Aging and Carcinogenesis

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Members

Theme Leader :
Toshiyuki Ishiwata, M.D., Ph.D.
Researcher :
Keisuke Nonaka, M.D., Ph.D., Yuuki Shichi, DVM., Ph.D.
Adjunct Researcher :
Seiichi Shinji, M.D., Ph.D., Fumio Hasegawa, Yasuko Hasegawa

Keywords

Aging, Cellular Senescence, Elderly Cancer, Pancreatic Cancer, Telomeres, Adrenal Gland, Cancer Stem Cells, Cancer Diversity, Epithelial-Mesenchymal Transition, Long Non-coding RNA, Anticancer Drug Resistance, Cancer Metastasis, Colon Cancer, Growth Factor Receptors, Pathology

Major Research Titles

Pancreatic Cancer Research:

  1. Development of senolytic therapy for pancreatic cancer
  2. Discovery of cancer stem cell-specific molecules
  3. Research on the diversity of pancreatic cancer
  4. Elucidation of the metastasis mechanism

Study of telomere length:

  1. Study of aging, stress, and adrenal telomere length
  2. Relationship between dementia, smoking and telomere length of nerve cells

Surgical pathological research:

  1. Clinicopathological research on pancreatic cancer, colorectal cancer, etc.

Profile

This group is conducting research on cancer in the elderly, mainly pancreatic cancer, and research on telomeres that shorten with age. Regarding the research on pancreatic cancer, we are doing (1) research on the differences in cancer cells among patients, (2) cancer stem cells, which are cells that play a central role in cancer recurrence and metastasis and prove to be difficult in eliciting a response to therapy, and (3) senolytic therapy for pancreatic cancer. In addition, by advancing the adrenal telomere research, which is attracting the attention of several researchers in relation to aging, we aim to clarify the relationship between aging, lifestyle, stress, and telomere length, and to extend the healthy life expectancy.

