Microbe–MUC1 Crosstalk in Cancer-Associated Infections

Please cite this article in press as: Bose and Mukherjee, Microbe–MUC1 Crosstalk in Cancer-Associated Infections, Trends in Molecular Medicine (2019), https://doi.org/10.1016/j.molmed.2019.10.003

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Review

Microbe–MUC1 Crosstalk in Cancer-Associated Infections Mukulika Bose1,* and Pinku Mukherjee1 Infection-associated cancers account for 20% of all malignancies. Understanding the molecular mechanisms underlying infection-associated malignancies may help in developing diagnostic biomarkers and preventative vaccines against malignancy. During infection, invading microbes interact with host mucins lining the glandular epithelial cells and trigger inflammation. MUC1 is a transmembrane mucin glycoprotein that is present on the surface of almost all epithelial cells, and is known to interact with invading microbes. This interaction can trigger pro- or anti-inflammatory responses depending on the microbe and the cell type. In this review we summarize the mechanisms of microbe and MUC1 interactions, and highlight how MUC1 plays contrasting roles in different cells. We also share perspectives on future research that may support clinical advances in infection-associated cancers.

Infection-Induced Cancer Diverse modifiable risk factors are associated with cancer incidence, such as an imbalanced diet and exposure to carcinogens and infectious agents including viruses, bacteria, and parasites. The human body harbors millions of bacteria, viruses, and fungi that are unique to each individual and make up their microbiome. This microbiome can regulate cancer susceptibility, progression, and response to therapy [1–3]. Infectious diseases represent the third leading cause of cancer incidence (https://www. wikiwand.com/en/Cancer_prevention#/preventable_causes_of_cancer) [4], and the fourth most important risk factor for cancer mortality in developed countries, causing about 10% of cancer mortality. During microbial infection, the mucous layer lining the epithelia plays a crucial role in host immunity. The mucous layer consists of transmembrane and secreted glycoproteins that form a protective layer, and the degree of glycosylation of the mucins determines their protective function [5]. The mucins undergo biochemical changes both in the extracellular domain (ED) and the cytoplasmic domain (CD) during infection, leading to either elimination of the microbe or infection followed by inflammation. In a pilot study of prioritization of cancer antigens, the National Cancer Institute (NCI) ranked mucin 1 (MUC1; also known as episialin, PEM, H23Ag, EMA, CA15-3 MCA) as the second best target antigen among 75 for the development of cancer vaccines [6]. Interestingly, MUC1 acts as an immunomodulatory (see Glossary) switch that plays either a proinflammatory or an anti-inflammatory role during various infections (Table 1). It is important to understand the mechanisms that regulate this switch so as to prevent the formation of infectioninduced malignancy. This article provides a synopsis of the proinflammatory versus anti-inflammatory roles of MUC1 during different infections which may lead to cancer, and provides perspectives to predict infection susceptibility, stratify individuals at high risk of cancer development, and to develop preventative vaccines and personalized therapeutic regimens.

Highlights Infection-induced cancers are the fourth leading cause of cancerrelated deaths worldwide. Invading microbes interact with the host through glycosylated mucin proteins that form a protective barrier. Changes in host mucin glycosylation cause inflammation, and infection-induced inflammatory signaling leads to changes in host glycosylation. Mucin protein MUC1 is a key modulator of NF-kB, the master regulator of cancer-associated inflammation. During microbial invasion into host epithelial cells, MUC1 plays a protective role and attenuates downstream inflammatory responses. A prolonged period of interaction with the microbe may alter MUC1 glycosylation, leading to a breach of the epithelial barrier, causing MUC1 to switch from being anti- to proinflammatory, depending on both cell type and pathogen, and leading to enhanced oncogenic signaling by the MUC1 cytoplasmic tail.

MUC1 is a Gatekeeper at the Mucosal Barrier Mucins are highly glycosylated in normal tissues but are overexpressed and aberrantly glycosylated in tumors [7]. In healthy tissues, mucins form a mucosal barrier and sense bacterial ligands and mucosal cell damage. Mucins further relay this information by activating immunomodulatory pathways, thus initiating differentiation or apoptosis of cells when required [8]. It appears that cancer cells use altered mucins to evade cell death signals and immune cell killing. The question is whether changes in host glycosylation cause inflammation, or whether infection-induced inflammatory signaling leads to changes in host glycosylation. Current knowledge of glycobiology reveals that both are true, and is described as the ’glyco-evasion hypothesis’ [9].

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1Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA

*Correspondence: [email protected]

https://doi.org/10.1016/j.molmed.2019.10.003 ª 2019 Elsevier Ltd. All rights reserved.

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Infectious agent

Cell type

Role of MUC1

Refs

Campylobacter jejuni

Gastrointestinal epithelial

Anti-inflammatory

[26,27]

Gastric epithelial cells,

Anti-inflammatory in normal

[11,18,30,34,

gastric cancer cells

gastric epithelial cells,

37–39]

cells Helicobacter pylori

proinflammatory in gastric cancer cells Haemophilus influenzae

Airway epithelial cells

Anti-inflammatory

[8,31,43,45]

Pseudomonas aeruginosa

Airway epithelial cells

Anti-inflammatory

[45,49,50,51,86]

Salmonella typhi

Gastric epithelial cells

Proinflammatory?

[23,53,58,59]

Escherichia coli

Bladder epithelial cells,

Proinflammatory

[60–62]

Proinflammatory

[67]

Vulvar epithelial cells,

Anti-inflammatory in

[75,76]

laryngeal cancer cells

vulvar epithelial cells and

colon epithelial cells, intestinal epithelial cells Epstein–Barr virus

Nasopharyngeal epithelial cells

Human papilloma virus

proinflammatory in laryngeal cancer cells Respiratory syncytial

Airway epithelial cells

Anti-inflammatory

[77]

Influenza A virus

Lung epithelial cells

Anti-inflammatory

[12]

Hepatitis C virus

Liver epithelial cells

Proinflammatory?

[87]

Opisthorchis viverrini

Bile duct cancer cells

Proinflammatory

[81]

virus

Table 1. Summary of Anti- versus Proinflammatory Roles of MUC1 in Different Infections and Cell Types

MUC1 was the first mucin to be structurally characterized [10] and there is expanding evidence that it plays a dynamic role as a host mucosal barrier to infection [11,12]. MUC1 is a single-pass type I transmembrane glycoprotein with a hyperglycosylated ED [13]. This ED extends up to 200–500 nm from the cell surface. MUC1 is expressed on the surface of almost all glandular epithelial cells, including those of the pancreas, breast, lung, stomach, and liver. In healthy tissues, MUC1 provides protection to the underlying epithelia. The extended sugar residues have a negative charge and form a physical barrier, conferring an anti-adhesive property on MUC1, which in turn prevents pathogen access. The chains of glycosyl residues form oligomers and give rise to a mucinous gel that has lubricating properties. This lubrication protects the underlying epithelia against desiccation, alterations in pH, and microbial infection [13]. On the one hand, the highly glycosylated ED of MUC1 (MUC1-ED) has a barrier function; on the other, phosphorylation of the intracellular cytoplasmic tail (MUC1-CT) can lead to activation of downstream signaling pathways. The turnover rate of MUC1 is probably maintained by a phenomenon known as ’shedding’ in which the CT is separated from the ED by proteolysis [14]. The mechanism of MUC1 shedding is well documented [15–17]. MUC1-ED can bind to bacteria and be shed from the epithelial surface. This shedding could activate a signal that leads to phosphorylation of MUC1-CT, thus regulating inflammatory responses, epithelial cell adhesion, differentiation, and apoptosis. The direct link between MUC1-ED shedding and activation of the MUC1-CT is not well established. However, it is known that MUC1 acts as a signaling receptor that senses the external environment and activates intracellular signal transduction pathways [18].

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Glossary Elimination: a phase in the cancer immunoediting process in which the immune system successfully eliminates the tumor cells. Equilibrium: a cancer immunoediting phase in which the immune system is engaged in a constant fight with the tumor cells; this is also a period of Darwinian selection which selects for immune-resistant tumor cells. Escape: a cancer immunoediting phase in which the tumor cells have already evaded the immune responses and established themselves. Glycome: the entire complement of sugars of an organism. Peptidomimetic: a small proteinlike sequence designed to mimic a peptide. Immunomodulatory: a molecule that modifies the immune response or the functioning of the immune system. Sugar code: the composition and structural variability of cellular glycans.

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Anti- versus Proinflammatory Roles of MUC1 during Bacterial Infection Bacteria have been largely neglected as cancer-causing factors compared with viruses, and only a few bacterial infections are known to be associated with cancer development, Bacteria may contribute to cancer development through inflammation, secretion of toxins and metabolites that damage DNA, and/or manipulation of host signaling pathways during infection [19,20]. Two well-known bacterial infections that are associated with cancer development are (i) Helicobacter pylori, that is associated with gastric cancer (GC) [21] and mucosa-associated lymphoid tissue (MALT) lymphoma [22], and (ii) Salmonella typhi, that is associated with gallbladder carcinoma in chronic typhoid carriers [23]. However, other bacterial infections may be associated with risk of developing cancer based upon their interaction with cell-surface mucins, in particular MUC1.

Campylobacter jejuni Infection C. jejuni is a Gram-negative, helical-shaped, nonspore-forming bacteria. It is among the most common causes of food poisoning and gastroenteritis in developed countries (www.foodsafety.gov). During colonization and infection of the host, Campylobacter must traverse the mucus layer of the intestine before it can adhere to and invade the intestinal epithelial cells, and subsequently cause the onset of gastroenteritis [24]. Once reaching the intestinal mucosal epithelium, Campylobacter encounters MUC1-ED expressed at the epithelial cell surface of the glycocalyx [25]. When Campylobacter recognizes and binds to the sialic acid residues of MUC1, the glycoprotein is released from the cell into the mucus layer for subsequent expulsion of MUC1-associated Campylobacter from the host [26]. Thus, MUC1 may function as a decoy receptor for bacterial ligands to protect the host against pathogens. The effectiveness of MUC1 in preventing C. jejuni pathology has been demonstrated using Muc1 knockout mice, which show increased susceptibility to C. jejuni invasion [27]. Given the high levels of sialylation and mannosylation of MUC1, C. jejuni is suggested to interact with MUC1 initially after its transition from the external environment into the host during colonization. However, direct binding to sialic acid and mannose structures is reduced once C. jejuni adapts to the conditions encountered within the host [27]. Prolonged interaction with MUC1 would be detrimental for C. jejuni because MUC1 acts as a decoy receptor in host defense against pathogens [26]. Therefore, MUC1 plays a protective anti-inflammatory role during Campylobacter infection. Whether this helps to prevent cancer development remains unknown.

Helicobacter pylori Infection Infection with H. pylori is common because these bacteria live in the digestive tract. After many years of persistent subtle infection, they can cause stomach ulcers and lead to stomach cancer. Exploration of the dynamics of cell-surface mucins during infection and the consequences of their deficiency indicates that mucins provide an important impediment to H. pylori. MUC1 is highly expressed on the stomach mucosal surface and is upregulated by H. pylori infection [28]. H. pylori has developed specific adhesins for MUC1 oligosaccharides and binds to MUC1 on cultured gastric epithelial cells. Despite this binding, when H. pylori is cocultured with MUC1-expressing gastric cells, there are fewer long-lasting adhesion events because MUC1 is shed from the cell surface and coats the outside of the bacteria. If bacterial adhesins are knocked out, then the bacteria do not bind to the cells. In this case MUC1 is not shed, but blocks the adhesion of non-MUC1-binding ligands on the cell surface by steric hindrance [29]. Mice lacking MUC1 were colonized by fivefold more H pylori within 1 day of infection and developed atrophic gastritis with loss of parietal cells [11,30]. Furthermore, MUC1 dampens Toll-like receptor (TLR 2–5, 7, and 9) and NOD1 signaling during infection [31,32], and suppresses NF-kB p65 activity through inhibition of inhibitory k kinase Ba (IkBa) phosphorylation and degradation, thus inhibiting inflammatory responses in the gastric epithelial cells in response to tumor necrosis factor (TNF)-a. MUC1 interacts directly with components of the NF-kB pathway during H. pylori infection. As shown in Figure 1, MUC1-CT interacts with inhibitory k kinase g (IKKg) and inhibits IkBa phosphorylation, thus blocking NF-kB activation and interleukin (IL)-8 production in response to H. pylori [11]. Upon TNF-a stimulation, MUC1 associates with the TNF-R1 complex and recruits TAK1 kinase, leading to phosphorylation of IKKb [33]. Polymorphisms in MUC1 have been linked to H. pylori-induced gastritis and GC [34]. Recently a meta-analysis of 10 studies on the MUC1 rs4072037 polymorphism and GC risk confirmed the

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Figure 1. Anti- versus Proinflammatory Role of MUC1. (A) During Helicobacter pylori infection the MUC1 cytoplasmic tail (MUC21-CT, orange tail) in gastric epithelial cells interacts with inhibitory k kinase (IKK)g (orange) and inhibits phosphorylation (P) of IKK-Ba, thus inhibiting activation of NF-kB (green) and attenuating downstream proinflammatory cues [11]. (B) In gastric cancer cells, the p65 subunit of NF-kB binds to MUC1-CT and the complex localizes to the nucleus to upregulate the expression of proinflammatory cytokines, for example tumor necrosis factor (TNF)-a and interleukin (IL)-6, as well as ZEB1, which in turn aids epithelial-to-mesenchymal transition (EMT) and invasion of the cells [38–40]. The MUC1 extracellular domain (MUC1-ED) in healthy cells is hyperglycosylated (pink branches), but in cancer cells is aberrantly glycosylated (yellow) and loses some residues, exposing its peptide backbone (figure drawn with the assistance of biorender.com).

protective effect of this polymorphism on the risk of GC [35]. These data suggest an anti-inflammatory role of MUC1 in the initial stages of H. pylori infection. However, the interaction between H. pylori and MUC1 is not simple. Although the apical expression of MUC1-ED on the gastric epithelial surface was reduced during H. pylori gastritis, the expression of MUC1-CT was significantly increased [34]. MUC1-ED might have been lost from the surface because of cleavage by H. pylori [34]. MUC1 acts as a decoy and limits the binding of H. pylori to the cell surface, which leads to MUC1-ED being shed and loaded onto H. pylori [29]. This suggests that there is a gastritis-related alteration in a glycoprotein epitope [36], and that H. pylori infection alters the peripheral glycosylation of MUC1. However, a proinflammatory effect of MUC1 on NF-kB and cyclooxygenase-2 (COX-2) [37] was reported for tumor cells, which contrasts with its role in healthy epithelial tissues. Significantly higher levels of COX-2 expression are associated with high MUC1 levels both in vitro and in vivo [37]. MUC1-CT was shown to bind to the COX2 promoter at the same locus where NF-kB p65 binds to the promoter [37]. In murine and human cancer cell lines, direct interaction of MUC1 with the NF-kB p65 subunit was shown for both the MUC1-CT domain [38] and for full-length MUC1, which depended on the length of the extracellular domain [39]. As shown in Figure 1, in these cells, the MUC1–p65 interaction has proinflammatory effects because it leads to upregulation of IL-6 and TNF-a at the transcriptional level [39]. Translocation of the MUC1–p65 complex into the nucleus of cancer cells also drives expression of epithelial-to-mesenchymal transition (EMT) marker ZEB1 by directly binding to its promoter [40]. Upregulation of ZEB1 leads to suppression of miR-200c

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expression, which in turn promotes EMT and cell invasion [40]. Studies have shown that MUC1 directly interacts with players of the NF-kB pathway and influences its functions in a cell-dependent manner [18]. Therefore, the role of MUC1 is paradoxical during H. pylori infection. In the initial stages it acts as a decoy receptor and suppresses inflammation, but in transformed cells it hastens proinflammatory signaling.

