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Carvalho, T. Tumor Microenvironment Features and in Pancreatic Ductal Adenocarcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/19816 (accessed on 01 September 2024).
Carvalho T. Tumor Microenvironment Features and in Pancreatic Ductal Adenocarcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/19816. Accessed September 01, 2024.
Carvalho, Tiago. "Tumor Microenvironment Features and in Pancreatic Ductal Adenocarcinoma" Encyclopedia, https://encyclopedia.pub/entry/19816 (accessed September 01, 2024).
Carvalho, T. (2022, February 23). Tumor Microenvironment Features and in Pancreatic Ductal Adenocarcinoma. In Encyclopedia. https://encyclopedia.pub/entry/19816
Carvalho, Tiago. "Tumor Microenvironment Features and in Pancreatic Ductal Adenocarcinoma." Encyclopedia. Web. 23 February, 2022.
Tumor Microenvironment Features and in Pancreatic Ductal Adenocarcinoma
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13236135

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. 

pancreatic ductal adenocarcinoma tumor microenvironment

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)) [2]. 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 [3]; (ii) cancer cell migration/invasion [4][5][6]; and (iii) drug penetration into the tumor [7]. 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 [8].
The TME was first proposed by Ioannides in 1993, and referred especially to the local environment where tumors occurred and developed [9]. Commonly, the TME of PDAC is characterized by abundant stroma, hypoxia, a deficient blood supply and elevated immunosuppression [10]. 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 [11]. 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 (pHe) 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 [12]. There are many factors that contribute to the failure of chemotherapy in this pathology, including the occurrence of desmoplasia in the PDAC TME [12].
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 [13]. 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 [14][15][16]. 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 [17][18][19][20]. Desmoplasia can be divided histopathologically into two groups: (i) overproduction of ECM proteins, and (ii) extensive proliferation of the PSCs [21][22].
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 [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 [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 [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 [34]. On other hand, the marked overproduction of ECM constituents in PDAC has been suggested to be a failed wound healing, leading to fibrosis [34]. The increased deposition of collagen type I, III, and IV in PDAC tissues [35][36][37] is directly linked to the TGFβ/Smad signaling and is a product of the activity of the fibroblasts [38]. Remarkably, in PDAC, the elevated levels of collagen I reduce tissue elasticity and raise interstitial fluid pressure, causing a reduction in drug perfusion [39].
The protein-free GAG, hyaluronan, is also an important component of the ECM, contributing to tissue rigidity and thereby decreasing elasticity [40] and its accumulation within damaged tissue is a product of increased secretion by CAFs in pancreatic cancer [41]. Moreover, hyaluronan maintains its interaction with water molecules, to preserve tissue hydration in normal pancreas [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 [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 [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) [45][46].
Cancers 13 06135 g001 550
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.
Lastly, fibronectin is also a crucial ECM component which binds to adhesion receptors in several cell types [47]. Additionally, it supports cell–ECM interactions and is a key factor for wound healing and development and the maintenance of tissue homeostasis [48][49][50][51][52]. While several cell types including tumor cells and endothelial cells are able to produce fibronectin, fibroblasts are the main producers [50]. The elevated expression of fibronectin is displayed by several solid tumors, particularly in pancreatic cancer [53]. Therefore, the interaction of multiple ECM proteins to produce the desmoplastic reaction in PDAC is a feature which clearly contributes to the pathogenesis and ultimately to chemoresistance.