References

  1. Nakano T, Okita K, Okazaki S, Yoshimoto S, Masuko S, Yagi H, Kato K, Tomioka Y, Imai K, Hamada Y, Masuko K, Shimada-Takaura K, Nagai N, Saya H, Arai T, Ishiwata T, Masuko T. CD44v, S1PR1, HER3, MET and cancer-associated amino acid transporters are promising targets for the pancreatic cancers characterized using mAb. FEBS Open Bio. 2025 Jan 5.
  2. Shinji S, Ogawa Y, Yamada T, Matsuda A, Uehara K, Yokoyama Y, Takahashi G, Iwai T, Miyasaka T, Kanaka S, Hayashi K, Shichi Y, Fujiwara M, Takahashi K, Arai T, Ishiwata T, Yoshida H. Morphological and functional analysis of colorectal cancer cell lines in 2D and 3D culture models. Sci Rep. 2025 Jan 24;15(1):3047.
  3. Shichi Y, Fujiwara M, Gomi F, Nonaka K, Hasegawa F, Shinji S, Rokutan H, Arai T, Takahashi K, Ishiwata T. Transmission electron microscopic analysis of pancreatic ductal adenocarcinoma cell spheres formed in 3D cultures. 2025 Apr 4.
  4. Nagashima T, Ochiai K, Takizawa Y, Koike Y, Saito T, Muramatsu A, Azakami D, Machida Y, Bonkobara M, Ishiwata T, Michishita M. Antitumor Effect of mTOR1/2 Dual Inhibitor AZD8055 in Canine Pulmonary Carcinoma. Cancers (Basel). 2025 Jun 14;17(12):1991.
  5. Nonaka K, Arakawa A, Hara M, Komatsu A, Nagasaka T, Kumasaka T, Kamino S, Rokutan H, Shichi Y, Murayama S, Kanemaru K, Jubishi C, Futami S, Ishiwata T, Saito Y, Arai T, Harada K, Ishikawa J. An autopsy case of myotonic dystrophy type 1 with　pancreatic intraductal papillary mucinous neoplasm. Cureus. 2024 Sep 26; 16(9): e70225.
  6. Nonaka K, Aida J, Hasegawa Y, Arai T, Ishiwata T, Takubo K. Telomere length measurement in human tissue sections by quantitative fluorescence in situ hybridization (Q-FISH). Methods Mol Biol. 2025:2857:9-14.
  7. Shichi Y, Gomi F, Hasegawa Y, Nonaka K, Shinji S, Takahashi K, Ishiwata T. Artificial intelligence-based analysis of time-lapse images of sphere formation and process of plate adhesion and spread of pancreatic cancer cells. Front Cell Dev Biol. 2023 Nov 17;11:1290753.
  8. Nonaka K, Takubo K, Aida J, Watai Y, Komatsu A, Gomi F, Shichi Y, Yamazaki Y, Ishiwata T, Sasano H, Arai T. Accelerated telomere shortening in adrenal zona reticularis in patients with prolonged critical illness. Front Endocrinol (Lausanne). 2023 Sep 4;14:1244553.
  9. Doshida Y, Hashimoto S, Iwabuchi S, Takino Y, Ishiwata T, Aigaki T, Ishigami A. Single-cell RNA sequencing to detect age-associated genes that identify senescent cells in the liver of aged mice. Sci Rep. 2023 Aug 30;13(1):14186.
  10. Arai T, Komatsu A, Kanazawa N, Nonaka K, Ishiwata T. Clinicopathological and　molecular characteristics of gastric papillary adenocarcinoma. Pathol Int. 2023　Aug;73(8):358-366.
  11. Takubo K, Aida J, Vieth M, Fujiwara M, Nemoto T, Arai T, Mukaisho KI, Nakazawa A, Ishiwata T. Cardiac mucosa in neonates. Pathol Res Pract. 2023 Jun;246:154498. doi: 10.1016/j.prp.2023.154498. Epub 2023 May 11.
  12. Itakura Y, Hasegawa Y, Kikkawa Y, Murakami Y, Sugiura K, Nagai-Okatani C, Sasaki N, Umemura M, Takahashi Y, Kimura T, Kuno A, Ishiwata T, Toyoda M. Spatiotemporal changes of tissue glycans depending on localization in cardiac aging. Regen Ther. 2023 Jan 7;22:68-78.
  13. Nonaka K, Kurata M, Tachibana M, Komatsu A, Shichi Y, Gomi F, Ishiwata T, Miyamoto K, Arai T. Chromosomal analysis of clonally related B-cell lymphomas with discordant immunoglobulin light-chain restrictions at different anatomical sites. Pathol Int. 2023 Feb;73(2):100-102.
  14. Michishita M, Ochiai K, Nakahira R, Azakami D, Machida Y, Nagashima T, Nakagawa T, Ishiwata T. mTOR pathway as a potential therapeutic target for cancer stem cells in canine mammary carcinoma. Front Oncol. 2023 Jan 27;13:1100602.
