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Targeting AURKA in treatment of peritoneal tumor dissemination in gastrointestinal cancer (本文)

小澤, 広輝 慶應義塾大学

2022.09.05

概要

Intraperitoneal (i.p.) tumor dissemination and the consequent malignant ascites remain unpredictable and incurable in patients with gastrointestinal (GI) cancer, and practical advances in diagnosis and treatment are urgently needed in the clinical settings. Here, we explored tumor biological and immunological mechanisms underlying the i.p. tumor progression for establishing more effective treatments.

　We established mouse tumor ascites models that murine and human colorectal cancer cells were both i.p. and subcutaneously (s.c.) implanted in mice, and analyzed peritoneal exudate cells (PECs) obtained from the mice. We then evaluated anti-tumor efficacy of agents targeting the identified molecular mechanisms using the ascites models. Furthermore, we validated the clinical relevancy of the findings using peritoneal lavage fluids obtained from gastric cancer patients.

　I.p. tumor cells were giant with large nuclei, and highly express AURKA, but less phosphorylated TP53, as compared to s.c. tumor cells, suggesting polyploidy-like cells. The i.p. tumors impaired phagocytic activity and the consequent T-cell stimulatory activity of CD11b+Gr1+PD1+ myeloid cells by GDF15 that is regulated by AURKA, leading to treatment resistance. Blocking AURKA with MLN8237 or siRNAs, however, abrogated the adverse events, and induced potent anti-tumor immunity in the ascites models. This treatment synergized with anti-PD1 therapy. The CD11b+PD1+ TAMs are also markedly expanded in the PECs of gastric cancer patients.

　These suggest AURKA is a determinant of treatment resistance of the i.p. tumors. Targeting the AURKA-GDF15 axis could be a promising strategy for improving clinical outcome in the treatment of GI cancer.

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参考文献

[1] N. Fang, H.Q. Zhang, B. He, M. Xie, S. Lu, Y.Y. Wan, et al., Clinicopathological characteristics and prognosis of gastric cancer with malignant ascites, Tumour Biol. 35 (2014) 3261–3268, https://doi.org/10.1007/s13277-013-1426-3.

[2] Z. Wang, J.Q. Chen, J.L. Liu, L. Tian, Issues on peritoneal metastasis of gastric cancer: an update, World J. Surg. Oncol. 17 (2019) 215, https://doi.org/10.1186/ s12957-019-1761-y.

[3] A.C. Gamboa, J.H. Winer, Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for gastric cancer, Cancers (Basel) 11 (2019) 1662, https://doi.org/ 10.3390/cancers11111662.

[4] D.K.A. Chia, J.B.Y. So, Recent advances in intra-peritoneal chemotherapy for gastric cancer, J. Gastric Cancer 20 (2020) 115–126, https://doi.org/10.5230/ jgc.2020.20.e15.

[5] F. Sun, M. Feng, W. Guan, Mechanisms of peritoneal dissemination in gastric cancer, Oncol. Lett. 14 (2017) 6991–6998, https://doi.org/10.3892/ol.2017.7149.

[6] Y. Chen, Q. Zhou, H. Wang, W. Zhuo, Y. Ding, J. Lu, et al., Predicting peritoneal dissemination of gastric cancer in the era of precision medicine: molecular characterization and biomarkers, Cancers (Basel) 12 (2020) 2236, https://doi.org/ 10.3390/cancers12082236.

[7] K. Stoletov, P.H. Beatty, J.D. Lewis, Novel therapeutic targets for cancer metastasis, Expert Rev. Anticancer Ther. 20 (2020) 97–109, https://doi.org/10.1080/14737140.2020.1718496.

[8] C. Kudo-Saito, Y. Ozaki, H. Imazeki, H. Hayashi, J. Masuda, H. Ozawa, et al., Targeting oncoimmune drivers of cancer metastasis, Cancers (Basel) 13 (2021) 554, https://doi.org/10.3390/cancers13030554.

[9] H. Song, T. Wang, L. Tian, S. Bai, L. Chen, Y. Zuo, et al., Macrophages on the peritoneum are involved in gastric cancer peritoneal metastasis, J. Cancer 10 (2019) 5377–5387, https://doi.org/10.7150/jca.31787.

