\r\n\tIncreasingly, governments and development institutions are recognizing the importance of addressing social exclusion for sustainable development. As such, the book will examine the role of government and the contribution of international development partners in the protection and support of marginalized groups and communities. Additionally, the role, responsibility, and response of academia as a socially accountable partner will form part of the discourse.
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The most commonly living microorganism of the human gastrointestinal tract and also the most common causative agent of bacterial urinary tract infection is E. coli [1]. Though they remain in a good relationship with their hosts, they might appear as a subject of consideration in immunocompromised hosts. This common inhabitant of the gastrointestinal tract usually remains in a symbiotic relationship with the host and plays a role in maintaining the homeostasis of the intestinal tract. Though most of the strains of E. coli are harmless, some serotypes can cause food poisoning. E. coli present in the normal human microbiota produces vitamin K2. Strains of E coli, however, obtaining ability to colonize inside the urinary tract and to make themselves safe from the host immune system, become uropathogenic E. coli. UPEC causes >80% of UTI [2]. Urinary tract infections are very common, and approximately 10% of people [3] and half of all women (at least one time) become infected throughout their life. According to a study, more than 100,000 patients in the United States are hospitalized annually due to urinary tract infections [4], and in the year 2011, 400,000 patients were hospitalized, and the estimated cost was about 2.8 billion USD [5]. Infections can occur in both upper and lower urinary tracts. Lower urinary tract infection is known as cystitis, and in the case of upper urinary tract infection, it is called pyelonephritis. Without distinction of site, in order to cause infection, the causative agent must at first dodge the host’s immune system and colonize in the urinary tract [6]. Several different virulent factors are needed for the bacterial population to cause infections [7]; for instance, pathogenic strains of E. coli express adherence factors which form pili or fimbriae of different types for their attachment in the sites where they usually do not live [7]; these are structural virulence factors and predominantly include P fimbriae and type 1 fimbriae [1]. Fimbrial adhesins such as PapG and CsgA are virulence factors that facilitate the attachment of E. coli [8]. In animal models, type 1 fimbriae aggrandize the chance survival of E. coli [9]. Beside these, UPEC can impair host immune system by a variety of ways [10], such as toxins and iron acquisition systems, and these are called secreted virulence factors. The production of these virulence factors by UPEC may cause an inflammatory response which makes a possible pathway for UTI symptoms [1]. However, both the host and the uropathogenic E. coli strain have different roles in the establishment and colonization process in the urinary tract [11]. Here in this chapter, different types of important virulence factors of uropathogenic E. coli will be discussed.
In Gram-negative and some Gram-positive bacteria, virulence genes are allocated in particular segments (about 10–200 kilo bases in size) of their genome which have different G + C content than the other parts of the genome that are termed as pathogenicity islands. They are present in the virulent strains but present rarely in the nonpathogenic strains of the same species. These sequences can be transferred horizontally from species to species [12]. Pathogenicity islands encode virulence factors such as adherence factors, toxins, and iron acquisition systems which are important virulence factors of UPEC.
Urine of uninfected person is sterile due to urinary flow and antimicrobial activity of uric acid. Regular flow of urine does not allow microorganism to colonize inside the urinary tract. However, attachment of E. coli to uroepithelial cells allows them to overwhelm the effect of urine flow. For many pathogenic microorganisms, it is considered as the first step in the colonization process [13, 14], and both the host and E. coli function in this process. The ability of UPEC to colonize depends upon the expression of different fimbrial adhesins. For a successful adherence to the host cell surface, UPEC expresses many adherence factors which are crucial for attachment and thus regarded as virulence factors. Many bacterial adhesins are organized in a thin filamentous structure called fimbriae or pili although there are evidences of presence of adhesins in the cell surface of bacteria. Adhesins of fimbrial nature are important during attachment process [15]. Fimbriae, also known as pili, are long hair-like structures contained in the cell surface of bacteria that recognize specific compounds usually carbohydrates of the target host cells [11]. Pili are the short form of fimbriae and might be used interchangeably with fimbriae. Fimbriae consist of oligomeric pilin proteins. These proteins are arranged in such a manner that they form a helical cylindrical structure and are both thinner and shorter than flagellum. These proteinaceous structures are expressed in uropathogenic strains of E. coli and are considered as virulence factors [11]. Most of the receptors for these fimbriae are carbohydrates. They include type 1 fimbriae, P fimbriae, and thin aggregative fimbriae [16]. Many bacterial pathogens can produce an array of these adhesins, and often inhibition of a single adhesin may cost enough to a bacterium to lose its virulence. Functions of pili or fimbriae are not limited only to adhesion and can help in many other crucial pathways for the microbe to survive and evade the immune system of the host. Evolution of different types of adhesins plays a role in tissue tropism.
