Abstract
BackgroundMetastatic medulloblastoma (MB) portends a poor prognosis. Amongst the 4 molecular subtypes, Group 3 and Group 4 patients have a higher incidence of metastatic disease, especially involving the neuroaxis. At present, mechanisms underlying MB metastasis remain elusive. Separately, inflammation has been implicated as a key player in tumour development and metastasis. Cytokines and their inflammation-related partners have been demonstrated to act on autocrine and, or paracrine pathways within the tumour microenvironment for various cancers. In this study, the authors explore the involvement of cerebrospinal fluid (CSF) cytokines in Group 3 and 4 MB patients with disseminated disease.MethodsThis is an ethics approved, retrospective study of prospectively collected data based at a single institution. Patient clinicpathological data and corresponding bio-materials are collected after informed consent. All CSF samples are interrogated using a proteomic array. Resultant expression data of selected cytokines are correlated with each individual’s clinical information. Statistical analysis is employed to determine the significance of the expression of CSF cytokines in Group 3 and 4 patients with metastatic MB versus non-metastatic MB.ResultsA total of 10 patients are recruited for this study. Median age of the cohort is 6.6 years old. Based on Nanostring gene expression analysis, 5 patients have Group 3 as their molecular subtype and the remaining 5 are Group 4. There are 2 non-metastatic versus 3 metastatic patients within each molecular subtype. Proteomic CSF analysis of all patients for both subtypes show higher expression of CCL2 in the metastatic group versus the non-metastatic group. Within the Group 3 subtype, the MYC-amplified Group 3 MB patients with existing and delayed metastases express higher levels of CXCL1, IL6 and IL8 in their CSF specimens at initial presentation. Furthermore, a longitudinal study of metastatic Group 3 MB observes that selected cytokines are differentially expressed in MYC-amplified metastatic Group 3 MB, in comparison to the non-MYC amplified metastatic Group 3 MB patient.ConclusionThis study demonstrates higher expression of selected CSF cytokines, in particular CCL2, in metastatic Group 3 and 4 MB patients. Although our results are preliminary, they establish a proof-of-concept basis for continued work in a larger cohort of patients affected by this devastating disease.
Highlights
Metastatic medulloblastoma (MB) portends a poor prognosis
In congruency with most human cancers whereby more than 90% of tumour deaths are metastasis-related [4], metastatic MB portends an extremely grim prognosis. This subset of patients usually succumbs to the disseminated spread of MB tumour cells both within and beyond the central nervous system (CNS) [2, 5, 6]
The extent of resection is based on postoperative imaging and defined as gross total resection (GTR; no residual tumour), near-total resection (NTR; less than 1∙5 cm2 remnant tumour), or subtotal resection (STR; more than or equal to 1∙5 cm2 remnant tumour) [14]
Summary
Metastatic medulloblastoma (MB) portends a poor prognosis. Amongst the 4 molecular subtypes, Group 3 and Group 4 patients have a higher incidence of metastatic disease, especially involving the neuroaxis. Inflammation has been implicated as a key player in tumour development and metastasis. Cytokines and their inflammation-related partners have been demonstrated to act on autocrine and, or paracrine pathways within the tumour microenvironment for various cancers. In congruency with most human cancers whereby more than 90% of tumour deaths are metastasis-related [4], metastatic MB portends an extremely grim prognosis. This subset of patients usually succumbs to the disseminated spread of MB tumour cells both within and beyond the central nervous system (CNS) [2, 5, 6]. Cytokines and their inflammation-related partners are known to coordinate various proinflammatory responses within the tumour microenvironment, acting on autocrine and, or paracrine pathways on both malignant and non-malignant cells [13]
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