Pancreatic cancer microenvironment: a current dilemma

Abstract

Pancreatic cancer is one of the leading causes of cancer-related death in the United States and survival outcomes remain dismal despite significant advances in molecular diagnostics and therapeutics in clinical practice. The microenvironment of pancreatic cancer carries unique features with increased desmoplastic reaction and is infiltrated by regulatory T cells and myeloid-derived suppressor cells which negatively impact the effector immune cells. Current evidence suggests that stellate cell-induced hypovascular stroma may have direct effects on aggressive behavior of pancreatic cancer. Preclinical studies suggested improvement in drug delivery to cancer cells with stroma modifying agents. However these findings so far have not been confirmed in clinical trials. In this article, we elaborate current-state-of-the science of the pancreatic cancer microenvironment and its impact on molecular behavior of cancer cells, chemotherapy resistance and druggability of stroma elements in combination with other agents to enhance the efficacy of therapeutic approaches.

Keywords: Chemosensitization; Desmoplasia; Hyaluronan; Immunotherapy; Microenvironment; Pancreatic cancer; Sonic hedgehog; Sonic hedgehog inhibitors; Targeted therapy.

Fig. 1

Unique characteristics of pancreatic cancer microenvironment. Pancreatic cancer stroma is enriched with pancreatic stellate cells (PSCs) that produce excessive amounts stromal elements such as collagens, laminin and fibronectin leading to desmoplasia, a process, which produces a hypovascular microenvironment, impairing local drug delivery, rendering tumors resistant to chemotherapeutics. Cancer stem cells (CSCs), which are known to be multidrug resistant also play a role in chemoresistance [1]. Pancreatic cancer microenvironment is “highly” infiltrated by a variety of immunosuppressive cell types such as myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) that mitigate the effector function of cytotoxic T cells (CTLs), leading to immune evasion. That constitutes an important factor for ineffectiveness of immunotherapies in pancreatic cancer along with the hypoimmunogenic nature of the cancer due to low mutation burden and lack of significant neoantigens [2]

Fig. 2

Sonic hedgehog signaling pathway. In the absence of sonic hedgehog ligand (Shh), the surface receptor Patched1 (PTCH1) inhibits Smoothened (SMO), resulting in sequestration of Gli1 in the cytosol by Suppressor of fused (SUFU). Binding of Shh to PTCH1 abolishes constitutive inhibition of SMO by PTCH1, leading to liberation of Gli1 from SUFU. Released Gli1, then, translocates to the nucleus, where it promotes gene expression. Sonic Hedgehog inhibitors IPI-926 (Saridegib) and Vismodegib block SMO activity