Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities

Author:

Myo Min Kay K.1,Ffrench Charlie B.1ORCID,Jessup Claire F.23,Shepherdson Mia24ORCID,Barreto Savio George24ORCID,Bonder Claudine S.13ORCID

Affiliation:

1. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia

2. College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia

3. Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia

4. Hepatopancreatobiliary & Liver Transplant Unit, Division of Surgery & Perioperative Medicine, Flinders Medical Centre, Bedford Park, SA 5042, Australia

Abstract

An overabundance of desmoplasia in the tumour microenvironment (TME) is one of the defining features that influences pancreatic ductal adenocarcinoma (PDAC) development, progression, metastasis, and treatment resistance. Desmoplasia is characterised by the recruitment and activation of fibroblasts, heightened extracellular matrix deposition (ECM) and reduced blood supply, as well as increased inflammation through an influx of inflammatory cells and cytokines, creating an intrinsically immunosuppressive TME with low immunogenic potential. Herein, we review the development of PDAC, the drivers that initiate and/or sustain the progression of the disease and the complex and interwoven nature of the cellular and acellular components that come together to make PDAC one of the most aggressive and difficult to treat cancers. We review the challenges in delivering drugs into the fortress of PDAC tumours in concentrations that are therapeutic due to the presence of a highly fibrotic and immunosuppressive TME. Taken together, we present further support for continued/renewed efforts focusing on aspects of the extremely dense and complex TME of PDAC to improve the efficacy of therapy for better patient outcomes.

Funder

Pankind

NHMRC Ideas

Flinders Foundation

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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