[10] S. Shalapour, M. Karin, Immunity, inflammation, and cancer: an eternal fight between good and evil, J. Clin. Invest. 125 (2015) 3347–3355, https://doi.org/ 10.1172/JCI80007.

[11] K.E. Pauken, E.J. Wherry, Overcoming T cell exhaustion in infection and cancer, Trends Immunol. 36 (2015) 265–276, https://doi.org/10.1016/j.it.2015.02.008.

[12] M.J. Overman, S. Lonardi, K.Y.M. Wong, H.J. Lenz, F. Gelsomino, M. Aglietta, et al., Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer, J. Clin. Oncol. 36 (2018) 773–779, https://doi.org/10.1200/JCO.2017.76.9901.

[13] J.J. Havel, D. Chowell, T.A. Chan, The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy, Nat. Rev. Cancer 19 (2019) 133–150, https://doi.org/10.1038/s41568-019-0116-x.

[14] C. Kudo-Saito, M. Yura, R. Yamamoto, Y. Kawakami, Induction of immunoregulatory CD271+ cells by metastatic tumor cells that express human endogenous retrovirus H, Cancer Res. 74 (2014) 1361–1370, https://doi.org/ 10.1158/0008-5472.CAN-13-1349.

[15] J. Coward, A. Harding, Size does matter: why polyploid tumor cells are critical drug targets in the war on cancer, Front. Oncol. 4 (2014) 123, https://doi.org/ 10.3389/fonc.2014.00123.

[16] S. Zhang, I. Mercado-Uribe, Z. Xing, B. Sun, J. Kuang, J. Liu, Generation of cancer stem-like cells through the formation of polyploid giant cancer cells, Oncogene 33 (2014) 116–128, https://doi.org/10.1038/onc.2013.96.

[17] S.R. Amend, G. Torga, K.C. Lin, L.G. Kostecka, A. de Marzo, R.H. Austin, et al., Polyploid giant cancer cells: unrecognized actuators of tumorigenesis, metastasis, and resistance, Prostate 79 (2019) 1489–1497, https://doi.org/10.1002/ pros.23877.

[18] C. Kudo-Saito, T. Miyamoto, H. Imazeki, H. Shoji, K. Aoki, N. Boku, IL33 is a key driver of treatment resistance of cancer, Cancer Res. 80 (2020) 1981–1990, https://doi.org/10.1158/0008-5472.CAN-19-2235.

[19] F.Y. Liew, J.P. Girard, H.R. Turnquist, Interleukin-33 in health and disease, Nat. Rev. Immunol. 16 (2016) 676–689, https://doi.org/10.1038/nri.2016.95.

[20] B. Griesenauer, S. Paczesny, The ST2/IL-33 axis in immune cells during inflammatory diseases, Front. Immunol. 8 (2017) 475, https://doi.org/10.3389/ fimmu.2017.00475.

[21] L. Rochette, M. Zeller, Y. Cottin, C. Vergely, Insights into mechanisms of GDF15 and receptor GFRAL: therapeutic targets, Trends Endocrinol. Metab. 31 (2020) 939–951, https://doi.org/10.1016/j.tem.2020.10.004.

[22] P.J. Emmerson, K.L. Duffin, S. Chintharlapalli, X. Wu, GDF15 and growth control, Front. Physiol. 9 (2018) 1712, https://doi.org/10.3389/fphys.2018.01712.

[23] J. Windrichova, R. Fuchsova, R. Kucera, O. Topolcan, O. Fiala, J. Finek, et al., MIC1/GDF15 as a bone metastatic disease biomarker, Anticancer Res. 37 (2017) 1501–1505, https://doi.org/10.21873/anticanres.11477.

[24] A. Spanopoulou, V. Gkretsi, Growth differentiation factor 15 (GDF15) in cancer cell metastasis: from the cells to the patients, Clin. Exp. Metastasis 37 (2020) 451–464, https://doi.org/10.1007/s10585-020-10041-3.

