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© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Recent studies have shown that the tumor microenvironment plays a significant role in the progression of solid tumors. As an abundant component of the tumor microenvironment, cancer‐associated fibroblasts (CAFs) have been shown to promote tumorigenesis and cancer aggressiveness, but their molecular characteristics remain poorly understood. In the present study, paired CAFs and normal fibroblasts (NFs) were isolated from five colorectal cancer (CRC) tissues from patients who underwent surgical resection. The gene expression profiles of CAFs and NFs identified by RNA sequencing were compared to understand the complex role of CAFs in cancer progression. Gene Set Enrichment Analysis revealed that the gene sets related to the Wnt signaling pathway were highly enriched in CAFs, as well as TGFβ signaling, which is considered to be a regulator of CAFs. Among the components of this pathway, Wnt2 was specifically expressed. The observations led us to speculate that Wnt2 is extremely involved in regulating CRC progression by CAFs. Thus, we performed immunohistochemical analysis on Wnt2 in 171 patients who underwent surgery for colorectal adenocarcinoma. Positive staining for Wnt2 was mainly observed in cancer stroma, although the immunoreactivity was weak in cancer cells. Wnt2 expression in CAFs was significantly correlated with depth of tumor (P < .001), lymph node metastasis (P = .044), TNM stage (P = .010), venous invasion (P < .001), and recurrence (P = .013). Subsequent in vitro analyses were conducted using conditioned medium (CM) from immortalized CAFs transfected with siRNA targeting Wnt2. As a result, cancer cell invasion and migration were significantly decreased in the CM from immortalized CAFs transfected with siRNA targeting Wnt2. Our findings indicated that Wnt2 protein released from CAFs enhances CRC cell invasion and migration. In conclusion, Wnt2 secreted by CAFs plays a key role in cancer progression and is a potential therapeutic target for CRC.

Details

Title
Cancer‐associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer
Author
Aizawa, Takashi 1 ; Karasawa, Hideaki 1   VIAFID ORCID Logo  ; Funayama, Ryo 2 ; Shirota, Matsuyuki 3 ; Suzuki, Takashi 4   VIAFID ORCID Logo  ; Maeda, Shimpei 1 ; Suzuki, Hideyuki 1 ; Yamamura, Akihiro 1 ; Naitoh, Takeshi 1 ; Nakayama, Keiko 2 ; Unno, Michiaki 1 

 Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan 
 Department of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan 
 Division of Interdisciplinary Medical Science, ART, Tohoku University Graduate School of Medicine, Sendai, Japan 
 Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan 
Pages
6370-6382
Section
CANCER BIOLOGY
Publication year
2019
Publication date
Oct 2019
Publisher
John Wiley & Sons, Inc.
e-ISSN
20457634
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2306361972
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.