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Observational Study
. 2020 Jun 15;20(1):554.
doi: 10.1186/s12885-020-07048-0.

Cerebrospinal fluid cytokines in metastatic group 3 and 4 medulloblastoma

Sharon Y Y Low  1   2   3   4 , Nurfahanah Bte Syed Sulaiman  5   6 , Enrica E K Tan  7 , Lee Ping Ng  8 , Chik Hong Kuick  9 , Kenneth T E Chang  6   9 , Phua Hwee Tang  10 , Ru Xin Wong  11 , Wen Shen Looi  11 , David C Y Low  8   5   12 , Wan Tew Seow  8   5   12
Affiliations
Observational Study

Cerebrospinal fluid cytokines in metastatic group 3 and 4 medulloblastoma

Sharon Y Y Low et al. BMC Cancer. .

Abstract

Background: 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. 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.

Methods: This 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.

Results: A 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.

Conclusion: This 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.

Keywords: Cerebrospinal fluid; Cytokines; Medulloblastoma; Metastasis.

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Conflict of interest statement

We, the authors of this manuscript, report no funding, financial support or industrial affiliations received for the writing of this article. In addition, we report no conflict of interest concerning the material or methods used in this paper. This manuscript has not been published and is not being considered for publication elsewhere.

Figures

Fig. 1
Fig. 1
(A) Proteome array blot of CSF all patients in study cohort at initial analysis. Patient labels are shown at the bottom left hand corner of each blot. Cytokines of interest are highlighted in coloured outlines and labelled in (B). Full-length blots are presented in Supplementary Fig. 3
Fig. 2
Fig. 2
Figures showing intensity quantification results of CCL2 for Group 3 MB (A) and Group 4 MB (B) from the immunoblot analysis. C* is Patient C who has high expression of CCL2 at the time of initial diagnosis but developed extraneural metastases later
Fig. 3
Fig. 3
Figures showing intensity quantification results of IL8 for Group 3 MB (A) and Group 4 MB (B) from the blot analysis. The 2 Group 3, MYC-amplified MB patients have similar trends of high IL8 expression. Conversely, only 1 of the Group 4 metastatic MB has high IL8 expression that is statistically significant
Fig. 4
Fig. 4
Figures showing intensity quantification results of CXCL1 and IL6 for Group 3 MB from the blot analysis in (A) and (B) respectively. Similar to the IL8 findings, the 2 Group 3, MYC-amplified MB patients express higher CXCL1 and IL6 in their CSF compared to the rest of Group 3 MB samples. CXCL1 and IL6 do not show sufficient expression in the Group 4 MB cohort after normalization to internal controls
Fig. 5
Fig. 5
(A) Temporal proteome blot depictions of the CSF samples in the Group 3 patients with metastases at various times of their disease. Cytokines of interest are highlighted in coloured outlines and labelled in (B). Full-length blots are presented in Supplementary Fig. 3
See this image and copyright information in PMC

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