Osteopontin is a prognostic circulating biomarker in patients with neuroendocrine neoplasms

Abstract

Purpose: Osteopontin (OPN), also called secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and which has been shown to be involved in tumorigenesis and metastasis in many malignancies. Its role in neuroendocrine neoplasms (NEN) remains to be established. The aim of the study was to analyze plasma concentrations of OPN in patients with NEN and to explore its diagnostic and prognostic value as a clinical biomarker.

Methods: OPN plasma concentrations were measured in a total of 38 patients with histologically proven NEN at three different time points during the course of disease and therapy (at the start of the study, after 3 and 12 months, respectively) as well as in healthy controls. Clinical and imaging data as well as concentrations of Chromogranin A (CgA) and Neuron Specific Enolase (NSE) were assessed.

Results: OPN levels were significantly higher in patients with NEN compared to healthy controls. High-grade tumors (grade 3) showed the highest OPN levels. OPN levels were neither different between male and female patients nor between different primary tumor sites. OPN correlated significantly with corresponding NSE levels, while there was no correlation with Chromogranin A. High OPN levels above a cutoff value of 200 ng/ml at initial analysis predicted a worsened prognosis with significantly shorter progression-free survival of patients with NEN, which also held true within the subgroup of well-differentiated G1/G2 tumors.

Conclusion: Our data indicate that high baseline OPN levels in patients with NEN are predictive of an adverse outcome with shorter progression-free survival, even within the group of well differentiated G1/G2 tumors. Therefore, OPN may be used as a surrogate prognostic biomarker in patients with NEN.

Keywords: Biomarker; Chromogranin A; Neuroendocrine neoplasm; Osteopontin; Survival.

Fig. 1

Plasma OPN levels are elevated in Patients with NEN. a Plasma concentration of Osteopontin was significantly higher in patients with neuroendocrine malignancies as compared to healthy controls. b OPN plasma concentrations revealed no influence of patient gender. Violin plots are shown; the median is indicated by the bold dotted line, the thin dotted lines indicate the quartiles. (Unpaired t-test p (*) < 0.05). OPN, osteopontin; NEN, neuroendocrine neoplasms; NEC, neuroendocrine carcinoma)

Fig. 2

OPN levels are significantly elevated in patients with G3 tumors. a The concentration of OPN was significantly higher in patients with G3 tumors throughout the course of disease and therapy in our patient cohort (a–c). Violin plots are displayed; the median is indicated by the bold dotted line, the thin dotted lines indicate the quartiles. (Unpaired t-test p (****) < 0.0001; p (**) < 0.003)

Fig. 3

Relevance of primary tumor localization. Circulating concentrations of OPN showed no correlation with primary tumor location. This could be observed at all three different time points when analyses were performed (a–c). Violin plots are displayed; the median is indicated by the bold dotted line, the thin dotted lines indicate the quartiles (Unpaired t-test, no significance)

Fig. 4

OPN levels and therapeutic response. OPN plasma levels were evaluated at three different time points and patients who remained stable were compared to patients that showed progressive disease. No significant correlation was found

Fig. 5

Correlation of OPN plasma levels (ng/ml) with Chromogranin A (CgA; ng/ml) and Neuron specific enolase (NSE; μg/l) levels. Circulating OPN levels were compared to corresponding CgA and NSE values at the start of surveillance (a&b). No correlation was found between OPN and CgA levels. OPN and NSE levels showed a significant correlation (p (***) < 0.0003)

Fig. 6

Correlation of OPN plasma levels (ng/ml) with Ki-67 levels (%). Circulating OPN levels were compared to corresponding Ki-67 values at the start of surveillance. We found a significant correlation between OPN and Ki-67 levels

Fig. 7

Correlation of circulating OPN levels with progression free survival (PFS). When using a cutoff concentration of 200 ng/ml we observed that lower plasma OPN concentrations indicated significantly longer PFS

Fig. 8

Correlation of circulating OPN levels with Progression free survival (PFS) in G1 and G2 cases. When using a cutoff concentration of 200 ng/ml we observed that lower plasma OSP concentrations still indicated significantly longer PFS