Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

Abstract

Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.

Keywords: APC; cancerogenesis; chemoprevention; estrogen; familial adenomatous polyposis; immune microenvironment; microbiota.

Figure 1

The simplified WNT/β-catenin pathway. (A) The WNT/β-catenin pathway in the absence of APC mutation (green) and without the ligand WNT: the “destruction complex” bounds, phosphorylates and targets β-catenin for ubiquitination; β-catenin is then degraded by proteasomes. (B) The WNT/β-catenin pathway in the absence of APC mutation (green) and with the presence of the ligand WNT: after WNT binds its receptor frizzled activating further intracellular molecules, β-catenin is no longer captured by the “destruction complex”; it accumulates in the cytoplasm and it migrates to the nucleus, where it acts as a transcription factor. (C) When APC is mutated (red), a faulty “destruction complex” is unable to bind and ubiquitinate β-catenin; as a result, it acts as an uncontrolled mitogenic signal, even in the absence of activation of the WNT signaling pathway by the ligand WNT. APC: adenomatous polyposis coli; C: conductin; GSK3b: glycogen synthase kinase 3 b; β-CAT: β-catenin; FZD: Frizzled receptor; DSH: Disheveled; P: phosphorylation.

Figure 2

The complex interplay between several factors contributing to cancer onset in FAP patients, which depend on the interaction between genetic, environmental, hormonal, microbial and immunological factors.