2018年比較腫瘍学常陸宮賞受賞者
The Awardee of the 2018 Prince Hitachi Prize for Comparative Oncology

"Elucidation of the mechanism of spontaneous regression of neuroblastoma and discovery of human de novo evolved gene product N-CYM"
神経芽腫の自然退縮の機序解明とヒト新規進化遺伝子産物N-CYMの発見

Akira Nakagawara
Chief Executive Officer (CEO),
Saga-ken Medical Center KOSEIKAN (Local Independent administrative Agency)(Until March, 2018) CEO, Saga-HIMAT Foundation

中川原 章 博士
(公財)佐賀国際重粒子線がん治療財団 理事長

略歴

中川原章博士は、1947年に佐賀県鳥栖市に生まれ、1966年九州大学医学部へ入学した。6年生の時、後に恩師となる池田恵一講師の臨床講義で、1歳未満の乳児に発生し、肝、骨髄、皮膚に転移していても自然に治癒する神経芽腫の存在を知り、この機構解明をライフワークに決めた。1972年、九州大学第2外科に入局し小児外科を専攻したが、当時は研究の具体的方法論がなかったため、1973年から4年間九州大学大学院(生化学)に進学、その後、1980年に米国ロックフェラー大学に留学し、Zanvil Cohn教授の研究室で免疫学を学んだ。1981年に帰国後は、九州大学病院において小児外科臨床をしながら小児がんの組織バンクを確立し、神経芽腫におけるMYCNがん遺伝子増幅の臨床的意義を追究した。その研究から、自然退縮も遺伝子レベルでのプログラム細胞死ではないかと考え、2度目の留学を決意した。
1990年、Rita Levi-Montalcini女史が神経成長因子(NGF)を発見しノーベル賞を受賞した米国ワシントン大学に留学し、Garrett Brodeur教授と共に、NGFの高親和性受容体であるTrkAが神経芽腫自然退縮の鍵を握る遺伝子であることを発見した。この時、中川原博士は、神経芽腫自然退縮の機構に関する独自の仮説を立てた。また、当時始まっていたヒトゲノムプロジェクトの実験手技を習得した。1993年、フィラデルフィア小児病院に移動し、そこで、神経芽腫の自然治癒研究の第一人者であるDr. Audrey Evans、 Dr. Dan D’Angioと合流し、Two-hit Theoryを提唱したDr. Alfred Knudsonと交流したことが、その後の研究人生に大きな影響を与えた。
1995年8月、千葉県がんセンター研究所生化学研究部長に着任し、2014年3月に同センター長を退官するまでの18年半の間、中川原博士は自らの仮説を証明するため、先ず全国の小児がん治療施設とのネットワークを作り、全国規模の神経芽腫組織バンクと遺伝子診断体制を構築した。また、その検体を用いて、発現遺伝子やゲノムの網羅的解析、MYCNやp53ファミリーを中心とする重要遺伝子の解析等を行い、神経芽腫自然退縮の分子機構を明らかにすると共に、de novo evolved gene productであるN-CYMを発見した。しかし、常に、今いる患者のために臨床応用を心掛けることを忘れなかった。
博士の業績に対し、2000年にAudrey Evans賞、2008年に第37回高松宮妃癌研究基金学術賞、2013年に日本対がん協会賞が贈られた。
2014年、184年の歴史を持つ故郷の佐賀県医療センター好生館理事長に就任し、鳥栖市にできた佐賀国際重粒子線がん治療財団理事長を兼務している。

