Abstract:Pancreatic cancer remains a highly recalcitrant disease despite the development of systemic chemotherapies. New treatment options are thus urgently required. Dense stromal formation, so‐called “desmoplastic stroma,” plays controversial roles in terms of pancreatic cancer growth, invasion, and metastasis. Cells such as cancer‐associated fibroblasts, endothelial cells, and immune cells comprise the tumor microenvironment of pancreatic cancer. Pancreatic cancer is considered an immune‐quiescent disease, but activ… Show more
“… 31 In addition, CAFs secrete several humoral factors such as TGF-β, IL-1α/β, IL-6, CXCL12, FGF, EGF, TNF-α, 35 – 39 which promote survival, proliferation and EMT of PDAC cells. 39 – 43 Fig. 1 PDAC initiation and establishment of desmoplastic stroma.…”
Section: Components Of Pdac Tumor Microenvironment (Tme) That Drive Ementioning
Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.
“… 31 In addition, CAFs secrete several humoral factors such as TGF-β, IL-1α/β, IL-6, CXCL12, FGF, EGF, TNF-α, 35 – 39 which promote survival, proliferation and EMT of PDAC cells. 39 – 43 Fig. 1 PDAC initiation and establishment of desmoplastic stroma.…”
Section: Components Of Pdac Tumor Microenvironment (Tme) That Drive Ementioning
Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.
“…Improving objective response rates and overcoming chemoresistance are key issues associated with PDAC treatment, and this is particularly difficult due to the tumor microenvironment (TME) associated with PDAC. Mechanisms of chemoresistance and immune evasion associated with the TME are manifold: there is the general mechanical barrier secondary to desmoplasia and hypoxia which inhibits delivery of drug agents; a high presence of molecules contributing to this dense stroma such as collagen, integrins, glycosaminoglycans (GAGs), and fibronectins; and signaling networks such as platelet-derived growth factor (PDGF), SHH, and many interleukins, which allow for cross-talk between cells of the stroma that contribute to an immunoquiescent and suppressive TME as previously discussed [ 166 , 167 , 168 , 169 ].…”
Section: Clinical Interventions For Pdacmentioning
Pancreatic adenocarcinoma (PDAC) originates in the glandular compartment of the exocrine pancreas. Histologically, PDAC tumors are characterized by a parenchyma that is embedded in a particularly prominent stromal component or desmoplastic stroma. The unique characteristics of the desmoplastic stroma shape the microenvironment of PDAC and modulate the reciprocal interactions between cancer and stromal cells in ways that have profound effects in the pathophysiology and treatment of this disease. Here, we review some of the most recent findings regarding the regulation of PDAC cell invasion by the unique microenvironment of this tumor, and how new knowledge is being translated into novel therapeutic approaches.
“…The pancreatic tumor microenvironment (TME) is composed of stromal cells and extracellular matrix (ECM) components [81]. The predominant populations of stromal cells in PDA include cancer-associated fibroblasts (or activated PSCs), regulatory T cells, and tumor-associated macrophages [81]. Soluble factors from activated PSCs can prime the primary tumor for metastasis and cell migration.…”
Section: Interactions With the Tumor Microenvironmentmentioning
Pancreatic ductal adenocarcinoma is an extremely aggressive disease with a high metastatic potential. Most patients are diagnosed with metastatic disease, at which the five-year survival rate is only 3%. A better understanding of the mechanisms that drive metastasis is imperative for the development of better therapeutic interventions. Here, we take the reader through our current knowledge of the parameters that support metastatic progression in pancreatic ductal adenocarcinoma, and the experimental models that are at our disposal to study this process. We also describe the advantages and limitations of these models to study the different aspects of metastatic dissemination.
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