2.2. The Contribution of Desmoplastic Components towards Chemoresistance

Desmoplasia can promote chemoresistance through several mechanisms which can be divided in two main groups: biological and physiological chemoresistance [22]. Biological chemoresistance can arise from different mechanisms. Target cells can (a) acquire resistance to drug uptake, (b) reduce their sensitivity to drugs by increasing the expression of anti-apoptotic proteins and activating protective mechanisms such as autophagy [54], (c) use DNA repair mechanisms to counteract the drug-dependent destruction of the tumor cell DNA [55][56] and (d) recruit more transporters/proteins responsible for drug efflux, thus preventing their action in the cancer cell. In PDAC, both physiological and biological chemoresistance are present and constitute a considerable problem for effective chemotherapy [22]. Moreover, the non-cellular components of the desmoplastic reaction can contribute to biological chemoresistance. Indeed, the binding of hyaluronan to its receptor, CD44, caused a Stat-3-mediated increase in the expression of the multi-drug resistance protein 1 (MDR1) in pancreatic cancer cell lines [57]. Moreover, the interaction of hyaluronan with CD44 is able to activate the phosphatidylinositol-3-kinase (PI3K/AkT) signaling pathway, which is upregulated in several cancers, resulting in the phosphorylation of Bad, and the consequent downregulation of apoptosis (Figure 2) [58][59].
Cancers 13 06135 g002 550
Figure 2. Binding of hyaluronan to CD44 unleashes a pro-tumoral intracellular signaling. The intracellular signaling functions of hyaluronan are triggered after its binding with CD44. This interaction results in the increased expression of the multi-drug resistance protein 1 (MDR1) through STAT3 activation and in the activation of phosphatidylinositol-3-kinase (PI3K/AkT) signaling pathway, causing phosphorylation of Bad, and the subsequent downregulation of apoptosis. The hyaluronan synthesis inhibitor, 4-methylumbelliferone (4-MU), inhibits cell migration, proliferation, and invasion by blocking the interaction between hyaluronan and CD44.
The ECM components are also involved in physiological chemoresistance and probably to a larger extent than in biological chemoresistance [60]. Physiological chemoresistance is due to poor tissue vascularization in the tumor tissue caused by the overproduction of ECM proteins and the consequent increased interstitial fluid pressure, which together produce a barrier to drug absorption into the target tissue [22]. As mentioned before, collagen type I, III, and IV are highly secreted into the PDAC TME and it was demonstrated, in a PDAC orthotopic xenograft mouse model, that the increased collagen I content decreased the penetration of nanoparticles, resulting in a significant reduction in the response to doxorubicin treatment [61]. Moreover, the collagen-reducing effects of the anti-hypertensive agent, losartan, resulted in a significant augmentation of nanoparticle penetration towards the target cells [61]. However, the decreased collagen I content induced a switch in cancer stem cells (CSCs) from slow growing, avascular-type cells to fast-growing, highly autophagic endothelial-like cells, creating a favorable mechanism for tumor progression and chemoresistance to gemcitabine [54][62]. Altogether, these data suggest that the correct manipulation of ECM collagen composition may be able to enhance the accessibility of drugs to tumor tissues and decrease chemoresistance.

