Among all non-cellular components of desmoplasia, the importance of many ECM proteins, namely collagen types I, III and IV, fibronectin, laminin, hyaluronan, as well as the glycoprotein osteonectin
[32,33][23][24] should be emphasized. Desmoplastic progression derives from the abnormal activation of several intercellular and intracellular signaling processes, such as the transforming growth factor beta (TGFβ), the basic fibroblast growth factor (bFGF), the connective tissue growth factor (CTGF) and interleukin-1β, which by stimulating ECM production drive desmoplastic progression
[34,35,36,37,38][25][26][27][28][29]. The ECM components can also be divided into two categories: the fibrous proteins, such as collagens, and the polysaccharide chain glycosaminoglycans (GAGs), such as hyaluronan
[39,40,41,42][30][31][32][33]. In the normal pancreas, GAGs structurally function to sustain compressive forces on the tissue, whereas the fibrous proteins act to support the tensile forces on the tissue
[43][34]. On other hand, the marked overproduction of ECM constituents in PDAC has been suggested to be a failed wound healing, leading to fibrosis
[43][34]. The increased deposition of collagen type I, III, and IV in PDAC tissues
[44,45,46][35][36][37] is directly linked to the TGFβ/Smad signaling and is a product of the activity of the fibroblasts
[47][38]. Remarkably, in PDAC, the elevated levels of collagen I reduce tissue elasticity and raise interstitial fluid pressure, causing a reduction in drug perfusion
[48][39].
The protein-free GAG, hyaluronan, is also an important component of the ECM, contributing to tissue rigidity and thereby decreasing elasticity
[49][40] and its accumulation within damaged tissue is a product of increased secretion by CAFs in pancreatic cancer
[50][41]. Moreover, hyaluronan maintains its interaction with water molecules, to preserve tissue hydration in normal pancreas
[51][42]. Nevertheless, in the “unhealthy” pancreas the increased deposition of hyaluronan might result in interstitial edema and, consequently, augmented interstitial fluid pressure that, in turn, leads to decreased fluid conveyance
[52][43]. Accordingly, this enhanced interstitial edema together with the absence of an efficient lymphatic system in tumor tissue, results in a remarkable reduction in the exchange of several substances with the bloodstream, including chemotherapeutics
[53][44]. Therefore, this significant deposition of hyaluronan in pancreatic cancer stroma is one of the main features of pancreatic TME responsible for decreased chemotherapeutic penetration (
Figure 1)
[54,55][45][46].
Figure 1. Role of hyaluronan in increasing tissue interstitial pressure. Hyaluronan forms long chains creating a highly osmotic environment that produces edema and increased interstitial pressure. Despite the fact that the diagram only shows a tetrasacharide, hyaluronan is a very lengthy unbranched chain of repeating disaccharides. Red arrows indicate the hydrophilic parts of glucuronic acid and N-acetyl glucosamine, proving the highly hydrophilic ability of hyaluronan. Increased hyaluronan in tumors is an early event occurring in TME, which leads to increased interstitial pressure due to its hygroscopic properties, causing an obstacle to the adequate delivery of chemotherapeutic drugs.