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medical news 분석 - 캘리포니아대학 연구자들이 암과 염증과의 사이에 분자적 연관 증명. 2004
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University of California, San Diego (UCSD) medical researchers are first to demonstrate molecular link between inflammation and cancer. (2004년도 cell지에 실린 문헌)
UCSD 연구자들이 암과 염증과의 사이에 분자적 연관 증명
* 염증과정에 포함된 유전자 불활성화하면 gastrointestinal 형태의 암을 가진 생쥐들에서 종양발생을 크게 감소시킬 수 있었다.
* I-kappa-B kinase (IKK beta)라는 전염증 유전자는 암을 일으키는 두가지 세포형에서 다르게 작용 한다.
* IKK beta 가 없으면 생쥐에서의 암 발생률과 종양성장이 거의 80% 까지 감소했다.
* NF-κB는 세균이나 바이러스 감염에 대한 반응으로 염증을 일으키는 마스터 스위치로 작용하는데, 이 NF-κB 활성을 위해서 IKK beta가 필요하다.
* 상피세포에서 NF-κB는 염증을 통해서가 아니라 apoptosis를 억제함으로써 암 발생을 촉진시킨다.
* Myeloid cells에서 NF-κB는 유전적으로 변형된 상피세포의 분열을 촉진하고 이로인해 종양 크기를 증가시키는 전염증성 분자를 발현시킨다.
* 염증재발과 만성감염이 많은 서로 다른 암들에 기여한다. 여기선 대장염 연관암 (CAC; colitis associated cancer) 으로 연구했는데, 대장염은 암의 위험이 높다.
* 이 연구에서 화학적 발암원들과 함께 작용하는 만성 염증으로부터 종양이 어떻게 발생하는지를 제시하였다.
* 만성감염에 대한 반응으로 면역세포와 장관 상피세포 사이에 상호작용이 있게 되고 이 결과 발암원에 의해 유전적 변형, 종양성장, apoptosis 억제가 초래된다.
* NF-κB는 종양생성과정 초기에 두가지 다른 방법으로 작용한다.
* 만성감염에 기인하는 암과 염증사이의 연관관계는 오랜 세월동안 기대는 되었지만 증명은 안되고 있었다.
* 염증과 암 연결의 증명 없이도 암 치료법들이 NF-κB를 억제하고 위장관암 위험을 감소시키는 화학예방제제로서 작용하는 NSAIDs(non-steroidal anti-inflammatory drugs)를 이용하도록 개발되어 있었다. 이러한 치료법들 중 일부가 부분적으로만 효과가 있었는데, 이는 치료에 의해 표적화된 정확한 분자적 경로가 알려져 있지 않았기 때문이다.
* NF-κB 연구시 쥐에게 두가지 화합물을 투여했다.
1. azomymethane (AOM) – procarcinogen으로 실험동물에게 보통 colorectal cancer 일으킴.
2. dextran sulfate sodium salt (DSS) – 장내세균이 상피세포로 들어가서 감염에 대한 싸움을 일으켜 염증이 생성되어 장관상피세포가 서서히 손상됨.
* 정상생쥐에서 이 두 화합물은 모두 염증을 일으켰고, 결과적으로 몇 달 후 adenocarcinoma가 생겼다.
* DSS와 AOM을 두그룹의 생쥐에게 투여했다.
1. 장 상피세포에서 IKK beta 없이 키운 생쥐
2. myeloid cell에서 IKK beta 없이 키운 생쥐. (myeloid cell은 염증을 유도해 감염과 싸우는 대식세포를 생성함으로써 면역에 중요한 역할을 함)
* IKK beta 없는 상피세포에 초점을 맞췄을 때
DSS는 NF-κB 활성 없이도 생쥐에게 염증 유도했다. 하지만 정상쥐와 비교해서 종양발생률은 80% 감소했다. IKK beta 없는 조직의 생화학적 분석을 통해 apoptosis가 암 발생 감소시켰다고 결론내리게 되었다.
* Apoptosis는 원치않는 세포의 성장을 막는 것으로 변이되거나 화학적으로 변형된 세포들을 죽이도록 몸이 이용하는 정상적인 과정으로, Apoptosis 회피는 암의 특징중 하나이다.
* UCSD 팀은 apoptosis가 IKK beta 없이 키운 쥐들에게서 증가했음을 발견했다.
특히 NF-κB 활성이 없으면 pro-apoptotic protein인 Bak와 Bax 가 증가하고 Bcl-xL는 감소했다.
* Myeloid cell들을 보면, IKK beta의 불활성은 염증과정에 기여하는 많은 유전자들의 발현을 감소시켰다.
* NF-κB 활성화가 안되면 DSS/AOM에 의한 종양발생은 50% 감소하고, 자란 종양도 두가지 화합물을 받은 정상적인 생쥐에서보다 사이즈가 현저하게 작았다.
BRM연구소의 평 :
염증이 암의 발생에 큰 영향을 미친다는 것은 이미 많이 알려져 왔다.
그러나 염증으로 부터 어떠한 기전을 통하여 암이 발생하는지에 대한 이해가 부족했다.
이 연구에 의하면 NF-κB가 염증관련 암에서 중심적인 역할을 하는 것 같다.
결국 NF-κB 경로를 차단하는 것이 암 예방과 치료에 있어 상당히 중요한 부분을 차지 할 것으로 고려되어야 할 듯 싶다.
UCSD researchers are first to demonstrate molecular link between inflammation and cancer
06 Aug 2004
First evidence of the molecular link between inflammation and cancer has been shown by researchers at the University of California, San Diego (UCSD) School of Medicine. Featured as the cover article in the August 6, 2004 issue of the journal Cell, the study also demonstrated that inactivation of a gene involved in the inflammatory process can dramatically reduce tumor development in mice with a gastrointestinal form of cancer.