Haemophilus influenzae Infection H. influenzae is a Gram-negative, facultatively anaerobic, opportunistic pathogen that mainly causes infection and inflammation of the respiratory system, which can lead to pneumonia in immunosuppressed patients [41]. Chronic obstructive pulmonary disease (COPD) is one of the risk factors for lung cancer, and is characterized by chronic inflammation and lung infections. The airways of patients with COPD are frequently colonized with nontypeable H. influenzae (NTHi) that lead to pulmonary inflammation. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the KRAS gene [42]. A recent study investigated the role of TLR signaling in the progression of Kras-induced early adenomatous lesions in the lung [42]. Wild-type (WT) and Tlr2 Tlr4 doubleknockout mice (Tlr2/4 / ) expressing an oncogenic Kras allele in lung epithelium were exposed to NTHi for 4 weeks. Tumor proliferation and growth increased in WT mice, but not in Tlr2/4 / mice. WT mice had significantly increased alveolar adenomatous hyperplasia and adenocarcinoma compared with Tlr2/4 / mice. The average size of tumors was significantly larger in WT mice. Therefore, NTHi-induced carcinoma was completely dependent on TLR activation [42]. Several in vitro studies have suggested that MUC1 has anti-inflammatory properties, including negatively regulating TLR signaling (Figure 2) [31]. Binding of MUC1 to TLR5 in airway epithelial cells prevents the attachment of MyD88 to MUC1-CT, thus inhibiting NF-kB signaling and activation [31,43]. In ocular epithelial cells, MUC1 inhibits signaling through TLR3 [8] and dampens TLR2 and TLR5 signaling [44]. In airway epithelial cells, MUC1 participates in a feedback mechanism to downregulate the production of TLR2-induced IL-8 and TNF-a following infection with NTHi [45]. Modulation of immune receptors by MUC1 can occur by various mechanisms (Figure 2), by which MUC1 could affect signaling by TLR [18]. First, glycosylated MUC1 could cover the extracellular domain of TLR and reduce interactions between specific ligands and their TLRs. Second, the formation of a MUC1–TLR complex might change the conformation of TLR, thus affecting ligand binding. Third, binding of MyD88 to the TLR intracellular tail could be inhibited by direct interaction of MUC1-CT with the intracellular tail of TLRs. Fourth, MUC1-CT could play a role downstream by interacting with components of the NF-kB pathway and regulate its activity [18]. These direct interactions between the extracellular and intracellular domains could be tested by protein–protein interaction studies during H. influenzae infection. However, evidence from in vitro studies indicates that MUC1 mostly plays an anti-inflammatory role in airway epithelial cells during infection by H. influenzae. Whether this provides protection against cancer development is not yet evident.

Pseudomonas aeruginosa Infection P. aeruginosa is an encapsulated, Gram-negative, opportunistic pathogen that mainly infects the airway in immunocompromised people [46]. It is known to cause mucosal infections leading to pneumonia in cystic fibrosis patients [46]. The human sialidase, neuraminidase-1 (NEU1), increases the binding affinity of P. aeruginosa flagellin to MUC1 [47]. NEU1 drives MUC1-ED desialylation, which promotes P. aeruginosa invasion of the airway epithelium, but MUC1-ED desialylation also increases its shedding [47]. However, shed MUC1-ED competitively blocks P. aeruginosa adhesion to membrane-associated MUC1-ED [47]. Thus, release of MUC1-ED into the airway lumen as a decoy receptor is a host response to combat pathogenesis during this infection. Compared with Muc1+/+ mice, Muc1 / mice showed increased P. aeruginosa clearance, more recruitment of neutrophils in the airway, increased levels of TNF-a in bronchoalveolar lavage fluid, and higher levels of TNF-a in the media of flagellin-stimulated alveolar macrophages [48]. MUC1 knockdown increased flagellininduced IL-8 production in human bronchial epithelial cells [48]. This suggests that MUC1 suppresses pulmonary innate immunity, and thus has an anti-inflammatory role during microbial infection. It is to be noted that P. aeruginosa induces phosphorylation of the MUC1 cytoplasmic tail by activating the epidermal growth factor (EGF) receptor [49] and MAP kinase [50]. MUC1 plays an anti-inflammatory

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Airway epithelial cells

(i)

Haemophilus influenzae infection

(ii) TLR2 MUC1-ED Cytoplasm TLR2-CD

MUC1-CT

(iii)

MyD88

(iv)

