Pancreatic ductal adenocarcinoma (PDAC) has a prominent desmoplastic stromal microenvironment that includes a dense extracellular matrix together with a series of activated cell types, hypoxia, and an acidic extracellular pH.
1. Introduction
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in western countries and is projected to be the second-leading cause of cancer-related death in the United States by 2030 [
1]. A prominent feature of the PDAC microenvironment is an extensive desmoplasia that consists of a highly fibrotic and stiff extracellular matrix (ECM) principally composed of collagen I, fibronectin and hyaluronan, which are secreted by alpha-muscle actin-positive fibroblasts (also known as myofibroblasts or activated pancreatic stellate cells (PSCs)) [
7]. Modifications that the ECM architecture suffers during cancer progression have been deeply explored, since it has been recognized that atypical ECM architecture influences therapeutic outcomes specifically by modulating (i) tumor biomechanics [
8]; (ii) cancer cell migration/invasion [
9,
10,
11]; and (iii) drug penetration into the tumor [
12]. The existence of this dense tumor microenvironment (TME) may be the main reason that therapies targeting specifically only cancer-associated molecular pathways have not given satisfactory results [
13].
The TME was first proposed by Ioannides in 1993, and referred especially to the local environment where tumors occurred and developed [
14]. Commonly, the TME of PDAC is characterized by abundant stroma, hypoxia, a deficient blood supply and elevated immunosuppression [
15]. Studies have shown that the TME, including cancer-related fibroblasts (CAFs), stellate cells, diverse immune cells and cytokines released by them, are involved in the control of the proliferation, metastasis, chemoresistance and immunotherapy of pancreatic cancer cells [
16]. Factors associated with TME such as cell plasticity, heterogeneity of the tumor, composition of the tumor stroma, epithelial-to-mesenchymal transition (EMT), reprogrammed metabolism, acidic extracellular pH (pH
e) and hypoxia can heavily impact treatment outcomes. Therefore, finding new therapeutic targets within the TME of PDAC is an encouraging and potential research direction in order to understand the lack of efficacy of current treatments for pancreatic cancer.
2. Desmoplastic Reaction in the Pancreatic Tumor Microenvironment
2.1. Desmoplasia: The Impact on Tumor Development and Progression
Despite the sizeable improvement in recent years, chemotherapy remains markedly incompetent in improving PDAC patient survival [
21]. There are many factors that contribute to the failure of chemotherapy in this pathology, including the occurrence of desmoplasia in the PDAC TME [
21].
Desmoplasia, also known as the desmoplastic reaction, consists of a dense ECM together with myofibroblast-like cells, including CAFs and is a fundamental feature of the pancreatic cancer TME [
22]. Initially, the role of this phenomenon was overlooked; however, many studies have since demonstrated that during PDAC development, the cancer cells expend a large amount of energy to promote the recruitment, proliferation, and activation of fibroblasts. Consequent to their activation, CAFs are able to deposit ECM components and secrete several types of factors that strongly affect the behavior of cancer cells [
23,
24,
25]. Indeed, pharmacologic inhibition of the desmoplastic reaction in combination with chemotherapy showed better results in inhibiting PDAC progression than chemotherapy alone, thus highlighting desmoplasia as a likely therapeutic target in pancreatic cancer [
26,
27,
28,
29]. Desmoplasia can be divided histopathologically into two groups: (i) overproduction of ECM proteins, and (ii) extensive proliferation of the PSCs [
30,
31].
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] 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]. 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]. 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]. On other hand, the marked overproduction of ECM constituents in PDAC has been suggested to be a failed wound healing, leading to fibrosis [
43]. The increased deposition of collagen type I, III, and IV in PDAC tissues [
44,
45,
46] is directly linked to the TGFβ/Smad signaling and is a product of the activity of the fibroblasts [
47]. Remarkably, in PDAC, the elevated levels of collagen I reduce tissue elasticity and raise interstitial fluid pressure, causing a reduction in drug perfusion [
48].
The protein-free GAG, hyaluronan, is also an important component of the ECM, contributing to tissue rigidity and thereby decreasing elasticity [
49] and its accumulation within damaged tissue is a product of increased secretion by CAFs in pancreatic cancer [
50]. Moreover, hyaluronan maintains its interaction with water molecules, to preserve tissue hydration in normal pancreas [
51]. 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]. 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]. 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].
This entry is adapted from the peer-reviewed paper 10.3390/cancers13236135