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Role of CD47 gene expression in colorectal cancer: a comprehensive molecular profiling study
Hiroyuki Arai1,2, Nishant Gandhi3, Francesca Battaglin1
1Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Background:
In patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-high tumors. Meanwhile, new immunotherapies targeting the innate immune system are attracting increasing attention. CD47 is a representative innate immune checkpoint involved in the evasion of tumor cell phagocytosis by macrophages. This large-scale study comprehensively examined the molecular significance of CD47 gene expression in CRC.
Methods:
We analyzed the next-generation sequencing data of DNA and RNA from 14,287 CRC cases included in the data set of a commercial Clinical Laboratory Improvement Amendments-certified laboratory (Caris Life Sciences). The cases were divided into two groups based on the median value of CD47 gene expression levels. The molecular and immune profiles between the groups were compared, and the relationship between CD47 expression and survival outcomes was further examined.
Results:
In CD47-high tumors, the proportion of consensus molecular subtypes 1 and 4 was significantly higher than in CD47-low tumors. The expression levels of damage-associated molecular pattern-related genes showed a positive correlation with CD47 expression levels. Major oncogenic pathways, such as mitogen-activated protein kinase, phosphoinositide 3-kinase, angiogenesis, and transforming growth factor beta, were significantly activated in CD47-high tumors. Additionally, the expression levels of a panel of adaptive immune checkpoint genes and estimates of immune cells constituting the tumor microenvironment (TME) were significantly higher in CD47-high tumors.
Conclusions:
CD47 expression in CRC was associated with the activation of several oncogenic pathways and an immune-engaged TME. Our findings may provide valuable information for considering new therapeutic strategies targeting innate immune checkpoints in CRC.
Insights
High CD47 expression in colorectal cancer (CRC) correlates with activated oncogenic pathways and an immune-engaged tumor microenvironment (TME). This suggests CD47 as a potential target for novel CRC immunotherapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Conventional immunotherapies for colorectal cancer (CRC) are limited in efficacy, particularly for microsatellite instability-low tumors.
- Innate immune system-targeting therapies are gaining traction, with CD47 identified as a key innate immune checkpoint.
- CD47 plays a role in tumor cells evading macrophage phagocytosis.
Purpose of the Study:
- To investigate the molecular significance of CD47 gene expression in a large cohort of colorectal cancer (CRC) cases.
- To compare molecular and immune profiles between tumors with high and low CD47 expression.
- To examine the association between CD47 expression and survival outcomes in CRC.
Main Methods:
- Analysis of next-generation sequencing data (DNA and RNA) from 14,287 CRC cases.
- Stratification of cases into high and low CD47 expression groups based on median expression levels.
- Comparison of molecular, immune, and survival data between the two groups.
Main Results:
- CD47-high tumors showed a higher prevalence of consensus molecular subtypes 1 and 4.
- Positive correlation observed between CD47 expression and damage-associated molecular pattern-related genes.
- Significant activation of oncogenic pathways (MAPK, PI3K, angiogenesis, TGF-β) and elevated adaptive immune checkpoint gene expression in CD47-high tumors.
- Increased immune cell infiltration within the tumor microenvironment (TME) in CD47-high tumors.
Conclusions:
- CD47 expression in CRC is linked to activated oncogenic pathways and an immune-supportive tumor microenvironment (TME).
- These findings highlight CD47 as a potential therapeutic target for novel immunotherapies in colorectal cancer.
- The study provides valuable insights for developing new treatment strategies targeting innate immune checkpoints in CRC.
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