がん微小環境の理解に基づく新たな診断法・治療法の開発

がん組織形態を基盤としてがん微小環境の理解を深め、新たな診断法・治療法の開発を進めています。がん組織はがん細胞に加え、血管、神経、免疫細胞、炎症細胞、細胞外基質等のがん細胞を取り巻く多様な要素で構成されており、これらがん微小環境とがん細胞との相互作用ががんの生物学的・臨床病理学的性質決定に寄与しています。私達はがん微小環境を構成する様々な要素の相互作用に着目し、そのがん生物学的な役割の理解を深めつつ、その中から新たなシーズを見つけ、革新的な診断法・治療法の開発につなげたいと考えています。

血管はがん組織内への免疫細胞の輸送や免疫活性の調整等、免疫系との関係において重要な役割を担っています。しかしがん組織内の血管はいわゆる腫瘍血管と呼ばれる機能不全の血管が多くを占め、抗腫瘍免疫反応に負に作用しています。私達は腫瘍内血管の機能不全の改善を通して抗腫瘍免疫に相乗効果をもたらす治療法の開発を試みています。また血管・免疫・神経の相互作用の上に成立する3次リンパ装置の形成に注目し研究開発を進めています。

• Fukuda H, Arai K, Mizuno H, Nishito Y, Motoi N, Arai Y, Hiraoka N, Shibata T, Sonobe Y, Kayukawa Y, Hashimoto E, Takahashi M, Fujii E, Maruyama T, Kuwabara K, Nishizawa T, Mizogushi Y, Yoshida Y, Watanabe S, Yamashita M, Kitano S, Sakamoto H, Nagata Y, Mitsumori R, Ozaki K, Niida S, Kanai Y, Hirayama A, Soga T, Tsukada K, Yabuki N, Shimada M, Kitazawa T, Natori O, Sawada N, Kato A, Yoshida T, Yasuda K, Ochiai A, Tsunoda H, Aoki K. Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments. Cancer Sci in press.
• Doi N, Ino Y, Fuse M, Esaki E, Shimada K, Hiraoka N. Correlation of vein-rich tumor microenvironment of intrahepatic cholangiocarcinoma with tertiary lymphoid structures and patient outcome. Mod Pathol 37:100401, 2024.
• Aoki K, Nishito Y, Motoi N, Arai Y, Hiraoka N, Shibata T, Sonobe Y, Kayukawa Y, Hashimoto E, Takahashi M, Fujii E, Nishizawa T, Fukuda H, Ohashi K, Arai K, Mizogushi Y, Yoshida Y, Watanabe S, Yamashita M, Kitano S, Sakamoto H, Nagata Y, Mitsumori R, Ozaki K, Niida S, Kanai Y, Hirayama A, Soga T, Maruyama T, Tsukada K, Yabuki N, Shimada M, Kitazawa T, Natori O, Sawada N, Kato A, Yoshida T, Yasuda K, Mizuno H, Tsunoda H, Ochiai A. Tumor-infiltrating leukocyte profiling defines three immune subtypes of NSCLC with distinct signaling pathways and genetic alterations. Cancer Res Commun. 3: 1026-40, 2023.
• Kometani T, Kamo K, Kido T, Hiraoka N, Chibazakura T, Unno K, Sekine K. Development of a novel co-culture system using human pancreatic cancer cells and human iPSC-derived stellate cells to mimic the characteristics of pancreatic ductal adenocarcinoma in vitro. Biochem Biophys Res Commun. 658:1-9, 2023.
• Sawada J, Hiraoka N, Qi R, Jiang L, Fournier-Goss AE, Yoshida M, Kawashima H, Komatsu M. Molecular Signature of Tumor-Associated High Endothelial Venules That Can Predict Breast Cancer Survival. Cancer Immunol Res. 10: 468-81, 2022.
• Nakajima K, Ino Y, Naito C, Nara S, Shimasaki M, Ishimoto U, Iwasaki T, Doi N, Esaki M, Kishi Y, Shimada K, Hiraoka N. Neoadjuvant therapy alters the collagen architecture of pancreatic cancer tissue via Ephrin-A5. Br J Cancer. 126: 628-39, 2022.
• Sato J, Kitano S, Motoi N, Ino Y, Yamamoto N, Watanabe S, Ohe Y, Hiraoka N. CD20(+) tumor-infiltrating immune cells and CD204(+) M2 macrophages are associated with prognosis in thymic carcinoma. Cancer Sci. 111: 1921-32, 2020.
• Nakajima K, Ino Y, Yamazaki-Itoh R, Naito C, Shimasaki M, Takahashi M, Esaki M, Nara S, Kishi Y, Shimada K, Hiraoka N. IAP inhibitor, Embelin increases VCAM-1 levels on the endothelium, producing lymphocytic infiltration and antitumor immunity. Oncoimmunology. 9: 1838812, 2020.
• Hiraoka N, Ino Y, Hori S, Yamazaki-Itoh R, Naito C, Shimasaki M, Esaki M, Nara S, Kishi Y, Shimada K, Nakamura N, Torigoe T, Heike Y. Expression of classical human leukocyte antigen class I antigens, HLA-E and HLA-G, is adversely prognostic in pancreatic cancer patients. Cancer Sci. 111: 3057-70, 2020.
• Saito Y, Muramatsu T, Kanai Y, Ojima H, Sukeda A, Hiraoka N, Arai E, Sugiyama Y, Matsuzaki J, Uchida R, Yoshikawa N, Furukawa R, Saito H. Establishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma. Cell Rep. 27: 1265-76 e4, 2019.
• Iwasaki T, Hiraoka N, Ino Y, Nakajima K, Kishi Y, Nara S, Esaki M, Shimada K, Katai H. Reduction of intrapancreatic neural density in cancer tissue predicts poorer outcome in pancreatic ductal carcinoma. Cancer Sci. 110: 1491-502, 2019.
• Ino Y, Oguro S, Yamazaki-Itoh R, Hori S, Shimada K, Hiraoka N. Reliable evaluation of tumor-infiltrating lymphocytes in pancreatic cancer tissue biopsies. Oncotarget. 10: 1149-59, 2019.
• Kawachi A, Yoshida H, Kitano S, Ino Y, Kato T, Hiraoka N. Tumor-associated CD204(+) M2 macrophages are unfavorable prognostic indicators in uterine cervical adenocarcinoma. Cancer Sci. 109: 863-70, 2018.
• Cui L, Nakano K, Obchoei S, Setoguchi K, Matsumoto M, Yamamoto T, Obika S, Shimada K, Hiraoka N. Small Nucleolar Noncoding RNA SNORA23, Up-Regulated in Human Pancreatic Ductal Adenocarcinoma, Regulates Expression of Spectrin Repeat-Containing Nuclear Envelope 2 to Promote Growth and Metastasis of Xenograft Tumors in Mice. Gastroenterology. 153: 292-306 e2, 2017.
• Hiraoka N, Ino Y, Yamazaki-Itoh R. Tertiary Lymphoid Organs in Cancer Tissues. Front Immunol. 7: 244, 2016.
• Oguro S, Ino Y, Shimada K, Hatanaka Y, Matsuno Y, Esaki M, Nara S, Kishi Y, Kosuge T, Hiraoka N. Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer. Cancer Sci. 106: 1750-60, 2015.
• Hiraoka N, Ino Y, Yamazaki-Itoh R, Kanai Y, Kosuge T, Shimada K. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br J Cancer. 112: 1782-90, 2015.