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"

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

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.

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.