TY - JOUR
T1 - Akt-girdin signaling in cancer-associated fibroblasts contributes to tumor progression
AU - Yamamura, Yumiko
AU - Asai, Naoya
AU - Enomoto, Atsushi
AU - Kato, Takuya
AU - Mii, Shinji
AU - Kondo, Yuji
AU - Ushida, Kaori
AU - Niimi, Kaoru
AU - Tsunoda, Nobuyuki
AU - Nagino, Masato
AU - Ichihara, Shu
AU - Furukawa, Koichi
AU - Maeda, Kengo
AU - Murohara, Toyoaki
AU - Takahashi, Masahide
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - PI3K-Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment.
AB - PI3K-Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment.
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UR - http://www.scopus.com/inward/citedby.url?scp=84928695162&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-14-1317
DO - 10.1158/0008-5472.CAN-14-1317
M3 - Article
C2 - 25732845
AN - SCOPUS:84928695162
SN - 0008-5472
VL - 75
SP - 813
EP - 823
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -