期刊
BIOCHEMICAL SOCIETY TRANSACTIONS
卷 50, 期 4, 页码 1129-1141出版社
PORTLAND PRESS LTD
DOI: 10.1042/BST20220162
关键词
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资金
- NHMRC
- Suttons
- NBCF
- Cancer Council NSW
- Cancer Institute NSW
- US Department of Defence
- St. Vincent's Clinic Foundation
- Len Ainsworth Pancreatic Cancer Fellowship
- White Walker Cancer Research Scholarship
- Tour de Cure
- Avner Pancreatic Cancer Foundation Grant
The dense desmoplastic and fibrotic stroma in pancreatic ductal adenocarcinoma (PDAC) plays a role in disease progression and treatment response. Reciprocal interactions between the tumor and stroma through integrin-mediated signaling, particularly Focal Adhesion Kinase (FAK), are important in regulating stromal remodeling and tissue stiffness. Targeting the PDAC stroma, including transient stromal manipulation via short-term FAK inhibition, may enhance the vulnerability of PDAC cells to chemotherapy. This article highlights the significance of treatment timing and suggests further exploration of anti-fibrotic therapies for PDAC and other fibrotic diseases.
The dense desmoplastic and fibrotic stroma is a characteristic feature of pancreatic ductal adenocarcinoma (PDAC), regulating disease progression, metastasis and response to treatment. Reciprocal interactions between the tumour and stroma are mediated by bidirectional integrin-mediated signalling, in particular by Focal Adhesion Kinase (FAK). FAK is often hyperactivated and overexpressed in aggressive cancers, promoting stromal remodelling and inducing tissue stiffness which can accelerate cancer cell proliferation, survival and chemoresistance. Therapeutic targeting of the PDAC stroma is an evolving area of interest for pre-clinical and clinical research, where a subtle reshaping of the stromal architecture prior to chemotherapy may prove promising in the clinical management of disease and overall patient survival. Here, we describe how transient stromal manipulation (or ???priming???) via short-term FAK inhibition, rather than chronic treatment, can render PDAC cells exquisitely vulnerable to subsequent standard-of-care chemotherapy. We assess how our priming publication fits with the recent literature and describe in this perspective how this could impact future cancer treatment. This highlights the significance of treatment timing and warrants further consideration of anti-fibrotic therapies in the clinical management of PDAC and other fibrotic diseases.
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