Personal History Outline

Dr. Akira Nakagawara was born in Tosu, Saga, in 1947 and entered Kyushu University School of Medicine in 1966. At a clinical lecture given by Dr. Keiichi Ikeda, who would later be his mentor, he was surprised to hear for the first time that a baby who suffered from neuroblastoma (NB) with metastases to its liver, bone marrow and skin might be cured spontaneously. He thus decided to choose elucidation of the molecular mechanism as his life work. In 1972, he entered the Second Department of Surgery, Kyushu University, and took pediatric surgery as his specialty. Since there was no way to do research on NB regression at that time, he took the PhD course of Biochemistry at Kyushu University from 1973 to 1977 and then learned immunology in the laboratory of Prof. Zanvil Cohn, at Rockefeller University, U.S.A. In 1981, after coming back to Japan, he started to collect NB tissue samples removed by surgery, and to analyze a clinical significance of MYCN amplification in NBs. The results he obtained suggested that spontaneous regression of NB might be a genetically regulated programmed cell death, and that encouraged him to decide to go to the U.S.A again.
In 1990, Dr. Nakagawara joined the laboratory of Prof. Garrett Brodeur at Washington University, St. Louis, where Prof. Rita Levi-Montalcini had discovered NGF and won the Nobel Prize. He discovered that TrkA, a high-affinity receptor of NGF, was a key molecule regulating spontaneous regression of NB, and made his own hypothesis regarding it. He also learned new technologies of the human genome project. In 1993, he moved to the Children’s Hospital of Philadelphia where he met with both Dr. Audrey Evans and Dr. Dan D’Angio who had first proposed the presence of NBs with spontaneous regression as well as Dr. Alfred Knudson who had proposed the “Two-hit Theory”, getting an enormous influence on his later research life.
In August, 1995, Dr. Nakagawara was appointed to be the head of Laboratory of Biochemistry at Chiba Cancer Center Research Institute where he worked for the following 18 years and a half to prove his hypothesis on NB. He at first established a nation-wide NB tissue bank as well as a genetic diagnosis system. Utilizing those clinical materials, he did comprehensive analyses of gene expressions and genomes of human NBs in addition to the analyses of important genes including MYCN and p53 families. He finally elucidated the molecular mechanism of spontaneous regression of NB and discovered N-CYM, a de novo evolved gene product. Importantly however, he has never forgot to try to apply his works to patients who were struggling against the cancer.
For those excellent achievements, Dr. Nakagawara was given the Audrey Evans Prize in 2000, the Princess Takamatsu Cancer Research Fund Award in 2008 and the Japan Cancer Association Prize in 2013.
In 2014, he was appointed to be the CEO of Saga-ken Medical Center KOSEIKAN which has a history of 184 years and is located at his home region. He also concurrently holds the position of the CEO of the SAGA HIMAT Foundation located at Tosu in Saga.

研究業績

神経芽腫は様々な動物に発生するが、転移していても自然治癒する神経芽腫は、ヒト乳児にのみに見られ特異的なもので、動物モデルも存在しない。そこで、中川原博士は、恩師池田恵一教授の「患者が教えてくれる」という言葉を肝に銘じ、自然治癒する乳幼児の神経芽腫と1歳以上で発症する悲惨な予後を辿る神経芽腫との比較研究を行った。MYCNがん遺伝子と臨床像の解析を行ったところ、MYCN遺伝子増幅と予後の悪さが見事に一致したため、自然退縮の機序はMYCN遺伝子増幅の対極にあると考えた。1990年、米国ワシントン大学に二度目の留学をした博士は、nerve growth factor (NGF) の高親和性受容体遺伝子であるTrkAが、神経芽腫自然退縮の鍵を握る遺伝子であることを発見し、消退する腫瘍細胞は、がんでありながらNGFに生存を依存していることを初めて明らかにした(1992, 1993)。そこで、博士は、正常な交感神経細胞の発生過程で起こるプログラムされた分化と細胞死が、がんである神経芽腫においても記憶されており、生存を微小環境に依存する発生のプログラムが神経芽腫の自然退縮を誘導するという仮説を立てた。 
1995年に帰国後、中川原博士は千葉県がんセンター研究所においてこの仮説を証明するための研究を行い、神経芽腫自然退縮の分子生物学的機序について、以下のことを明らかにした。

