Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase

Abstract

Elevated interstitial fluid pressure can present a substantial barrier to drug delivery in solid tumors. This is particularly true of pancreatic ductal adenocarcinoma, a highly lethal disease characterized by a robust fibroinflammatory response, widespread vascular collapse, and hypoperfusion that together serve as primary mechanisms of treatment resistance. Free-fluid pressures, however, are relatively low in pancreatic ductal adenocarcinoma and cannot account for the vascular collapse. Indeed, we have shown that the overexpression and deposition in the interstitium of high-molecular-weight hyaluronan (HA) is principally responsible for generating pressures that can reach 100 mmHg through the creation of a large gel-fluid phase. By interrogating a variety of tissues, tumor types, and experimental model systems, we show that an HA-dependent fluid phase contributes substantially to pressures in many solid tumors and has been largely unappreciated heretofore. We investigated the relative contributions of both freely mobile fluid and gel fluid to interstitial fluid pressure by performing simultaneous, real-time fluid-pressure measurements with both the classical wick-in-needle method (to estimate free-fluid pressure) and a piezoelectric pressure catheter transducer (which is capable of capturing pressures associated with either phase). We demonstrate further that systemic treatment with pegylated recombinant hyaluronidase (PEGPH20) depletes interstitial HA and eliminates the gel-fluid phase. This significantly reduces interstitial pressures and leaves primarily free fluid behind, relieving the barrier to drug delivery. These findings argue that quantifying the contributions of free- and gel-fluid phases to hydraulically transmitted pressures in a given cancer will be essential to designing the most appropriate and effective strategies to overcome this important and frequently underestimated resistance mechanism.

Metabolic Interactions in the Tumor Microenvironment

“…Cytokines recruit immune cells, which secrete extracellular matrix remodeling factors. Together these processes change the architecture of the organ creating a stiff fibrotic matrix, marked by increased interstitial pressure, which hinders the activity of the vascular system [14–16]. Deregulated proliferation and growth factor release further influences blood vessel development, which is characterized by leaky vessels that inefficiently deliver nutrients and remove waste products of cellular metabolism, like lactate [17, 18].…”

Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts

“…It has also been revealed that poor prognosis is associated with severe hypoxia in the primary tumor [14][15][16]. Moreover, the interstitial fluid pressure (IFP) has been reported to be elevated [17][18][19], and it has been suggested that highly elevated IFP together with a dense and extensive stroma may cause resistance to treatment by inhibiting the distribution of chemotherapeutic agents [19].…”

The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma

“…This remodeling of the microenvironment surrounding the cancer cells contributes to the elevation of the internal pressure in the cancerous tissue [9]. Moreover, in this process, the deposition of hyaluronan causes the compression of the intratumoral microvasculature and consequently prevents the drug from reaching the cancer cells [10]. In addition, hyaluronan works as a ligand for some receptors on the cell membrane and enhances the progression of cancer.…”