Adenomatous polyposis coli in cancer and therapeutic implications

Abstract

Inactivating mutations of the adenomatous polyposis coli (APC) gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests APC mutations are also found in gastric, breast and other cancers. The APC gene, located on chromosome 5q, is responsible for negatively regulating the β-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3β, and CK1. In the event of an APC mutation, β-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to APC mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with APC mutations.

OTX1 promotes tumorigenesis and progression of cervical cancer by regulating the Wnt signaling pathway

“…AXIN2, a direct target of Wnt signaling pathway, restricts the Wnt signaling pathway via a negative feedback loop (40). AXIN2 gene is a negative regulator of the Wnt signaling pathway in colorectal cancer (41). Here, OTX1 silencing significantly decreased levels of Wnt9b and β-catenin and increased levels of APC, GSK-3β and AXIN2.…”

Systemic TM4SF5 overexpression in ApcMin/+ mice promotes hepatic portal hypertension associated with fibrosis

“…Mutation of Apc is a well-known cause of intestinal adenomas and carcinomas in murine models ( 8 ), an initiating factor in roughly 80% of all colorectal cancers, and increasingly being investigated in other cancers ( 24 ). TM4SF5 is involved in non-alcoholic steatohepatitis ( 5 ), fibrosis ( 6 ), and cancerous cell growth ( 3 ).…”

Alpha Mangostin and Cisplatin as Modulators of Exosomal Interaction of Ovarian Cancer Cell with Fibroblasts

“…The APC protein is involved in the regulation of the cell cycle in several steps: during the G1/S and G2/M transition and during base excision repair. Inhibition of the APC protein activity leads to unregulated cell progression, which has been extensively studied and described for example in colorectal cancer [ 52 , 53 , 54 ]. In our experiment, we noted a decrease in the expression of the APC gene in fibroblasts after treatment with ovarian cancer-derived exosomes.…”