Clinical involvement of Dickkopf protein‐related protein 3 (DKK3) and Prolyloligopeptidase with tumor progression and metastasis onset of Glioblastoma multiforme
Authors: Esposito Emanuela , Giovanna Casili , Caffo Maria , Campolo Michela , Paterniti Irene , Cuzzocrea Salvatore 
Published: May 2022

Glioma are common malignant brain tumors, among which glioblastoma multiforme (GBM) has the worst prognosis. GBM is characterized by diffuse infiltration of the brain tissue surrounding the bulk of the tumor, associated with chromosomal and genetic mutations that determine the uncontrolled growth of brain cells and tumor cell chemoresistance. Glioblastomas only rarely metastasize to sites outside the central nervous system, for reasons that are poorly understood, however, recent investigations of other tumor types have suggested that particular molecular features may correlate with metastatic potential such as the activation of many angiogenic factors. Aberrant Wnt signaling has been described as a key player in the initiation of and/or maintenance and development of glioma and Dickkopf protein‐related protein 3 (Dkk‐3), as a tumor suppressor, represents the most promising modulators of the Wnt pathway. Moreover, prolyl‐oligopeptidase (PREP) is a serine protease involved in the angiogenesis and inflammatory process and many research studies highlighted the role of this protein in the metastasis spread.

The aim of the present study was to evaluate the possible correlation between Dkk‐3 expression and different GBM patients’ parameters in the regulation of tumor growth processes, by investigating the possible role of PREP in GBM‐related metastasis.

Biopsies of GBM and GBM‐related metastasis were taken from patients operated at the Neurosurgery of the Polyclinic “G. Martino” of Messina. The study included 20 cases of GBM of different histological grading, taken by female and male patients, aged between 43 to 77 years. The statistical analysis was performed correlating the extent of Dkk‐3 expression of the single GMB samples with different patient parameters: gender, age, survival and % Ki‐67 labeling index as well the evaluation of PREP modulation in GBM‐related metastasis.

Clinical data showed that the down‐regulation of Dkk‐3 was correlated with survival and age; specifically, a low expression of Dkk‐3 tends to be higher in male patients compared to female patients, with an age media of 57 years. Instead, the analysis between Dkk‐3 expression and survival after the first GBM surgery did not show a statistically significant correlation. Also, increased reactivity for Ki67 and ATRX was found in biopsies of patients with Dkk‐3 overexpression, associated with an incidence of the mutation in the gene encoding the isocitrate dehydrogenase IDH132. Moreover, a significant PREP expression was found in both GBM primary tumor and GBM‐related metastasis.

In conclusion, the overexpression of Dkk‐3 on GBM samples showed a significant reduction of these markers in biopsies of cancer patients compared to controls, while PREP modulation could slow down metastatic expansion by reducing angiogenesis, suggesting new possible molecular targets for future therapeutic protocols.