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Faculty of Medicine School of Medicine Oncopathology and morphopathology |
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Assistant Professor |
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KIWAKI Takumi
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Papers 【 display / non-display 】
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Patient-Derived Organoids of Colorectal Cancer: A Useful Tool for Personalized Medicine Invited Reviewed
Kiwaki T., Kataoka H.
Journal of Personalized Medicine 12 ( 5 ) 2022.5
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Personalized Medicine
Colorectal cancer is one of the most important malignancies worldwide, with high incidence and mortality rates. Several studies have been conducted using two-dimensional cultured cell lines; however, these cells do not represent a study model of patient tumors very well. In recent years, advancements in three-dimensional culture methods have facilitated the establishment of patient-derived organoids, which have become indispensable for molecular biology-related studies of colorectal cancer. Patient-derived organoids are useful in both basic science and clinical practice; they can help predict the sensitivity of patients with cancer to chemotherapy and radiotherapy and provide the right treatment to the right patient. Regarding precision medicine, combining gene panel testing and organoid-based screening can increase the effectiveness of medical care. In this study, we review the development of three-dimensional culture methods and present the most recent information on the clinical application of patient-derived organoids. Moreover, we discuss the problems and future prospects of organoid-based personalized medicine.
DOI： 10.3390/jpm12050695
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Umekita Y., Kiwaki T., Kawaguchi M., Yamamoto K., Ikenoue M., Takeno S., Fukushima T., Sato Y., Kataoka H.
Pathology, research and practice 266 155809 2025.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Pathology, research and practice
Hepatocyte growth factor activator inhibitor-1 (HAI-1) is an epithelial type-1 transmembrane protease inhibitor that regulates the pericellular activities of hepatocyte growth factor activator and type-2 transmembrane serine proteases. It is strongly expressed in the stratified squamous epithelium and functions on the cell surface. We previously reported that the cell surface immunoreactivity of HAI-1 was reduced at the invasion front of oral squamous cell carcinoma. In this study, we investigate the relationship between cell surface HAI-1 (csHAI-1) and prognosis of esophageal squamous cell carcinoma (ESCC) after surgery. The effect of HAI-1 knockdown on cultured ESCC cells was also analyzed in vitro. HAI-1 exhibited distinct cell surface immunoreactivity in normal esophageal epithelium. In contrast, alterations in HAI-1 immunoreactivity were frequent in cancer cells, which exhibited aberrant intracytoplasmic localization and decreased cell surface immunoreactivity. The preservation of csHAI-1 immunoreactivity was a sign of a well-differentiated phenotype of ESCC cells. The decreased csHAI-1 was associated with shorter overall survival (OS) and disease-free survival (DFS) in the patients. In 55 cases of early (T1) ESCC cases, decreased csHAI-1 also predicted poor OS and DFS. The loss of HAI-1 enhanced migration and invasion of ESCC cells in vitro. These results suggest that the decreased cell surface immunoreactivity of HAI-1 is associated with a less differentiated phenotype and worse prognosis in ESCC. The cell surface-localized HAI-1 may serve as a promising marker for predicting recurrence and prognosis of ESCC.
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Metastasis of malignant melanoma to urinary tract: a case report Reviewed
Ueno T., Kiwaki T., Betsunoh H., Ito K., Murashima T., Fujii M., Nagai T., Mukai S., Sawada A., Kamoto T.
Journal of Medical Case Reports 18 ( 1 ) 2024.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Medical Case Reports
Introduction: Metastasis of malignant melanoma to urinary tract is reported to be rare. According to retrospective analysis of a single center study, improvement of overall survival was observed in patients with metastasis to the gastrointestinal tract that had undergone metastasectomy with curative intent. However, there is no significant evidence regarding resection for metastasis to urinary tract. Case presentation: Case 1: an 86-year-old Japanese man was diagnosed with a small bladder tumor by computed tomography scan during post operative follow-up of malignant melanoma in the choroid of the left eye. Cystoscopy revealed black, nonpapillary tumors, suggesting metastatic malignant melanoma. Because no apparent invasive growth to muscle layer was observed by magnetic resonance imaging, transurethral resection was performed. Pathological appearance was compatible with metastatic malignant melanoma. No recurrence in urinary tract was observed; however, multiple liver metastasis was diagnosed at 3 months after surgery. Case 2: a 57-year-old Japanese man was diagnosed with right hydronephrosis due to ureteral tumor. He had a past history of subungual malignant melanoma to the left thumb 2 years prior to his visit. Right nephroureterectomy was performed, and pathological evaluation revealed metastatic malignant melanoma. He revisited 2 years later due to dysuria, and a large bladder tumor was revealed by ultrasound. Cystoscopy showed black-colored nonpapillary tumor, suggesting malignant melanoma. Total cystectomy was recommended; however, the patient withheld consent. Therefore, we performed transurethral resection. The resulting pathological finding was compatible with metastatic malignant melanoma without invasion to muscle layer. He remained free from local recurrence and metastasis for 22 years after surgery. Conclusion: We successfully performed metastasectomy for bladder and ureteral metastases without recurrence in the urinary tract. Long recurrence-free survival was observed in case 2. Complete resection for metastasis of malignant melanoma may have the potential to improve survival.
