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Aging and Carcinogenesis


Members

Theme Leader :
Toshiyuki Ishiwata, M.D., Ph.D.
Vice-Chief Researcher :
Junko Aida, D.D.S., Ph.D.
Researcher :
Naoshi Ishikawa, M.D., Ph.D.
Adjunct Researcher :
Kaiyo Takubo, M.D., Ph.D., Ken-ichi Nakamura, Ph.D., Masanori Terai, D.D.S., Ph.D., Hasegawa Fumio, Hasegawa Yasuko

Keywords

Aging, Telomere, Q-FISH, Geriatric Disease, Cancerization, Pancreatic Cancer, Cancer Stem Cell, Epithelial-mesenchymal transition, 3D-culture, Growth Factor Receptor

Major Research Titles

  1. Elucidation of the relationship between aging and cancerization:
    1. 1. Study of telomere metabolism from molecular and cellular viewpoints
    2. 2. Cancer stem cells and epithelial-mesenchymal transition in carcinogenesis and progression

Profile

Cancer incidence is known to increase sharply in the elderly, thought to be owing to a synergistic effect of telomeric dysfunction, micro-environmental change, and accumulation of epigenetic changes. The Nobel Prize in Physiology and Medicine in 2009 was awarded for work on telomeres. Telomeres are located at the ends of chromosomes and have a role in protecting them against fusion events. Telomeres become shortened in cultured cells as they undergo repeated mitosis. As telomeres shorten with cellular aging, the chromosomes become unstable and cells become more prone to mutations, often resulting in cytostasis, cellular immortalization, or cancerization.
We have demonstrated that the telomeres present in human organs and tissues also undergo shortening in vivo. Furthermore, we have estimated the telomere lengths from most human tissues using both Southern blotting and an original tissue Q-FISH method. This has allowed us to analyze telomere metabolism at both the molecular and cellular levels, demonstrating that telomere shortening and chromosomal instability occur in the background mucosa (e.g., oral and esophageal epithelia, skin, and pancreatic duct epithelia) adjacent to cancerous tissue in the absence of any apparent histological change. We found that the telomeres in basal cells were significantly shorter in alcoholics than in age-matched healthy controls, indicating that telomere shortening may be associated with the frequent occurrence of squamous cell carcinoma in alcoholics. On the other hand, our in vitro studies by metaphase Q-FISH have revealed chromosomal abnormality with telomere shortening in senescent human fibroblasts and cancer cells. In addition, we have been studying the pathological background in age-related diseases, such as Type II diabetes mellitus, arteriosclerosis, and neurological aging from a telomere viewpoint. Recently, we have found and reported an inverse correlation between HbA1c and telomere length in pancreatic β-cells (Figures 1, 2).
Despite new therapeutic approaches, recurrence and metastasis remain major problems for patients with advanced cancer. Recently, cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are reported to play important roles in cancer aggressiveness. CSCs that are resistant to chemoradiotherapy and survive can contribute to the recurrence of cancer. Cancer cells have the ability to form colonies in spherical aggregates under non-adherent culture conditions, which indicates self-renewal capability (Fig. 3). During cancer metastasis, CSCs undergo EMT migrating to adjacent stromal tissues, and invading blood or lymph vessels. We are attempting to elucidate the roles of CSCs and EMT in cancer and find possible therapies for cancers.
The members of our team are conducting histopathological diagnoses and autopsies at Tokyo Metropolitan Geriatric Hospital. We are also studying cancers (e.g., esophageal and pancreatic) of the aged, and have been investigating the pathological conditions of geriatric diseases in detail. We have launched a website to provide details of the recent progress of our group's research.

Figure 1
Figure 1. Representative FISH images with insulin immunofluorescence of specimens from a control individual and a patient with type 2 diabetes mellitus. Original magnification, ×40. (A and B) Cytoplasmic green: insulin-Cy5 signals. Nuclear red: telomere-Cy3 signals: Nuclear green: centromere-FITC signals: Nuclear blue: DAPI counterstaining for DNA. Multiple small signals of telomeres and centromeres are clearly evident within the nuclei. Stromal yellow signals: non-specific fluorescence. (A) Image of a normal control specimen from a 65-year-old woman. The NTCR of insulin signal-positive cells was 1.98. (B) Images of a specimen from a 78-year-old woman with type 2 diabetes mellitus. The NTCR of insulin signal-positive cells was 0.49.

Figure 2
Figure 2. Correlation between maximum recorded HbA1c level and NTCR (β). Solid circles indicate patients with type 2 diabetes mellitus, and clear circles indicate controls.

