Discover how scientists have uncovered the links between inflammatory proteins and endometrial cancer risk, with IL-6 emerging as a potential target for future prevention and treatment strategies.
Study: Circulating inflammatory and immune response proteins and endometrial cancer risk: a nested case-control study and Mendelian randomization analyses. Image Credit: Vink Fan / Shutterstock.com
A recent study published in the journal eBioMedicine identifies potential inflammatory and immune biomarkers of endometrial cancer.
What are the key drivers of endometrial cancer?
Over the past several decades, the prevalence of endometrial cancer has continued to rise throughout the world. In addition to genetic mutations, several other factors contribute to the proliferation of dormant mutated cells and subsequent development of endometrial cancer.
Inflammation and immune dysregulation, for example, are considered major contributors to endometrial carcinogenesis. Moreover, diseases characterized by chronic low-grade inflammation, such as obesity, are well-established risk factors for this type of cancer.
Previous studies have identified several inflammatory and immune biomarkers that are associated with endometrial carcinogenesis risk, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), C-reactive protein (CPR), and certain chemokines. However, these studies were limited by their smaller sample size and fewer number of circulating biomarkers tested, which restricted the identification of specific inflammatory and immune pathways that may be involved in the pathogenesis of endometrial cancer.
Study overview
In the current study, scientists utilize multiplex protein panels to identify any associations that may exist between circulating inflammatory, immune biomarkers, and endometrial cancer risk in a large European population. A total of 152 circulating biomarkers were measured in pre-diagnostic samples obtained from 624 endometrial cancer case-control pairs within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
The EPIC cohort comprises 519,978 participants recruited from multiple centers across ten European countries. Eligible female participants within the EPIC cohort who were not diagnosed with any type of cancer at recruitment were included in the current study.
Incident endometrial cancer cases were identified through cancer registries or active follow-up. For each cancer case, one matched control was randomly selected using incidence density sampling.
A two-sample Mendelian Randomization analysis was performed for circulating biomarkers that were associated with endometrial cancer risk with available genome-wide association study (GWAS) data. Biomarker-associated genetic variants were identified from the United Kingdom Biobank GWAS summary data. Instrumental variables for each protein were extracted from the Endometrial Cancer Association Consortium (ECAC) GWAS summary data.
Key observations and findings
Among endometrial cancer patients, the average age at cancer diagnosis was 62 years. About 89% of these patients were diagnosed with type I endometrioid cancers, whereas 11% had type II non-endometrioid cancers.
The analysis of pre-diagnostic circulating biomarkers revealed that IL-6, hepatocyte growth factor (HGF), phosphoinositide 3-kinase adapter protein 1 (PIK3AP1), and C-type lectin domain family 4 member G (CLEC4G) are positively associated with endometrial cancer risk. Comparatively, hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1), Skp1/cullin/F-box protein (SCF), and chemokine ligand 25 (CCL25) are negatively or inversely associated with endometrial cancer risk.
Proteins associated with endometrial cancer risk in the observational analysis were subjected to the Mendelian Randomization analysis. These findings revealed consistent positive and inverse associations between IL-6 and HSD11B1, respectively, and endometrial cancer risk. A suggestive positive association between IL-6 receptor and endometrial cancer risk was also observed in the Mendelian Randomization analysis.
Additional insights from protein clustering and sensitivity analyses
The researchers also conducted clustering of correlated proteins and sensitivity analyses to explore additional associations. For instance, certain protein clusters, such as those containing TWEAK (TNF-related weak inducer of apoptosis) and MCP3 (CCL7), showed potential links to cancer risk. The study's sensitivity analyses also accounted for the influence of BMI and waist circumference, providing a more comprehensive understanding of the potential confounding factors involved.
Study strengths and methodology
Both observational and Mendelian Randomization analyses were performed in a large study population of predominantly European ancestries, which revealed that altered IL-6 signaling and reduced glucocorticoid activity through HSD11B1 may be involved in endometrial cancer development.
Several confounding factors were adjusted in the primary analysis, including reproductive and lifestyle factors, adiposity, serum C-peptide, and post-menopausal estradiol and estrone levels. Moreover, the Mendelian Randomization analysis utilized a random allocation of genetic variants to reduce the risk of reverse causation and potential effects of confounding factors, which may not be accounted for in traditional observational studies.
Conclusions and implications
IL-6 and HSD11B1 were identified as potential contributors to endometrial cancer development, with IL-6 showing a positive association and HSD11B1 showing an inverse association.
Existing evidence indicates that the missense IL6 receptor variant Asp358Ala is associated with increased conversion of membrane IL-6 receptor to soluble IL-6 receptor, thereby leading to downregulation of IL-6 classical signaling and upregulation of trans-signaling.
IL-6 trans-signaling is associated with strong pro-inflammatory activities. Trans-signaling of IL-6 on endothelial and smooth cells increases the secretion of monocyte chemoattractant protein 1 (MCP-1), a significant risk factor for endometrial cancer. IL-6 also promotes tumor growth in a paracrine manner by increasing aromatase expression and estrogen production in the surrounding stromal cells.
HSD11B1 is an enzyme that catalyzes the activation of glucocorticoids in tissues. Glucocorticoids mitigate the mitogenic effect of excess estrogen in endometrial tissue; therefore, reduced glucocorticoid activity through HSD11B1 may facilitate estrogen-induced endometrial cell proliferation and increase endometrial cancer risk.
Journal reference:
- Wang, S. E., Viallon, V., Lee, M., et al. (2024). Circulating inflammatory and immune response proteins and endometrial cancer risk: a nested case-control study and Mendelian randomization analyses. eBioMedicine. doi:10.1016/j.ebiom.2024.105341.