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Kawaguchi M, Kataoka H, Kiwaki T, Liang W, Nagata S, Kitamura K, Fukushima T
FEBS open bio 13 ( 4 ) 713 - 723 2023.2
Language：English Publishing type：Research paper (scientific journal) Publisher：FEBS Open Bio
Adrenomedullin (AM) is a peptide with pleiotropic physiological functions that attenuates intestinal mucosal inflammation. However, the mechanism underpinning mucosal protection by AM is not fully understood, and its effect on intestinal epithelial cells remains unclear. Here, we investigated the effects of AM on junctional molecules in primary-cultured murine intestinal epithelial cells and discovered that AM upregulates claudin-4 expression. In a mouse model of dextran sulfate sodium-induced colitis, AM administration also enhanced claudin-4 expression and accelerated mucosal regeneration. Furthermore, AM reversed TNFα-mediated downregulation of claudin-4 and loss of cell–cell adhesion of the HCT116 human intestinal epithelial cell line in vitro. These results indicate that AM may enhance intestinal epithelial integrity by upregulating claudin-4 expression.
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Fujii M, Akioka T, Kimura S, Nagai T, Kiwaki T, Fukushima T, Mukai S, Kamoto T
Human cell 36 ( 2 ) 775 - 785 2023.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Human Cell
MET is a high-affinity receptor tyrosine kinase of HGF (hepatocyte growth factor). HGF is secreted as an inactive single-chain precursor (pro-HGF), which requires proteolytic activation for conversion to an active form. HGF activator inhibitor (HAI)-2 is a transmembrane Kunitz-type serine protease inhibitor, which inhibits all pro-HGF-activating enzymes. In RCC, increased expression of MET and decreased expression of HAI-2 were reported to be poor prognostic factors. In the current study, we tried to inhibit the growth of RCC cells by dual inhibition of both MET phosphorylation and pro-HGF-activation using MET inhibitor and HAI-2 overexpression. A transgenic mouse model which expressed human HGF (HGF mouse) was used for in vivo analysis to evaluate the HGF/MET signaling axis accurately. Initially, doxycycline-induced HAI-2 overexpression RCC cells (786-O-HAI2) were prepared. The cells were cultured with pro-HGF, and inhibitory effect of MET inhibitor (SCC244) and HAI-2 was evaluated by phosphorylation of MET and cell proliferation. Next, the cells were subcutaneously implanted to HGF mice and the growth inhibition was determined by SCC244 and HAI-2. Single use of each inhibitor showed significant inhibition in MET phosphorylation, migration and proliferation of 786-O-HAI2 cells; however, the strongest effect was observed by combined use of both inhibitors. Although in vivo analysis also showed apparent downregulation of MET phosphorylation and growth inhibition in combined treatment, statistical significance was not observed compared with single use of MET inhibitor. Combined treatment with MET-TKI and HAI-2 suggested to consider as a candidate for new strong therapy for RCC.
Presentations 【 display / non-display 】
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ヒト HGF 導入 SCID マウスを用いた HGF-MET シグナル解析と阻害治療の開発 Invited
木脇 拓道
第３８回日本ヒト細胞学会学術集会
Event date： 2020.8.22 - 2020.8.23
Language：Japanese Presentation type：Symposium, workshop panel (nominated)
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A synthetic small molecule inhibitor of pro-HGF activation, ZFH7116, suppresses the growth of SAS squamous cell carcinoma line in human HGF knock-in SCID mice: A pilot study International conference
Takumi Kiwaki, Makiko Kawaguchi, Koji Yamamoto, James W. Janetka, Hiroaki Kataoka
ASBMB Symposia: Serine Proteases in Pericellular Proteolysis and Signaling (Potomac, Md., USA) American Society for Biochemistry and Molecular Biology
Event date： 2019.9.12 - 2019.9.15
Language：English Presentation type：Poster presentation
Venue：Potomac, Md., USA
Awards 【 display / non-display 】
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優秀研究奨励賞
2024.8 日本ヒト細胞学会 LRP11はUBA7発現を抑制し，肺腺癌の増殖を亢進させる
木脇 拓道
Award type：International academic award (Japan or overseas)
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Best Case Report Award (Young Pathologist Encouragement Award) from the Kyushu-Okinawa Branch of the Japanese Society of Pathology
2020.5 The Kyushu-Okinawa Branch of the Japanese Society of Pathology
Takumi Kiwaki
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
Grant-in-Aid for Scientific Research 【 display / non-display 】
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がん細胞の HGF 活性制御分子に着目した HGF-MET 依存性転移機構の解明
Grant number：23K06444 2023.04 - 2026.03
日本学術振興会 科学研究費基金 基盤研究(C)
Authorship：Principal investigator
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がん組織におけるHGF-METシグナル活性化機構の解明と、その阻害療法の開発
Grant number：20K16175 2020.04 - 2023.03
独立行政法人日本学術振興会 科学研究費補助金 若手研究
Authorship：Principal investigator