Colon cancer is the third most common cancer in the United States, affecting both men and women. It arises from the abnormal growth of cells in the colon or rectum.

A key protein plays a crucial role in colon cancer development and progression but has long remained elusive to researchers.

The role of Wnt signaling pathway in colon cancer

Colorectal cancer development is characterized by alterations in the Wnt signaling pathway, a crucial pathway that controls gene expression and cell fate.

Wnt signaling is essential for cell proliferation and differentiation during embryonic development, but deregulation of the pathway in adult tissues can lead to cancer. In particular, inactivating mutations in APC (Adenomatous Polyposis Coli) gene, a negative regulator of the Wnt pathway, are commonly found in colon cancer.

The role of β-catenin in Wnt pathway

β-catenin is a critical downstream effector of the Wnt pathway. In the absence of Wnt activation, β-catenin is phosphorylated by the destruction complex, composed of APC, Axin, and GSK-3β, resulting in its degradation by the proteasome.

When Wnt is activated, it inhibits the destruction complex, allowing β-catenin to accumulate in the cytoplasm and translocate to the nucleus, where it interacts with TCF/LEF transcription factors and activates Wnt target genes involved in cell proliferation and survival.

The elusive role of Axin in colon cancer

Axin is a scaffold protein that interacts with both APC and GSK-3β to form the destruction complex. It acts as a negative regulator of the Wnt pathway by promoting the phosphorylation and degradation of β-catenin.

Oxidative stress-induced phosphorylation of Axin was shown to regulate its stability and Wnt antagonistic activity in colon cancer cells. However, the exact role of Axin in colon cancer remains elusive, and its potential as a therapeutic target is still under investigation.

The role of CK1α in colon cancer

Casein kinase 1α (CK1α) is a serine/threonine kinase that phosphorylates β-catenin and regulates its turnover. CK1α-mediated phosphorylation of β-catenin primes it for additional phosphorylation by GSK-3β, leading to its degradation.

CK1α also activates the Wnt pathway by phosphorylating and destabilizing Axin, promoting β-catenin stabilization. CK1α was found to be overexpressed in colon cancer, and its inhibition reduced tumor growth in preclinical models, suggesting its potential as a therapeutic target in colon cancer.

The role of RNF43/ZNRF3 in Wnt signaling

RNF43 and ZNRF3 are E3 ubiquitin ligases that target the Frizzled receptor, a transmembrane protein that mediates Wnt signaling, for lysosomal degradation.

They act as negative regulators of the pathway by limiting Wnt ligand-receptor interactions and signaling. RNF43/ZNRF3 mutations were found in a subset of colorectal cancers characterized by high Wnt pathway activity.

Their inhibition was shown to activate the Wnt pathway and promote cancer cell proliferation, suggesting their potential as therapeutic targets in RNF43/ZNRF3 mutated colon cancer.

The role of Wnt5a in colon cancer

Wnt5a is a non-canonical Wnt ligand that activates alternative pathways, such as the planar cell polarity pathway and the Wnt/Ca2+ pathway, rather than the β-catenin-dependent pathway.

Wnt5a was found to be overexpressed in colon cancer and to promote tumor cell invasion and metastasis by inducing epithelial-mesenchymal transition and activating the Notch pathway. Its inhibition was shown to reduce colon cancer cell migration and invasion, suggesting its potential as a therapeutic target in colon cancer.

The role of immune system in colon cancer

The immune system plays a crucial role in colon cancer development and progression.

The tumor microenvironment is characterized by the presence of immune cells, such as T cells, B cells, natural killer cells, and myeloid-derived suppressor cells, that interact with tumor cells and promote or suppress their growth and invasion. Immune checkpoints, such as PD-1 and CTLA-4, are upregulated in colon cancer and inhibit T cell function. Immunotherapy, targeting immune checkpoints or using adoptive T cell therapy, has shown promising results in advanced colon cancer patients.

The potential of precision medicine in colon cancer

Precision medicine aims to personalize cancer treatment based on the underlying genetic and molecular alterations of the tumor.

It involves genomic profiling of the tumor to identify actionable targets and the use of targeted therapies or immunotherapies to treat the patient. In colon cancer, precision medicine has shown promising results, especially in patients with RAS/RAF mutations, BRAF mutations, or microsatellite instability-high tumors, who are more likely to respond to targeted or immunotherapy.

The future of colon cancer research

Colon cancer research is a rapidly evolving field, with new discoveries and advances emerging every year.

The integration of genomics, proteomics, and immunology is providing new insights into the molecular mechanisms of colon cancer development and the tumor microenvironment. The development of new technologies, such as organoids, patient-derived xenografts, and liquid biopsies, is enabling more accurate and personalized cancer modeling and diagnostics.

The identification of new drug targets and the development of combination therapies hold promise for improving patient outcomes and reducing the morbidity and mortality associated with colon cancer.