  15. Shichi Y, Gomi F, Ueda Y, Nonaka K, Hasegawa F, Hasegawa Y, Hinata N, Yoshimura H, Yamamoto M, Takahashi K, Arai T, Ishiwata T. Multiple cystic sphere formation from PK-8 cells in three-dimensional culture. Biochem Biophys Rep. 2022 Sep 7;32:101339.
  16. Ueda Y, Miura Y, Tomishige N, Sugimoto N, Murase M, Kawamura G, Sasaki N, Ishiwata T, Ozawa T. Mechanistic insights into cancer drug resistance through optogenetic PI3K signaling hyperactivation. Cell Chem Biol. 2022 Nov 17;29(11):1576-1587.e5.
  17. Sasaki N, Hirano K, Shichi Y, Itakura Y, Ishiwata T, Toyoda M. PRC2-dependent regulation of ganglioside expression during dedifferentiation contributes to the proliferation and migration of vascular smooth muscle cells. Front Cell Dev Biol. 2022 Oct 13;10:1003349.
  18. Shinji S, Shichi Y, Yamada T, Takahashi G, Ohta R, Sonoda H, Matsuda A, Yonaga K, Iwai T, Takeda K, Ueda K, Kuriyama S, Miyasaka T, Ueda Y, Sasaki N, Takahashi K, Ohashi R, Ishiwata T, Arai T, Yoshida H. A New Anorectal melanoma cell line derived from a primary human rectal tumor. J Nippon Med Sch. 2022 Aug 27;89(4):368-376.
  19. Miki A, Matsuda Y, Aida J, Watanabe J, Sanada Y, Sakuma Y, Lefor AK, Fukushima N, Sata N, Arai T, Takubo K, Ishiwata T. Telomere attrition in intraductal papillary mucinous neoplasms of the pancreas associated with carcinogenesis and aging. Pancreas. 2022 Jul 1;51(6):678-683.
  20. Ueda Y, Abe M, Ishiwata T, Ozawa T. Sphingomyelin localization in the intestinal crypt surface. Biochem Biophys Res Commun. 2022 Jun 30;611:14-18.
  21. Shichi Y, Gomi F, Sasaki N, Nonaka K, Arai T, Ishiwata T. Epithelial and mesenchymal features of pancreatic ductal adenocarcinoma cell lines in two- and three-dimensional cultures. J Pers Med. 2022 May 4;12(5):746.
  22. Sasaki N, Hirano K, Shichi Y, Gomi F, Yoshimura H, Matsushita A, Toyoda M, Ishiwata T. Gp130-mediated STAT3 activation contributes to the aggressiveness of pancreatic cancer through H19 long non-coding RNA expression. Cancers (Basel). 2022 Apr 19;14(9):2055.
  23. Sasaki N, Shinji S, Shichi Y, Ishiwata T, Arai T, Yamada T, Takahashi G, Ohta R, Sonoda H, Matsuda A, Iwai T, Takeda K, Yonaga K, Ueda K, Kuriyama Sho, Miyasaka T, Yoshida H. TGF-β1 increases cellular invasion of colorectal neuroendocrine carcinoma cell line through partial epithelial-mesenchymal transition. Biochemistry and Biophysics Reports. 2022 Mar 1; 30: 101239.
  24. Shinji S, Shichi Y, Yamada T, Takahashi G, Ohta R, Sonoda H, Matsuda A, Yonaga K, Iwai T, Takeda K, Ueda K, Kuriyama S, Miyasaka T, Ueda Y, Sasaki N, Takahashi K, Ohashi R, Ishiwata T, Arai T, Yoshida H. Establishment and characterization of a novel anorectal melanoma cell line derived from primary human rectal tumor. J Nippon Med Sch. 2022 Jan 25.
  25. Aida J, Takubo K, Vieth M, Neuhaus H, Fujiwara M, Arai T, Ishiwata T. Telomere lengths in Barrett's esophagus as a precancerous lesion. Esophagus. 2021 Sep 24.
  26. Yoshimura H, Moriya M, Yoshida A, Yamamoto M, Machida Y, Ochiai K, Michishita M, Nakagawa T, Matsuda Y, Takahashi K, Kamiya S, Ishiwata T. Involvement of Nestin in the Progression of Canine Mammary Carcinoma. Vet Pathol. 2021 May 31;3009858211018656.
  27. Sasaki N, Toyoda M, Ishiwata T. Gangliosides as signal regulators in cancer. International Journal of Molecular Sciences, 2021, 22 (10), 5076.
  28. Minami F, Sasaki N, Shichi Y, Gomi F, Michishita M, Ohkusu-Tsukada K, Toyoda M, Takahashi K, Ishiwata T.　 Morphofunctional analysis of human pancreatic cancer cell lines in 2- and 3-dimensional cultures. Sci Rep. 2021 Mar 24;11(1):6775.
  29. Gomi F, Sasaki N, Shichi Y, Minami F, Shinji S, Toyoda M, Ishiwata T. Polyvinyl alcohol increased growth, migration, invasion, and sphere size in the PK-8 pancreatic ductal adenocarcinoma cell line. Heliyon. 2021 Feb 4;7(2):e06182.