The investigators found that a gene called I-kappa-B kinase (IKK beta), a pro-inflammatory gene, acts differently in two cell types to cause cancer. When IKK beta was deleted, the cancer incidence and tumor growth in mice was decreased by nearly 80 percent.
IKK beta is required for activation of a protein called nuclear factor kappa B (NF-kB), that acts as a master switch to turn on inflammation in response to bacterial or viral infections. In epithelial cells, NF-kB promotes the development of cancer not through inflammation, but through inhibition of a cell-killing process called apoptosis. In myeloid cells, NF-kB causes the __EXPRESSION__ of pro-inflammatory molecules that stimulate the division of genetically altered epithelial cells and thereby increase tumor size.
Because recurrent inflammation and chronic infections contribute to a large number of different cancers, the researchers chose one of these cancers – colitis associated cancer (CAC) – as their model for study. CAC occurs in people suffering from chronic colitis, which puts them at very high risk for cancer.
"We've shown how tumors arise from chronic infection and inflammation that act together with chemical carcinogens," said the study's senior author, Michael Karin, Ph.D., UCSD professor of pharmacology, American Cancer Society Research Professor, and a member of the Rebecca and John Moores UCSD Cancer Center.
"In response to chronic infection, the interplay between immune cells and the epithelial cells of the intestinal tract, which become genetically transformed to give rise to malignant cells by the carcinogen, results in increased tumor growth and suppression of apoptosis, whose role is to reduce cancer incidence," Karin added. "Our studies show how NF-kB acts very early in the carcinogenesis process, in two different ways."
The relationship between cancer and inflammation due to chronic infection has been suspected, but not proven, for many years. In a 1986 study, for example, one researcher compared the inflammatory response to a wound healing response, saying tumors were wounds that do not heal. Even without proof of the inflammation-cancer link, cancer therapies have been developed that utilize non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit NF-kB and other mediators of inflammation, and to act as chemo-preventive agents that reduce the risk of gastrointestinal cancers. Some of these therapies, however, have been only partially effective because the precise molecular pathway targeted by the treatment has not been known.
In their study of NF-kB, the researchers began by administering two compounds to mice. The first was a pro-carcinogen called azoxymethane (AOM), which is commonly used to induce colorectal cancer in experimental animals. The second compound was a pro-inflammatory irritant called dextran sulfate sodium salt (DSS), that eroded the intestinal-tract epithelial cells, allowing the entrance of enteric bacteria, with resulting inflammation generated by the body to fight the infection.
In normal mice, these two compounds trigger both inflammation and, a few months later, tumors called adenocarcinomas. In this study, DSS and AOM were given to two additional groups of mice – one group bred without IKK beta in the epithelial cells of the intestine; the second group without IKK beta in myeloid cells, which play an important role in the immune system by generating white blood cells called macrophages to induce inflammation and fight infection.
Focusing on the epithelial cells deficient in IKK beta, the researchers found that DSS induced inflammation in the mice, even without NF-kB activation. And yet, the incidence of tumor development decreased by 80 percent as compared to normal mice. Using biochemical analysis of the tissue without IKK beta, the scientists determined that stimulation of a process called apoptosis had decreased cancer development.
A form of cell suicide, apoptosis prevents the growth of unwanted cells. It is a normal process the body uses to kill mutated or chemically transformed cells, as well as useful cells that have outlived their purpose. Evading apoptosis is one of the hallmarks of cancer.
In their study, the UCSD team found that apoptosis was increased in mice bred without IKK beta. Specifically, without NF-kB activation, there was an increase of pro-apoptotic proteins Bak and Bax, and a decrease in a protein called Bcl-xL, known to inhibit apoptosis.
Turning their focus to myeloid cells, the team found that inactivation of IKK beta reduced the __EXPRESSION__ of many genes that contribute to the inflammatory process. When NF-kB was not activated, there was a 50 percent reduction in tumors caused by DSS/AOM. The tumors that grew were 75 percent smaller in size than those in the normal mice that had received the two compounds.
To understand how IKK beta in myeloid cells affects tumor development, the researchers first examined the affect of IKK beta deletion on apoptosis and found none. What they discovered, instead, was that IKK beta deletion in myeloid cells decreased the __EXPRESSION__ of pro-inflammatory molecules such as cyclooxygenase, also known as COX-2, and interleukins 1 and 6, which are expressed at sites of inflammation.
"Our findings establish for the first time the role of myeloid cells in inflammation-associated tumor promotion in addition to their role in tumor progression and invasiveness," the authors stated in the Cell paper.
The authors added that "in addition to identifying a key molecular mechanism connecting inflammation and cancer, our results suggest that specific pharmacological inhibition of IKK beta may be very effective in prevention of colitis associated cancer."
In addition to Karin, the study's authors were first author Florian R. Greten, M.D., UCSD Department of Pharmacology; and Lars Eckmann, M.D., UCSD Department of Medicine; Jin Mo Park, Ph.D., UCSD Department of Pharmacology; Zhi-Wei Li, Ph.D., UCSD Department of Pharmacology and the Moffit Cancer Center and Research Institute, Tampa, Florida; Laurence J. Egan, M.D., UCSD Department of Medicine and the Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota; and Martin F. Kagnoff, M.D., UCSD Department of Medicine.
The study was supported by grants from the National Institutes of Health, the Superfund Research Program, the Crohn's and Colitis Foundation of America, and the Deutsche Forschungsgemeinschaft.
Contact: Sue Pondrom
spondrom@ucsd.edu
619-543-6163
University of California - San Diego
Article URL: http://www.medicalnewstoday.com/medicalnews.php?newsid=11734
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