Stromal Inflammation in Pancreatic Cancer: Mechanisms and Translational Applications
Pancreatic ductal adenocarcinoma is the most severe form of pancreatic cancer because of pronounced inflammation and desmoplasia leading to hypoxia, metabolic reprogramming, and immune suppression that ultimately promote tumor growth and metastasis. The conventional wisdom is that patient survival is hobbled by the inability of currently available therapies to penetrate the tumor and its dense stromal microenvironment. The pancreatic cancer stromal microenvironment is a heterogeneous population of cancer cells, immune cells, cancer-associated fibroblasts, vascular endothelial cells, and neurons. While a detailed understanding of the cells, mediators, and receptors influencing stromal dynamism continues to emerge, interactions between these cells influence tumor suppression as well as tumor promotion. The specific roles for the inflamed stroma in pancreatic cancer immune evasion, progression, metastasis, and therapeutic resistance likely depend on stage of tumor development and distinct biophysical features within the dynamic cellular micro-niches of the tumor. Uncovering the stromal mechanisms of tumor development and progression should prompt the discovery of key windows of opportunity for multimodal therapies in pancreatic cancer.
KeywordsInflammation Stellate Cell Cytokine Desmoplasia Cancer-Associated Fibroblast T Cell Tumor-Associated Macrophage Immune Evasion Stromal Remodeling
The authors thank past and present members of the Dwinell Laboratory as well as Dr. Ishan Roy, Dr. Bryon Johnson, and Dr. Edna Cukierman for constructive conversations about mucosal inflammation and stromal interactions within the pancreatic cancer microenvironment. Work in the laboratory is supported by the National Cancer Institute (U01 CA178960) and continuing philanthropic support from the Bobbie Nick Voss Charitable Foundation and the We Care Fund. The authors gratefully acknowledge and apologize to numerous colleagues whose excellent work could not be cited due to space restrictions.
In memory of Martin F. Kagnoff, MD who succumbed to complications of pancreatic cancer in 2014. His enduring legacy and passion for understanding the pathophysiologic mechanisms of mucosal inflammation remain an inspiration to his trainees and colleagues.
Disclosures MBD is cofounder and has financial interests in Protein Foundry, LLC, a biotech startup that manufactures recombinant chemokines for biomedical research. MBD has been granted a patent [US Patent 8,404,640] for the use of recombinant CXCL12 as an antitumor agent.
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