Intestinal cancer, also known as colorectal cancer, is a leading cause of death worldwide. It is estimated that every year around 1.8 million people are diagnosed with this deadly disease, accounting for 9.2% of all cancer-related fatalities. Although it can affect people of all ages, it is more common in those who are over 50, and it is more prevalent in developed countries.

There are many risk factors for developing intestinal cancer, including age, genetics, lifestyle, and other conditions^[1-2].

• Age: As one grows older, the time for various pathogenic factors to stimulate intestinal cancer also increases. According to the National Cancer Institute, the average age of diagnosis is 67.

• Lifestyle: Unhealthy eating habits, carcinogens or radiation, chronic stress and anxiety, and chronic constipation all raise the risk of intestinal cancer.

• Family history: People with a family history of intestinal cancer are 8 times more likely to develop this disease than the general population and about 1/4 of new patients have a family history of intestinal cancer.

• Personal medical history: Certain colon diseases, such as Crohn's disease or ulcerative colitis, may increase the chance of developing intestinal cancer, and their risk is 30 times that of the general population. Most colorectal cancer develops from small pre-cancerous lesions called polyps, among which villous adenomatous polyps are more likely to develop into cancers, with an average chance at about 25%. The malignant transformation rate of tubular adenomatous polyps is 1–5%.

• Genetic background: Familial adenomatous polyposis (FAP) is a common autosomal dominant and inherited disease. FAP patients usually develop polyps around the age of 20 and may develop intestinal cancer between 30 and 40 years old.

Thankfully, researchers have uncovered a relationship between the APC (adenomatosis polyposis coli) gene and intestinal cancers. APC is a tumor suppressor gene that has been found to be mutated not only in most colon cancers but also in liver cancer and some other malignancies. The APC gene product is a 312 kDa protein with multiple domains that interact with a variety of proteins such as beta-catenin, axin, CtBP, Asefs, IQGAP1, EB1, and microtubules. APC suppresses canonical Wnt signaling, which is required for tumorigenesis, development, and homeostasis in a range of cell types, including epithelial and lymphoid cells, according to studies in mutant mice and cultured cells. Further studies have suggested that APC play a role in other cellular processes,  including cell adhesion and migration, actin and microtubule network organization, spindle formation, and chromosomal segregation. Deregulation of these pathways caused by APC mutations is linked to the onset and progression of intestinal cancers.

It is worth emphasizing that mutations in the FAP and APC genes are closely correlated. The dysregulation of the Wnt pathway, which is primarily driven by APC-β-catenin-TCF, is the main mechanism underlying FAP. In FAP patients, genetic mutations typically lead to loss of function of the APC protein, which in turn results in the stabilization of β-catenin and its accumulation in the cytoplasm, followed by translocation to the nucleus and activation of the Wnt signaling pathway. This uncontrolled cell proliferation process eventually leads to the formation of numerous adenomas and polyps, of which 80% develop into intestinal cancers^[2-5].

Canonical Wnt signaling pathway^[6]

GemPharmatech's transgenic mouse model targeting the APC gene is an indispensable tool to improve our understanding of intestinal cancers and develop effective treatments to combat this disease. The APC-min mouse has a nonsense mutation at the 850^th amino acid of the protein, which leads to premature termination of APC transcription and suppression of expression of this tumor suppressor gene. Consequently, the APC-min mouse is susceptible to spontaneous intestinal adenomas. Under high-fat diet conditions, male and female heterozygous mice develop significantly more intestinal adenomas, primarily in the ileum and cecum. The APC-min mouse model is an ideal model for studying intestinal tumorigenesis.

Intestinal histopathology of APC-min mice on control diet (CD) and high-fat diet (HFD)

Adenoma (black arrow), Inflammatory cell infiltration (blue arrow), Fibrosis (red arrow).

Our APC-min model has been published in multiple peer-reviewed research papers, helping researchers understand the mechanisms of APC gene expression and function, and leading to the discovery of new treatment modalities that target specific pathways.

Reference:

1. Nieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol. 2007 Feb;61(2):153-61.

2. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004 Feb 18;96(4):261-8.

3. Markowitz SD, Bertagnolli MM.“Molecular origins of cancer: Molecular basis of colorectal cancer”.New England Journal of Medicine361(25) (2009):2449–60.2.

4. Valvezan AJ, Zhang F, Diehl JA, Klein PS. "Adenomatous Polyposis Coli (APC) Regulates Multiple Signaling Pathways by Enhancing Glycogen Synthase Kinase-3 (GSK-3) Activity". J Biol Chem. 287 (2012);:3823-3832.

5. Cleary SP, Kim H, Croitoru ME, Redston M, Knight JA, Gallinger S, Gryfe R. "Missense polymorphisms in the adenomatous polyposis coli gene and colorectal cancer risk". Dis Colon Rectum.51 (2008):1467-1473.

6. Sharma A, Mir R, Galande S. Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer. Front Genet. 2021 Sep 6;12:681053.