シンポジウム 8

Patient-derived xenograft models for astrategy to develop drugs targeting cancer
cells and microenvironment interaction

Yohei Miyagi
Molecular Pathology and Genetics Division
Kanagawa Cancer Center Research Institute

Clinical cancer tissue consists of cancer cells and surrounding microenvironment, which[References]includes stromal cells such as fibroblasts and smooth muscle cells, immune/inflammatory cells,

1.

extracellular matrices, nerves or vessels. Although it is gathering attention that cancer cells
are genetically or epigenetically heterogeneous, microenvironment is also highly heterogeneous

under Normoxia and Hypoxia. Int J Mol Sci 17(9). pii: E1430, 2016.
2.

Miyagi Y, Nakamura M. Establishment of patient-derived cancer xenografts in immunodeficient NOG

supplies. Heterogeneity of microenvironment can also change time to time even in short periods.
by hypoxia and deprivation of nutrients, especially lipids, and the change impacts on cancer cell
survival, motility or invasiveness1.

Chijiwa T, Kawai K, Noguchi A, Sato H, Hayashi A, Cho H, Shiozawa M, Kishida T, Morinaga S,Yokose T, Katayama M, Takenaka N, Suemizu H, Yamada R, Nakamura Y, Ohtsu T, Takano Y, Imai K,

from the aspects of not only its composing cells or matrices but also oxygen and nutrient
Previously we reported that expression of some genes in cancer cells is synergistically enhanced

Koizume S, Miyagi Y. Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival

mice. Int J Oncol 47(1):61-70, 2015.
3.

Komura D, Isagawa T, Kishi K, Suzuki R, Sato R, Tanaka M, Katoh H, Yamamoto S, Tatsuno K,Fukayama M, Aburatani H, Ishikawa S. CASTIN: a system for comprehensive analysis of cancerstromal interactome. BMC Genomics 17(1):899, 2016.

Despite significant efforts are payed on development of anticancer therapeutics, most ofthem are result in fail and only 5% of anticancer drug-candidates are now evaluated for clinicaluse. Good preclinical cancer models to be used for precise evaluation of the efficacy are eagerly
needed for developing anticancer drugs or treatment modalities and also for personalized cancer
treatment. Many preclinical human cancer models are available including immortalized cancer
cell lines, cancer cell organoids/spheroids, or patient-derived xenograft (PDX) with merits anddemerits in each model. PDX may have some advantages to study cancer microenvironment.
Although organoids/spheroids can be used for a source of PDX, differences in cancer cells andmicroenvironment between original PDX and organoids/spheroids-derived PDX are not yet
clearly addressed.
Pancreatic ductal carcinomas are known as interstitium-rich tumor and themicroenvironment is revealed to play pivotal roles in the initial carcinogenesis, progression oracquisition of treatment resistance. We are attempting to develop anticancer drugs or novel
treatment modalities targeting pancreatic cancer—microenvironment interaction by using PDX
2in immunodeficient mice . When we decipher the interaction between pancreatic cancer cells
and their surrounding microenvironment, the PDX consisting of human cancer cells and mice
microenvironment is a good material because of its availability to differentially evaluate gene
expression between the two by NGS. Komura et al. has reported this technology as the CASTIN
system3. I would like to preset some our progress in this attempt.

30

Yohei Miyagi, MD, PhD
Director, Kanagawa Cancer Center Research Institute ／ Biospecimen Center
1986
1992
1990
1994
1996
2000
2012
2018

Yokohama City University (YCU) School of Medicine, MD
PhD, Instructor, Department of Pathology, YCU Post Graduate School of medicine
Research Resident, Biophysics Division, National Cancer Center Research InstitutePost-doctral fellow, Dept. Immunol. Hematol., The Scripps Research Institute, San Diego
Associate Professor, Department of Pathology, YCU Post Graduate School of medicine
Staff Scientist, Kanagawa Cancer Center Research InstituteChief, Div. Molecular Pathol. & Genetics, Kanagawa Cancer Center Research InstituteDirector, Kanagawa Cancer Center Research Institute31