In gram-negative bacteria like UPEC, adhesins are unveiled by chaperone-usher-assisted pathway. This pathway involves two proteins, one is a periplasmic chaperone, and the other is a protein called usher. Usher act as the base of the structure, and the function of chaperone is folding and recruitment of the subunits [17, 18]. In absence of the chaperone, pilin proteins are degraded and misfolded and thus cannot be assembled in the form of a mature pilus. On the other hand, usher helps to mature the fimbriae and its transportation through the outer assuring integrity of the outer membrane. The constituents of usher proteins are an N-terminal domain (NTD), 24-stranded beta-barrel channel, a plug domain, and two C-terminal domains (CTD). In uropathogenic E. coli strains, chaperone-usher family fimbriae are more abundant.
In 99% of E. coli strains, genes to encode type 1 fimbriae are present [19], and during urinary tract infections, they damage urinary tract cells by mediating an increased inflammation [20]. In order to enter into the host cells of the urinary tract, type 1 fimbriae play a great role. Type 1 fimbriae are remarkably versatile virulence factors of UPEC that can stabilize the attachment of the bacteria to different type of cells throughout the urinary tract. Though in Bowman’s capsules and glomerulus their binding sites could not be identified, a strong affinity of type 1 fimbriae was found in proximal tubules and vessel walls. In the bladder, they bind strongly to muscular layers and moderately to vessel walls. Receptors for type 1 fimbriae were also found in the distal tubules and collecting ducts. They can also induce their binding to the surface of macrophages [9]. These fimbriae recognize uroplakin from bladder epithelial cells and mannoside-containing host proteins. Unlike many other important types of adhesins, these are encoded by the bacterial backbone DNA [21] and are mainly composed of FimA proteins along with FimF, FimG, and FimH [17]. FimA proteins are most in number but are not pivotal for virulence. Among other subunits of type 1 fimbriae, allelic variations of FimH determine the sugar specificity and deletion of fimHresults in less amount of colonization in mouse models of ascending UTI, and colonization could be restored by expression of plasmid with fimH gene [20]. FimH alone or in association with LPS can stimulate toll-like receptor 4 (TLR4) to initiate particular signaling cascade that may activate the humoral immune response. Many studies revealed that expression of type 1 fimbriae results in virulence and loss of expression results in loss of expression but their presence cannot be correlated with UTI as normal fecal strains also have equally expressed type 1 fimbriae [22]. However, type 1 fimbriae-mediated attachment is a crucial stage for cystitis. Adhesins of these fimbriae are mannose sensitive.
P-fimbriated E. coli are pyelonephritogenic and attach to the carbohydrate structure alpha-D-Galp-(1-4)-beta-D-Galp. In the kidney, they bind strongly to Bowman’s capsule, glomerulus, and endothelial cells of vessel walls. This highly organized composite structure is composed of six subunits at least. Once P fimbriae expressed E. coli enter the urinary tract, they establish bacteriuria and help to cross the epithelial barrier to enter the bloodstream and can cause hemagglutination of erythrocytes [14]. This type of fimbriae is encoded by pap gene cluster (also known as fso and fst), and pap + strains remain longer in the intestinal flora than pap- strains [23]. P antigens are expressed in the cell surface of red blood cells and in various cells lining in the urinary tract. P1 (present in glycoproteins in human), P, PK, and LKE antigens act as the receptors for P-fimbriated UPEC. P-fimbriated E. coli cannot agglutinate red blood cells that lack P antigen. Isolated P fimbriae can bind to a synthetic analogue of its receptor, and experimental application of that analogue impedes infection process.