2.3. Targeting the Desmoplasia Improves Chemotherapy Outcomes

Several stroma-targeting drugs are currently being tested as new treatment strategies to reduce chemoresistance in PDAC. One of the more appealing targets of the tumor stroma is the potent cytokine TGFβ which regulates developments, differentiation, and homeostasis in mammalian [63]. TGFβ binds to TGFβ receptor 1 or 2 to inhibits cell proliferation, motility, invasion, EMT, and metastasis [64] and its tumor-inhibitory effect is controlled by Smad-dependent TGFβ signaling [65]. Indeed, in human prostate cancer, overexpression of TGFβ1 correlates with collagen I levels, suggesting that TGFβ can be directly linked to the desmoplastic process [26]. Furthermore, knocking down Smad 3 abolishes collagen fibrosis induced by the EMT-regulator Snail, hence corroborating the role of TGFβ as a crucial signaling pathway in the propagation of the desmoplastic reaction [66]. Moreover, Smad4 is frequently mutated in PDAC and this could be one of the reasons for the resistance to the growth inhibitory effects of TGFβ [26]. In this line, some TGFβ receptor 1 inhibitors, such as SB431542 and SB525334, have been developed and tested in combination with gemcitabine, resulting in a higher cytotoxic effect compared to gemcitabine alone due to an increased delivery and penetration of the drugs into the tumor (desmoplastic) tissues [67].
Moreover, the hyaluronan cell surface receptor CD44 has a critical role in pancreatic carcinogenesis [68] such that disruption of the hyaluronan-CD44 complex is a crucial therapeutic target to prevent PDAC drug resistance [68]. Indeed, the compound, 4-methylumbelliferone (4-MU), by inhibiting hyaluronan synthesis and accumulation on cancer cells and their surrounding stroma, blocked cell proliferation, migration, and spreading in several tumor cell types [69][70] and reduced bone metastases in breast cancer (Figure 2) [71]. In both PDAC cell lines and in vivo, 4-MU slowed the development and progression of the disease and also increased tumor response to gemcitabine [72][73][74]. In a similar way, PEGylated human recombinant PH20 hyaluronidase (PEGPH20) acted as a hyaluronan “consumer” enhancing the delivery of chemotherapeutic agents such as doxorubicin and gemcitabine [46][75]. Injection of PEGPH20 into KPC mice tumors rapidly degraded hyaluronan, restored the patency of intra-tumoral vessels, increased vessel diameter and highly reduced the high interstitial fluid pressure within the tumors to normal levels [7]. Importantly, these alterations increased the macromolecules permeability and the combined treatment of gemcitabine with PEGPH20 remarkably improved treatment efficacy by reducing metastases and doubling the median survival time in mice [76].
Further, the enzymatic degradation of ECM components has also been proposed as a possible complementary therapeutic approach against PDAC. Several studies using hyaluronidase showed improved cancer sensitivity to chemotherapeutics and enhanced permeability to drugs in cultured multicellular spheroids [77]. Similarly, collagenases have also displayed beneficial characteristics by increasing the penetration of macromolecules. However, their sensitivity to and stability at physiological pH might be a therapeutic hindrance that has not yet allowed this enzyme to be clinically available [78]. It has proposed a double edged targeting of the hyaluronan-CD44 pathway by combining 4-MU as hyaluronan production inhibitor and bromelain as CD44 inhibitor [79], since this combination has not been experimentally tested yet. Lastly, Hedgehog (Hh) is a signaling pathway that is abnormally activated in most pancreatic cancers leading to cancer initiation, progression and metastatic development [80][81]. More recently, it has been related to the beginning and maintenance of the desmoplastic reaction. Indeed, Hh stimulates the differentiation of myofibroblasts and induces stroma-derived growth promoting molecules [82][83]. There is also some evidence that supports the existence of an interplay between Hh signaling and TGFβ, both being tightly connected with the desmoplastic reaction and involved in fibrosis [83]. Further, it was demonstrated that blocking Hh signaling, both in vitro and in vivo, with the small molecule compound, cyclopamine, markedly improved drug delivery and abrogated pancreatic metastasis [84][85]. Multiple studies have been conducted to verify whether the combined treatment of Hh signaling inhibitors with chemotherapeutic agents can have synergistic anticancer effects [86]. Indeed, the inhibition of the Hh signal with the semisynthetic analogue of cyclopamine, IP-926, reduced the desmoplastic reaction and improved tumor vascularity [87]. A phase Ib trial demonstrated that IPI-926 reduced tumor desmoplasia and increased gemcitabine delivery, such that 31% of patients displayed a partial response and 63% of them showed a reduced expression of the marker Carbohydrate Antigen 19-9 (CA 19-9) in their tumor tissues [88].
In summary, the desmoplastic reaction creates a unique microenvironment, which stimulates tumor growth/progression and forms a “physical barrier” to chemotherapy permeability. Hence, several strategies have arisen to improve chemotherapeutic efficacy by blocking or interfering with the desmoplastic process and enhance tumor penetration, accumulation, and drug distribution. Thus, targeting stroma components of the desmoplastic reaction might be a promising new area of investigation in pancreatic cancer treatment.

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Subjects: Biochemistry & Molecular Biology
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Tiago Carvalho
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