이있다. 펩티드는이러한단점을극복할수있을것으로생각된다. 12 높은종양특이성을갖는펩티드를개발하는것은쉽지않지만, 최근 Wang 그룹에서는 13 in vivo phage display 방법을통해선종에잘부착할것으로생각되는펩티드를선별하였고, 여기에 FITC 를부착시킨후, 마우스내시경및공초점현미경을통해분석 Fig. 2. Histology and NIRF findings in BALB/c mice treated with AOM/DSS. AOM, azoxymethane; DSS, dextran sodium sulfate; IHC, immunohistochemical stain; MMP, matrix metalloproteinase; NIRF, near-infrared fluorescence; NP, nano-particle (From Yoon SM, Myung SJ, Ye BD, et al. Near-infrared fluorescence imaging using a protease-specific probe for the detection of colon tumors. Gut Liver 2010;4: ; with permission)

Jong Wook Kim, et al:molecular Imaging of Gastrointestinal Malignancies 한결과, 이펩티드가이형성 (dysplasia) 이있는부위에는부착하지만, 과형성 (hyperplasia) 부위에는부착하지않음을보였다.

4 Jong Wook Kim, et al:molecular Imaging of Gastrointestinal Malignancies 한결과, 이펩티드가이형성 (dysplasia) 이있는부위에는부착하지만, 과형성 (hyperplasia) 부위에는부착하지않음을보였다. 항체나펩티드를사용하는방법외에도, 동물또는세포실험에서양자점 (quantum dot) 이나금속나노입자 (metallic nanoparticle) 에더강력한형광단 (fluorophore) 을부착하여사용함으로써극미량의표적물질도영상화하고, 여러개의바이오마커에대한리간드 (ligand) 를부착할수도있지만, 인간에서는독성으로인해사용이제한되고있다. 위의표지물질은모두표적물질에대한직접적인부착에의한원리로영상을얻고있다. 이에반해, smart probe는평소에는 quencher에의해비활성화되어있다가, 종양에서과발현되는특정바이오마커에의해 quencher가떨어져나가면서활성화되는원리로작용하며, 이를통해 signal-to-background ratio가높은것으로알려져있다. 여기에는단백분해효소에의한활성화와, 14 종양세포내로흡수된후리소좀내의 ph의변화에의한활성화방법이있다. 15 이중단백분해효소는세포증식, 침윤, 세포자멸사, 혈관형성및전이에중요한역할을하는것으로알려져있으며, 소화기암의분자영상학적진단의중요한표적이다. 예를들면, cathepsin B는염증, 괴사, 혈관형성, 이형성및암에서상향조절되는것이보여졌다. 14 Weissleder 그룹 16 은소화기내시경분야에서는처음으로백색광과형광영상을동시에취득할수있는장치를장착한마이크로카테터를개발하였고, 마우스대장종양의분자영상을 cathepsin B activatable smart probe 정주후마이크로카테터를사용하여취득한결과, 매우높은 target-to-background ratio를보이는이미지를얻을수있었다. 17 이를통해, 백색광만을사용하였을때보다분자영상을추가하였을때더많은정보를얻을수있음을보였다. MMP 또한 Wnt 신호전달체계의표적으로여겨지고있다. 최근의한연구에서는 MMP-2, -3, -9, 및 -13 에의해활성화되는 MMPSense TM 680 (VisEn Medical Inc., Woburn, MA, USA) 를사용한분자영상을통해종양의악성도가심해짐에따라영상의신호세기도증가하며, 이를 MMP-9에대한면역화학염색을통해검증하였다 (Fig. 2). 18 저자등도 MMP에의해활성화되는 MMP-activatable probe를사용하여 azoxymethane을통해유발된대장선종및암의분자영상을취득하여발표한바있다. 19 현재까지분자 probe에대한약동학 / 약역학적및안전성검증을받은제제는없는실정이다. 그러나진단방사선및핵의학영역에서는방사능물질로표지된 probe 를사용하고있으며, 이와유사하게형광표지 probe 의사용프로토콜도개발이될것으로생각된다. 소화기암에서는내시경을통한국소적인표지자물질의적용이가능하며, 표지자와표적물질의결합이내시경시술동안확인가능할정도의시간인수분내에일어나야한다. 표적물질은위장관의관강쪽에발현되거나, 아니면표지자물질이표적물질쪽으로급속하게확산되어결합할수있어야한다. 2. 분자영상에사용되는장치 분자영상에사용되는장치는종양또는염증에서발견되는분자의변화를비침습적으로발견해낼수있어야하며, 또한기존의진단및치료내시경의형태에서크게벗어나지않으면서분자표지자를검출할정도의충분한민감도를지녀야한다. 소화기영역에는크게공초점현미경을내시경에적용한현미경내시경을사용하는방법과 wide-area endoscopy가있다. 1) 현미경내시경 (Endomicroscopy) 인간을대상으로하여처음개발된현미경내시경은기존내시경의선단부에소형화된스캐너를장착한것이었다 (EC-3870CIFK, Pentax, Tokyo, Japan). 스캐 Fig. 3. Endomicroscopy systems. The two types of presently available confocal endomicroscopy systems have different imaging options. (Top) In the confocal laser endomicroscope, the laser scanner is integrated into the endoscope. User adapted variable imaging plane depth yields serial en face optical sections through the mucosa at high resolution. (Bottom) The miniprobebased system is compatible with use through the working channel of most conventional endoscopes, however, offers lower resolution and a fixed imaging plane depth. Both systems yield sections parallel to the tissue surface (From Goetz M and Kiesslich R. Advanced imaging of the gastrointestinal tract: research vs. clinical tools? Curr Opin Gastroenterol 2009;25: ; with permission)

