Carcinoma Associated Fibroblast: a Paradoxical Role in Pancreatic Cancer Microenvironment and a Promising Target for Therapy

Abstract

Pancreatic cancer is a grave malignancy showing an upward trend in morbidity and mortality during the recent decades. For reasons of late diagnosis, chemoresistance, low potential respectable rate and high post-operative recurrence rate, it has been the 6th most common cause of cancer death in China. As one of the most aggressive malignancies and the most common type of pancreatic cancer, pancreatic adenocarcinoma (PDAC) represents a significant therapeutic challenge. Conventional chemotherapeutic cytotoxic agents are proved to be with a poor survival benefit. Though the current first-line therapy FOLFIRINOX increased the median survival time compared with gemcitabine, it has been still unsatisfactory. Another direction enlighted by the treatement experience in other tumors is targeting certain molecules that participate in specific signaling pathways mediating cancer cell proliferating, angiogenesis, chemoresistance or metastasis. Unfortunately, none of the established "targeted" therapy agents that have been approved to be effective in some other tumors has a similar effect on PDAC, suggesting that there are some unique and decisive elements in the microenvironment of PDAC to facilitate its extensive drugresistance. Thus, the spotlight has been turned on immunotherapy, which is theoretically curative regardless of the complex molecular and cellular heterogeneity while the concrete strategies on PDAC are still in the dark. Revisiting the complex biology of PDAC, three prime characteristics will never be missed: almost 90% of patients with oncogene mutation of KRAS, as well as loss of tumor suppressor genesTP53 and SMAD4; mostly hypovascular; and tumor desmoplasia by persistent activation of fibroblasts/ pancreatic stellate cells (PSC). The last one, which is the defining feature of PDAC, as the target of therapy is the focus of this review.