  1. 神経芽腫発がんの標的経路は、発生母地を同じくする褐色細胞腫と同様、NGF/TrkAシグナル伝達経路であり、MYCN増幅やALK変異で分化・生存が抑制されている(1993, 2013)。
  2. TrkA依存性受容体の下流で機能する第二の新規依存性受容体遺伝子UNC5Dを発見した(2013)。
  3. 退縮する神経芽腫組織において、NGFの相対的欠乏がTrkA受容体依存性にプログラム細胞死(PCD)を誘導し、BMCC1, KIF1Bb, UNC5D, E2F1, p53, p63が発現誘導され、さらに、UNC5D/E2F1/ p53/ p63がpositive feedback loopを形成して、PCDが不可逆的に進行する仕組みを明らかにした(2013)。
  4. 一方、神経芽腫の悪性化機構の主体はMYCN(N-MYC)であるが、MYCN蛋白質の安定化はGSK3bとLIN28B/let-7/AURKAの経路で制御されている。中川原博士らは、MYCNのcis-antisense geneであるNCYMが蛋白質N-CYMをコードし、ヒトとチンパンジーでのみ機能的蛋白質となっているde novo evolved geneであることを、ヒトがんで初めて発見した(2014)。NCYMとMYCNは同じ遺伝子座にあるため、ヒト神経芽腫では常に共発現・共増幅している。N-CYMはGSK3bの抑制を介してN-MYCを安定化し、腫瘍の悪性化と転移を促進している。N-CYMはさらに、リプログラミング因子を誘導して神経芽腫がん幹細胞性の制御に関与すると共に、非対称分裂を誘導する。
  5. 神経芽腫の自然退縮誘導機構と悪性化の分子機構の間を結ぶスイッチとして、p63が機能していることを見出した。事実、p53 familyの中で、p63のみが自然退縮する腫瘍で発現が高く、予後不良の腫瘍で発現が抑制されていた。

Academic Achievement

Neuroblastoma (NB) develops in various animal species. However, NB which regresses spontaneously even with distant metastases is specifically observed in human infants and has never been reported in any other species. Impressed by the words of his mentor, Prof. Keiichi Ikeda, that “The patient teaches the doctor.”, Dr. Nakagawara decided to devote his life to exploring the mystery of spontaneous regression in neuroblastoma, and started with clinical investigations. When he compared infant patients with patients of over one year of age whose tumors were very aggressive, he found that MYCN amplification exactly matched the poor clinical course of the patients, thus giving him an idea that the mechanism of spontaneous regression might be different from that of MYCN amplification in NB. To further explore this idea, he went to U.S.A. again in 1990. At Washington University in St. Louis, he discovered that TrkA, a high-affinity receptor of nerve growth factor (NGF), was a key molecule in understanding the spontaneous regression of NB and that regressing tumor cells were dependent on NGF for their survival (1992, 1993). Based on these observations, he proposed a novel hypothesis that the programmed differentiation and cell death of developing sympathetic neurons which NB derives from are still memorized in the tumor cells and that the tumor microenvironment, which is also regulated developmentally, may control induction of the spontaneous regression of NB.
After returning back to Japan in 1995, Dr. Nakagawara continued to work to prove his hypothesis at the Chiba Cancer Center Research Institute. His group unveiled the molecular and genetic mechanisms of the spontaneous regression of NB as follows.

  1. Similar to pheochromocytoma, the NGF/TrkA signaling pathway is targeted in NB which originates from the same sympathetic neurons as pheochromocytoma, and is inhibited by MYCN amplification and ALK mutations (1993, 2013).
  2. His group has identified a novel UNC5D as the second dependence receptor functioning downstream of the TrkA receptor to transduce NGF-mediated survival signal (2013).
  3. In regressing NB tissue, the relative deficiency of NGF induces programmed cell death (PCD) through the TrkA dependence receptor. During that process, expressions of BMCC1, KIF1Bβ, UNC5D, E2F1, p53 and p63 as well as the UNC5D/E2F1/p53/p63 positive feedback loop are induced to cause the tumor cells death (2013).
  4. The protein stability of the master molecule MYCN (N-MYC) is regulated by GSK3β and LIN28B/let-7/AURKA pathways in NB. Dr. Nakagawara’s group has discovered that NCYM, a cis-antisense gene of MYCN, is a de novo evolved gene whose protein product is functional only in humans and chimpanzees (2014). Actually, N-CYM is the first de novo evolved gene product found in human cancer. Because both NCYM and MYCN are transcribed at the same genomic locus, they are always co-amplified and co-expressed at similar levels in NB. In addition, his group has revealed that N-CYM stabilizes N-MYC through inhibiting GSK3β, leading to human NB more aggressive and metastatic. N-CYM is also involved in regulating stemness of NB by inducing some reprograming factors and in induction of asymmetric division of NB cells.
  5. His group has finally discovered that p63 is a key molecule switching between the molecular machinery of the spontaneous regression and aggressiveness in NB. Indeed, only p63 among the p53 family members is expressed at significantly higher levels in favorable NBs with a tendency to regress than in unfavorable NBs.