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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 7  |  Page : 142-149

Role of Toll-like receptors in microbiota-associated gastrointestinal cancer metastasis


Department of Surgery, Huadong Hospital, Fudan University, Shanghai 200 040, China

Date of Web Publication30-Nov-2013

Correspondence Address:
Hao Ding
Department of Surgery, Huadong Hospital, Fudan University, 221 Yanan Xi Road, Shanghai 200040
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.122509

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 > Abstract 

Toll-like receptors (TLRs) serve as specific pattern recognition molecules that bind to microbial components to activate innate immunity and instruct and modulate adaptive immunity in the face of immunological danger. Accumulating evidence supports that TLR signaling pathway responses to luminal microbes participate in the development of gastrointestinal malignancies. This review summarizes current knowledge on the roles of TLR in microbiota-associated gastrointestinal cancer metastasis, focusing on TLR recognition of microbiota ligands, initiating inflammation, and promoting tumorigenesis, as well as the therapeutic strategies to target TLR. Studying the link between TLR signaling and gastrointestinal malignancies offers the possibility to identify novel ways to both prevent and treat gastrointestinal cancer.

Keywords: Apoptosis, cancer metastasis, cell invasion, gastrointestinal cancer, inflammation, microbiota, Toll-like receptors


How to cite this article:
Lu Q, Ding H, Li W. Role of Toll-like receptors in microbiota-associated gastrointestinal cancer metastasis. J Can Res Ther 2013;9, Suppl S2:142-9

How to cite this URL:
Lu Q, Ding H, Li W. Role of Toll-like receptors in microbiota-associated gastrointestinal cancer metastasis. J Can Res Ther [serial online] 2013 [cited 2019 Aug 19];9:142-9. Available from: http://www.cancerjournal.net/text.asp?2013/9/7/140/122509


 > Introduction Top


The gastrointestinal tract (including the esophagus, stomach, small and large intestine) has a higher incidence of cancer development and cancer mortality than any other system in the body. [1] Gastrointestinal tract cancers affect the stomach, bowel (colon, rectum), esophagus, pancreas, and liver, and they collectively rank as the highest cause of cancer mortalities in the world. Digestive cancers are a significant health care burden worldwide. In the United States in 2008, it was estimated that more than 270,000 patients were diagnosed with cancers of the digestive system and more than 135,000 died of these cancers. Of the gastrointestinal tract malignancies, gastrointestinal cancer (GC) and colorectal cancer (bowel) (CRC) have the highest worldwide incidence rates, with approximately 2 million people diagnosed annually. [2],[3]

Commensal bacteria present in the gastrointestinal tract also help to maintain mucosal homeostasis. Dysbiosis of the microbiota results in chronic inflammation, leading to an imbalance in epithelial cell proliferation and death. [4] However, triggering a tumor microenvironment may lead to a higher incidence of malignancies within the gastrointestinal tract. Therefore, microbiota plays a significant role in the development of gastrointestinal malignancies. A number of individual bacterial species can facilitate intestinal tumorigenesis in animal models. The discovery that Helicobacter pylori is responsible for development of gastric cancer may be the most direct proof that bacterial signaling and the response of the host can result in carcinogenesis. [5] Gastric cancer almost always occurs in the setting of prolonged gastric atrophy and hypochlorhydria, a condition that predisposes to enteric bacterial overgrowth. In patients with CRC, the pathogenic bacteria of intestinal microbiota are enriched, compared with healthy controls. Conversely, Roseburia and other butyrate-producing members of the Lachnospiraceae family are less abundant in the gut microbiome of patients with CRC. [6] Inflammatory bowel diseases (IBD) and CRC are the major diseases of the lower gastrointestinal tract. [7]

Toll-like receptors (TLRs), which gather increasing attention in innate immunity, are a major class of pattern-recognition receptors that are present on intestinal epithelial cells (IEC). [8] Recently, growing evidences have implied the involvement of TLRs signaling in tumor development, especially microbiota-associated gastrointestinal cancer progression and metastasis. [9],[10] Earlier studies [11],[12] have shown that lipopolysaccharide (LPS), which is the major component of the outer membrane of Gram-negative bacteria, promotes tumor invasion through the TLR4-mediated nuclear factor-kappa B (NF-kB) pathway.

Accordingly, in this review, we will focus on the contribution of TLRs in the recognition of micriobiota ligands and involvement in tumor microenvironment, and on their potent proinflammatory and oncogenic properties in the gastrointestinal tract. [13] We hope to provide new insight into the pathogenesis and progression of gastrointestinal tract cancers and more importantly, into the potential for TLRs as targets of therapeutics.


 > TLRs and Their Ligands Top


TLRs are a family of transmembrane receptors that function as pattern-recognition receptors of innate immunity system for the detection and response to microbial infection. These receptors are evolutionarily conserved to recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), [14] which include a broad spectrum of microbial components, such as molecules from pathogenic Gram-positive and -negative bacteria, RNA and DNA viruses, pathogenic fungus and parasitic protozoa, as well as the endogenous molecules released by injured tissue. [15]

The TLRs constitute 10 members in humans (TLR1-10) and 12 members (TLR1-9 and TLR11-13) in mice. [16],[17] TLRs can be classified into two subpopulations with regard to their cellular localization. TLRs 3, 7, 8, and 9 are located mainly in intracellular vesicles such as the endosome or lysosome and the endoplasmic reticulum, while the others are located on the cell surface. [18]

TLRs are demonstrated to recognize specific ligands. TLR2 and TLR4 recognize products of Gram-positive and Gram-negative bacterial cell wall, respectively. Many viral protein components are also being sensed by TLR2 and TLR4. Moreover, TLR2 complexed with TLR1 or TLR6 recognizes bacterial lipoprotein, peptidoglycan, and lipoteichoic acid (LTA). [14],[15],[19] TLR4 effectively recognizes LPS or endotoxin on Gram-negative bacteria with the help of CD14, MD-2 (the latter two proteins either exist in soluble form or as bound to cell membrane or to TLR itself), and the accessory protein LBP (LPS-binding protein found in serum). [20],[21] TLR5 responds to a structural epitope of bacterial flagellin. [22] TLRs 3, 7, and 8 play important roles in host cell responses to viruses. [23],[24],[25] TLR7, TLR8, and TLR9, which have high sequence homology, recognize a range of RNA and DNA molecules. [26],[27] TLR9 is also activated by Aspergillus.[28]

In addition to detecting pathogen-derived ligands, TLRs also recognize host molecules, including antimicrobial molecules such as murine-defensin 2 (mDF2), [29] proteins released from dead or dying cells, such as high-mobility group protein B1 (HMGB1), [30] fibrinogen, [31] and surfactant protein A, [32] breakdown products of extracellular matrix, such as fragments of fibronectin, [33] hyaluronic acid oligosaccharides, [34] eosinophil-derived neurotoxin (EDN), [35] and reactive oxygen species (ROS). [36] Heat shock proteins (Hsp) such as Hsp60, Hsp70, and Hsp90 (gp90) have also been reported to induce proinflammatory cytokine production by monocyte-macrophages and the maturation of dendritic cell (DC) through TLRs. [37],[38]

TLRs are preferentially expressed on human immune cells, including macrophages, DCs, monocytes, neutrophils, eosinophils, natural killer (NK) cells, platelets, and T and B lymphocytes. [28] Several studies have shown that TLRs are expressed not only on immune cells but also on epithelial cells [39],[40] and tumor cells, for example, gastric and IEC constitutively express TLR2, TLR4, and MD-2, and the intestinal myofibroblasts express increased levels of TLR2, TLR3, TLR4, TLR6, and TLR7 after LPS or LTA stimulation. [41],[42] More recently, increasing evidence indicates that engagement of TLRs can promote cancer cell growth, induce evasion of immune surveillance, and enhance tumor metastasis and chemoresistance, or rather, induction of tumor cell apoptosis depending on ligands. [43] It has been demonstrated that tumor cells with high expression of TLR3 or mononuclear inflammatory cells with high expression of TLR4 are significantly implicated with a higher probability of metastasis. [44] TLR9 overexpression and stimulation with hypomethylated DNA augment the migratory capacity of cancer cells. [45],[46]


 > TLRs Bridge Microbiota and Inflammation in Gastrointestinal Cancer Top


Over the past decade, emerging studies have paid great attention to the microenvironment of gastrointestinal tumors because it is important for tumor initiation, progression, and metastasis. [4] Bacteria dysbiosis and/or an epithelial cell barrier defect induce DNA damage, genetic alterations, and inflammation with recruitment of more inflammatory cells, finally leading to activation of a tumor-promoting signaling network, which is conducive to a tumor microenvironment that leads to carcinogenesis. [47]

As mentioned earlier, the expression of TLRs has also been detected in the gastrointestinal tract. For example, in the human stomach, TLR2, TLR4, TLR5, and TLR9 are known to be expressed by epithelial cells. [47],[48],[49] The small intestine (including duodenum, jejunum, and ileum) and the large intestine express most of the TLRs, but normally TLR signaling in IEC appears to be downregulated. [50],[51],[52] Ligand binding to TLRs activates transcription factors, leading to production of inflammatory mediators. Increasing evidences showed that TLRs play a critical role in gut homeostasis and bacterial regulation, balancing inflammatory and anti-inflammatory responses against luminal antigens. [53]

The human gastrointestinal tract is heavily colonized by microbes, mainly composed of bacteria, archaea, and fungi. [54] To date, 500 different species of bacteria have been detected in the intestinal tract, and the highest microbiota concentration reaches 10 12 -10 14 cells/ml in the distal ileum and colon. [55],[56] Under physiologic conditions, the microbiota helps to maintain intestinal homeostasis for mutually beneficial symbiosis. However, any dysbiosis, such as microbiota composition alteration or host genetic susceptibility, could induce an unwarranted immune response and many inflammatory diseases, even cancers. The gut mucosal epithelium serves as an interface between the vast microbiota and internal host tissues. The interaction between the microbiota and the intestinal mucosa epithelia through TLRs is crucial to the maintenance of gut epithelial homeostasis and protection against gut injury. [57] In normal conditions, intestinal epithelia strongly express TLR3 and TLR5, whereas TLR4 and TLR2 expression is weak. [58] Additionally, TLRs contribute to maintain tissue homeostasis by regulating tissue repair and regeneration. [59]

H. pylori is a Gram-negative bacterium that colonizes the gastric mucosa and causes chronic gastritis and ulcers. [60],[61] H. pylori-derived LPS, a major virulence factor for induction of gastritis, can be recognized by TLR4/MD-2 system in the stomach. TLR4 is also upregulated in IBD. [62] Similarly, TLR5 may also play a role in the pathogenesis of IBD. [63] While IBD-related colon cancers are associated with a severe inflammatory response, which is an important microenvironment required for inflammation-associated tumor development. [64] These results indicate that TLR may be one of the causes of tumor progression.

During tumor progression, TLRs can recruit different myeloid cells, T cells, and cancer-associated fibroblasts (CAFs) to the sites of inflammation and create a microenvironment that promotes epithelial proliferation and prevents apoptosis due to an imbalance of protumorigenic and antitumorigenic factors. [10] Finally, external and host factors can create an inflammatory environment in the intestine, which is fertile for tumor development.


 > TLR and Tumor Microenvironment Top


Given the relationship between inflammation and carcinogenesis, investigators have begun to address the role of TLRs and innate immune responses in inflammation-associated carcinogenesis in the gastrointestinal tract. [9],[41] Szczepanski et al. showed the expression of TLRs 2, 3, and 4 in the tumor microenvironment of human laryngeal carcinoma cells. [65] Similarly, TLRs 2-5 were expressed in ovarian cancer cell lines. [66] Positive TLR2 expression in the tumor microenvironment suggests that immune surveillance is activated against the altered epithelial cells, whereas TLR2 expression by malignant keratinocytes may be indicative of resistance to apoptosis as a prosurvival mechanism. [67]

TLRs are expressed in a variety of immune cells including macrophages, DCs, B cells, and specific types of T cells. It is notable that most of the TLR proteins are expressed in DCs. [68] It has been suggested that TLR signaling may both promote and prevent tumorigenesis. [69] This two-blade function may be explained by the existence of different TLRs and different origins of tumor cells. For example, epithelial TLR4 signaling promotes tumorigenesis, but TLR4 signaling in DCs may help to enhance antigen presentation to promote antitumor immunity. [70]

TLRs' activation augments antitumor via several mechanisms, one of which is through their modulation of DC maturation and leading to lymphocyte activation. [71] Upon TLR activation and subsequent signal transduction, DCs undergo maturation by upregulation of cell surface major histocompatibility complex (MHC) molecules containing pathogen-derived peptide fragments and co-stimulatory molecules (CD40, CD80, and CD86). [72] The enhanced secretion of type 1 T helper (Th1) cytokines [especially interleukin (IL)-12] and antigen presentation to lymphocytes result in the generation of effector T cells and antigen-specific B cells. Tumor cells block TLR3- and TLR4-ligand induced expression of MHCII, co-stimulatory molecules CD40 and CD86, and the production of cytokines IL-12, tumor necrosis factor (TNF)-α, and IL-6 by DCs. [15] Furthermore, activation of TLR7 has been shown to alter the tumor microenvironment and create an inflammatory environment suitable for antigen cross-presentation and infiltration by effector T cells and DCs with cytotoxic potential. [72]

Macrophages produce the major inflammatory cytokines and prostaglandins in tumor tissues. Tumor-associated macrophages (TAMs) are a heterogeneous and plastic population of immune cells, which have been shown to promote the progression and metastasis of cancer. [73] Activation of TLRs 7, 8, and 9 induces interferon (IFN)-α, promoting more effective antigen presentation, cytotoxic T-lymphocyte activation, and polarized Th1 responses. [15],[74] Recent studies have shown that some immune responses are beneficial, while others could be deleterious in anticancer therapy. [75] In addition, in the tumor microenvironment, Th17 cells, derived from naive T cells, T regulatory (Treg) cells, which can inhibit the Th17 cell responses, B cells, [4],[76],[77] myeloid-derived suppressor cells (MDSCs), and CAFs also contribute to suppress tumor growth or promote the proliferation and metastasis of gastrointestinal cancers. [4] From these researches, it can be indicated that TLRs are important for the tumor microenvironment in the gastrointestinal cancer.


 > TLR-Associated Pathways in Gastrointestinal Cancer Top


Emerging evidence suggests a dual important role of TLRs, in which they may simultaneously induce tumorigenesis and promote antitumor immunity. [78] TLRs may induce tumor cell proliferation by activating cell survival signaling mainly via inflammation, providing favorable conditions and tissue homeostasis to tumor cells for growth and survival. [79] On the contrary, TLR agonists trigger the intrinsic innate immune response against the microbial components and bridge the response from innate to adaptive immune response against the tumor tissue, promoting antitumor immunity. [69]

Ligand engagement of TLR induces activation of two distinct signaling pathways, the myeloid differentiation primary response 88 (MyD88)-dependent and -independent pathways, which are necessary for the activation of the NF-kB transcriptional complex and mitogen-activated protein kinase (MAPK) cascade to induce an inflammatory response. [29] The initial step of TLR signal transduction is mediated through several adaptor molecules, including MyD88, Toll receptor-associated activator of interferon (TRIF), MyD88-adaptor-like/TIR-associated protein (MAL/TIRAP), and Toll receptor-associated molecule (TRAM), to the inflammatory pathways involving NF-kB, Janus kinase (JNK)/p38 kinase, and IFN regulatory factors (IRF) 3, 5, and 7. [80],[81] Finally, TLR signal transduction induces various transcripts, including cytokines and IFN-inducible genes.

Accumulating evidence suggests that the neoplastic process may impede TLR signaling pathways to favor cancer progression. [82] Chronic infection with H. pylori increases TLR4 and MD-2 expression in gastric epithelial cells, and recognition of H. pylori LPS augments NF-kB activation in tumor cells and immune cells. [48],[83],[84]

Because the imbalance between epithelial cell proliferation and apoptosis is important for the process of inflammation-associated malignant transformation, MyD88-dependent TLR4 signaling pathway may play a pivotal role in the malignant transformation in IEC. [55] TLR4 is also important for healing of the injured intestinal epithelium. [85] Many researches have described that TLR4- or MyD88-deficient mice decreased epithelial cell proliferation. [57],[86] Meanwhile, apoptosis of epithelial cells increased after mucosal injury caused by dextran sulfate sodium (DSS) treatment in the TLR4- or MyD88-deficient mice. [87] It indicates that TLRs may be involved in the apoptosis pathways in the gastrointestinal cancer.

Additionally, it is possible that tumor cell proliferation causes tissue damage, releasing endogenous ligands for TLRs, thus resulting in their activation. [88] The activation of TLR4 on human colon cancer cells can increase the phosphorylation of extracellular signal-regulated kinase (ERK), regulate the expression of IL-8 and caspase-7, and promote the proliferation and migration of human colon cancer cells. [43] TLR4 signaling has also been found to be responsible for cyclooxygenase-2 (COX-2) induction, prostaglandin E2 (PGE2) production, and epidermal growth factor receptor (EGFR) phosphorylation, which promote the development of colitis-associated colorectal tumors. [9] In the setting of intestinal injury, LPS (e.g., H. pylori LPS) exposure of IEC (possibly basolaterally) and lamina propria macrophages results in a variety of signaling pathways culminating in transcription factor translocation and engagement of the COX-2 promoter, especially TLR4/MyD88 signaling pathway, [87],[89] which can modulate epithelial cell proliferation in response to mucosal injury. [90] Moreover, other TLR signaling molecules, TLR2 and TLR9, have also been implicated in the upregulation of COX-2 through activation of Src and NF-kB in PI-PLCg/PKCα/c-Src/IKKα/β and NIK/IKKα/β pathways in H. pylori-infected mucosa. [91],[92],[93] Activation of TLR3 on human cancer cells with poly (I:C) inhibits cell proliferation, triggers apoptosis, and keeps the tumors more differentiated. [94] The TLR signaling critically overlaps with apoptotic cascades. The regulation of apoptosis by TLR ligands represents an attractive anticancer treatment modality.

Blocking TLR4 signaling in colon cancer cells results in a reduction of tumor growth in a subcutaneously implanted mouse model. [41],[48] Meanwhile, tumor cells also utilize the TLR4 signaling pathway to escape immune surveillance and enhance tumor cell invasion and metastasis. [92] Moreover, LPS-induced TLR4 signaling activates the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and promotes downstream β1 integrin function, thereby increasing the adhesiveness and metastatic capacity of CRC cells. Thus, LPS (and, therefore, TLR) signaling is strongly involved in the accelerated metastatic tumor growth that follows excisional surgery for apparent cancer cure. [95],[96] The high expression of TLR4/MyD88 in CRC is associated with liver metastasis, earlier relapse, and poor disease-free survival and overall survival. [90]


