Lung adenocarcinoma invasion in TGFbetaRII-deficient cells is mediated by CCL5/RANTES

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Lung adenocarcinoma subtypes exhibit varying histological invasiveness.
• Type II transforming growth factor-beta receptor (TGFbetaRII) expression is lower in more invasive lung adenocarcinoma subtypes.
• TGF-beta signaling pathways are implicated in cancer progression.

Purpose of the Study:

• To investigate the role of chemokine CCL5 (RANTES) as a mediator of TGF-beta signaling in lung adenocarcinoma invasion.
• To determine if RANTES is essential for invasion and progression in TGFbetaRII-deficient lung cancer cells.
• To assess the clinical relevance of the RANTES-CCR5 pathway in human lung adenocarcinoma.

Main Methods:

• Utilized a tumor cell invasion system to identify downstream mediators of TGF-beta signaling.
• Examined invasion in TGFbetaRII-deficient cells treated with RANTES inhibitors (Met-RANTES) and a CCR5 receptor-blocking antibody.
• Performed immunostaining for RANTES and CCR5 in human lung adenocarcinoma specimens and correlated expression with clinical outcomes.

Main Results:

• TGFbetaRII knockdown-induced invasion was blocked by inhibiting RANTES activity or CCR5.
• Moderate to high expression of both RANTES and CCR5 was significantly associated with an increased risk of death in lung adenocarcinoma patients (P=0.014 and P=0.002, respectively).
• RANTES signaling was confirmed to be necessary for invasion in TGFbetaRII-deficient cells.

Conclusions:

• RANTES signaling is a critical mediator of invasion in lung adenocarcinoma, especially in the context of TGFbetaRII deficiency.
• The RANTES-CCR5 pathway represents a potential therapeutic target for lung adenocarcinoma prevention and treatment.
• Inhibition of CCR5 may be a viable strategy to impede lung cancer progression.