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. 2024;4(1):31-39.
doi: 10.54457/dr.202401005. Epub 2024 Apr 23.

Interferons in Colorectal Cancer Pathogenesis and Therapy

Lucy Petrova  1 , Fred Bunz  1
Affiliations

Interferons in Colorectal Cancer Pathogenesis and Therapy

Lucy Petrova et al. Dis Res. 2024.

Abstract

As key modulators of the immune response, interferons play critical roles following infection and during the pathogenesis of cancer. The idea that these cytokines might be developed as new therapies emerged soon after their discovery. While enthusiasm for this approach to cancer therapy has waxed and waned over the ensuing decades, recent advances in cancer immunotherapy and our improved understanding of the tumor immune environment have led to a resurgence of interest in this unique class of biologic drug. Here, we review how interferons influence the growth of colorectal cancers (CRCs) and highlight new insights into how interferons and drugs that modulate interferon expression might be most effectively deployed in the clinic.

Keywords: Cancer; Colorectal; Interferons; P53; Therapy.

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Conflict of interest statement

Conflicts of interest All authors declared that there are no conflicts of interest.

Figures

Fig. 1.
Fig. 1.. Activation of JAK/STAT signaling pathways.
The association of extracellular interferons with their corresponding heterodimeric receptors on the cell surface results in receptor dimerization and JAK activation. Activated JAK proteins phosphorylate tyrosine residues (yellow circles) on the receptor, thereby creating docking sites for monomeric STAT proteins. After docking, STATs are then tyrosine-phosphorylated as well which leads to their dissociation from the receptor to form homodimers or heterodimers composed of different STAT subunits. STAT dimers enter the nucleus and specifically bind to interferon-stimulated response elements (ISREs) in the promoters of downstream ISGs, thus increasing their transcription. Several ISG products, such as the suppressor of cytokine signaling (SOCS) proteins and protein inhibitor of activated STAT (PIAS) proteins inhibit STAT docking and phosphorylation, and thereby form a regulatory feedback loop.
Fig. 2.
Fig. 2.. Inflammation during colorectal tumorigenesis.
Tumors in the colorectal epithelia arise in stages that are each associated with recurrent genetic alterations, as indicated. The mutational inactivation of the adenomatous polyposis coli (APC) gene, or mutational activation of the gene that encodes the APC associated protein β-catenin (CTNNB1), initiates the initial stages of tumor development resulting in the formation of small adenomas. The growth and molecular evolution of adenomas is subsequently facilitated by the activation of RAS signaling, either through mutation of KRAS or BRAF, and constitutive activation of the regulatory pathway modulated by the opposing functions of phosphatase and tensin homolog (PTEN) and PIK3CA. Loss of the tumor suppressor p53 in large adenomas causes them to become invasive carcinomas. The tumors that arise in otherwise healthy tissues typically become inflamed (red glow) at this later invasive stage. In the setting of IBD, chronic inflammation distorts the normal cell architecture and is a component of all lesions that arise. Ulcerative colitis causes increased rates of tumorigenesis in the colon epithelia and is also associated with the formation of distinct lesions called inflammatory polyps (also known as ‘pseudopolyps’). These lesions are also composed of epithelial and stromal tissues but have low malignant potential. As illustrated, interferons can alternatively drive tumor growth or tumor clearance, depending on the quality, intensity and duration of downstream signals.
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