Gastroenterology

Gastroenterology

Volume 144, Issue 6, May 2013, Pages 1210-1219
Gastroenterology

Biology of the Pancreas
Review
A Starring Role for Stellate Cells in the Pancreatic Cancer Microenvironment

https://doi.org/10.1053/j.gastro.2012.11.037Get rights and content

Pancreatic ductal adenocarcinoma is a devastating disease, and patient outcomes have not improved in decades. Treatments that target tumor cells have largely failed. This could be because research has focused on cancer cells and the influence of the stroma on tumor progression has been largely ignored. The focus of pancreatic cancer research began to change with the identification of pancreatic stellate cells, which produce the pancreatic tumor stroma. There is compelling in vitro and in vivo evidence for the influence of pancreatic stellate cells on pancreatic cancer development; several recent preclinical studies have reported encouraging results with approaches designed to target pancreatic stellate cells and the stroma. We review the background and recent advances in these areas, along with important areas of future research that could improve therapy.

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.

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