Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression.
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.
Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan. Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Yumiko
Y
Yamamura
Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Naoya
N
Asai
Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Atsushi
A
Enomoto
Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Takuya
T
Kato
Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Shinji
S
Mii
Department of Biochemistry, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Yuji
Y
Kondo
Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Kaori
K
Ushida
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Kaoru
K
Niimi
Department of Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Nobuyuki
N
Tsunoda
Department of Surgery, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Masato
M
Nagino
Division of Pathology, Department of Advanced Diagnosis, Nagoya Medical Center, Nagoya, Aichi, Japan.
Shu
S
Ichihara
Department of Biochemistry, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Koichi
K
Furukawa
Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Kengo
K
Maeda
Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Toyoaki
T
Murohara
Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan. mtakaha@med.nagoya-u.ac.jp.
Masahide
M
Takahashi
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D033921:Vesicular Transport Proteins; C502451:CCDC88A protein, human; C527550:Ccdc88a protein, mouse