Search

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain tumour in adults. Despite the current clinical management of surgical resection, followed by radiation and chemotherapy, the median survival time is still a dismal 15 months. This may be due to treatment-resistant GBM stem cells (GSCs) that survive and migrate, resulting in tumour recurrence. Therefore, elucidating the mechanisms of GSC migration and studying ways of limiting this process will be beneficial in the treatment of GBM. A key molecule of interest is polysialylated neural cell adhesion molecule (PSA-NCAM). During normal development and adult neurogenesis, its presence on the cell surface reduces interactions with the extracellular matrix and aids in cellular migration. However, it has also been associated with malignant brain tumours and with negative patient prognosis. METHODS: We investigated PSA-NCAM’s role in tumour recurrence by immunohistologically evaluating over 160 surgically resected brain tumour specimens for PSA-NCAM expression and correlating this with patient outcomes. We also utilized GSCs isolated from the same patient specimens to investigate the role of PSA-NCAM in tumour cell migration. RESULTS: Univariate and Cox proportional hazard analysis showed that PSA-NCAM expression was a strong predictor of rapid tumour progression, even more so than the cell proliferation marker Ki67, which is often used to assess tumour grade. In addition, high-content image analysis revealed that PSA-NCAM was highly expressed by migrating patient-derived GSCs in vitro, and drugs that limited their migration also decreased PSA-NCAM expression. This led to investigations that aimed to elucidate the effects of PSA-NCAM removal on GSC migration. SUMMARY: Our work highlights the potential role of PSA-NCAM in GSC migration and tumour progression. This opens up avenues to pharmacologically and genetically manipulate PSA-NCAM to reduce GBM cell migration and curb tumour recurrence.

The present study investigates whether the anti-schizophrenic drug risperidone may evoke changes in the expression of NCAM/PSA-NCAM proteins, an indispensable element in the remodeling of synaptic arrangements, in the medial prefrontal cortex (mPFC). Rats were treated with risperidone (0.2 mg/kg, i.p.) either once or repeatedly (once a day, for 21 days). The expression of NCAM and PSA-NCAM proteins was analyzed via western blot and immunohistochemistry at intervals of 3 h and 3, 6, and 9 days after the single or the last risperidone dose. Repeated (but not acute) administration of risperidone was found to increase the expression of NCAM-180, NCAM-140 and PSA-NCAM proteins at 3 or 6 days after treatment. PSA-NCAM immunoreactivity was found in cell bodies, perisomatic-like sites, and in the neuropil of the mPFC. Neither single nor repeated risperidone administration changed the number of PSA-NCAM neurons in the mPFC. In contrast, the repeated risperidone treatment increased the number of PSA-NCAM perisomatic-like sites and the length density of PSA-NCAM positive neuropil at 3 days after the last injection. The data obtained indicate that risperidone, given repeatedly, may promote the remodeling of the structure of presumably GABA-ergic interneurons and that it may evoke the rearrangement of the synaptic contact in the mPFC.

Contains fulltext : 135126.pdf (Publisher’s version ) (Closed access)

Recent data indicating that addictive substances are able to alter brain plasticity and its morphology inclined us to determine whether acute and chronic cocaine administration could modify the expression of a polysialylated form of the neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus of the rat hippocampus. Alterations in the PSA-NCAM expression are known to effect a variety of neuroanatomical rearrangements in the brain structure. Cocaine was administered acutely (15 mg/kg, i.p.) or repeatedly (15 mg/kg, i.p. once a day for five consecutive days). The number of PSA-NCAM immunopositive cells was determined at six time points after cocaine treatment: 6 h and 1, 2, 4, 6, and 10 days (both in acute and repeated treatment). It was found that a single injection of cocaine induced a time-dependent decrease in the number of PSA-NCAM cells in the dentate gyrus. The decrease was observed on day 1 after cocaine treatment and lasted for at least 6 days. In contrast, an increase in the number of PSA-NCAM-positive cells in the dentate gyrus was observed 2 and 4 days after the last dose of repeated cocaine. It is concluded that cocaine can evoke long-lasting changes in the PSA-NCAM protein expression in the dentate gyrus and that the direction of cocaine-induced PSA-NCAM changes depends on the regimen of cocaine administration. It is postulated that cocaine may have impact on hippocampal plasticity and subsequent processes that are controlled by plastic changes in the hippocampal structure.