There are at least nine genes in the pap gene cluster with two restriction sites at two ends. The regulatory part starts the following Eco R1 consisting of papI and papB. Then papA, papH, papC, papD, papE, papF, and papG are situated, and after these, Bam HI is present. Approximately 1000 of subunits form a P fimbria, being united in a helical manner. Among them the major constituent is the protein subunit PapA (19.5 KD), and minor subunits are PapE (16.5 KD), PapF (15 KD), and PapG (35 KD). In the periplasmic space, PapD (27.5 KD) may be present and can also be incorporated in the structure. Another protein PapC, which is the largest one with 80 KD of mass, assists the process by transporting the subunits outside the part of the cell. Though PapA is the major constituent, it is not mandatory for attachment, and among many serotypes, PapA molecules show high homology with the amino acids of N and C termini. PapA also has an average level of similarity with structural subunits of other E. coli fimbriae including type 1 fimbriae. The minor subunits at the tip of fimbria determine the specificity to the receptor. Many mutational analyses revealed that mutation in PapA does not affect the adherence, while mutation in other genes (i.e. papEFG) does not hamper fimbrial structural appearance. In the fine structure of P fimbriae, a PapF-PapG complex is formed which is attached to PapA (bulk potion of the structure) subunits through PapE subunits. Finally, PapH terminates the assembly of the fimbriae and attaches thereby [16]. An important thing is that the amino acid sequence of PapG is approximately similar to that of Shiga toxin. Shiga toxin is found in some serotypes of E. coli. Another role of PapG was found in some variants of P fimbriae which is they can initiate subunit polymerization [14].
Many experiments show that expression of these fimbriae is not relevant to urinary tract infection, while more sophisticated other experiments have concluded about their role in pathogenesis. However, during infection in immunocompromised patients, less expression of P fimbriae is observed, which indicated that P fimbriae are needed to overcome certain types of host immune attacks. Although P fimbriae can initiate inflammatory responses by activating TLR4 [24], it protects UPEC from human polymorphonuclear leukocytes (hPMNLs). In the rapidly changing environment through the urinary tract, environmental influences affect the expression of P fimbriae. Expression of P fimbriae is favored at 37°C and inhibited at a range of 18–22 °C, but there are some variations in this phenomenon. The temperature-dependent expression is controlled by a region close to papB of the pap gene cluster.
Dr blood group antigen is a membrane protein of red blood cells and located on the decay accelerating factor (DAF) that protects red blood cells from being degraded or lysed by autologous complements. Another important function of DAF is to regulate complement cascade [25]. These antigens are recognized by Dr and Afa adhesin family of uropathogenic E. coli. There are both fimbrial (F1845 and O75X) and non-fimbrial (AFA I and AFA II) types of adhesins. Immuno-invasion of UPEC by hiding from the host humoral immune response is somehow mediated by Dr family of adhesins [26]. These microscopically invisible fimbriae are present in the cell wall, and their structural and organization properties are quite different from other types of fimbriae [13]. Chloramphenicol can inhibit O75X binding to a specific part of the Dr antigen, but it cannot inhibit other adhesins of this family which indicates that Dr family adhesins can recognize specific sites at the Dr [25]. For years, several studies were conducted to identify specific sites for binging of Dr family hemagglutinins. For instance, a strong affinity of O75X was found to Bowman’s capsule, proximal and distal tubules, and the collecting duct basement membranes. In the bladder, they strongly bind to connective tissues.
F1C is a virulence factor responsible for urinary tract infections, which is encoded by an operon of seven genes, i.e., focAICDFGH, where FocA is the major subunit and FocH is the tip adhesin [26]. F1C receptors are present in bladder endothelium and muscular layer. They cannot bind to the epithelium. They bind to glomeruli, distal tubules, collecting ducts, and vascular endothelial cells. Studies show that F1C fimbriae and pyelonephritis are correlated though there is a little difference in the prevalence of type 1 fimbriae in UTI strains and normal fecal isolates. Prevalence of F1C fimbriae in normal fecal isolates is 10% which is 16% in UTI strains [26]. S fimbriae are genetically identical to F1C fimbriae and differ only by the tip adhesin SfaS. Criteria that are needed to be recognized as a virulence factor were determined by different studies regarding S fimbriae. There are some other adhesins that are not crucial for the survival of UPEC strains such as F9 fimbriae.
Several toxic substances or proteins secreted by uropathogenic strains of E. coli play a consequential role as virulence factors in UTIs. However, toxins have the ability to alter the host cell signaling cascade and modulate inflammatory responses. Several in vitro and in vivo studies showed that toxins also contribute to the stimulation of the host cell death and releasing of necessary nutrients, which provide the ability to access deeper tissues within the urinary tract [27]. In 1987, CDT toxin (cyclomodulins) was first reported as virulent toxin in UPEC [28] which opened a new door in the study of the pathogenesis of UTIs, and then many other toxins in UPEC were reported including α-hemolysin (HlyA), cytotoxic necrotizing factor 1 (CNF1), secreted autotransporter toxin (SAT), cytolysin A, plasmid-encoded toxin (PET), vacuolating autotransporter toxin (VAT), Shigella enterotoxin-1 (ShET-1), arginine succinyl-transferase (AST), etc.
Among all the toxins, α-hemolysin (HlyA) is very important which is a lipoprotein and belongs to the RTX (repeats in toxin) toxins family [13, 29, 30]. HlyA is a pore-forming toxin and causes inducible nitric-oxide-synthase (iNOS)-mediated cell membrane injury and apoptosis [31]. However, HlyA can lyse erythrocytes and nucleated host cells at high concentration by a process enabling UPEC which may damage the host immune effector cells for gaining enhanced access to the host nutrients and iron stores. But when the concentration is low, HlyA can induce the apoptosis of target host cells and promote the exfoliation of bladder epithelial cells [13, 32, 33]. Besides, HlyA can also contribute to nephropathogenicity, which was proved by infecting mice transurethrally or intravesically with toxin producer and nonproducer isogenic clone pairs of E. coli [34]. A recent study showed that HlyA regulates the dephosphorylation of Akt, which is a multifunctional signaling regulator and responsible for controlling inflammatory responses in the host, as well as the cell cycle control [35]. Moreover, HlyA has the role in the increased production of IL-6 and IL-8 by inducing Ca2+ oscillations in renal epithelial cells [36].
Another virulence factor secreted by E. coli named cytotoxic necrotizing factor 1 (CNF1) is also involved in UTIs and stimulates actin stress fiber formation and membrane ruffle formation in a Rho GTPase-dependent manner that results in the entry of E. coli into the cells [37]. The toxin has a remarkable effect on the actin skeletal of HEp-2 cells and produces large vacuoles in HEp-2 cells [28]. However, several in vitro and in vivo studies showed that this protein interferes with polymorphonuclear phagocytosis and evokes apoptotic death of bladder epithelial cells and may lead to bladder cell exfoliation and to enhanced bacterial access to underlying tissue [38, 39]. In addition, there is also a possibility of the association of CNF1 with the hemolysin in the virulence mechanism, which is beneficial for the bacteria [28].
Secreted autotransporter toxin (SAT) may also be important as a virulence factor for the pathogenesis of UTIs being had a toxin activity against cell lines of bladder or kidney origin. SAT is a serine protease autotransporter which falls within one subgroup of autotransporters recently classified as the SPATE (serine protease autotransporters of Enterobacteriaceae) family and associated with pyelonephritic E. coli strains [40, 41]. SAT may have the cytopathic activity that results in the damage of the host tissue and may increase the propagation ability of the UPEC. However, this toxin may facilitate entry of pyelonephritogenic strains into the bloodstream resulting from specific damage to the glomeruli and proximal tubules [40].