NF- B

Nucleus

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Figure 2. Anti-inflammatory Role of MUC1 during Haemophilus influenzae Infection in Airway Epithelial Cells. During nontypeable H. influenzae infection, it is well documented that Toll-like receptor (TLR)2 binds to its ligand, lipoprotein P6, on the bacteria and causes inflammation [88,89]. However, we hypothesize that MUC1 masks TLR2 from binding to lipoprotein P6, and thus inhibits the attachment of MyD88 to cytoplasmic TLR2. This inhibits NF-kB signaling and activation, thus downregulating interleukin (IL)-8 and tumor necrosis factor (TNF)-a [45] and prevents inflammation. MUC1 could affect TLR2 signaling by various mechanisms. (i) The extracellular domain of TLR2 may be masked by the MUC1 extracellular domain (MUC1-ED) leading to reduced interaction of TLR2 with its ligand lipoprotein P6. (ii) Interaction of MUC1-ED and the extracellular domain of TLR2 may lead to conformational changes in the binding epitopes on TLR2, thus preventing attachment of lipoprotein P6. (iii) Direct interaction of the MUC1 cytoplasmic tail (MUC1-CT) and the intracellular domain of TLR2 may inhibit MyD88 binding to intracellular domain of TLR2. (iv) Inhibition of MyD88 binding to the TLR2 intracellular domain may lead to inhibition of NF-kB activation and subsequent transcriptional activation of IL-8 and TNF-a [18] (figure drawn with the assistance of biorender.com).

role in P. aeruginosa-mediated lung infection (also a potential precursor to lung cancer). Alveolar macrophages play a crucial role in the clearance of P. aeruginosa from the airways. However, bacterial clearance can be hampered by hyperactivation of macrophages, leading to morbidity and mortality. MUC1 counter-regulates inflammation on the apical surface of mucosal epithelial cells, and also macrophages [51]. P. aeruginosa upregulates the expression of MUC1 in primary human alveolar macrophages and THP-1 macrophages. This increased expression of MUC1 in these cells prevents their hyperactivation, and this appears to play a significant role in host defense against the pathologic effects of P. aeruginosa-mediated lung infection [51]. Therefore, it is evident that, in healthy tissues, MUC1 provides defense against pathogens, and the changes that it undergoes are correlated with the pathogenicity of the microbe. Again, in this case the anti-inflammatory role of MUC1 is predominant and suggests protection against cancer development.

Salmonella typhi Infection Salmonella is a rod-shaped, Gram-negative, facultative anaerobe and a food-borne pathogen. Salmonella infection causes gastroenteritis and remains a major public health concern worldwide [52]. To establish infection, Salmonella needs to cross the protective mucus layer and invade the epithelial cells from the apical surface. However, the apical surface of intestinal epithelial cells is covered with

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the large glycosylated mucins which prevent contact between the Salmonella type III secretion needle and the plasma membrane. It has been reported recently that MUC1 facilitates Salmonella invasion [53]. The Salmonella giant adhesin SiiE engages MUC1, and the interaction is mediated by the glycans. Another study on intestinal epithelial cells suggests that SiiE interacts with MUC1 in a zipper-like manner that involves repetitive domains in both proteins [54], and that MUC1 facilitates Salmonella invasion [54]. Adhesin–receptor interactions are crucial for invasion of host cells by pathogens. Many studies have shown that Salmonella manipulates host cell signaling pathways and facilitates colon cancer development in genetically predisposed mice [53,55]. Severe infection with Salmonella from contaminated food was shown to be specifically associated with increased colon cancer risk in humans [53]. Salmonella secretes effector proteins into host cells to activate various pathways that are implicated in many cancers, such as AKT and ERK [23]. Both these pathways are modulated by MUC1 [56,57]. For example, AvrA is a Salmonella effector that activates host b-catenin signaling and promotes colon carcinogenesis in mice [58,59]. Targeting the SiiE–MUC1 invasion pathway during Salmonella infection might be useful for preventing infection and possible development of colon malignancy. Because MUC1 assists Salmonella invasion into the intestinal epithelium, it is possible that it plays a proinflammatory role during Salmonella infection.

Escherichia coli Infection Enteroaggregative E. coli (EAEC) causes inflammation of the intestine worldwide. These strains are characterized by the presence of aggregative adherence fimbriae (AAF) which mediate attachment to the intestinal mucosa, thus triggering inflammatory responses in the host [60]. One pioneering study showing a proinflammatory role of MUC1 in the host response to an intestinal pathogen was based on EAEC infection [60]. This study reported that MUC1 is an intestinal receptor for EAEC and that it interacts with the bacterial AAF to facilitate adhesion. Furthermore, it was shown that EAEC infection upregulates the expression of MUC1 in inflamed human intestinal tissues [60]. MUC1 was also shown to facilitate AAF-dependent migration of neutrophils across the epithelium during EAEC infection [60]. Although various strains of E. coli have been linked to different types of carcinoma, for example, colorectal cancer (CRC) [61] and bladder cancer [62], there is debate whether the association is a cause or a consequence of malignancy [63]. However, MUC1 acts as a proinflammatory molecule in the case of E. coli infection by facilitating its entry into gastric epithelial cells.

