Exploring the Role of Matrix Metalloproteinases as Biomarkers in Sporadic Lymphangioleiomyomatosis and Tuberous Sclerosis Complex. A Pilot Study

Abstract

Background: Lymphangioleiomyomatosis can develop in a sporadic form (S-LAM) or in women with tuberous sclerosis complex (TSC). The matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes potentially involved in cystic lung destruction, and in the process of migration of LAM cells. The aim of the study was to explore the role of MMP-2 and MMP-7, such as vascular endothelial growth factor (VEGF) -C and -D in women with LAM, including patients with minor pulmonary disease (i.e., <10 lung cysts), and TSC with or without LAM. Methods: We evaluated 50 patients: 13 individuals affected by S-LAM, 20 with TSC-LAM, of whom six with minor pulmonary disease, and 17 with TSC without pulmonary involvement. Sixteen healthy women were used as controls. Results: MMP-2 resulted higher in LAM compared to healthy volunteers, and TSC patients (p = 0.040). MMP-7 was higher in TSC-LAM patient, with even greater values in patients with TSC-LAM minor pulmonary disease, than in S-LAM patients, and in controls (p = 0.001). VEGF-D level was lower than 800 pg/mL in all healthy controls and resulted higher in S-LAM and TSC-LAM than in TSC patients and controls (p < 0.001). VEGF-C values were not statistically different in the study population (p = 0.354). The area under ROC curves (AUCs) of MMP-2, and MMP-7 for predicting LAM diagnosis were of 0.756 ± 0.079 (p = 0.004), and 0.828 ± 0.060 (p < 0.001), respectively. Considering only patients with TSC, the AUCs for MMP-2, and MMP-7 in predicting LAM were 0.694 ± 0.088 (p = 0.044), and 0.713 ± 0.090 (p = 0.027), respectively. Conclusions: Our data suggest that MMP-2 and MMP-7 could be promising biomarkers for LAM diagnosis.

Keywords: biomarkers; lymphangiomeiomyomatosis; matrix metalloproteinases; tuberous sclerosis complex; vascular endothelial growth factor.

Figure 1

Distribution of MMP-2 (A) p = 0.040, MMP-7 (B) p = 0.001, VEGF-D (C) p < 0.001, VEGF-C (D) p = 0.354, in the study population (p refers to ANOVA); LAM, lymphangioleiomyomatosis; TSC, tuberous sclerosis complex; minor pulmonary disease: patients with <10 cysts identified at chest CT scan; bar represents the median value, dashed line represents VEGF-D value of 800 pg/mL.

Figure 2

(A) VEGF-D was an effective diagnostic test to predict LAM [area under curve (AUC): 0.879 ± 0.049 (95% CI: 0.782–0.975), p < 0.001] continuous line, respect to MMP2 [AUC: 0.756 ± 0.079 (95% CI: 0.601–0.910)], dotted line, and MMP7 [0.828 ± 0.060 (95% CI: 0.710–0.945), p < 0.001], punctuate line. (B) Specificity of VEGF-D for LAM disease in TSC patients was lower than in previous analysis but remains significant [AUC: 0.791 ± 0.077 (95% CI: 0.640–0.941), p = 0.003], continuous line. MMP-2 has lower accuracy than VEGF-D with an AUC of 0.694 ± 0.088 (95% CI: 0.521–0.867), p = 0.044, dotted line and similarly MMP-7 has an AUC of 0.713 ± 0.090 (95% CI: 0.538–0.889), p = 0.027, punctuate line.