Abstract
Pregnancy-associated plasma protein-A (PAPP-A) and its homolog PAPP-A2 are enzymes that modulate the availability and mitogenic activity of insulin-like growth factor-I (IGF-I). PAPP-A has been implicated in numerous cancers but reports on PAPP-A2 in malignancy are non-existent. In a prospective observational study of 689 patients under suspicion of lung cancer, we examined levels of PAPP-A and PAPP-A2 and their relationship with mortality. Serum PAPP-A and PAPP-A2 concentrations were determined in pre-diagnostic blood samples using ELISA, and immunohistochemical staining of PAPP-A and PAPP-A2 was performed in malignant tissue from five operable patients. A total of 144 patients were diagnosed with lung cancer, whereas the diagnosis was rejected in 545 subjects, who served as a control group. PAPP-A2 concentrations were higher in patients with lung cancer [median (IQR): 0.33 (0.21–0.56) ng/mL] than in controls [0.27 (0.17–0.39) ng/mL], p < 0.001, whereas PAPP-A levels did not differ. Presence of PAPP-A and PAPP-A2 were confirmed in tumor specimens, and staining occurred in a heterogeneous pattern. Patients were observed for a median (range) of 7 (6; 8) years, during which 114 patients (79.2%) died. Patient mortality differed according to PAPP-A2 tertile (p < 0.001). PAPP-A2 was associated with mortality with an unadjusted hazard ratio (95% CI) per doubling in protein concentration of 1.30 (1.12; 1.53), p = 0.001. In a multivariable model adjusted for age, sex, and BMI, PAPP-A2 remained predictive of the endpoint with a hazard ratio per doubling in protein concentration of 1.25 (1.05; 1.48), p = 0.013. Collectively, PAPP-A2, but not PAPP-A, is elevated in patients with lung cancer and associated with mortality. This novel role of PAPP-A2 in cancer warrants further functional studies as well as validation in external cohorts.
Highlights
Lung cancer is one of the most common human malignancies worldwide with considerable attendant societal costs
PAPP-A2 was recently established as a regulator of the IGF axis in human physiology [14], the biology of PAPP-A2 is poorly understood compared to plasma protein-A (PAPP-A) [15], and there are currently no reports linking PAPP-A2 protein and cancer mortality [9]
Patients with squamous non-small cell lung carcinoma (NSCLC) exhibited a distinct pattern in their biochemical profile, suggesting a higher degree of inflammation than in patients with other subtypes
Summary
Lung cancer is one of the most common human malignancies worldwide with considerable attendant societal costs. Insulin-like growth factor I (IGF-I) is a pivotal player in the multifaceted process of malignant disease, including lung cancer, and signaling through the IGF-I receptor (IGF-IR) stimulates mitogenesis, metabolism, and anti-apoptosis [1, 2]. Pregnancy-associated plasma protein-A (PAPP-A) and PAPPA2 comprise the only two known members of the pappalysin family of metalloproteinases, sharing 45% amino acid identity [3, 4]. They are responsible for proteolytic cleavage of a subset of IGF-binding proteins (IGFBPs), through which they increase IGF availability and potentiate its growth stimulatory effects [5]. PAPP-A2 was recently established as a regulator of the IGF axis in human physiology [14], the biology of PAPP-A2 is poorly understood compared to PAPP-A [15], and there are currently no reports linking PAPP-A2 protein and cancer mortality [9]
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