Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis

Abstract

The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in three NF2-associated and five sporadically operated recurrent VS after primary irradiation. We compared these findings with 49 non-irradiated (36 sporadic and 13 NF2-associated) VS through gene-expression profiling and pathway analysis. Furthermore, we stained the key molecules of the distinct pathway by immunohistochemistry. A total of 195 differentially expressed genes in sporadic and NF2-related comparisons showed significant differences based on the criteria of p value < 0.05 and a two-fold change. These genes were involved in pathways that are known to be altered upon irradiation (e.g., mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF) signaling). We observed a combined downregulation of PTEN signaling and an upregulation of mTOR signaling in progressive NF2-associated VS after irradiation. Immunostainings with mTOR and PTEN antibodies confirmed the respective molecular alterations. Taken together, mTOR inhibition might be a promising therapeutic strategy in NF2-associated VS progress after irradiation.

The biological underpinnings of radiation therapy for vestibular schwannomas: Review of the literature

“…Furthermore, the same tumors demonstrated downregulation of phosphate and tensin homolog (PTEN) signaling; PTEN downregulation leads to increased mTORC1 signaling via overactivation of the AKT/PKB pathway. Together, these findings suggest that increased mTORC1 activity plays a key role in VS radioresistance 95 . Mutations affecting the mTOR and PTEN pathway may therefore play a role in tumor transformation leading to recurrence or treatment escape following radiation therapy.…”

Collagen Family Genes Associated with Risk of Recurrence after Radiation Therapy for Vestibular Schwannoma and Pan-Cancer Analysis

“…[ 26 ] The expression of three collagen family genes (COL5A1, COL3A1, and COL4A1) was negatively correlated with the expression of NPY, which was found to promote the migration of macrophages in collagen in vitro [ 27 ]. The crosstalk between collagen production and radiotherapy has been studied extensively [ 16 , 17 ]. We have revealed an important function of these four collagen family genes ( COL5A1 , COL3A1 , COL4A1 , and COL15A1 ) in VS, and their high expression may be associated with VS radiotherapy recurrence.…”

“…Indeed, if the molecular biological features associated with VS recurrence can be identified, more precise VS treatments can be achieved. The GSE141801 dataset from the Gene Expression Omnibus (GEO) database analyzes the transcriptomic profile of tumors between patients with VS who relapsed after radiation therapy alone and another group of patients who underwent direct surgery without radiation therapy [ 16 ].…”

Understanding the Radiobiology of Vestibular Schwannomas to Overcome Radiation Resistance

“…In a retrospective investigation comparing 8 irradiated and 49 nonirradiated VS, Gugel et al found that progressive NF2-associated VS after irradiation demonstrated downregulation of phosphatase and tensin homolog (PTEN) and upregulation of mTOR signaling. These findings suggest that NF2-associated VS may resist radiation by downregulating the tumor suppressor PTEN while promoting PI3K/Akt signaling and overexpression of mTOR [ 215 , 216 ]. Because PTEN can initiate cell cycle arrest by inhibition of cyclin D [ 217 ], downregulation of PTEN may lead to radiation resistance in VS by promoting cell cycle progression and cell proliferation.…”