Signaling Networks That Control Cellular Plasticity in Pancreatic Tumorigenesis, Progression, and Metastasis

Abstract

Pancreatic ductal adenocarcinoma is one of the deadliest cancers, and its incidence on the rise. The major challenges in overcoming the poor prognosis with this disease include late detection and the aggressive biology of the disease. Intratumoral heterogeneity; presence of a robust, reactive, and desmoplastic stroma; and the crosstalk between the different tumor components require complete understanding of the pancreatic tumor biology to better understand the therapeutic challenges posed by this disease. In this review, we discuss the processes involved during tumorigenesis encompassing the inherent plasticity of the transformed cells, development of tumor stroma crosstalk, and enrichment of cancer stem cell population during tumorigenesis.

Keywords: Cancer Stem Cells; Pancreatic Cancer Associated Fibroblasts; Pancreatic Cellular Plasticity; Signaling Crosstalk.

Figure 1

The crosstalk between epithelial cells and components of the microenvironment is regulated by oncogenic Kras. Activation of MAPK/ERK signaling downstream of Kras is required for epithelial cell de-differentiation. In presence of oncogenic Kras, macrophages are polarized to promote tumorigenesis. In contrast, lineage-specific transcription factors and macrophages associated with the tissue repair process antagonize carcinogenesis.

Figure 2

Cancer stem cells. Hypoxia, therapy, and nutritional stress within a pancreatic tumor reprograms a population of cells with increased survival advantage. These are the cells that show classic CSC attributes of therapeutic resistance, decreased apoptosis, and quiescence. This enables them to endure the therapeutic pressure, which shrinks the bulk tumor. The enrichment of the CSC population induces metastatic properties, which enable these cells to leave the primary tumor site and recur at a distant location as a metastatic tumor.