The 12th symposium

Speech

Special　Lecture1

“Epigenetic regulation underlying malignant phenotypes of NRF2-addicted cancers”
Hozumi Motohashi, IDAC, Tohoku University

While, a transcription factor NRF2 is transiently stabilized in response to oxidative stress and/or electrophilic stress, NRF2 is constitutively stabilized in many human cancer cells, driving their malignancy. Such cancer cells with persistent activation of NRF2 often fall in NRF2 addiction in terms of their proliferation, survival and therapeutic resistance. To obtain new therapeutic targets for such NRF2-addicted cancer cells, we explored NRF2 target genes unique to NRF2-addicted cancer cells. We found NRF2-dependent enhancer formation unique to NRF2-addicted cancer cells, which plays important roles in promoting malignant phenotypes. Intriguingly, constitutively stabilized NRF2 generates novel regulation of gene expression, which is distinct from that directed by transiently activated NRF2.

Special　Lecture2

“Control of Pancreatic Cancer as Viewed from a Pancreatic Carcinogenesis Model ⎯ via Control of the Cancer Microenvironment”
Hideaki Ijichi, Department of Clinical Nutrition Therapy, The University of Tokyo Hospital

The incidence of pancreatic cancer has been steadily increasing over the years, and this cancer currently ranks the fourth among all deaths from cancer in Japan. As for the prognosis of this disease, pancreatic cancer is overwhelmingly the most intractable malignancy as compared to other types of cancer, with an overall 5-year survival rate of as low as 8%-9%. Hence, elucidation of the pathophysiology of pancreatic cancer and development of appropriate therapy are critical challenges. We have established and reported a murine pancreatic carcinogenesis model by pancreatic epithelium-specific mutant Kras gene expression in combination with transforming growth factor-beta (TGF-β) II receptor knockout, and have demonstrated that the system accurately reproduces the clinical features of human pancreatic cancer. The murine model exhibits features of adenocarcinoma with stromal proliferation and pronounced fibrosis (desmoplasia), and dies from the cancer as early as at 8 weeks of age. One of the advantages of the genetically-engineered pancreatic carcinogenesis model is that the microenvironment of the cancer, including the immune systems, remains intact, unlike in the conventional transplant models. Particularly in cancer types that possess an abundance of stroma, such as pancreatic cancer, the microenvironment is considered to have a great impact on the pathophysiologic status of the cancer, underscoring the importance of evaluating the effects of therapeutic agents in vivo under the prevailing microenvironment.
We have been pursuing research, using the aforementioned murine model, from the viewpoint of seeking possible control of pancreatic cancer via control of the microenvironment. There is the possibility that inhibition of tumor-stroma interactions in such a cancer microenvironment may contribute to improvement of the prognosis of pancreatic cancer. Furthermore, heterogeneity of the microenvironment of pancreatic cancer has recently drawn attention, and a better understanding of this aspect may lead to the development of effective therapies for pancreatic cancer. I would like to state my view on the control of pancreatic cancer from the perspective of regulating the microenvironment in the murine pancreatic carcinogenesis model.