Biology of the PancreasReviewA Starring Role for Stellate Cells in the Pancreatic Cancer Microenvironment
Section snippets
Interactions Between PaSC and Cancer Cells in Culture
Coculture experiments with PaSCs and pancreatic cancer cell lines, or in which one cell type is exposed to conditioned medium from the other, support the concept that pancreatic cancer cells recruit PaSCs, which promote tumor growth and local invasion (Figure 2). Although it has been proposed that under conditions of chronic inflammation, fibroblasts can induce transformation of epithelial cells, this concept has not been tested with PaSCs and pancreatic epithelial cells.
Pancreatic cancer cells
In Vivo Studies
Although there is strong evidence from in vitro studies that cancer cell interact with PaSCs, it is important that these observations are validated in animal models, such as mice with tumor xenografts or genetic-engineered mouse (GEM) models. Bachem et al7 subcutaneously injected human pancreatic cancer cells, alone or in combination with human PaSCs, into the flanks of immunocompromised mice. They found that cancer cells coinjected with PaSCs proliferated and formed tumors more rapidly than
Roles for PaSCs and Leukocytes
Clinical and experimental evidence indicates that inflammation is a significant risk factor for PDAC. Patients with chronic pancreatitis have an increased risk of developing PDAC,28, 29, 30 and 40% of patients with hereditary pancreatitis develop pancreatic cancer.31, 32, 33 Consistent with these clinical observations, induction of chronic pancreatitis with cerulein in different Kras overexpressing GEM models of PDAC speed the development of the primary cancer and formation of metastases.34, 35
Interactions Between PaSCs and Endothelial Cells
Clinical and experimental studies have shown that that pancreatic cancer cells produce the angiogenic factors vascular endothelial growth factor (VEGF) and fibroblast growth factor.54 Overexpression of VEGF in tumor tissues has been linked to poor prognosis of patients with PDAC.55 However, despite evidence of increased angiogenic signaling, PDACs also have vascular abnormalities that contribute to poor perfusion and hypoxia.27, 56 Pancreatic cancer cells appear to thrive under hypoxic
Roles for Neural Components
The pancreas is a highly innervated organ that receives neural inputs from preganglionic fibers of the sympathetic and parasympathetic systems and from postganglionic fibers that emanate from intrapancreatic ganglia. Terminal axons surround almost all acini, in close proximity with periacinar PaSC, pancreatic ducts, blood vessels, and islets.68 Histopathologic analysis of pancreatic tissue samples from patients with PDAC frequently reveals extensive neural remodeling within the tumor stroma,
Potential for PaSCs to Mediate the Effects of Risk Factors
Risk factors for PDAC include age, chronic pancreatitis, smoking, obesity, diabetes, and, to a lesser extent, heavy alcohol intake without pancreatitis.3, 85 Alcohol abuse and smoking are associated with development of chronic inflammatory and fibrosing pancreatitis, which involves activation of PaSCs. Activation of PaSCs by alcohol abuse or smoking might therefore be involved in pancreatic carcinogenesis.1, 39 However, most patients with PDAC with one or more risk factors do not have clinical
Targeting PaSCs in the Microenvironment
It is clear that the pancreatic tumor stroma promotes pancreatic cancer development and is an important target for new therapeutics. Recent preclinical studies of reagents that target PaSCs have reported some encouraging results. Von Hoff et al99 reported significant depletion of the stromal reaction after nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was administered to subcutaneous, patient-derived xenograft tumors in mice. The stromal depletion was accompanied by the presence of
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Conflicts of interest The authors disclose no conflicts.