[25] C.C. Yen, S.C. Chen, G.Y. Hung, P.K. Wu, W.Y. Chua, Y.C. Lin, et al., Expression profiledriven discovery of AURKA as a treatment target for liposarcoma, Int. J. Oncol. 55 (2019) 938–948, https://doi.org/10.3892/ijo.2019.4861.

[26] J. Wang, T. Hu, Q. Wang, R. Chen, Y. Xie, H. Chang, et al., Repression of the AURKA-CXCL5 axis induces autophagic cell death and promotes radiosensitivity in non-small-cell lung cancer, Cancer Lett. 509 (2021) 89–104, https://doi.org/ 10.1016/j.canlet.2021.03.028.

[27] V. Bavetsias, S. Linardopoulos, Aurora kinase inhibitors: current status and outlook, Front. Oncol. 5 (2015) 278, https://doi.org/10.3389/fonc.2015.00278.

[28] A. Tang, K. Gao, L. Chu, R. Zhang, J. Yang, J. Zheng, Aurora kinases: novel therapy targets in cancers, Oncotarget 8 (2017) 23937–23954, https://doi.org/10.18632/ oncotarget.14893.

[29] F. Fei, D. Zhang, Z. Yang, S. Wang, X. Wang, Z. Wu, et al., The number of polyploid giant cancer cells and epithelial-mesenchymal transition-related proteins are associated with invasion and metastasis in human breast cancer, J. Exp. Clin. Cancer Res. 34 (2015) 158, https://doi.org/10.1186/s13046-015-0277-8.

[30] B. Xuan, D. Ghosh, E.M. Cheney, E.M. Clifton, M.R Dawson, Dysregulation in actin cytoskeletal organization drives increased stiffness and migratory persistence in polyploidal giant cancer cells, Sci. Rep. 8 (2018) 11935, https://doi.org/10.1038/ s41598-018-29817-5.

[31] Y. Sugita, K. Yamashita, M. Fujita, M. Saito, K. Yamada, K. Agawa, et al., CD244(+) polymorphonuclear myeloidderived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model, Oncol. Rep. 45 (2021) 106, https:// doi.org/10.3892/or.2021.8057.

[32] I. Wertel, J. Surowka, G. Polak, B. Barczynski, W. Bednarek, J. Jakubowicz-Gil, et al., Macrophage-derived chemokine CCL22 and regulatory T cells in ovarian cancer patients, Tumour Biol. 36 (2015) 4811–4817, https://doi.org/10.1007/s13277-015-3133-8.

[33] D. Lu, Z. Ni, X. Liu, S. Feng, X. Dong, X. Shi, et al., Beyond T Cells: understanding the role of PD-1/PD-L1 in tumor-associated macrophages, J. Immunol. Res. 2019 (2019), 1919082, https://doi.org/10.1155/2019/1919082.

[34] Y. Kono, H. Saito, W. Miyauchi, S. Shimizu, Y. Murakami, Y. Shishido, et al., Increased PD-1-positive macrophages in the tissue of gastric cancer are closely associated with poor prognosis in gastric cancer patients, BMC Cancer 20 (2020) 175, https://doi.org/10.1186/s12885-020-6629-6.

[35] T.S. Lim, V. Chew, J.L. Sieow, S. Goh, J.P. Yeong, A.L. Soon, et al., PD-1 expression on dendritic cells suppresses CD8(+) T cell function and antitumor immunity, Oncoimmunology 5 (2016), e1085146, https://doi.org/10.1080/ 2162402X.2015.1085146.

[36] S.R. Gordon, R.L. Maute, B.W. Dulken, G. Hutter, B.M. George, M.N. McCracken, et al., PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity, Nature 545 (2017) 495–499, https://doi.org/10.1038/ nature22396.

[37] P. Dhupkar, N. Gordon, J. Stewart, E.S. Kleinerman, Anti-PD-1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases, Cancer Med. 7 (2018) 2654–2664, https://doi.org/10.1002/ cam4.1518.

[38] J. Xin Yu, V.M. Hubbard-Lucey, J Tang, Immuno-oncology drug development goes global, Nat. Rev. Drug Discov. 18 (2019) 899–900, https://doi.org/10.1038/ d41573-019-00167-9.

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