Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients. The complex environment surrounding pancreatic tumors helps these deadly malignancies to fend off chemotherapy. A drug called gemcitabine is commonly used for pancreatic ductal adenocarcinoma (PDAC), but most tumors become resistant, and patients have only an 8% chance of surviving five years after diagnosis. Xianjun Yu at China's Fudan University in Shanghai and colleagues review how the stroma, the dense mesh of proteins and connective tissue surrounding PDAC tumors, helps promote resistance. They show that the various components of the stroma prevent malignant cells from processing gemcitabine into its active, toxic form, but also help cells to survive the lethal effects of the fully processed drug. Compounds that break down the stromal layer could improve treatment outcome, but researchers first require a deeper understanding of its contents and how they sustain cancerous growth.