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TIMP1 Derived from Mesenchymal Stem Cells Promotes Bladder Cancer Progression by Regulating the Formation of VDIMs

Pan Li1,2, Enguang Yang1, Xinyu Zhang1

  • 1Department of Urology, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.

International Journal of Biological Sciences
|April 20, 2026
PubMed

Insights

Mesenchymal stem cells (MSCs) promote bladder cancer (BC) by secreting TIMP1, which activates the RAP1 pathway. Inhibiting this MSCs-TIMP1-RAP1 axis offers a potential new therapy for BC.

Area of Science:

  • Oncology
  • Cancer Biology
  • Stem Cell Biology

Background:

  • The role of mesenchymal stem cells (MSCs) in bladder cancer (BC) progression is not fully understood.
  • Identifying specific molecular mechanisms by which MSCs influence BC is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the pro-tumorigenic function of MSCs in bladder cancer.
  • To identify key molecules secreted by MSCs that drive BC progression.
  • To elucidate the underlying molecular mechanisms and evaluate therapeutic strategies targeting the MSCs-BC axis.

Main Methods:

  • Integration of clinical cohorts, organoid models, and patient-derived xenografts (PDX).
  • Multiplex fluorescent immunohistochemistry and enzyme-linked immunosorbent assays to assess MSCs infiltration and TIMP1 levels.
  • Single-cell data analysis, mass spectrometry, and mechanistic studies involving signaling pathway analysis (cMet, RAP1).

Main Results:

  • Elevated MSCs infiltration and TIMP1 levels in BC tissues and urine correlate with advanced stage, lymphovascular invasion, and poorer survival.
  • TIMP1 is the predominant cytokine secreted by MSCs, acting via ADAM10 to stabilize cMet phosphorylation and activate the RAP1 pathway.
  • MSC-derived TIMP1 promotes BC proliferation by enhancing intracellular Ca2+ and VDAC1 expression, impacting mitochondrial quality control.
  • A TIMP1 inhibitor (FXR agonist 3) suppressed BC proliferation and tumor growth in PDX models by disrupting the cMet-RAP1 pathway without toxicity.

Conclusions:

  • MSCs-derived TIMP1 is a key driver of bladder cancer progression through the cMet-RAP1 signaling axis.
  • Targeting the MSCs-TIMP1-RAP1 axis represents a promising novel therapeutic strategy for bladder cancer.
Keywords:
Bladder cancerRAS-related protein 1Tissue inhibitor of metalloproteinases 1Vesicles derived from the inner mitochondrial membrane.

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