Hypoxia Drives the Formation of Lung Micropapillary Adenocarcinoma-like Structure Through Hypoxia-inducible Factor-1α

Overview

Journal Sci Rep

Specialty Science

Date 2024 Dec 31

PMID 39738173

Authors

Daisuke Umeda

Akikazu Harada

Daisuke Motooka

Shinichiro Tahara

Masako Kurashige

Kansuke Kido

Tsuyoshi Takashima

Hiroki Kiyokawa

Koto Ukon

Takahiro Matsui

Shinji Matsumoto

Yasushi Shintani

Daisuke Okuzaki

Akira Kikuchi

Satoshi Nojima

Eiichi Morii

Affiliations

Soon will be listed here.

Abstract

Micropapillary adenocarcinoma (MPC) is an aggressive histological subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Hypoxia induced the formation of MPC-like structures (MLSs) in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited a gene expression signature similar to that of lung MPC. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. Our findings suggest that hypoxia drives lung MPC formation through HIF-1α and that immune escape from natural killer cells might underlie the aggressiveness of MPC.

References

Jin M, Jin W . The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Target Ther. 2020; 5(1):166. PMC: 7447642. DOI: 10.1038/s41392-020-00280-x. View

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

Liu K, Datta A, Yu W, Brakeman P, Jou T, Matthay M . Rac1 is required for reorientation of polarity and lumen formation through a PI 3-kinase-dependent pathway. Am J Physiol Renal Physiol. 2007; 293(5):F1633-40. DOI: 10.1152/ajprenal.00053.2007. View

Kawakami T, Nabeshima K, Makimoto Y, Hamasaki M, Iwasaki A, Shirakusa T . Micropapillary pattern and grade of stromal invasion in pT1 adenocarcinoma of the lung: usefulness as prognostic factors. Mod Pathol. 2007; 20(5):514-21. DOI: 10.1038/modpathol.3800765. View

Yu W, Shewan A, Brakeman P, Eastburn D, Datta A, Bryant D . Involvement of RhoA, ROCK I and myosin II in inverted orientation of epithelial polarity. EMBO Rep. 2008; 9(9):923-9. PMC: 2529350. DOI: 10.1038/embor.2008.135. View

Campbell F, Loughrey M, McClements J, Deevi R, Javadi A, Rainey L . Mechanistic Insights into Colorectal Cancer Phenomics from Fundamental and Organotypic Model Studies. Am J Pathol. 2018; 188(9):1936-1948. PMC: 6240511. DOI: 10.1016/j.ajpath.2018.05.021. View

Nassar H, Pansare V, Zhang H, Che M, Sakr W, Ali-Fehmi R . Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Mod Pathol. 2004; 17(9):1045-50. DOI: 10.1038/modpathol.3800166. View

Cadioli A, Rossi G, Costantini M, Cavazza A, Migaldi M, Colby T . Lung cancer histologic and immunohistochemical heterogeneity in the era of molecular therapies: analysis of 172 consecutive surgically resected, entirely sampled pulmonary carcinomas. Am J Surg Pathol. 2014; 38(4):502-9. DOI: 10.1097/PAS.0000000000000154. View

Kamiya K, Hayashi Y, Douguchi J, Hashiguchi A, Yamada T, Izumi Y . Histopathological features and prognostic significance of the micropapillary pattern in lung adenocarcinoma. Mod Pathol. 2008; 21(8):992-1001. DOI: 10.1038/modpathol.2008.79. View

10.

Wu Q, You L, Nepovimova E, Heger Z, Wu W, Kuca K . Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. J Hematol Oncol. 2022; 15(1):77. PMC: 9166526. DOI: 10.1186/s13045-022-01292-6. View

11.

Nicholson A, Tsao M, Beasley M, Borczuk A, Brambilla E, Cooper W . The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. J Thorac Oncol. 2021; 17(3):362-387. DOI: 10.1016/j.jtho.2021.11.003. View

12.

Semenza G . Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3(10):721-32. DOI: 10.1038/nrc1187. View

13.

Bryant D, Roignot J, Datta A, Overeem A, Kim M, Yu W . A molecular switch for the orientation of epithelial cell polarization. Dev Cell. 2014; 31(2):171-87. PMC: 4248238. DOI: 10.1016/j.devcel.2014.08.027. View

14.

Shi R, Bao X, Unger K, Sun J, Lu S, Manapov F . Identification and validation of hypoxia-derived gene signatures to predict clinical outcomes and therapeutic responses in stage I lung adenocarcinoma patients. Theranostics. 2021; 11(10):5061-5076. PMC: 7978303. DOI: 10.7150/thno.56202. View

15.

Jubelin C, Munoz-Garcia J, Griscom L, Cochonneau D, Ollivier E, Heymann M . Three-dimensional in vitro culture models in oncology research. Cell Biosci. 2022; 12(1):155. PMC: 9465969. DOI: 10.1186/s13578-022-00887-3. View

16.

Sakamoto K, Watanabe M, De La Cruz C, Honda H, Ise H, Mitsui K . Primary invasive micropapillary carcinoma of the colon. Histopathology. 2005; 47(5):479-84. DOI: 10.1111/j.1365-2559.2005.02241.x. View

17.

Mikami Y, Hisatsune A, Tashiro T, Isohama Y, Katsuki H . Hypoxia enhances MUC1 expression in a lung adenocarcinoma cell line. Biochem Biophys Res Commun. 2009; 379(4):1060-5. DOI: 10.1016/j.bbrc.2009.01.002. View

18.

Vitale M, Parodi M . Blocking HIF to Enhance NK Cells: Hints for New Anti-Tumor Therapeutic Strategies?. Vaccines (Basel). 2021; 9(10). PMC: 8539190. DOI: 10.3390/vaccines9101144. View

19.

Gonzalez H, Hagerling C, Werb Z . Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018; 32(19-20):1267-1284. PMC: 6169832. DOI: 10.1101/gad.314617.118. View

20.

Somlyo A, Somlyo A . Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev. 2003; 83(4):1325-58. DOI: 10.1152/physrev.00023.2003. View