A starring role for stellate cells in the pancreatic cancer microenvironment

Abstract

Pancreatic ductal adenocarcinoma is a devastating disease, and patient outcomes have not improved in decades. Treatments that target tumor cells have largely failed. This could be because research has focused on cancer cells and the influence of the stroma on tumor progression has been largely ignored. The focus of pancreatic cancer research began to change with the identification of pancreatic stellate cells, which produce the pancreatic tumor stroma. There is compelling in vitro and in vivo evidence for the influence of pancreatic stellate cells on pancreatic cancer development; several recent preclinical studies have reported encouraging results with approaches designed to target pancreatic stellate cells and the stroma. We review the background and recent advances in these areas, along with important areas of future research that could improve therapy.

Figure 1

Identification of activated PaSCs in the stroma of PDAC and PanIN. (A) Immuno-histochemistry for α–smooth muscle actin (αSMA) (brown) and procollagen α1(I) (blue) on human PDAC tissues indicates that active PaSCs are the main source of collagens in the tumor stroma. Low- (A) and high- (B) power views of a representative section of human pancreatic cancer tissue. (C,D) Immunohis-tochemical staining for αSMA (brown) reveals abundant activated PaSCs surrounding Pan-INs in human pancreas. (E, F) Sirius red (red; E) and αSMA (brown; F) staining on pancreatic tissue from a GEM model (Kras^LSL-G12D/+; Pdx^cre/+) illus- trates the abundance of collagens and activated PaSCs surrounding PanINs.

Figure 2

Close relationship between pancreatic cancer cells and PaSCs pancreatic cancer cells recruit PaSCs to their immediate vicinity and promote fibrogenic responses in PaSCs. PaSCs reciprocate by facilitating cancer cell growth as well as local invasion.

Figure 3

Role of inflammation in progression of PDAC. An inflammatory stimulus activates PaSCs in the periacinar area, leading to recruitment of inflammatory cells (monocytes, T cells, neutrophils, macrophage, and mast cells). These cells produce IL-6, which activate signal transducer and activator of transcription 3 (STAT3) to promote development of PanIN and PDAC in susceptible tissue (such as with activating mutations in Kras). The activated PaSCs also produce galectin-1, which causes apoptosis of T cells to prevent anti-tumor immunity.

Figure 4

Role of PaSCs in mediating the effects of environmental risk factors for pancreatic cancer. Potential relationships between environmental risk factors and the activation state of PaSCs that could promote tumor progression.

Figure 5

Components of the tumor. The components of PDAC and potential interactions between the stroma and cancer cells should be considered in developing therapeutic approaches for pancreatic cancer.