Signaling in the microenvironment of pancreatic cancer: Transmitting along the nerve

Pancreatic ductal adenocarcinoma (PDA) is a dismal malignant disease with the lowest stage-combined overall survival rate compared to any other cancer type. PDA has a unique tumor microenvironment (TME) comprised of a dense desmoplastic reaction comprising over two-thirds of the total tumor volume. The TME is comprised of cellular and acellular components that all orchestrate different signaling mechanisms together to promote tumorigenesis and disease progression. Particularly, the neural portion of the TME has recently been appreciated in PDA progression. Neural remodeling and perineural invasion (PNI), the neoplastic invasion of tumor cells into nerves, are common adverse histological characteristics of PDA associated with a worsened prognosis and increased cancer aggressiveness. The TME undergoes dramatic neural hypertrophy and increased neural density that is associated with many signaling pathways to promote cell invasion. PNI is also considered one of the main routes for cancer recurrence and metastasis after surgical resection, which remains the only current cure for PDA. Recent studies have shown multiple cell types in the TME signal through autocrine and paracrine mechanisms to enhance perineural invasion, pancreatic neural remodeling and disease progression in PDA. This review summarizes the current findings of the signaling mechanisms and cellular and molecular players involved in neural signaling in the TME of PDA.