Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, with a five-year survival rate of only ~10%. Pancreatic tissue becomes increasingly fibrotic (known as desmoplasia) during cancer development and progression. This extensive, heterogeneous reaction is largely mediated through the actions of stromal cells such as cancer-associated fibroblasts (CAFs). In this review, we will discuss how heterotypical reciprocal tumor-stromal and tumor-immune cell interactions in the pancreatic tumor microenvironment (TME) can both promote and restrain PDAC development and progression, with particular focus on the role of extracellular matrix (ECM) in potentiating tumor cell proliferation, survival, metastasis, and treatment resistance. We also give a snapshot of the current and emerging stromal co-therapies used in combination with chemotherapy or immunotherapy to treat this highly deadly disease.Many cancer studies now recognize that disease initiation, progression, and response to treatment are strongly influenced by the microenvironmental niche. Widespread desmoplasia, or fibrosis, is fundamental to pancreatic cancer development, growth, metastasis, and treatment resistance. This fibrotic landscape is largely regulated by cancer-associated fibroblasts (CAFs), which deposit and remodel extracellular matrix (ECM) in the tumor microenvironment (TME). This review will explore the prognostic and functional value of the stromal compartment in predicting outcomes and clinical prognosis in pancreatic ductal adenocarcinoma (PDAC). We will also discuss the major dynamic stromal alterations that occur in the pancreatic TME during tumor development and progression, and how the stromal ECM can influence cancer cell phenotype, metabolism, and immune response from a biochemical and biomechanical viewpoint. Lastly, we will provide an outlook on the latest clinical advances in the field of anti-fibrotic co-targeting in combination with chemotherapy or immunotherapy in PDAC, providing insight into the current challenges in treating this highly aggressive, fibrotic malignancy.
Highlights
Licensee MDPI, Basel, Switzerland.Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer representing 95% of all patients and remains one of the most lethal forms of human cancer worldwide, with >90% of patient deaths occurring within one year of diagnosis [1].pancreatic ductal adenocarcinoma (PDAC) is projected to increase to the second-deadliest cancer type in the US by 2030, unless treatment options are improved [1,2]
Despite this high genetic diversity, mutation and activation of the KRAS oncogene is almost always required for the initiation of pancreatic intraepithelial neoplasm (PanIN), with KRAS mutations found in 90% of all PDAC samples, driving cancer cell proliferation and survival [16,17,18]
The cellular and architectural compartments of the PDAC tumor microenvironment (TME) play a significant role in disease development, progression, and therapeutic response (Figure 4)
Summary
Several large-scale epidemiological and genetic studies have recently led to the identification of a large range of potential oncogenic drivers of the disease [13,14,15] Despite this high genetic diversity, mutation and activation of the KRAS oncogene is almost always required for the initiation of PanINs, with KRAS mutations found in 90% of all PDAC samples, driving cancer cell proliferation and survival [16,17,18]. In addition to this high genetic and molecular diversity, PDAC is one of the most stromally-dense cancer types across all malignancies, with stromal desmoplasia or fibrosis accounting for up to 90% of the total tumor volume [27] This desmoplasia is characterized by short and long-range reciprocal interactions between cancer cells and stromal components, including cancer-associated fibroblasts (CAFs), endothelial and immune cells as well as extracellular matrix (ECM), which influence all stages of tumorigenesis as well as therapeutic efficacy and resistance (Figure 1) [28,29]. Overall, understanding more about the transcriptional and microenvironmental drivers of CAF phenotype and function in PDAC will be critical to understanding their context-dependent influence on all stages of pancreatic tumorigenesis and will inform how best to target these pro-tumorigenic features
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