Intest Res : Vol. 9, No. 2, 2011 너는 488 nm 파장의활성화를통해서 205-585 nm 파장의방출을영상화할수있으며, 표면으로부터 250μm 까지 4μm 간격으로영상취득이가능하다 (Fig. 3). 20 그러나내시경선단부 4 cm에걸쳐서공초점현미경이위치하고있기때문에, 선단부가덜유연한단점이있다.

5 Intest Res : Vol. 9, No. 2, 2011 너는 488 nm 파장의활성화를통해서 nm 파장의방출을영상화할수있으며, 표면으로부터 250μm 까지 4μm 간격으로영상취득이가능하다 (Fig. 3). 20 그러나내시경선단부 4 cm에걸쳐서공초점현미경이위치하고있기때문에, 선단부가덜유연한단점이있다. 최근에는굴곡형공초점프로브가개발되어, 기존내시경의겸자공을통해삽입하여, 심지어는담도까지진입이가능한모델도개발되어있으며 (Cellvizio, Mauna Kea Technology, Paris), 이는고정된깊이의영상취득만이가능하다. 동물을대상으로한모델인 FIVE1 (Optiscan, Notting Hill, Australia) 도개발되어있으며, 마우스의장내에서병변에수직으로영상을취득해야하는단점을극복하기위해측시경형태의현미경내시경도개발되어있다 (Fig. 4). 21 2) Wide-area endoscopy Wide-area endoscopy는거시적으로 (mm-cm) 고해상 Fig. 4. In vivo side-view endomicroscopy. (Top) Schematic of a laser-scanning side-view endoscope. The raster-scanned beam in x and y dimensions is relayed by grade-index lenses in the probe and directed by a 90 o prism to a side-view window. ζ and φ represent the axial and circumferential coordinates, respectively, in the imaging plane. θ denotes the rotation angle of the probe, or the angle between x and φ axes. (Bottom) In the imaging setup, the laser beam emitted from the endoscope is projected to a stage. Dashed lines depict the outline of the beam diverging after going through the imaging plane. Inset, distal tip of the probe. (From Kim P, Chung E, Yamashita H, et al. In vivo wide-area cellular imaging by side-view endomicroscopy. Nat Methods 2010;7: ; with permission.) 21 도영상을넓은면적에서취득하여, 병변의위치를보다더빨리얻을수있는장점이있다 (Fig. 5). 22 이를통해고위험부위를기존의조직검사와같은방법을통해 ex vivo 에서의조직병리학적검사로종양을진단하게된다. 이와같은방법으로자가형광을이용하여바렛식도, 궤양성대장염, 대장내시경검사에서연구된것이있지만, 23,24 아직까지큰규모의연구는없는실정이다. 3. 소화기영역에서의분자영상을사용한임상시험 소화기영역에서는내시경을통한분자표지자의국소적인적용이가능하여정맥을통한전신적인투여보다는부작용에대한우려가매우적지만, 국소반응에대한위험은존재한다. 또한, 각표지자에따라점막을통한흡수율이다르고, 이에따른전신적인부작용이일어날가능성도있다. 따라서새로이개발된표지자를사용하여인간을대상으로한임상시험을시작하기전에는식품의약품안전청에반드시시험용신약신청 (investigational new drug application) 을하여야한다. 여기에는신청대상의약품에대한개발계획, 소개서, 연구계획서, chemistry manufacturing and control 자료, 약리및독성학자료등을제출하여야한다. 따라서인간을대상으로한임상시험은현재까지는많이부족한실정이지만, 현재까지수행되어알려진연구로는크게두개의연구가있다. Lu 와 Wang 25 은바렛식도가있는환자들에게 FITC 가부착된 target peptide 용액 3 ml 정도를내시경카테타를사용하여원위식도에도포한후 5 분정도가지난후물로세척한후형광영상을취득하였다. 이를통해얻어진형광영상을바탕으로조직검사를시행하였고, 고도이형성을증명하였다. Hsiung 등 12 은 VRPMPLQ 라는특정 heptapeptide sequence 를합성하여형광물질과결합시킨후대장내시경을시행받는환자들에게이를적용하여형광영상을취득하였다. 그결과형광물질이주변의정상대장점막보다선종의이형성을보이는세포에더잘부착되며, 민감도 81% 및특이도 82% 를보임을보고하였다. 4. 추후필요한연구내용 내시경을통한선별검사의효과를극대화하기위해서분자영상기법의도입이절실한상황이다. 추후이러한기법이도입되면바렛식도, 위의장피화생, 편 94

