Abstract
Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.
Highlights
Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer
To determine whether the altered expression of stem cell and differentiation markers by cancer stem cells (CSCs) is accompanied by reduced self-renewal capacity, we tested the sphere-forming ability of CSCs treated with dexamethasone for 6 days and subsequently cultured in a dexamethasone-free medium; sphere formation was reduced following dexamethasone treatment (Fig. 1D)
Despite clinical studies aiming to determine the effect of glucocorticoids on solid tumor growth or response per se in a variety of nonhematologic cancers, their efficacy has not yet been proven except for the modest benefit of glucocorticoid monotherapy in breast and prostate cancer treatment [21, 23]
Summary
Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. The efficacy of dexamethasone in solid tumors has never been determined in clinical trials properly designed to evaluate drugs that target CSCs. Dexamethasone inhibits CSCs from pancreatic cancer and other solid tumors by promoting their differentiation via glucocorticoid receptor activation
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