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Cellular determinants and therapeutic implications of inflammation in pancreatic cancer.

ABSTRACT: Inflammation is a hallmark of cancer. For pancreatic ductal adenocarcinoma (PDAC), malignant cells arise in the context of a brisk inflammatory cell infiltrate surrounded by dense fibrosis that is seen beginning at the earliest stages of cancer conception. This inflammatory and fibrotic milieu supports cancer cell escape from immune elimination and promotes malignant progression and metastatic spread to distant organs. Targeting this inflammatory reaction in PDAC by inhibiting or depleting pro-tumor elements and by engaging the potential of inflammatory cells to acquire anti-tumor activity has garnered strong research and clinical interest. Herein, we describe the current understanding of key determinants of inflammation in PDAC; mechanisms by which inflammation drives immune suppression; the impact of inflammation on metastasis, therapeutic resistance, and clinical outcomes; and strategies to intervene on inflammation for providing therapeutic benefit.

SUBMITTER: Stone ML

PROVIDER: S-EPMC6708742 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Cellular determinants and therapeutic implications of inflammation in pancreatic cancer.

Stone Meredith L ML Beatty Gregory L GL

Pharmacology & therapeutics 20190531

Inflammation is a hallmark of cancer. For pancreatic ductal adenocarcinoma (PDAC), malignant cells arise in the context of a brisk inflammatory cell infiltrate surrounded by dense fibrosis that is seen beginning at the earliest stages of cancer conception. This inflammatory and fibrotic milieu supports cancer cell escape from immune elimination and promotes malignant progression and metastatic spread to distant organs. Targeting this inflammatory reaction in PDAC by inhibiting or depleting pro-t ...[more]

PMID: 31158393

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <10%. Compelling evidence suggests that the devastating disease outcome of PDAC patients is linked to a high degree of intra- and interindividual tumor heterogeneity, which is predominantly installed at the level of gene transcription. The cellular and molecular complexities of the disease explain the poor efficacy of "one-size-fits-all" therapeutic approaches in PDAC treatment and strongly argue for pursuing tailored therapeutic strategies to tackle PDAC. In a highly dynamic manner, a network of transcription factors and epigenetic regulatory proteins temporally and spatially control the diverse transcriptomic states determining PDAC heterogeneity. Given the reversibility of epigenetic processes, pharmacological intervention with key epigenetic drivers of PDAC heterogeneity appeals as a promising concept to shift the transcriptomic phenotype of PDAC toward a less aggressive and more chemosensible state.SummaryIn this review, we discuss the chances and pitfalls of epigenetic treatment strategies in overcoming and shifting molecular and cellular PDAC heterogeneities in order to combat PDAC. To this end, we utilized the keywords "pancreatic cancer," "heterogeneity," and "epigenetics" to search for relevant articles on the database PubMed and selected interventional studies enrolling PDAC patients as displayed in clinicaltrails.gov to generate a synopsis of clinical trials involving epigenetic targeting.Key messagesTargeting epigenetic regulators in PDAC represents a promising concept to reprogram molecular and cellular tumor heterogeneities in the pancreas and hence to modulate the PDAC phenotype in favor of a less aggressive and more therapy susceptible disease course. However, we just start to understand the complex interactions of epigenetic regulators in controlling PDAC plasticity, and a clinical breakthrough utilizing epigenetic targeting in PDAC patients has not been achieved yet. Nevertheless, increasing translational efforts which consider the pleiotropic effects of targeting epigenetic regulation in different cellular compartments of the tumor and that focus on the utility and sequence of combinatory treatment approaches might pave the way toward novel epigenetic treatment strategies in PDAC therapy.

Dataset Information

Cellular determinants and therapeutic implications of inflammation in pancreatic cancer.

Publications

Cellular determinants and therapeutic implications of inflammation in pancreatic cancer.

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