Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma

Abstract

The microenvironment influences the pathogenesis of solid tumors and plays an outsized role in some. Our understanding of the stromal response to cancers, particularly pancreatic ductal adenocarcinoma, has evolved from that of host defense to tumor offense. We know that most, although not all, of the factors and processes in the microenvironment support tumor epithelial cells. This reappraisal of the roles of stromal elements has also revealed potential vulnerabilities and therapeutic opportunities to exploit. The high concentration in the stroma of the glycosaminoglycan hyaluronan, together with the large gel-fluid phase and pressures it generates, were recently identified as primary sources of treatment resistance in pancreas cancer. Whereas the relatively minor role of free interstitial fluid in the fluid mechanics and perfusion of tumors has been long appreciated, the less mobile, gel-fluid phase has been largely ignored for historical and technical reasons. The inability of classic methods of fluid pressure measurement to capture the gel-fluid phase, together with a dependence on xenograft and allograft systems that inaccurately model tumor vascular biology, has led to an undue emphasis on the role of free fluid in impeding perfusion and drug delivery and an almost complete oversight of the predominant role of the gel-fluid phase. We propose that a hyaluronan-rich, relatively immobile gel-fluid phase induces vascular collapse and hypoperfusion as a primary mechanism of treatment resistance in pancreas cancers. Similar properties may be operant in other solid tumors as well, so revisiting and characterizing fluid mechanics with modern techniques in other autochthonous cancers may be warranted.

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].…”

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

“…As a result, the cancer cells acquire an appropriate microenvironment to survive, proliferate, and invade by the interaction between hyaluronan and its receptors. The other important role of the accumulation of hyaluronan in cancer progression is that it increases the interstitial fluid pressure (IFP), which makes drug perfusion difficult [9,10]. Hyaluronidase treatment was shown to reduce the IFP within two hours in a mouse model of PDAC and to significantly improve the response to gemcitabine, one of the key drugs for PDAC treatment [33].…”

“…These difficulties in PDAC treatment are partly due to the desmoplastic change of the extracellular matrix (ECM), which is characterized by the accumulation of cancer-associated fibroblasts (CAF) and increased fibrous ECM components, including collagen, proteoglycans, and hyaluronan [8]. 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].…”

Cancer Manipulation of Host Physiology: Lessons from Pancreatic Cancer

“…The end result is the generation of a dense, gel-like extracellular matrix with unique physicochemical properties [75]. Several macromolecules of the gel-like ECM, such as hyaluronic acid (HA), absorb and retain significant amounts of water, thus increasing the interstitial fluid pressure (IFP) of the tumor; this dramatically elevated IFP is evident by the collapsed blood vessels in areas of desmoplasia, and appears to be an important hurdle to adequate delivery of drugs in the tumor milieu, due to both inadequate perfusion and opposition to their extravasation [75]. …”