Recurrent Glioblastomas Exhibit Higher Expression of Biomarkers with Stem-like Properties

Abstract

Background:Despite advances in the treatment of glioblastoma (GBM), the prognosis of patients continues to remain dismal. This unfavorable prognosis is mainly attributed to the tumor's propensity for progression and recurrence, which in turn is due to the highly aggressive nature of the persisting GBM cells that actively egress from the main tumor mass into the surrounding normal brain tissue. Such a recurrent tumor described to have a more malignant potential is highly invasive and resistant to current therapies, probably due to increased stemness and preferential selection of therapy-resistant clones of tumor cells. However, there is a paucity of literature on the expression of biomarkers in the recurrent GBM tumors that could have a role in conferring this aggressiveness.Aim:To identify the differences in the expression pattern of selected biomarkers in paired tissue samples of GBM.Material and Methods:A retrospective study on 30 paired samples of GBM (newly diagnosed/primary and recurrent) archived in the Department of Neuropathology, NIMHANS (2006–2009), was carried out. After obtaining clinical and demographic details, tumors were characterized histomorphologically and immunohistochemically on formalin-fixed paraffin-embedded tissues with reference to expression of biomarkers such as p53, epidermal growth factor receptor (EGFR), insulin-like growth factor binding protein 3 (IGFBP-3), sex determining region Y-box 2 (SOX2), and topoisomerase 2 A (Top2A). The results were statistically analyzed.Results:It was observed that while p53 and IGFBP-3 expression remained unaltered in paired samples, a significant increase in the expression of EGFR (P < 0.01) was noted in the recurrent tumors. Among the other biomarkers, SOX2 expression was higher in the recurrent tumors when compared to the primary tumors (P < 0.01). Conversely, the expression of Top2A was reduced in recurrent tumors (P = 0.05). Mild elevation in the expression of IGFBP-3 was observed in recurrent tumors but was not statistically significant.Conclusion:A significant increase in the expression of SOX2 in recurrent tumors probably indicates the presence of undifferentiated cells with stem-like properties in these tumors. EGFR is known to mediate SOX2 expression thereby resulting in stemness of the glioma cancer cells, which could further explain its overexpression in recurrent GBMs. Furthermore, a decreased expression of TOP2A observed in the recurrent tumors could probably be due to reduction in chemosensitivity to temozolomide, which has been shown in earlier studies. We also noted that p53 expression remained unaltered in the recurrent tumors when compared to the primary, suggesting the absence of preferential clonal expansion of p53 mutant cells following exposure to radiochemotherapy. Our study reiterates the fact that GBM recurrences are associated with molecular alterations that probably contribute to radiochemoresistance, increased invasiveness, therapeutic efficacy, and stemness.

The p53 Pathway in Glioblastoma

“…The prevalence of p53 mutations differs in the different GBM molecular subtypes (proneural, mesenchymal, neural and classical) (54%, 32%, 21% and 0%, respectively) [ 15 ]. TP53 expression has been compared in newly diagnosed patients and recurrent tumors with inconsistent results as to whether expression is altered upon recurrence [ 16 , 17 , 18 ]. In this review, we summarize the current understanding of p53 in GBM.…”

Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma

“…Developing a therapy directed against these stem cells could be the “treatment of choice”. However, expression patterns of candidate stem cell markers between primary and recurrent tumors and their possible impact on survival have not been investigated thoroughly so far [ 37 – 40 ]. We identified a significant increase of Musashi and Nestin expression from primary to recurrent tumors in our cohort.…”

Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53–PUMA Apoptosis Pathway

“…GBM arises de novo (primary GBM) or via the dedifferentiation of lower-grade glioma (secondary GBM) (42). While distinct mutations are predominant in each subtype, alterations of the tumor suppressor p53 are the most common (43). These molecular alterations of GBM significantly affect tumor susceptibility to chemotherapy and, thus, patient prognosis (19)(20)(21).…”