Anti- versus Proinflammatory Roles of MUC1 during Virus infection Epstein–Barr Virus and MUC1 Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is commonly associated with nasopharyngeal carcinoma (NPC), Hodgkin’s lymphoma, Burkitt’s lymphoma, natural killer (NK)/T cell lymphomas, and some gastric carcinomas [64,65]. EBV-associated NPC has highly metastatic characteristics and poor prognosis. As a key effector in EBV-driven malignancies, EBV latent membrane protein 1 (LMP1) displays oncogenic properties in epithelial cell lines and confirms that EBV infection contributes to the malignant phenotype of NPC [66]. In EBV-negative nasopharyngeal cell lines, transient expression of LMP1 induced the expression of MUC1 protein and mRNA [67]. LMP1 induces binding of STAT1 and STAT3 to the MUC1 promoter and increases its expression in NPC cell lines [67]. Furthermore, LMP1-induced MUC1 reduces cell adhesion to the extracellular matrix and enhances cell invasiveness in vitro. Thus, LMP1 induces MUC1, which, together with the induction of other oncogenic signaling pathways, may act sequentially and lead to metastasis of EBV-infected tumor cells [67]. Therefore, in EBV-infected NPC cells, MUC1 plays a proinflammatory role.

Human Papillomavirus and MUC1 Human papilloma virus (HPV) is the most common sexually transmitted virus and is known to cause cervical cancer. Although cervical cancer incidence is substantially higher than other HPV-related cancers [68,69], the incidence of HPV-related anal and head and neck cancers (HNCs) has recently increased [70–73]. HPV also causes cancers of the vulva, vagina, penis, and other parts [69,74]. The expression levels of MUC1 in 10 vulvar condyloma acuminate (VCA), 15 vulvar intraepithelial neoplasia (VIN), and 30 vulvar squamous cell carcinomas (VSCCs) were investigated and compared

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with the clinicopathologic features of VSCC [75]. Patients with HPV-negative VSCC showed higher levels of MUC1 expression than did HPV-positive patients. It was speculated that MUC1 expression correlates negatively with HPV infection because MUC1 levels gradually increased significantly from well to poorly differentiated VSCC [75]. Therefore, it appears that MUC1 might initially play a protective role during HPV infection. However, in another study on HPV-associated laryngeal cancer specimens and normal tissues, a significant correlation was found between MUC1 expression and tumor grade/stage, and no correlation was found in normal tissues [76]. There was a positive trend for a correlation between MUC1 and tumor-suppressor protein p16, which is commonly used to diagnose a HPV-associated cancer [76]. Given this positive trend, it was suggested that targeting MUC1 would improve tumor therapy [76]. This study suggests that in HPV-infected cancer cells the role of MUC1 switches to proinflammatory, thus aiding in tumor progression.

Respiratory Syncytial Virus and MUC1 MUC1 is reported to suppress virus-induced inflammatory responses in respiratory syncytial virus (RSV) infections. In lung adenocarcinoma cell line A549, MUC1 is upregulated during RSV infection as a result of increased TNF-a levels [77]. A similar result was obtained with primary mouse tracheal surface epithelial cell cultures prepared from Muc1 double-knockout mice. TNF-a interacts with its receptor TNFR, which in turn suppresses further production of TNF-a by RSV, thus forming a negative feedback loop that controls RSV-induced inflammation [77]. These results are in line with the anti-inflammatory role of MUC1 during airway P. aeruginosa infection and in the initial stages of HPV infection. Therefore, these studies suggest that MUC 1 has anti-inflammatory activity in both bacterial and viral infections. Whether the anti-inflammatory signals protect against development of malignancy remains debated.

Influenza A Virus and MUC1 A study on human lung epithelial cells found that influenza A virus (IAV) binds to sialic acid on MUC1 during invasion [12]. By contrast, overexpression of MUC1 led to a reduction of IAV infection in epithelial cells [12]. Direct physical interaction between IAV and MUC1 was shown with lysates of CHO-K1 cells transfected with either MUC1 or control vector that were coated onto plates and probed with PR8 virus [12]. Antibodies specific for PR8 hemagglutinin (HA) were then used to detect bound virus. Significantly more virus was bound to plates containing lysates from MUC-expressing CHO-K1 cells than from control CHO-K1 cells, suggesting that MUC1 was responsible for binding the additional virus [12]. IAV-infected Muc1 / mice showed enhanced early inflammatory responses to infection. The number of CD45+ leukocytes present in bronchoalveolar lavage fluid (BALF) was significantly higher in Muc1 / mice compared with WT mice for the duration of infection. After 3 days of infection, there was an increase in the number of neutrophils and macrophages in PR8-infected Muc1 / mice relative to WT mice. BALF from Muc1 / mice contained significantly higher amounts of the proinflammatory cytokines IL-6, MCP, and TNF-a than did WT mice at day 3 [12]. These data suggest that MUC1 is a crucial component of the host innate immune response and adds to its anti-inflammatory role, suggesting that it may afford protection against cancer development.

Parasites Common parasitic infections that can lead to cancer include Schistosoma haematobium, the only blood fluke that infects the urinary tract, and Opisthorchis viverrini, a liver fluke that infects the bile duct, causing opisthorchiasis. Schistosoma infection causes urinary schistosomiasis, and is the second leading cause of squamous cell carcinoma of the bladder, the first being tobacco smoking [78,79]. Opisthorchis viverrini increases the risk of cholangiocarcinoma (CC), a cancer of the bile ducts [80]. Cholangiocarcinoma is a malignancy of bile duct epithelia. Although a relatively rare cancer in Western countries, it is predominant in Southeast Asia and remains a public health challenge [81]. Liver flukes inhabit the biliary tract, leading to chronic inflammation, proliferation, and consequent dysplasia of bile duct, and eventually to the development of CC [81]. Because CC is a slow-growing

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tumor, it is diagnosed when the tumor is large enough to obstruct the biliary tract. Thus, most patients are diagnosed at later stages of tumor development, which leads to poor survival. An early-stage biomarker for detecting and monitoring of the CC tumors might improve the prognosis and therapeutic management of the disease. The expression of MUC1 was examined in CC tissues from 87 intrahepatic cholangiocarcinoma (ICC) patients with a history of O. viverrini infection [81]. Immunohistochemistry and PCR analysis showed that MUC1 was expressed in 77% (67/87) of ICC patients, and 39.1% (34/87) of the patients had high levels of expression. Moreover, statistical analysis revealed that high expression of MUC1 significantly correlated with poor prognosis. A positive correlation was also found between MUC1 expression and vascular invasion [12]. This study suggested that high MUC1 expression in tumors may help to predict prognosis in ICC patients [81]. However, there is a huge gap in research on cancers caused by parasite infections, and there is little evidence to demonstrate that MUC1 is involved in immune regulation in such cases. However, the positive correlation between MUC1 expression and poor prognosis in CC suggests that MUC1 may play a proinflammatory role.

Concluding Remarks Studying microbe–MUC1 crosstalk in different infection-induced cancers may open avenues for further research (Figure 3, Key Figure). These interactions modulate local and systemic inflammatory responses, oncogenic signaling, and tumor progression. The concept of cancer-immunoediting states that the process of cancer development comprises three phases that collectively denote the three ’E’s of cancer immunoediting: elimination, equilibrium, and escape (Box 1) [82].

Key Figure

Potential Impacts of Microbe-MUC1 Interactions

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Figure 3. The mechanisms of microbiome–MUC1 crosstalk will open avenues for research into the development of glycome signatures for personalized medicine, new preventative vaccines, and therapeutic targets, and holds potential to develop the ‘cancer-equilibrium phase’ model (figure created with the assistance of biorender.com).

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Box 1. The Equilibrium Phase of Cancer-Immunoediting: The Challenge To Develop a Model

Clinician’s Corner

The ’cancer immunoediting’ theory proposes that the interaction between the immune system and cancer comprises three phases – the three ’E’s of cancer immunoediting: elimination, equilibrium, and escape [82].

Currently, the prevention of infection-induced cancers relies on vaccines that target the pathogen. This is feasible for completely foreign pathogenic microbes, for example, Gardasil 9 for cervical cancer. However, it is challenging to develop vaccines against opportunistic pathogens. The study of microbe–MUC1 crosstalk mechanisms provides insights into biochemical changes in the interacting proteins that could be targeted to prevent the formation of malignancies after infection. The sugar code of each tissue is different. Therefore, the way in which the mucins interact with one microbe in a cell type differs from their interaction with the same microbe in another cell type. In addition, because of altered glycosylation, the same mucin can act differently in cancer cells and normal cells. Therefore, the specific glycome signature of different tissues and infections can be used to determine the susceptibility and response to therapy of an individual, allowing the development of personalized medicine. Monitoring the period from infection to tumor formation will be necessary to provide insights that will help to develop the cancerequilibrium phase model. This is a phase of Darwinian selection when new resistant tumor variants arise. It is essential to detect and study this phase to capture the infected cells before they escape the immune system, and this will help to identify new biomarkers.

Elimination is the original concept of cancer immune surveillance for the successful eradication of developing nascent tumor cells. Even when the immune system fails to prevent the formation of a tumor, the interplay continues and the tumor is in a state of functional dormancy [90]. Some tumor cells undergo genetic and epigenetic changes as a result of constant immune pressure. Therefore, this stage is also referred to as a phase of Darwinian selection. The tumor cell variants that evolve in this stage become immune-resistant through antigen loss, defects in antigen presentation, or induction of immunosuppression. This highlights the enigma of how immunologically competent organisms develop tumors that are not attacked by the immune system [91]. Of the three phases of immunoediting, most research has focused on the escape phase. At present, the equilibrium phase is mostly hypothetical and needs more data to prove its existence. Most knowledge on tumor dormancy derives from experimental models. It is extremely difficult to isolate dormant tumor cells from humans, and this is the biggest limitation of using animal models. In patients under complete remission from solid tumors, the frequencies of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) are around one per million. This makes it immensely difficult to perform functional immunological assays using patient-derived tumor cells. Therefore, caution must be exercised in extrapolating hypotheses from experimental models to humans. To stringently test the existence of the equilibrium phase, it will be crucial to establish new tumor models during primary tumor development. This will help to establish the effects of experimentally controlled variable periods of equilibrium on the immunogenic potential of established cancers in immunocompetent hosts. Recent experimental and clinical studies have confirmed the occurrence of this dormant phase in cancers [92]. It is important to explore the cancer–immune equilibrium because this may help in preventing the progression and spread of the cancer, thus converting it from a deadly into a chronic disease.