  30. Wang T, Matsuda Y, Nonaka K, Kakizaki M, Ishiwata T, Kanazawa N, Uegaki S,Muramatsu M, Sawabe M, Mori S, Tanaka M, Kitagawa M, Arai T. Clinicopathological characteristics of gastric cancer with carbohydrate antigen 19-9 expressionoccurring in elderly individuals: An autopsy study. Pathol Int. 2020Feb;70(2):92-100.
  31. Sasaki N, Gomi F, Hasegawa F, Hirano K, Fujiwara M, Toyoda M, Ishiwata T.Characterization of the metastatic potential of the floating cell component of MIA PaCa-2, a human pancreatic cancer cell line. Biochem Biophys Res Commun. 2020 Feb 19;522(4):881-888.
  32. Aida J, Yokoyama A, Hara S, Ishizaki T, Fujiwara M, Arai T, Ishiwata T, Takubo K. Telomere shortening in the oral epithelium in relation to alcohol intake,alcohol dehydrogenase (ADH-1B), and acetaldehyde dehydrogenase (ALDH-2) genotypes　and clinicopathologic features. J Oral Pathol Med. 2020 Jan;49(1):82-90.
  33. Sasaki N, Gomi F, Yoshimura H, Yamamoto M, Matsuda Y, Michishita M, Hatakeyama H, Kawano Y, Toyoda M, Korc M, Ishiwata T. FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer. Cancers (Basel). 2020 Oct 14;12(10):2976.
  34. Sasaki N, Hirabayashi K, Michishita M, Takahashi K, Hasegawa F, Gomi F,Itakura Y, Nakamura N, Toyoda M, Ishiwata T. Ganglioside GM2, highly expressed in the MIA PaCa-2 pancreatic ductal adenocarcinoma cell line, is correlated with growth, invasion, and advanced stage. Sci Rep. 2019 Dec 18;9(1):19369.
  35. Shinji S, Sasaki N, Yamada T, Koizumi M, Ohta R, Matsuda A, Yokoyama Y,Takahashi G, Hotta M, Hara K, Takeda K, Ueda K, Kuriyama S, Ishiwata T, Ueda Y,Murakami T, Kanazawa Y, Yoshida H. Establishment and characterization of a novel neuroendocrine carcinoma cell line derived from a human ascending colon tumor. Cancer Sci. 2019 Dec;110(12):3708-3717.
  36. Matsuda Y, Fujii Y, Matsukawa M, Ishiwata T, Nishimura M, Arai T.Overexpression of carbohydrate sulfotransferase 15 in pancreatic cancer stroma isassociated with worse prognosis. Oncol Lett. 2019 Oct;18(4):4100-4105.
  37. Matsuda Y, Kimura W, Matsukawa M, Aida J, Takubo K, Ishiwata T, Furukawa T,Mino-Kenudson M, Arai T. Association Between Pancreatic Cystic Lesions and High-grade Intraepithelial Neoplasia and Aging: An Autopsy Study. Pancreas. 2019 Sep;48(8):1079-1085.
  38. Shichi Y, Sasaki N, Michishita M, Hasegawa F, Matsuda Y, Arai T, Gomi F, Aida J, Takubo K, Toyoda M, Yoshimura H, Takahashi K, Ishiwata T. Enhanced morphological and functional differences of pancreatic cancer with epithelial or mesenchymal characteristics in 3D culture. Sci Rep. 2019 Jul 26;9(1):10871.
  39. Michishita M, Saito N, Nozawa S, Furumoto R, Nakagawa T, Sato T, Ochiai K,Azakami D, Katayama K, Nakahira R, Tazaki H, Machida Y, Ishiwata T. Metabolite profiling in sphere-forming cells from canine mammary adenocarcinoma cell lines using gas chromatography-mass spectrometry. J Vet Med Sci. 2019 Sep 3;81(9):1238-1248.
  40. Nonaka K, Aida J, Takubo K, Yamazaki Y, Takakuma S, Kakizaki M, Matsuda Y,Ishikawa N, Ishiwata T, Chong JM, Arai T, Sasano H. Correlation Between Differentiation of Adrenocortical Zones and Telomere Lengths Measured by Q-FISH.J Clin Endocrinol Metab. 2019 Nov 1;104(11):5642-5650.
  41. Nonaka K, Matsuda Y, Kakizaki M, Takakuma S, Hamamatsu A, Sakashita Y, Matsubara T, Murayama S, Ishiwata T, Yamanaka N, Itabashi M, Takei T, Nakajima N,Hasegawa H, Arai T. Acute Liver Failure Associated with Influenza A Virus Infection: an Autopsy Case Report. Jpn J Infect Dis. 2019 Sep 19;72(5):347-349.
  42. Kawata R, Ii T, Hori T, Machida Y, Ochiai K, Azakami D, Ishiwata T,Michishita M. Leydig cell tumor in an Amur tiger (Panthera tigris altaica). J Vet Med Sci. 2019 Feb 9;81(2):186-189.