Colorectal cancer (CRC) is a global health concern with nearly 2 million new cases annually, and its incidence is expected to rise. Therefore, understanding of its intricate molecular mechanisms and delves into the role of eotaxins and their receptors, particularly Eotaxin-1, Eotaxin-2, Eotaxin-3, and CCR3, in CRC development and progression is very important.
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Introduction of Eotaxins
Discovered in 1994, the eotaxin family initially gained attention for its selective recruitment of eosinophils, particularly Eotaxin-1, which acts as a potent chemoattractant for these immune cells. Eotaxin-2 and Eotaxin-3, subsequently identified, exhibit varying binding specificities, with Eotaxin-1 demonstrating the highest selectivity for CCR3 receptors.
Fig. 1 Eotaxins and their receptors (Zajkowska M., Mroczko B. 2020).
Eotaxins in Inflammatory Diseases
Eotaxins play pivotal roles in inflammatory diseases, including atopic dermatitis, allergic rhinitis, asthma, and parasitic infections. The concentration of eotaxins is elevated in these diseases, suggesting their involvement in immune responses. Notably, the inflammatory milieu is a common feature of malignant tumors, including CRC, sparking interest in understanding the role of eotaxins in cancer biology.
Eosinophils and Colorectal Cancer
The association between eosinophils and cancer was recognized over a century ago, yet their exact role in CRC remains elusive. Recent observations indicate that eosinophils in the tumor microenvironment exhibit regulatory functions towards other immune cells or direct cytotoxic effects against cancer cells. This dual nature raises questions about the pro- or anti-tumor activity of eosinophils in CRC.
The pathogenetic mechanism of eotaxin participation in CRC development is closely linked to the presence of a substantial number of eosinophils, particularly in tissues with high cellular turnover like the colon and rectum. Eotaxins regulate the presence of eosinophils in these tissues, influencing wound repair and contributing to eosinophil infiltrates in solid tumors. Tumor-associated tissue eosinophilia (TATE) and eosinophil degranulation are correlated with improved prognosis in various cancers, including CRC.
Eotaxin-1: Expressions and Controversies
Eotaxin-1, expressed physiologically in the gastrointestinal tract, exhibits contrasting expressions in CRC patients. While some studies demonstrate higher plasma or serum levels in inflammatory bowel disease and colorectal cancer, others report lower concentrations in CRC patients. The contradictory findings underline the need for larger cohorts to validate these observations. Additionally, studies suggest a potential role of Eotaxin-1 in the anti-cancer effects induced by CD40L transfer and its correlation with inflammatory markers post-surgery.
Eotaxin-2: Stromal Expression and Cancer-Specific Mortality
Similar to Eotaxin-1, Eotaxin-2 shows higher expression in stromal cells than glandular cells in CRC tissues. Studies reveal an association between elevated plasma levels of Eotaxin-2 and cancer-specific mortality.
Eotaxin-3: Correlations with TNM Stage and Poor Prognosis
Physiologically expressed in various tissues, Eotaxin-3 demonstrates high expression in CRC and liver metastatic tissues. Its levels correlate positively with the TNM stage of cancer and PRL-3 expression, indicating a potential connection to CRC invasion and metastasis. The significance of Eotaxin-3 in CRC underscores the need for comprehensive research on its serum concentrations for improved cancer detection.
Receptor for Eotaxins: CCR3 in CRC
CCR3, the receptor for eotaxins, is not exclusive to CRC but is found on eosinophils, basophils, and macrophages. Studies highlight its high expression in CRC tissues, especially in metastases, suggesting a potential correlation with the malignant status of CRC cells. The complex interplay between CCR3, eotaxins, and other chemokines in the tumor microenvironment may influence the immune response against cancer cells.
In conclusion, the current understanding of eotaxins and their receptors in colorectal cancer is hindered by the limited number of studies. The majority of the available evidence points towards elevated expressions of eotaxins and CCR3 in CRC, suggesting a potential role in CRC progression. The intricate balance between these chemokines, eosinophils, and other immune cells in the tumor microenvironment warrants further exploration.
References
- Zajkowska M.; Mroczko B. Eotaxins and their receptor in colorectal cancer-a literature review. Cancers. 2020, 12(6): 1383.
- Cheadle E. J.; et al. Eotaxin-2 and colorectal cancer: a potential target for immune therapy. Clinical Cancer Research. 2007, 13(19): 5719-5728.
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