From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression
Recommended Citation
Graham S, Dmitrieva M, Vendramini-Costa DB, Francescone R, Trujillo MA, Cukierman E, and Wood LD. From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression. Carcinogenesis 2024; 45(11):801-816.
Document Type
Article
Publication Date
11-22-2024
Publication Title
Carcinogenesis
Abstract
This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.
Medical Subject Headings
Humans; Pancreatic Neoplasms; Disease Progression; Tumor Microenvironment; Carcinoma, Pancreatic Ductal; Carcinoma in Situ; Mutation; Animals; Proto-Oncogene Proteins p21(ras); Precancerous Conditions
PubMed ID
39514554
Volume
45
Issue
11
First Page
801
Last Page
816