 > TLRs as New Therapeutic Targets in Gastrointestinal Cancer Top


TLRs are currently viewed as important targets for the development of new vaccines and innovative therapies to prevent and treat human diseases. Despite the notion that TLRs may benefit tumor progression, TLRs are considered as important targets for anticancer therapy. [97] For example, synergistic activation of TLR3 and TLR9 resulted in an enhanced antimetastatic effect. [93],[98] TLR agonists are being developed for the treatment of cancer, allergies, and viral infections, and as adjuvants for vaccines to prevent or treat cancer and infectious diseases. Today, only three TLR agonists are approved by the US Food and Drug Administration (FDA) for use in human beings: The Bacillus Calmette-Guιrin (BCG), [99] monophosphoryl lipid A (MPL), and imiquimod. BCG (an attenuated strain of Mycobacterium bovis) [100] is mainly used as a vaccine against tuberculosis, and is also used for the immunotherapy of in situ bladder carcinoma, which, together with long-used (and relatively effective) anticancer preparation Coley's toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria), has recently been shown to potently activate TLR2 and TLR4. [101] MPL (derived from the LPS of Salmonella minnesota) is included in the formulation of Cervarix, a vaccine against human papillomavirus-16 and -18. [102] Imiquimod (a synthetic imidazoquinoline) is routinely employed for actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata). It was found to function as a TLR7 agonist. Similarly, resiquimod (also a synthetic imidazoquinoline compound) is a ligand for TLR8. [103]

Another antitumor strategy is the induction of apoptosis by TLR signaling. It has been observed that cells stimulated with TLR ligands undergo programmed cell death by Fas-associated death domain protein and subsequent caspase recruitment. [103] Studies have shown increased apoptosis of cancer cells by stimulating with the TLR3 agonist, suggesting that the TLR3 agonist may be another option for anticancer immunotherapy. Double-stranded RNA (dsRNA) activates TLR3 on DCs to release type 1 IFN that induces tumor cell apoptosis and NK cytotoxicity. [43]

With respect to TLR-related biomarkers and therapeutic targets, other potential candidates include ligands/agonists that signal via TLR. For instance, the TLR2/4 agonists HMGB1and S100A9 have been identified as potential biomarkers for CRC, as they are significantly upregulated in CRC and have been shown to be regulated by signal transducer and activator of transcription 3 (STAT3), which is hyperactivated in approximately 90% of colorectal tumor biopsies. [104] Pancreatic adenocarcinoma upregulated factor (PAUF), which is a novel endogenous TLR2 and TLR4 ligand, promotes metastasis by regulating TLR/CXCR4 (C-X-C chemokine receptor type 4) activation. [105] In addition, peroxiredoxin 1 (Prx1), an antioxidant and molecular chaperone, induces endothelial cell proliferation, migration, and differentiation in a TLR4-dependent manner. [106] LPS (TLR4 agonist) and poly (I:C) (TLR3 agonist) have the ability to inhibit NF-kB activation. [107]

Thus, targeted inhibition of specific TLR pathways may provide an effective strategy in preventing the development of selected gastrointestinal malignancies. Because the gastrointestinal tract can be accessed without the need for systemic delivery, TLR antagonists may be developed to interrupt oncogenic pathways and for delivering locally.


 > Conclusion Top


In summary, TLRs play a crucial role in the inflammation and host defense against the invading microorganisms by recognizing PAMPs. Emerging evidences focus on the importance of the tumor microenvironment, with its complex network of cells, cytokines, and chemokines, in tumor initiation, formation, growth, and metastasis. Indeed, on the host side, TLRs recognize PAMPs and DAMPs to initiate innate immunity and modulate adaptive immunity, defending the exogenous pathogens and protecting the host tissues, while under some circumstances, the activation of TLR signaling results in inflammation, which triggers formation of tumor microenvironment leading to cancer development, even metastasis.

Given the relationship of TLR signaling with inflammation and gastrointestinal cancers, TLRs may be an attractive target for the therapies against gastrointestinal cancers. However, the TLR signaling axis emerges as a "double-edged sword." Hence, it is required to carefully select the therapeutic target in the TLR signaling cascade and closely regulate the degree of pathway activity so as to attain the desired therapeutic end-point. Moreover, a number of microbial components functioning as ligands of TLRs present anticancer effects and have been used as adjuvants for the immunotherapy of cancers. Thus, a better understanding of this complicated receptor family will shed light on the generation of effective strategies to treat many gastrointestinal diseases in future.

 
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