期刊
CANCER LETTERS
卷 372, 期 2, 页码 210-218出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.01.016
关键词
Pancreatic cancer; Hypoxia; Pancreatic stellate cell; PLOD2; ECM remodeling
类别
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) [26108010, 26293305, 15H04933, 25293285]
- Grants-in-Aid for Scientific Research [26670607, 15H04933, 25293285, 26108001, 26462062, 15K19895, 25461024, 26293305, 25462117, 26861084, 15K10185, 26462063, 26108010] Funding Source: KAKEN
Desmoplasia and hypoxia in pancreatic cancer mutually affect each other and create a tumor-supportive microenvironment. Here, we show that microenvironment remodeling by hypoxic pancreatic stellate cells (PSCs) promotes cancer cell motility through alteration of extracellular matrix (ECM) fiber architecture. Three-dimensional (3-D) matrices derived from PSCs under hypoxia exhibited highly organized parallel patterned matrix fibers compared with 3-D matrices derived from PSCs under normoxia, and promoted cancer cell motility by inducing directional migration of cancer cells due to the parallel fiber architecture. Microarray analysis revealed that procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in PSCs was the gene that potentially regulates ECM fiber architecture under hypoxia. Stromal PLOD2 expression in surgical specimens of pancreatic cancer was confirmed by immunohistochemistry. RNA interference-mediated knockdown of PLOD2 in PSCs blocked parallel fiber architecture of 3-D matrices, leading to decreased directional migration of cancer cells within the matrices. In conclusion, these findings indicate that hypoxia-induced PLOD2 expression in PSCs creates a permissive microenvironment for migration of cancer cells through architectural regulation of stromal ECM in pancreatic cancer. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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