Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Tumor-associated endothelial cells (TECs) influence tumor progression and aggressiveness.
• The mechanisms by which TECs confer stem cell-like properties to tumors are not fully understood.

Purpose of the Study:

• To elucidate the role of TEC-expressed insulin growth factor binding protein-7 (IGFBP7) in regulating tumor stem-like cells (TSCs).
• To identify the molecular pathways involved in TECs' regulation of tumor aggressiveness and chemoresistance.

Main Methods:

• Utilized in vivo murine and human tumor models.
• Investigated the expression and function of IGFBP7, IGF1, IGF1R, FGF4, FGFR1, and ETS2 in TECs and TSCs.
• Analyzed the impact of chemotherapy on these molecular interactions.

Main Results:

• TECs express IGFBP7, which acts as a tumor suppressor by blocking IGF1 and inhibiting IGF1 receptor-positive (IGF1R+) TSC expansion.
• Chemotherapy downregulates TEC IGFBP7, leading to IGF1R+ TSCs expressing FGF4.
• This triggers a feedforward FGF4-FGFR1-ETS2 angiocrine cascade, promoting tumor cell conversion to chemoresistant TSCs and facilitating invasion.

Conclusions:

• Loss of IGFBP7 and upregulation of IGF1 activate the FGF4-FGFR1-ETS2 pathway in TECs.
• This pathway converts naive tumor cells into chemoresistant TSCs, driving tumor invasiveness and progression.
• IGFBP7 acts as a crucial tumor-suppressive checkpoint regulated by TECs.