Targeted imaging of flat and depressed colonic neoplasms. Gastrointest Endosc Clin N Am 2010;20:579-583; with permission). 22 평 / 함몰성대장선종, 궤양성대장염, 악성및양성담도협착등의조기진단및감별진단에큰도움이될것으로기대된다.

6 Jong Wook Kim, et al:molecular Imaging of Gastrointestinal Malignancies Fig. 5. Targeted endoscopic imaging using wide-area endoscopy. (A) A 10 mm lesion (CIS, carcinoma-in-situ) is seen on white light endoscopy. (B) Targeted image using topical administration of fluorescent-labeled peptides reveals tumor margins. (From Wang T. Targeted imaging of flat and depressed colonic neoplasms. Gastrointest Endosc Clin N Am 2010;20: ; with permission). 22 평 / 함몰성대장선종, 궤양성대장염, 악성및양성담도협착등의조기진단및감별진단에큰도움이될것으로기대된다. 현재로서는분자영상마커의종양성질환에대한특이도가검증되는것이가장필요할것으로생각된다. 단순염증인경우에도혈액이울혈되어마커가국소적으로농축되면서분자영상신호강도가세지는경우가많아서, 이에대한보완이요구되는상태이다. 분자영상마커의형광신호의세기역시조기병변에서도충분한정도의민감도를보일만큼의강도를지닐필요도있다. 또한, 추후인체에대한연구를더진행하기위해서는외부로부터투여된마커의인체에대한독성및생역학적요소들에대한임상정보도필요하다. 추후분자영상이가능한내시경을개발하기위한연구들과세가지의영상기법이모두가능한장치의개발이필요할것으로생각된다. 첫째로고해상도백색광영상이가능해야하며, 이는넓은시야의영상, 위장관내에서의내시경의조작및치료술기를위해필수적이다. 둘째로는거시적으로형광영상이가능해야하는데, 이를통해분자적인색소내시경이가능해지고, 고위험병소를쉽게인식할수있게될것으로생각된다. 셋째로는공초점현미경영상을통해정확한부위에서의조직검사및궁극적으로는실시간으로조직학적진단이가능해질것으로기대된다. 결 소화기영역에서색소내시경을통한소화기암의조기진단이이루어질수있지만, 그사용이용이하지않고종양세포의기능적인측면을알수는없다는단점이있었다. 이에반해, 분자영상은종양세포의특성을분자수준에서실시간으로보여줄수있으며, 특히소화기종양의진단에서항암제에대한반응을판단할수있는잠재력을지니고있고, 종양의조직검사의표본추출의오류를줄일수도있을것으로생각된다. 현재인간을대상으로한초기임상연구들이시행되고있는실정이며, 추후새로운표지자물질의개발을통해더많은연구결과들이나올것으로기대된다. 론 REFERENCES 1. Goetz M, Wang TD. Molecular imaging in gastrointestinal endoscopy. Gastroenterology 2010;138: Pierce MC, Javier DJ, Richards-Kortum R. Optical contrast agents and imaging systems for detection and diagnosis of cancer. Int J Cancer 2008;123: Tung CH, Mahmood U, Bredow S, Weissleder R. In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. Cancer Res 2000;60: Bremer C, Bredow S, Mahmood U, Weissleder R, Tung CH. Optical imaging of matrix metalloproteinase-2 activity in tumors: feasibility study in a mouse model. Radiology 2001;221: Kang HW, Torres D, Wald L, Weissleder R, Bogdanov AA Jr. Targeted imaging of human endothelial-specific marker in a 95

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Jkbcs016(92-97).hwp

Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean