Toll-like Receptors Mediated Inflammation in Pancreatic Cancer Pathophysiology: Comparison
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Please note this is a comparison between Version 2 by Vivi Li and Version 1 by Pellegrino Mazzone.

Pancreatic cancer (PC) is one of the most lethal forms of cancer, characterized by its aggressiveness and metastatic potential. Despite significant improvements in PC treatment and management, the complexity of the molecular pathways underlying its development has severely limited the available therapeutic opportunities. Toll-like receptors (TLRs) play a pivotal role in inflammation and immune response, as they are involved in pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Activation of TLRs initiates a signaling cascade, which in turn, leads to the transcription of several genes involved in inflammation and anti-microbial defense. TLRs are also deregulated in several cancers and can be used as prognostic markers and potential targets for cancer-targeted therapy.

  • pancreatic cancer
  • toll-like receptor
  • inflammation
  • chemotherapy

1. Introduction

Pancreatic cancer (PC) is a lethal malignancy with a high mortality rate that is projected to become the second leading cause of cancer death in the next ten years [1]. Based on the GLOBOCAN 2020, it has been estimated that pancreatic cancer causes more than 466,000 deaths per year worldwide, ranking as the seventh cause of cancer death in males and females [2]. Because of the lack of early diagnosis, about 80% of patients show unresectable tumor or metastases with a 5-year survival rate of about 10%. This parameter can increase to 58% in a small percentage of patients in which tumor is detected at early stages [3]. The standard treatment for patients affected by PC is surgical resection followed by chemotherapy. This strategy, supported by different studies, results in the improvement of survival outcome. In particular, the CONKO-001 study shows that the addition of gemcitabine treatment after tumor resection results in an increased 5-years survival rate with a slight increase in the overall survival [4]. Other clinical trials are carried out in order to identify the best therapeutic regime that improves patient survival. For example, dual treatment with capecitabine and gemcitabine after tumor resection results in the amelioration of the median overall survival [5]. Another therapeutic approach that is often applied to PC patients is the administration of FOLFIRINOX (5FU, leucovorin, irinotecan and oxaliplatin). This latter strategy appears to lead to a higher overall survival, progression-free survival and response rate when compared to gemcitabine single treatment [6]. However, due to its toxicity, this therapeutic regime is not suitable for all patients making gemcitabine the standard drug used in the PC treatment [6]. Despite the advances in the understanding of pancreatic cancer pathogenesis, the causes of the insurgence of this neoplasia still remain unknown. Environmental factors, such as smoking, obesity, diabetes mellitus and chronic pancreatitis, represent a potential risk for the PC insurgence [7]. Moreover, several studies demonstrated that hereditary germline or somatic mutations are responsible for tumor progression. Particularly, mutations in genes that are associated with cell death and proliferation as well as mutations in genes associated with telomerase shortening result in PC insurgence and metastasis [8,9][8][9]. Apart from the alteration of tumor suppressor genes and of the ones involved in the cell cycle regulation, cytokines have been shown to have a role in the malignant transformation [10]. Chronic inflammation, indeed, can lead to the production of several cytokines that activate different signaling pathways. This cascade results in the upregulation of other proinflammatory cytokines, such as interleukin-6 (IL-6) which affect the progression of the pancreatic cancer [11]. Among these pathways, Toll-like receptors (TLRs) seem to be activated during pancreas inflammation in response to damage-associated molecular patterns (DAMPs) [12]. Upon activation, TLRs, through different pathways, lead to the transcriptional factor NF-κB which supports the inflammatory microenvironment [13]. Several studies demonstrated that TLRs are upregulated in different neoplasia such as breast, lung and colon cancer where they are associated with a favorable or with a poor prognosis [14]. Recent reports demonstrated that TLRs are highly expressed also in pancreatic cancer where they are involved in the regulation of cancer physiology and therefore, they may represent a novel target for the cancer therapy [15,16,17][15][16][17]. 

2. Toll-like Receptors

Toll-like receptors (TLRs) belong to the pattern recognition receptors (PRRs) family, which is involved in the activation of the innate immune response [18]. The PRRs family is able to recognize several pathogen-associated molecular patterns (PAMPs) deriving from pathogenic bacteria or fungi, viruses and protozoa [19]. TLRs consist of type I integral membrane glycoproteins with an extracellular N-terminal domain, that contains leucine-rich repeats (LRRs), and an intracellular C-terminal domain defined Toll/IL-1 receptor (TIR) domain [20,21][20][21]. TLRs family includes ten members: TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, which are expressed extracellularly and TLR3, TLR7, TLR8, TLR9, that are expressed in the endosomes [22,23][22][23]. Furthermore, TLRs are classified according to the PAMPs that they are able to bind to: TLR1, TLR2, TLR4 and TLR6 recognize lipids, TLR5 and TLR10 detect proteins and TLR3, TLR7, TLR8 and TLR9 bind nucleic acids (Table 1) [24]. Upon stimulation, most of these receptors activate a signaling cascade that includes Myeloid differentiation primary response protein 88 (MyD88). This pathway, through the activation of several intermediates such as tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF-6), IL-1R-associated kinases (IRAK) and mitogen-activated kinases, leads to the activation of the transcriptional factor NF-κB [25], a pleiotropic factor involved in the activation of pro-inflammatory genes [26] (Figure 1). In addition, TLRs, in particular TLR3 and TLR4, are able to activate a non-MyD88-dependent pathway that involves TIR-domain-containing adapter-inducing interferon-β (TRIF) protein and is responsible for the synthesis of interferon (IFN) and/or NF-κB activation [27,28][27][28]. Defects in the activation of TLRs result in the alteration of immune homeostasis that is sustained by the upregulation of NF-κB and the production of pro-inflammatory cytokines. This contributes to the development and progression of several diseases including cancer, diabetes type 1 and autoimmune diseases [29,30,31][29][30][31] (Figure 1).
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Figure 1. Localization and ligands of toll-like receptors (TLRs). The surface-expressed TLRs recognize bacterial compounds while the intracellular receptors recognize virus-associated nucleic acids. Almost all these receptors activate a signaling pathway that, through Myd88, leads to the activation of the transcriptional factor NF-κB. TLR3 and TLR4 activate a Myd88-independent signaling which culminates in the activation of transcriptional factor IRF3.
Table 1. Toll-like receptors expressed in human pancreatic cancer cell lines.
TLRs Localization PAMPs Adaptor Pancreatic Cancer Cell Line Refs.
TLR1 Plasma membrane Triacyl lipopeptides Myd88/TIRAP Not reported [19,32][19][32]
TLR2 Plasma membrane Lycolipids, lipoprotein, lipoteichoic acid, peptidoglycan, zymosan Myd88/TIRAP BxPC-3; MIA PaCa-2, MDA Panc-28, SU 8686, SW-1990, AsPC-1, Panc-1 [19,33,34,35][19][33][34][35]
TLR3 Endosome Double-stranded RNA TRIF AsPC-1, Colo357, Panc-89, PancTu-1, Pt45P1 [36,37,38][36][37][38]
TLR4 Plasma membrane Lipopolysaccharide (LPS), heat shock proteins Myd88/TIRAP AsPC-1, BxPC-3, CFPAC, MIA PaCa-2, MDA Panc-28, Panc-1, Sw-1990 [34,35,39][34][35][39]
TLR5 Plasma membrane Flagellin
TLR2 expression profile varies among cell types with higher expression levels found on the plasma membrane of immune cells. Besides its role in inflammatory diseases, TLR2 plays, also, an antitumor activity that is exerted by several mechanisms such as enhancement of T-cell immunity, induction of apoptosis in TLR2-positive tumors and enhancement of the innate immunity [50]. In pancreatic cancer, increased TLR2 expression has a controversial role in the regulation of the pathophysiology of this neoplasia (Table 2). In particular, in pancreatic cancer cells, upon the binding of HMGB1 (High mobility group box1) to TLR2, the PI3K/pAKT pathway is activated with subsequential induction of the epithelial-mesenchymal transition necessary for the metastatic phenotype [33,34][33][34]. Furthermore, previous reports also described a role of TLR2 in the maintenance of stemness in ovarian and breast cancer cells Lately, a recent study demonstrated that, in pancreatic cancer cells, the interaction HMGB1 with TLR2 leads to the activation of Wnt/β-catenin in CD133+ cancer cells and it is responsible for the activation of stem cell genes, such as NANOG, OCT4 and SOX2 [35]. Leppanen et al. further discussed TLR2 expression in the pancreatic intraepithelial neoplasia (PanIN), a precursor of pancreatic cancer. Particularly, TLR2 expression varies among the different grades of severity of these lesions with lower expression in PanIN1 and higher TLR2 expression in PanN3 [51].
Table 2. Association between TLRs expression and pancreatic cancer prognosis.
TLRs Expression Pancreatic Cancer Prognosis Refs.
TLR1 High Favorable [49]
TLR2 High Favorable [15]
Unfavorable [33,34,35,51][33][34][35][51]
TLR3 High Unfavorable [36]
Myd88 Not reported [32]
TLR4 High Favorable [15] TLR6 Plasma membrane
Unfavorable [39,[52,3953,54]Diacyl lipopeptides, lipoteichoic acid ]Myd88/TIRAP Not reported [52][53][54[32]
] TLR7 Endosome Single-stranded RNA Myd88 Colo357, MIA PaCa-2, MDA Panc-28, Panc-1, Sw-1990, Panc-89, PancTu-1, BxPC-3 [[38
TLR5 High55,56][55][56],40,41,42][38][40][41][42]
Unfavorable TLR8 Endosome Single-stranded RNA Myd88 Panc-1 [
TLR7 High41]
Unfavorable [16,41,57][ TLR9 Endosome DNA (CpG) Myd88 GER, MIA PaCa-2, MDA Panc-28, Panc-1, Sw-1990, T3M4 [34,43,44][34][43][44]
TLR10 Endosome Unknown Unknown Not reported [32]

