Cancer Associated Fibroblasts Promote Renal Cancer Progression Through a TDO/Kyn/AhR Dependent Signaling Pathway.

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Cancer-associated fibroblasts (CAFs) are key players in tumor development.
• The precise mechanisms by which CAFs drive renal cancer progression are not fully understood.
• CAFs are frequently found in malignant tumors, suggesting a significant role.

Purpose of the Study:

• To investigate the role of CAFs in renal cancer progression and drug resistance.
• To elucidate the molecular mechanisms linking CAFs to renal cancer.
• To identify potential therapeutic targets for renal cancer treatment.

Main Methods:

• Isolation and characterization of CAFs from renal cancer tissues.
• In vitro and in vivo experiments to assess CAF-mediated tumor promotion and drug resistance.
• Analysis of signaling pathways including TDO, kynurenine, AhR, AKT, and STAT3.
• Evaluation of therapeutic interventions targeting the identified pathways.

Main Results:

• Enriched CAFs were observed in high-grade malignant renal tumors.
• Isolated CAFs promoted tumor progression and drug resistance in vitro and in vivo.
• CAFs up-regulated TDO expression, increasing kynurenine secretion.
• Kynurenine activated the AhR, leading to AKT and STAT3 pathway activation.
• Inhibition of AKT suppressed proliferation; inhibition of STAT3 reversed drug resistance and migration.
• AhR inhibition (DMF) suppressed metastasis and enhanced sorafenib/sunitinib efficacy.

Conclusions:

• CAFs promote renal cancer progression and drug resistance through the TDO-kynurenine-AhR-AKT/STAT3 axis.
• Targeting the kynurenine pathway and AhR presents a novel therapeutic strategy for renal cancer.
• Combined inhibition of AhR and standard therapies shows potential for improved clinical outcomes.