Cytolethal distending toxin, having a unique property of damaging the DNA of the target cell, was first reported in pathogenic E. coli in 1987 [28, 42]. This toxin has the ability to arrest the cell cycle and contributes to the pathogenesis of UTIs [43, 44]. However, CDT is an operon product encoding three proteins including CdtA, CdtB, and CdtC proteins which are encoded by cdtA, cdtB, and cdtC genes, respectively [28]. CDT has DNase I-like enzymatic activity and attacks DNA, while the other bacterial toxins attack the cell membrane or different targets within the cytoplasm [45]. This unique property of attacking DNA damages the target cell DNA which results in progressive cell distending leading to cell death [27].
Some others including cytolysin A and toll/interleukin (IL-1) receptor (TIR) domain-containing protein (Tcp) are also considered as virulence factors in UTIs [46, 47]. The former causes apoptosis of the host cells [47], while the other has the ability to subvert TLR signaling that gives a survival advantage during UTIs [46]. However, Tcp is associated with pyelonephritis but rare in environmental E. coli, in fecal flora of healthy children and in less severe forms of UTI [27]. Besides these, Tcp has also the role in the human avoidance system and cytopathic effect on the kidney [48].
In addition to these toxins, vacuolating autotransporter toxin (VAT), Shigella enterotoxin-1 (ShET-1) and arginine succinyltransferase (AST) may also contribute to UTIs. VAT has the cytotoxic effect on the bladder and kidney, while the two others are involved in the invasion of the infections [48]. However, VAT is a highly protected immunogenic protein that belongs to the protease family of SPATE [28].
Iron is a very important molecule for all living beings, and E. coli uses iron for transporting and storing oxygen, DNA synthesis, electron transport, and metabolism of peroxides. But the amount of iron availability is reduced in the host urinary tract during UTIs [49]. In response to this, E. coli possesses some multiple functionally redundant systems that mediate iron uptake by secreting low-molecular-weight Fe3+-chelating molecules which are known as siderophores [50]. Iron utilization, mediated by these siderophores, is critical for colonization of the urinary tract by UPEC [51]. There are four distinct siderophore systems found in E. coli such as yersiniabactin, aerobactin, enterobactin, and salmochelin [52]. These systems also include some genes such as ent genes encoding enterobactin, iuc genes encoding aerobactin, and iro genes encoding an ent-like system. However, all these systems are expressed under low-iron conditions and are negatively regulated by ferrous iron and the ferric uptake regulator Fur [53].
Aerobactin is a low-weight molecule and a hydroxamate siderophore with a higher Fe3+-binding stability in acidic environments and is maximally produced at low pH [44, 53]. This siderophore extracts Fe3+ from host iron-binding proteins and is taken up through an outer membrane receptor protein [44]. However, aerobactin has many advantages over other siderophores and is formed from the condensation of two lysine molecules and one citrate catalyzed by an enzyme named aerobactin synthase [13, 25, 30].
Enterobactin is another specialized highly prevalent catecholate siderophore which is less soluble and less stable than aerobactin [53, 54, 55]. But this siderophore has a higher iron affinity and can deferrate transferrin more rapidly than aerobactin in aqueous solution [13, 54]. However, iron is released from enterobactin through the hydrolysis of this siderophore [13]. Besides these, enterobactin may afford UPEC the ability to colonize within an iron-limiting environment such as the urinary tract [56]. But this siderophore has a limitation that it can be inactivated by host proteins such as serum albumin and siderocalin [25].
Yersiniabactin, a mixed-type siderophore, is widespread in Enterobacteriaceae including E. coli and encoded on the high-pathogenicity island [53]. Yersiniabactin has a high iron affinity and produced yersiniabactin-Fe3+ complex binding to the iron molecule which recognizes the specific bacterial outer membrane TonB-dependent receptor and Fyu (Psn). The iron molecule is released from yersiniabactin in the cytosol with the help of membrane-embedded proteins [57]. In addition, this siderophore increases resistance to copper stress by chelating Cu2+ [10].
