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Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
Tumor-associated macrophages in SHH subgroup of medulloblastomas
Ashley S Margol1, Nathan J Robison1, Janahan Gnanachandran2
1Children's Hospital Los Angeles and The Saban Research Institute, Los Angeles, California. Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
Purpose:
Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature.
Methods:
Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC).
Results:
A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells.
Conclusions:
These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target.
Insights
Tumor-associated macrophages (TAMs) are more prevalent in Sonic Hedgehog medulloblastoma, indicating a unique tumor microenvironment. These findings highlight TAMs as a potential therapeutic target for pediatric medulloblastoma.
Area of Science:
- Pediatric oncology
- Cancer immunology
- Molecular subtyping of tumors
Background:
- Medulloblastoma, a common pediatric brain tumor, has distinct molecular subgroups.
- The tumor microenvironment's role in medulloblastoma progression and subgroup association is largely unknown.
- Tumor microenvironment components are critical therapeutic targets in various cancers.
Purpose of the Study:
- To investigate the correlation between tumor-associated macrophage (TAM) gene expression and medulloblastoma molecular subgroups.
- To determine if TAMs contribute to a diagnostic signature for medulloblastoma.
- To explore the tumor microenvironment's role in medulloblastoma subgroup-specific characteristics.
Main Methods:
- Gene-expression profiling of 168 medulloblastoma samples to identify molecular subgroups and inflammation-related genes.
- Development of a 45-gene signature using 83 samples to predict medulloblastoma subgroups.
- Immunohistochemistry (IHC) assessment of TAMs in 54 medulloblastoma samples across four molecular subgroups.
Main Results:
- A 31-gene signature, including TAM-related genes (CD163, CSF1R), achieved 98% accuracy in classifying medulloblastoma subgroups.
- Sonic Hedgehog (SHH) subgroup medulloblastomas exhibited significantly higher inflammation-related gene expression and TAM infiltration compared to Group 3 and Group 4.
- IHC confirmed a strong association between TAM location and proliferating tumor cells within medulloblastomas.
Conclusions:
- SHH medulloblastomas possess a distinct tumor microenvironment characterized by increased TAMs.
- Interactions between TAMs and SHH medulloblastoma cells may drive tumor growth.
- TAMs represent a promising therapeutic target for SHH medulloblastoma.
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