3. Toll-like Receptor 1

TLR1 is expressed on the membrane of several lymphoid cell lines, including monocytes and lymphocytes and neuronal cells, such as CHP-212 and NT2-N [45,46][45][46]. This receptor is able to form a heterodimer with other TLRs acquiring the ability to recognize a broad range of antigens, such as bacterial proteins upon binding to TLR2 [47], and fungi upon binding to TLR6 [48]. Little is known about the role of this receptor in pancreatic cancer. Recently, a multivariate analysis has reported a positive correlation between the higher TLR1 expression and a better prognosis in pancreatic cancer patients who had received no post-operative adjuvant chemotherapy [49].

4. Toll-like Receptor 2

16
]
[
41
]
[
57
]
TLR8 High Unfavorable [41,57][41][57]
TLR9 High Favorable [43,58,59,60][43][58][59][60]
Unfavorable [44,61][44][61]

5. Toll-like Receptor 3

TLR3 is an endosomal receptor expressed in monocytes and dendritic cells with the ability to recognize double-stranded RNAs. Upon stimulation, this receptor activates a signaling pathway that ends up either in the activation of NF-κB or in the interferon-beta (IFNβ) production upon IRF3 activation. Previous evidence demonstrated the interplay between TLR3 and Wnt5a signaling in pancreatic cancer (Table 2). Particularly, PC cells show high expression levels of TLR3 associated with increased cancer cell proliferation and with constitutive activation of the Wnt5a signaling [36]. However, despite TLR3 expression in PC cells, it is still unclear which role it plays in pancreatic cancer pathophysiology.

6. Toll-like Receptor 4

TLR4 is a surface receptor, expressed either as homodimer or heterodimer together with TLR6 on the membrane of many immune cells, that recognizes the lipopolysaccharide (LPS), the major component of Gram-negative bacteria. Upon stimulation, TLR4 activates a downstream cascade which involves several adaptor molecules and culminates in the activation of the transcription factor NF-κB [62,63,64][62][63][64]. TLR4 expression is linked to several diseases. It has been reported that high TLR4 activation, upon LPS stimulation, is involved in the alteration of cytosolic Ca2+ and in cell death promotion, thus contributing to Alzheimer’s disease pathogenesis [65,66][65][66]. Moreover, PAMPs-induced TLR4 activation plays also a crucial role in inflammatory skin diseases [67,68][67][68]. Particularly, TLR4 stimulation activates a signaling that, through the recruitment of members of the CBM complex, leads to the activation of NF-κB-induced genes necessary for the maintenance of the inflammatory state [69,70][69][70]. Furthermore, TLR4 activation is involved in the promotion of several cancers, such as cervical [71], colorectal [72], and prostate cancer [73]. TLR4 upregulation has been found also in pancreatic cancer where it plays a central role in tumor progression. It has been demonstrated that stromal leukocytes from pancreatic cancer patients show high TLR4 expression levels. These data were confirmed by in vivo experiments in which KRAS mutated mice show upregulated levels of TLR4 both in stromal and epithelial cells while, on the other hand, TLR4−/− mice had a reduction in tumor growth. Moreover, the high expression of TLR4 results in the activation of several NF-κB-induced genes, such as matrix metalloproteinases 2 and 9 (MMP2 and MMP9). Previous evidence reported that the proteolytic activity of these metalloproteinases is increased in pancreatic cancer cells co-cultured with M2-polarized macrophages in which the epithelial-mesenchymal transition (EMT) program is activated by TLR4/IL10 signaling pathway [52].
TLR4 upregulation is also involved in pancreatic cancer angiogenesis. It is well known that hypoxia upregulates different pro-angiogenic pathways that promote vessel growth [53]. Among these, the induction of TLR4 receptor by hypoxia-inducible transcription factor 1 alpha (HIF-1α) may facilitate pancreatic cancer growth as demonstrated in vitro by the exposure of PANC1 cells to hypoxic stress. Moreover, the regulation of TLR4 mediated by HIF-1α has been confirmed by knockdown experiments in which HIF-1α depletion is associated with inhibition of hypoxia-induced TLR4 overexpression and to pancreatic cancer regression [39].
Recently, a new role for TLR4 in pancreatic cancer progression has been reported. Specifically, the stimulation of TLR4 and CAP1 receptors with Resistin, a hormone released by macrophages in the cancer microenvironment, activates the STAT3 pathway that confers to pancreatic cancer cells the ability to resist cancer therapy [54]. Lately, Lanki et al. described a positive correlation for TLR2 and TLR4 in pancreatic cancer regression. In particular, they showed that the expression of these TLRs correlates with a favorable prognosis in patients with small tumor size and lymph-node-negative disease [15].
However, further investigation should be performed to shed light on the role of these receptors in pancreatic cancer pathogenesis.

7. Toll-like Receptor 5

TLR5 is expressed on the surface of several cell lines, such as adipocytes, leukocytes, intestinal and lung epithelial cells and in some tumor cells. Upon stimulation with flagellin, from mobile bacteria, TLR5 activates a signaling pathway that regulates several processes including insulin resistance, maintenance of lung and intestinal homeostasis and cancer [74]. Little is known about the role of TLR5 in pancreatic cancer. However, it has recently been shown that ligands within the gut microbiome of pancreatic cancer patients are recognized by TLR5, which, upon interaction with TLR2, activates a signaling cascade that leads to the cancer growth enhancement and to the suppression of innate and adaptive immune response [55,56][55][56].
Furthermore, in other cancers, polymorphisms in TLR5 receptor drive a differential cancer-promoting inflammation that is responsible for different clinical outcomes of cancer patients. Indeed, in breast cancer, deficiency in TLR5 activity is associated with an increased cancer progression while, on the other hand, TLR5 upregulation in ovarian cancer has a negative effect on long-term survival [75].

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