TY - JOUR
T1 - Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma
T2 - Challenges and Opportunities
AU - Myo Min, Kay K.
AU - Ffrench, Charlie B.
AU - Jessup, Claire F.
AU - Shepherdson, Mia
AU - Barreto, Savio George
AU - Bonder, Claudine S.
PY - 2023/4/18
Y1 - 2023/4/18
N2 - 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.
AB - 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.
KW - desmoplasia
KW - immunotherapy
KW - pancreatic ductal adenocarcinoma
KW - targeted therapy
KW - tumour microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85153930801&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/2021009
U2 - 10.3390/cancers15082354
DO - 10.3390/cancers15082354
M3 - Review article
AN - SCOPUS:85153930801
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 8
M1 - 2354
ER -