Abstract
Simple SummaryThere is currently no effective treatment for Pancreatic Ductal Adenocarcinoma (PDAC), and it is still the deadliest cancer, despite great research efforts in recent decades. The complexity in the tumor microenvironment (TME) is one of the main roots for the refractory nature of PDAC to treatment. Components of the PDAC TME are complex, dynamic, and closely reciprocate with each other from the early stages of pre-neoplastic lesion and during tumor progression. Detailed insight of the PDAC tumor microenvironment is needed for developing combined therapeutics that would target cancer cells and their supportive milieu for more efficient PDAC treatment.Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.
Highlights
Pancreatic cancer is the most lethal human malignancy, and there has been no major improvement in the therapeutic progress against this disease in the last 40 years [1,2]
The tumor microenvironment (TME) plays an important role in the initial pancreatic intraepithelial neoplasia (PanIN) stages, tumor growth, metastasis, and drug resistance of pancreatic ductal adenocarcinoma (PDAC)
There has been an accumulation of new knowledge in PDAC biology over the past few decades, there are still no effective treatments for PDAC
Summary
Pancreatic cancer is the most lethal human malignancy, and there has been no major improvement in the therapeutic progress against this disease in the last 40 years [1,2]. Despite huge efforts in research, PDAC still shows an extremely poor prognosis, and tumor relapse occurs in many post-surgical patients [2] This dismal scenario of PDAC patients is caused by the late diagnosis, aggressive disease progress with early metastases, tumor complexities, and inefficient therapeutics. In the pre-neoplastic lesions, cells accumulate genetic and epigenetic alterations in oncogenic genes and trigger aberrant signaling cascades, which promote tumorigenesis and metastasis [11] These molecular alterations influence the metabolic reprogramming within the tumor microenvironment (TME) [11,12]. In current treatment strategies for PDAC patients, its stroma-rich TME limits the access of systemic therapies to cancer cells and contributes to poor clinical outcomes [13,14]. The intratumor heterogeneity includes the clonal evolution of cancerous cells, differentiation and dedifferentiation of cell identity, and a complicated crosstalk between cellular and acellular compartments in the peri-tumor microenvironment [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
