Differential Expression of Somatostatin Receptors, P44/42 MAPK, and mTOR Activation in Medulloblastomas and Primitive Neuroectodermal Tumors

Abstract

Recently, somatostatin receptors (SSR) have been identified on medulloblastomas and proposed as a new target for chemotherapy including inhibitory somatostatin analogs. Activation of SSRs inhibit growth, in part, by activating phosphatases that dephosphorylate/deactivate growth stimulatory signaling of the MEK1-p44/42 MAPK and PI3K-Akt-mTOR pathways. These SSR-inhibited signaling pathways have not been characterized or correlated with SSR expression in medulloblastomas or primitive neuroectodermal tumors (PNETs), yet may represent additional targets for combined chemotherapy. We evaluated the distribution and extent of SSR1 and SSR2 expression and correlated it with activation of downstream MEK1-p44/42 MAPK and PI3K-Akt-mTOR pathways in medulloblastomas and PNETs. Sections from 22 medulloblastomas and 9 PNETs were compared using immunohistochemistry with monoclonal antibodies to SSR1, SSR2, p44/42 MAPK, phosphorylated p44/42 MAPK, and phosphorylated mTOR. SSR1 was detected in 50% of medulloblastomas, extensive in 46%, and similar in classic, desmoplastic, and large cell/anaplastic subtypes. SSR1 was detected in 78% of PNETs and extensive in the majority. SSR2 was found in 18% of medulloblastomas and 33% of PNETs. Activated/phosphorylated pMAPK 44/42 was detected in 82% of medulloblastomas, all subtypes, and in 62.5% of PNETs with coexpression of SSR1 in one third. Activated/phosphorylated mTOR was found in only 18% of medulloblastomas but in 88% of PNETs. SSR1 coexpression with activated/phosphorylated mTOR was identified in 75% of PNETs. These findings suggest that addition of an mTOR inhibitor may potentiate growth inhibitory effects of SSR agonists in the treatment of PNETs. Immunohistochemical identification of mTOR activation/phosphorylation in biopsies of initial and treatment-resistant PNETs may facilitate development of clinical trials and therapeutic decisions.

Immunohistochemical assessment and clinical, histopathologic, and molecular correlates of membranous somatostatin type-2A receptor expression in high-risk pediatric central nervous system tumors

“…Medulloblastomas in our cohort consistently expressed tumoral cell surface SST2A, in accord with previous reports describing SST2A expression within this histopathologic diagnosis when evaluated through a combination of different assays, including IHC, mRNA levels, somatostatin receptor autoradiography, somatostatin receptor scintigraphy, and/or SST2A-radiolabeled nuclear imaging (e.g., DOTATATE PET) ( 13 – 16 , 20 , 21 , 26 – 31 ). Our findings confirm and expand upon this earlier work by illustrating a high prevalence of membranous (i.e., functional and targetable) SST2A protein expression among medulloblastoma cases assessed by strict immunohistochemical measures.…”

“…Heterogeneous membranous SST2A expression was identified across other pediatric embryonal tumors. Earlier reports described mixed results regarding SST2A expression by IHC or mRNA in small series of supratentorial CNS-PNETs, with SST2A positivity noted in some studies ( 17 , 28 , 31 ), but absent expression in others ( 29 ). Our findings expand upon this previous work, demonstrating varied membranous SST2A expression in non-medulloblastoma embryonal tumors—present in pineoblastoma, absent in ATRT and ETMR, wide-ranging in remaining cases.…”

“…There is emerging evidence that certain pediatric CNS tumors express SST2A, with corresponding uptake on somatostatin-receptor radiolabeled nuclear imaging ( 12 – 39 ). SST2A expression has been described in medulloblastoma ( 13 , 26 – 31 ), other embryonal tumors ( 17 , 28 , 31 ), meningiomas ( 25 , 32 , 33 ), high-grade gliomas ( 17 , 27 , 34 – 38 ), and ependymomas ( 17 , 39 ), though with variable frequencies and lower levels in the latter two histologic diagnoses. Case reports/series have demonstrated treatment response (disease stabilization or regression) to somatostatin receptor-targeted therapy in children and young adults with relapsed medulloblastoma, high-grade glioma, meningioma, and brain metastases of neuroendocrine tumors ( 19 , 22 – 25 , 40 – 46 ), suggesting sufficient CNS penetration to achieve therapeutic benefit.…”

CD13 is a useful tool in the differential diagnosis of meningiomas with potential biological and prognostic implications

“…In these scenarios, various immunohistochemical markers have been proposed for helping pathologists to handle the most difficult cases, but even with the most promising ones, the diagnostic problem may sometimes remain unsolved. For instance, somatostatin receptor 2A (SSTR2A) expression has been severally accustomed to meningiomas, reaching high levels of sensitivity and specificity, but it can also be observed in a significant amount of SFT/HPCs and other tumors involving the nervous system, like synovial sarcomas, pPNET, gliosarcomas, and perineuromas [2,3,14]- [15].…”

Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood

“…Expression of SSTRs has also been documented in other CNS tumours in adults, i.e. oligodendroglioma, medulloblastoma and meningioma [18][19][20][21].…”