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Updated: Jun 16, 2026

An Orthotopic Model of Murine Bladder Cancer
Published on: February 6, 2011
ADGRD1 promotes bladder cancer progression and angiogenesis via the PI3K/AKT/mTOR-mediated pro-angiogenic secretome
Chen Li1, Zhichao Yang2, Jialei Zhang2
1Department of Urology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China.
Background:
Bladder cancer (BLCA) remains a major cause of cancer-related mortality, particularly in advanced and metastatic stages. Identifying molecular drivers of tumor aggressiveness is critical for developing targeted therapies. Adhesion G protein-coupled receptor D1 (ADGRD1, also known as GPR133) is an orphan aGPCR recently implicated in tumorigenesis. However, its role in bladder cancer and underlying signaling mechanisms remain unknown.
Methods:
The clinical significance of ADGRD1 was analyzed using GEPIA3 datasets, focusing on clinical stage and prognosis. Stable ADGRD1-knockdown and overexpression BLCA cell lines were established. qPCR, Western blot, CCK-8, colony formation, wound-healing, Transwell, and HUVEC tube formation assays were used to assess proliferation, migration, invasion, and angiogenesis. Xenograft models were used to evaluate in vivo tumor growth. PI3K/AKT/mTOR pathway activity was examined by Western blot, and its function validated using SC79 (AKT activator) and LY294002 (PI3K inhibitor).
Results:
ADGRD1 expression was significantly enriched in advanced-stage and high-grade BLCA, where it serves as a robust predictor of poor overall survival and progression-free interval. Functional assays demonstrated that ADGRD1 promotes BLCA cell proliferation, migration, invasion, and endothelial tube formation in vitro, and enhances tumor growth and angiogenesis in vivo. Importantly, ADGRD1-high cells enhanced endothelial tube formation by upregulating a secretome rich in VEGF, PDGF, and IL-8. Mechanistically, ADGRD1 activated the PI3K/AKT/mTOR signaling cascade, as evidenced by increased phosphorylation of pathway components. Pharmacological inhibition of PI3K/AKT/mTOR reversed the oncogenic and pro-angiogenic effects of ADGRD1.
Conclusions:
This study identifies ADGRD1 as a key progression-associated driver in BLCA. By modulating the PI3K/AKT/mTOR signaling axis and the pro-angiogenic microenvironment, ADGRD1 facilitates tumor growth and neovascularization. ADGRD1 may serve as a promising prognostic biomarker and therapeutic target for advanced BLCA.
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Activation of Integrins
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
