Cancer-associated fibroblasts in therapeutic resistance of pancreatic cancer: Present situation, predicaments, and perspectives

Pancreatic cancer is highly lethal, and the most effective treatment is curative resection followed by chemotherapy. Unfortunately, chemoresistance is an extremely common occurrence, and novel treatment modalities, such as immunotherapy and molecular targeted therapy, have shown limited success in clinical practice. Pancreatic cancer is characterized by an abundant stromal compartment. Cancer-associated fibroblasts (CAFs) and the extracellular matrix they deposit account for a large portion of the pancreatic tumor stroma. CAFs interact directly and indirectly with pancreatic cancer cells and can compromise the effects of, and even promote tumorigenic responses to, various treatment approaches. To eliminate these adverse effects, CAFs depletion strategies were developed. Instead of the anticipated antitumor effects of CAFs depletion, more aggressive tumor phenotypes were occasionally observed. The failure of universal stromal depletion led to the investigation of CAFs heterogeneity that forms the foundation for stromal remodeling and normalization. This review analyzes the role of CAFs in therapeutic resistance of pancreatic cancer and discusses potential CAFs-targeting strategies basing on the diverse biological functions of CAFs, thus to improve the outcome of pancreatic cancer treatment.