Elevated circulating DKK1 is associated with pulmonary vascular remodeling in early-stage non-small cell lung cancer
M X Xu, M M Li, X L Liu, X Li, S Dai, M ZhangAbstract
Background
As lung cancer enters the era of chronic management, comorbidities increasingly impact long-term survival. Notably, pulmonary vascular remodeling and secondary pulmonary hypertension (PH) significantly compromise cardiopulmonary reserve and increase mortality, largely independent of tumor stage. Although clinical evidence links lung cancer to PH, the mechanisms remain elusive. Dickkopf-1 (DKK1), a secreted glycoprotein upregulated in lung cancer, promotes progression and is currently a therapeutic target in trials. However, whether elevated DKK1 acts as a "bridging molecule" to mediate lung cancer-associated pulmonary vascular remodeling remains unknown.
Purpose
To evaluate the association of circulating DKK1 with pulmonary artery systolic pressure (PASP) and pulmonary vascular remodeling in early-stage non-small cell lung cancer (NSCLC), and to characterize DKK1 expression and localization in tumor tissues and the pulmonary vasculature.
Methods
Plasma DKK1 levels were measured via ELISA in 97 early-stage NSCLC patients and 30 age- and sex-matched controls. PASP was estimated using echocardiography. The correlation between DKK1 and PASP was analyzed. Pulmonary arteriole remodeling was evaluated histologically in patient tissues. In vivo, orthotopic A549 tumor-bearing and LSL-Kras^G12D/+ genetically engineered mice were established. Distal pulmonary arteriole muscularization was assessed using Elastica-Masson and α-SMA staining. Hemodynamics and right heart remodeling were evaluated via right ventricular systolic pressure (RVSP) and the Fulton index [RV/(LV+S)]. DKK1 localization was determined via immunofluorescence.
Results
Plasma DKK1 was significantly elevated in NSCLC patients compared to healthy controls (median 2,285 vs. 636 pg/mL, P<0.01). DKK1 positively correlated with PASP (r=0.48, P<0.01), and patients in the highest DKK1 tertile exhibited significantly higher PASP than those in the lowest tertile (P=0.01). Histopathology revealed prominent pulmonary arteriole remodeling within tumor regions. In both murine models, elevated circulating DKK1 was accompanied by aggravated pulmonary vascular remodeling, significantly increased RVSP, RV/(LV+S), and distal arteriole muscularization (all P<0.001). Dual immunofluorescence demonstrated enhanced DKK1 signals in both tumor tissues and pulmonary artery endothelial cells.
Conclusion
Elevated circulating DKK1 in early-stage NSCLC is strongly associated with higher PASP and pulmonary arteriole remodeling. The upregulation of DKK1 in tumor tissues and pulmonary artery endothelial cells suggests its potential involvement in lung cancer-associated pulmonary vascular abnormalities. DKK1 holds significant promise as a novel biomarker and therapeutic target for tumor-associated PH, warranting further mechanistic investigations.