Cancer-Associated Fibroblasts and Tumor Cells in Pancreatic Cancer Microenvironment and Metastasis: Paracrine Regulators, Reciprocation and Exosomes

Simple Summary Cancer-associated fibroblasts in the stromal tumor microenvironment play a key role in cancer progression, invasion, metastasis, and therapy resistance. Cancer-associated fibroblasts communicate with tumor cells through diverse factors, such as growth factors, hedgehog proteins, cytokines, and chemokines, regulating signaling activity in paracrine as well as paracrine-reciprocal ways. Furthermore, cancer-associated fibroblasts, not only tumor cells, secrete exosomes that drive pre-metastatic niche formation and metastasis. Pancreatic cancer is currently the fourth leading cause of cancer deaths in the United States, and the overall 5 year survival rate is still only around 10%. Pancreatic cancer exhibits a remarkable resistance to established therapeutic options such as chemotherapy and radiotherapy, in part due to the dense stromal tumor microenvironment, where cancer-associated fibroblasts are the major stromal cell type. Cancer-associated fibroblasts further play a key role in cancer progression, invasion, and metastasis. Cancer-associated fibroblasts communicate with tumor cells, not only through paracrine as well as paracrine-reciprocal signaling regulators but also by way of exosomes. In the current manuscript, we discuss intercellular mediators between cancer-associated fibroblasts and pancreatic cancer cells in a paracrine as well as paracrine-reciprocal manner. Further recent findings on exosomes in pancreatic cancer and metastasis are summarized.