Figure 3
Figure 3. Scanning electron microscopy (SEM) analysis revealed that the spheres from human pancreatic cancer cells exhibited a grape-like appearance, harboring cancer cells with smooth or rough surfaces.

References

  1. 1. Sasaki N, Ishiwata T, Hasegawa F, Michishita M, Kawai H, Matsuda Y, Arai T, Ishikawa N, Aida J, Takubo K, Toyoda M. Stemness and anti-cancer drug resistance in ABCG2 highly expressed pancreatic cancer is induced on 3D-culture condition. Cancer Sci. 2018 Feb 14. [Epub ahead of print]
  2. 2. Ishiwata T, Hasegawa F, Michishita M, Sasaki N, Ishikawa N, Takubo K, Matsuda Y, Arai T, Aida J. Electron microscopic analysis of different cell types in human pancreatic cancer spheres. Oncol Lett. 15:2485-2490, 2018.
  3. 3. Aoki Y, Aida J, Kawano Y, Nakamura KI, Izumiyama-Shimomura N, Ishikawa N, Arai T, Nakamura Y, Taniai N, Uchida E, Takubo K, Ishiwata T. Correction to: Telomere length of gallbladder epithelium is shortened in patients with congenital biliary dilatation: measurement by quantitative fluorescence in situ hybridization. J Gastroenterol. 53: 302-303, 2018.
  4. 4. Ishiwata T. Role of fibroblast growth factor receptor-2 splicing in normal and cancer cells. Front Biosci (Landmark Ed).1; 23: 626-639, 2018.
  5. 5. Yoshimura H, Matsuda Y, Yamamoto M, Kamiya S, Ishiwata T. Expression and role of long non-coding RNA H19 in carcinogenesis. Front Biosci (Landmark Ed). 1; 23: 614-625, 2018.
  6. 6. Matsuda Y, Seki A, Nonaka K, Kakizaki M, Wang T, Aida J, Ishikawa N, Nakano Y, Kaneda D, Takata T, Takahashi-Fujigasaki J, Murayama S, Takubo K, Ishiwata T, Sawabe M, Arai T. Clinicopathological characteristics of distant metastases of adenocarcinoma, squamous cell carcinoma and urothelial carcinoma: An autopsy study of older Japanese patients. Geriatr Gerontol Int.18(2):211-215, 2018.
  7. 7. Matsuda Y, Furukawa T, Yachida S, Nishimura M, Seki A, Nonaka K, Aida J, Takubo K, Ishiwata T, Kimura W, Arai T, Mino-Kenudson M. The Prevalence and Clinicopathological Characteristics of High-Grade Pancreatic Intraepithelial Neoplasia: Autopsy Study Evaluating the Entire Pancreatic Parenchyma. Pancreas. 46:658-664, 2017.
  8. 8. Matsuda Y, Ishiwata T, Yoshimura H, Yamahatsu K, Minamoto T, Arai T. Nestin phosphorylation at threonines 315 and 1299 correlates with proliferation and metastasis of human pancreatic cancer. Cancer Sci. 108: 354-361, 2017.
  9. 9. Ishiwata T. Cancer stem cells and epithelial-mesenchymal transition: Novel therapeutic targets for cancer. Pathol Int. 66: 601-608, 2016.
  10. 10. Tamura Y, Izumiyama-Shimomura N, Kimbara Y, Nakamura K, Ishikawa N, Aida J, Chiba Y, Matsuda Y, Mori S, Arai T, Fujiwara M, Poon SSS, Ishizaki T, Araki A, Takubo K, Ito H. Telomere attrition in beta and alpha cells with age. Age (Dordr). 38: 61, 2016.
  11. 11. Hatakeyama H, Yamazaki H, Nakamura K, Izumiyama-Shimomura N, Aida J, Suzuki H, Tsuchida S, Matsuura M, Takubo K, and Ishikawa N. Telomere attrition and restoration in the normal teleost Oryzias latipes are linked to growth rate and telomerase activity at each life stage. AGING 8 :62-76, 2016.
  12. 12. Ishikawa N, Nakamura K, Izumiyama-Shimomura N, Aida J, Matsuda Y, Arai T and Takubo K. Changes of telomere status with aging: An update. Geriatr Gerontol Int, 16 (Suppl. 1): 30-42. doi: 10.1111/ggi.12772. 2016.
  13. 13. Matsuda Y, Ishiwata T, Yoshimura H, Yamashita S, Ushijima T, Arai T. Systemic administration of siRNA targeting human nestin inhibits pancreatic cancer cell proliferation and metastasis. Pancreas 45 :93-100, 2016.