In infection-induced cancers there is a prolonged period of interaction between an invading pathogen and epithelial barriers such as MUC1. During this interaction, biochemical changes induced in the mucins may elicit changes in immunomodulatory cues downstream that mark the immune– cancer equilibrium phase (Box 1). To understand how infections manifest as malignancies, it is important to develop a proper immune–cancer equilibrium model. Continuous monitoring of infection-induced cancers may help to develop an equilibrium phase model. Ultimately, this also opens avenues for early-phase biomarker detection and the development of vaccines against pathogeninduced modifications of self-antigens. This is in line with the glyco-evasion hypothesis which states that infection can lead to changes in host glycosylation, thus modulating host protein and cell function, which in turn can lead to inflammation, susceptibility to infection, and overall immune dysfunction [9]. The current focus should be to monitor the glyco-evasion axis and develop strategies to prevent infection-mediated transformation of host cells. For example, MUC1 is present at the interface of the invading microbe and the host cell, and undergoes biochemical changes following interaction with a pathogen, including shedding of glycosyl residues from the extracellular N-terminal domain and phosphorylation of the intracellular C-terminal tail. These changes could be tracked to develop biomarkers for different cancers. One challenge to distinguish between pathogen-induced changes and other environment-induced changes is the redundancy of the biochemical changes taking place at a specific position on MUC1. To address this issue, close observation of specific microbe– MUC1 interactions is needed, and the antigen type, load, and chemistry of attachment should be studied. In cases where MUC1 plays proinflammatory roles, peptidomimetics can be introduced as therapeutics that are inert to self-antigens but attach to the pathogen by mucin-like properties and neutralize proinflammatory cues, thus acting as MUC1 antagonists and preventing the formation of malignancies. Similarly, in cases where MUC1 acts as an anti-inflammatory molecule, self-inert peptidomimetics could be introduced that act as MUC1 agonists to amplify anti-inflammatory signals. The main challenge in using these peptidomimetics is that many host–microbe interactions occur through glycans and do not involve the core peptide of the mucin. In that case, peptidomimetics should be synthetically modified to prepare conformational analogs not only of the protein to be

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Box 2. Glycome: An Overview

Outstanding Questions

Glycans are long sugar chains that cover all cells. According to the National Academy of Sciences, creating a map to determine their location and structure will open a new avenue for modern medicine. This is because the human glycome – the entire collection of sugars within our body – harbors glycans which have not yet been discovered but that have the potential to aid physicians in diagnosing and treating their patients (www. healthcare-economist.com/2018/08/28/what-is-the-the-sugar-code/). Sugars have huge physiological importance beyond being a source of energy and structural components. They vary in parameters such as linkage positions, ring size, addition of branches, and site-specific substitutions. These glycans have cell type-dependent features. The often-limited intramolecular flexibility and variety of contact points for intermolecular interactions of these oligosaccharides is ideal for binding interactions. Glycan-based codes can be translated into physiological processes by their receptors, the lectins.

MUC1 can play both pro- and antiinflammatory roles in different infections and in different cell types. Which factors regulate the switch to determine whether MUC1 will play a pro- or anti-inflammatory role? The glycosylation status of MUC1 regulates its activity. Is it possible to develop a glycome signature for tissue-specific infection-induced cancers, and develop that into a predictor of infection-susceptibility and response to therapy? Peptidomimetics are synthetic molecules that mimic the function of the original molecule. How can we develop antagonistic and agonistic peptidomimetics of MUC1 and other mucins that are involved in modulating inflammatory signals after invasion by microbes? The longest phase of cancer immunoediting is the equilibrium phase, where the tumor cells are shaped to become immune-resistant. How can we exploit the immune–cancer equilibrium model to capture infected cells before they escape the immune system and develop biomarkers to detect such escape?

mimicked but also of the specific glycosylation changes that facilitate pathogen removal or attenuate pathogen invasion. Intense research will be necessary to investigate the amount of these specialized therapies to be administered because imbalance might cause immunosuppression and make patients susceptible to secondary infections. All glycoproteins, including mucins, contain specific sugar residues in different tissues: this is known as the sugar code [83]. The entire combination of the sugars in the body of an individual, or the entirety of carbohydrates in a cell, is termed the glycome and has immense physiological importance (Box 2). Deciphering the sugar code holds potential to develop a signature of susceptibility to specific pathogens and act as a predictor of response to therapy (see Outstanding Questions). In addition, blocking oncogenic signaling via the cytoplasmic tail might be beneficial post-infection to avoid the formation of malignant cells. Many small molecules and antibodies are known to block MUC1-CT signaling [84,85]. MUC1 is essentially a modulator of infectioninduced cancers, and exploration of this avenue holds great potential to combat infection-induced cancers.

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