Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma

By Paolo P. Provenzano, C. Cuevas, Amy E Chang, V. Goel, D. V. Von Hoff, S. Hingorani. Cancer Cell, 2012

2,019 citations recorded by the source corpus.

SUMMARY Pancreatic ductal adenocarcinomas (PDA) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFP), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses resulting in a near doubling of overall survival.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/2998183c2332af7dcc9d3ed931590abccacc8d6f

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Citations in the corpus

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer (2016, background): “Although CCA’s TME contributes to high resistance to therapy, it may also present a therapeutic opportunity (204, 205).”
Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy (2014, positive): “VDR genomic targets of importance in PDA include the extracellular matrix (Jacobetz et al., 2013; Provenzano et al., 2012), the Shh pathway (Olive et al.”
Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Diminished Survival (2014, positive): “In this regard, the potential role of HA, independent of type I collagen, in determining interstitial fluid pressure in PDAC tissue needs further mechanistic unraveling, and clinical trials with PEGPH20 will offer more insights in the future (Provenzano et al., 2012).”
Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “Excessive tumor-stromal HA together with collagen usually results in substantial vessel compression, which blocks the delivery of peripheral immune cells and drugs into tumor vessels [363].”
Angiogenic signaling pathways and anti-angiogenic therapy for cancer (2023, background): “These factors affect the drug treatment and benefit tumor proliferation, adhesion, invasion, and metastasis, eventually leading to tumor resistance and malignant lesions.(68,69) Because of the tenacious viability, various proangiogenic factors are secreted by tumor cells to stimulate endothelial cel”
Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. (2014, result): “Rather, our findings are consistent with a model in which mesenchymal stromal cells exert an antiangiogenic effect on endothelial cells, possibly acting either directly or indirectly to elevate interstitial fluid pressure, which then represses blood vessel growth (Jacobetz et al., 2013; Provenzano e”
Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels (2013, neutral): “Hyaluronan has been proposed to be the primary matrix molecule responsible for vessel compression 12 , but its exact mechanism remains unclear.”
Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. (2019, background): “A major source of solid stress in PDAC tumors is hyaluronan (7), and the enzymes responsible for hyaluronan production are uniquely and specifically expressed in iCAFs (HAS1 and HAS2 in the human data; Has1 and Has2 in the mouse data).”