  14. 14. Matsuda Y, Ishiwata T, Yachida S, Suzuki A, Hamashima Y, Hamayasu H, Yoshimura H, Honma N, Aida J, Takubo K, Arai T. Clinicopathological features of 15 occult and 178 clinical pancreatic ductal adenocarcinomas in 8339 autopsied elderly patients. Pancreas 45: 234-40, 2016.
  15. 15. Matsuda Y, Yoshimura H, Ishiwata T, Sumiyoshi H, Matsushita A, Nakamura Y, Aida J, Uchida E, Takubo K, Arai T. Mitotic index and multipolar mitosis in routine histologic sections as prognostic markers of pancreatic cancers: a clinicopathological study. Pancreatology 16: 127-32, 2016.
  16. 16. Matsuda Y, Ishiwata T, Izumiyama-Shimomura N, Hamayasu H, Fujiwara M, Tomita K, Hiraishi N, Nakamura K, Ishikawa N, Aida J, Takubo K, Arai T. Gradual telomere shortening and increasing chromosomal instability among PanIN grades and normal ductal epithelia with and without cancer in the pancreas. PLoS One 10: e0117575. 2015.
  17. 17. Aida J, Vieth M, Shepherd NA, May A, Neuhaus H, Ishizaki T, Nishimura M, Fujiwara M, Arai T, Takubo K. Is carcinoma in columnar-lined esophagus always located adjacent to intestinal metaplasia?-A Histopathologic assessment. Am J Surg Pathol 39 (2), 188-196, 2015.
  18. 18. Matsuda Y, Ishiwata T, Yoshimura H, Hagio M, Arai T. Inhibition of nestin suppresses stem cell phenotype of glioblastomas through the alteration of post-translational modification of heat shock protein HSPA8/HSC71. Cancer Lett. 357 (2), 602-11, 2015.
  19. 19. Aida S, Aida J, Hasegawa K, Kumasaka T, Shimazaki H, Tamai S, Takubo K. Telomere length of human adult bronchial epithelium and bronchogenic squamous cell carcinoma measured using tissue quantitative fluorescence in situ hybridization. Respiration 90(4): 321-326, 2015.
  20. 20. Tamura Y, Izumiyama-Shimomura N, Kimbara Y, Nakamura K, Ishikawa N, Aida J, Chiba Y, Mori S, Arai T, Aizawa T, Araki A, Takubo K, Ito H. Beta Cell Telomere Attrition in Diabetes: Inverse Correlation Between HbA1c and Telomere Length. J Clin Endocrinol Metab. 99(8), 2771-7, 2014.
  21. 21. Takubo K, Vieth M, Aida J, Matsutani T, Hagiwara N, Iwakiri K, Kumagai Y, Hongo M, Hoshihara Y, Arai T. Histopathologic diagnosis of adenocarcinoma in Barrett's esophagus. Digest Endosc, 26(3), 322-30, 2014.
  22. 22. Ikeda H, Aida J, Hatamochi A, Hamasaki Y, Izumiyama-Shimomura N, Nakamura K, Ishikawa N, Poon SS, Fujiwara M, Tomita K, Hiraishi N, Kuroiwa M, Matsuura M, Sanada Y, Kawano Y, Arai T, Takubo K. Q-FISH measurement of telomere length in skin with/without sun exposure or actinic keratosis. Hum Pathol. 45, 473-480, 2014.
  23. 23. Kawano Y, Ishikawa N, Aida J, Sanada Y, Izumiyama-Shimomura N, Nakamura K, Poon SSS, Matsumoto K, Mizuta K, Uchida E, Tajiri T, Kawarasaki H, Takubo K. Q-FISH measurement of hepatocyte telomere lengths in donor liver and graft after pediatric living-donor liver transplantation: Donor age affects telomere length sustainability. PLoS ONE, 9(4): e93749. doi:10.1371/journal.pone.0093749.
  24. 24. Sanada Y, Kawano Y, Miki A, Aida J, Nakamura K, Izumiyama NS, Ishikawa N, Arai T, Hirata Y, Yamada N, Okada N, Wakiya T, Ihara Y, Urahashi T, Yasuda Y, Takubo K. Maternal grafts protect daughter recipients from acute cellular rejection after pediatric living donor liver transplantation for biliary atresia. Transpl Int, doi: 10.1111/tri.12273. 2014.
  25. 25. Nakamura K, Ishikawa N, Izumiyama N, Aida J, Kuroiwa M, Hiraishi N, Fujiwara M, Nakao A, Kawakami T, Poon SSS, Matsuura M, Sawabe M, Arai T, Takubo T. Telomere lengths at birth in trisomies 18 and 21 measured by Q-FISH. Gene, 533(1), 199-207 doi: 10.1016/j.gene.2013.09.086. 2014.