Abstract
Vitamin D receptor (VDR) inhibits tumor–stroma crosstalk by inducing stromal reprogramming.
Major finding: Vitamin D receptor (VDR) inhibits tumor–stroma crosstalk by inducing stromal reprogramming.
Mechanism: VDR-regulated transcription inhibits pancreatic stellate cell activation and enhances angiogenesis.
Impact: Vitamin D treatment may improve the delivery and efficacy of chemotherapy in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense extracellular matrix (ECM) that limits intratumoral vascularization and impairs the delivery and efficacy of chemotherapeutic agents. Chronic activation of pancreatic stellate cells (PSC) in response to pancreatic injury results in the secretion of ECM proteins and growth factors that induce fibrosis and promote tumor growth. Sherman and colleagues hypothesized that reversion of cancer-associated PSCs (CAPSC) to a quiescent state might limit tumor–stroma crosstalk and enhance chemotherapeutic efficacy. Sequencing of activated murine PSCs and PSCs isolated from patients with PDA identified a cancer-associated gene signature consisting of numerous genes with tumor-supporting potential, including growth factors, inflammatory cytokines, ECM components, and genes that regulate angiogenesis. Unexpectedly, PSCs expressed high levels of the vitamin D receptor (VDR), which has been shown to regulate the fibrogenic gene network in hepatic stellate cells. Activation of VDR via treatment with the vitamin D analog calcipotriol inhibited expression of genes associated with PSC activation and the PSC cancer gene signature in primary human CAPSCs and murine PSCs. In addition, calcipotriol treatment reduced inflammation and fibrosis in mice with chronic or acute pancreatitis, consistent with a decrease in PSC activation and suggestive of a shift to PSC quiescence. Stromal VDR activation in PSCs also induced broad expression changes in pancreatic cancer cells via paracrine signaling, including reduced activation of genes implicated in proliferation, survival, and chemoresistance. Importantly, vitamin D and gemcitabine combination therapy decreased stromal activation and increased intratumoral vascularization in mouse models of PDA, resulting in elevated intratumoral gemcitabine concentrations, significantly reduced tumor volume, and prolonged survival compared with mice treated with gemcitabine alone. These findings suggest that VDR-mediated transcriptional reprogramming of the tumor stroma may improve the efficacy of current PDA therapies.