Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

Abstract

Pancreatic cancer is a highly lethal disease. Conventional therapeutics targeting pancreas cancer cell compartment using cytotoxics improved patient survival but at the expense of significant toxicity. Microscopically, the tumor is characterized by thick desmoplastic stroma that surrounds islands of pancreatic cancer cells. The tumor microenvironment has been found to play important roles in carcinogenesis, the development of drug resistance, and mediating immunosuppression. The understanding the tumor-stromal interaction has led to the development of novel therapeutic approaches. Here, we review the strategies that are currently in (or, near to) clinical evaluation and the underlying preclinical rationales.

Keywords: Pancreatic cancer; cancer-associated fibroblast (CAF); clinical trials; pancreatic adenocarcinoma; stroma.

Figure 1

Interaction of stromal constituents with pancreatic ductal adenocarcinoma (PDA). (A) Cancer-associated fibroblasts (CAFs), which expressed α-smooth muscle actin (αSMA), facilitate themselves as well as tumor growth through Hedgehog (Hh), Wnt/β-catenin, Notch, K-ras signaling or production of growth factors; (B) secretion of chemokine (C-X-C motif) ligand 12 (CXCL12), the ligand of chemokine (C-X-C motif) receptor 4 (CXCR4) and interleukin-17 (IL-17) results in suppression of T cells; (C) hyaluronan (HA) reduces the therapeutic indices of chemotherapy agents and enzymatic ablated HA by PEGylated human recombinant PH20 hyaluronidase (PEGPH20) provides promising efficacy in clinical trials; (D) programmed cell death 1 receptor (PD-1), cytotoxic T lymphocyte associated protein 4 (CTLA-4) and IL-17 signaling generated by cancer cell promote to create the immunosuppressive microenvironment; (E) GVAX [granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine] combined with CRS-207 (an attenuated listeria monocytogenes) enhances T cell’s anti-tumor effect; (F) CD40 stimulation may led to macrophage-mediated cancer cell kill and stromal depletion; (G) targeting of CXCL12 and IL-17 may reverse intra-tumor immune-suppression that enhance the effects of immune checkpoint inhibitors (PD-1, CTLA-4); (H) reprogramming the PDA stroma using vitamin D or all-trans retinoic acid (ATRA) may induce stromal quiescence and reverse tumor progression.