Positive feedback is the basis of powerful dynamic and phenotypic switching in noisy environments, causing conversion from analog input signals to digital outputs and triggering cell fate decisions and phenotypic changes ( 18). And it is explained the latest research in the intervention of feedback loops to enhance the therapeutic effect of drugs in pancreatic cancer. Here we summarize the feedback loops that exist in related fields, which should play critical roles in the progression of pancreatic cancer and treatment resistance. Researchers are interested in the role of feedback loops in the development of pancreatic cancer, but specific roles of feedback crosstalk remain elusive. As one of the solid tumors with high incidence, the signal regulation of pancreatic cancer has been extensively studied and flourishing in recent years. Accumulating evidences show that feedback loop regulation must be directly associated with cancer development, progression and metastasis ( 17). Feedback loops have been considered to be involved in important cellular modulated methods that cause autophagy, epithelial-mesenchymal transition, intracellular signaling and hypoxia ( 12– 16). Inhibiting or activating upstream and downstream signaling proteins will produce clear positive or negative feedback, and sometimes also form feedback loops that act crucial roles in cancer progression ( 11). There are two essences of feedback regulation, namely negative feedback loop and positive feedback loop, which give different attributes and dynamic characteristics of network dynamics. The concept of feedback loops is the basis for understanding signal transduction and maintaining homeostasis. It is suggested that modulation of feedback loops holds promise for enhancing therapeutic benefits of pancreatic cancer treatment. Recently, emerging evidence has revealed that the failure of targeted therapies to improve the outcome of advanced pancreatic cancer may be due to signal feedback loops, intermolecular crosstalk and induced drug insensitivity in the disease ( 9, 10). Sadly, most targeted drugs fail to improve the survival rate of patients for evaluations of treatment alone or combined with chemotherapy ( 7, 8). However, if surgery alone is not supported by other treatments, most patients will relapse and die of cancer. Surgery is still the main treatment for pancreatic cancer, and this method has evolved from a high-risk operation to a relatively safe operation today ( 6). Most cases of pancreatic cancer are thought to arise from the production of microscopic precursors called pancreatic intraepithelial neoplasia ( 5). Due to its extremely poor prognosis, pancreatic cancer is already the fourth leading cause of cancer-related deaths in western developed countries ( 2), and it may become the second leading cause of cancer-related deaths within the next ten years ( 3, 4). The individual incidence of pancreatic cancer is about 1.562%, the median survival rate is less than 11 months, and the 5-year survival rate is only 5% ( 2). Pancreatic ductal adenocarcinoma patients account for more than 90% of pancreatic cancer ( 1). Pancreatic cancer is the most common type malignant tumor with a high degree of malignancy and poor prognosis, which has now become a major medical dilemma and formidable challenge. Therefore, we review researches on the role of feedback loops in the progression of pancreatic cancer, and summarize the connection between feedback loops and several signaling pathways in pancreatic cancer, as well as recent advances in the intervention of feedback loops in pancreatic cancer treatment, highlighting the potential of capitalizing on feedback loops modulation in targeted therapy for pancreatic cancer. Numerous studies have associated feedback loop regulation with the development and therapeutic response of cancers including pancreatic cancer. The complex and variable signal regulation networks are one of the important reasons why it is difficult for pancreatic cancer to develop precise targeted therapy drugs. Pancreatic cancer is the leading cause of cancer-related deaths worldwide, with limited treatment options and low long-term survival rates. 2Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China.1Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.Weigang Gu 1 HongZhang Shen 1 Lu Xie 1 Xiaofeng Zhang 1,2* Jianfeng Yang 1*
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