Salmochelin is a glucosylated derivative of enterobactin which is not recognized by siderocalin and thus escapes from the host immune response [53]. However, siderocalin, neutrophil gelatinase-associated lipocalin is also known as lipocalin 2 that binds enterobactin and prevents its uptake [53, 56]. To overcome this, enterobactin is modified to salmochelin by glucosylation via the action of glucosyltransferase and is not recognized by lipocalin 2 [56]. However, a recent study found that salmochelin siderophore receptor IroN is involved in the invasion of urothelial cells, and thus IroN may play both an iron uptake receptor and an internalization factor in the establishment of urinary tract infections [26].
There is another iron acquisition system called hemin uptake system including ChuA and Hma, which involves direct upregulation of haem receptors. This system uptakes free iron during UTIs, and several studies found its role in bacterial growth and biofilm formation [48, 58, 59]. ChuA expression is regulated by other regulatory proteins, for instance, in uropathogenic E. coli strain 536, increase in RfaH level induces the expression of ChuA [60]. But the other receptor Hma functions independently of ChuA, and a residue, Tyr-126, is necessary for its function. However, both ChuA and Hma contribute to haem utilization which is required for the maximum kidney colonization [51].
The main role of a capsule is to cover and protect the bacterium from various unfavorable conditions as well as the host immune system, which is mainly constituted of polysaccharide [1]. The capsule provides protection against engulfment and complement-mediated bactericidal effect in the host, also including antimicrobial resistance and antiserum activity [1, 48]. Certain capsulars, such as K1 and K5, prevent a proper humoral immune response of the infected host by showing a molecular mimicry to tissue components [1]. The K1 polysaccharide, a linear α2–8-linked sialic acid homopolymer, has a very important role in IBC development as well as in the multiple stages of UTI pathogenesis [27, 50].
Lipopolysaccharide (LPS) is an integral component of the cell wall and consists of the highly conserved lipid A-core and repeating O-antigen subunits that differ greatly between strains based on the sugar residues and their linkage patterns within the repeating subunits [37, 61]. LPS is very well known to activate host response and to induce nitric oxide and cytokine (IL-1, TNF-α) production which enhances the inflammatory response [1, 15]. It also induces the synthesis of specific antibodies to the somatic antigen and exerts an immune-adjuvant effect that promotes the humoral immune response to other antigens of the pathogen. However, certain antigenic types of LPS are also involved in resistance of the pathogen to the killing effect of the normal human serum [46]. According to study upon animal models, acute renal failure due to LPS depends on the systemic response to LPS and does not depend on expression of functional LPS receptor, TLR4, in the kidney. But it is not clear whether LPS plays a role in mediating a renal failure and acute allograft injury in patients with ascending UTIs [1].
Flagellum is an organelle that is responsible for bacterial motility and plays a role in the initial adhesion phase of biofilm formation [1, 62]. A recent study showed that motility is involved in the migration of the infection from the bladder to the kidneys [63]. About 70–90% of all urinary tract infections is caused by flagellated UPEC, and pathogenesis involves contact between the bacteria and epithelial cell surface of the urinary tract [1]. However, flagellar motility enhances the ability of E. coli by adaptive responses to attractive or repellent environmental stimuli [15].
Toll-like receptor 4 (TLR4) in the epithelial cells of the mammalian bladder can recognize lipopolysaccharides (LPS) of bacterial cell wall, and the downstream signaling cascade produces IL-6 and IL-8, of which IL-8 is well known as an important chemoattractant for neutrophils. Urinary levels of IL-6 and IL-8 are measurable in UPEC-infected human and murine models. There is another pathway parallel to this one that is responsible for increased levels of IL-6 and IL-8 in urine. Upon TLR-4 activation by LPS, intracellular level of cAMP is increased and results in of Ca2+ influx. Later, cAMP response element-binding protein (CREB) becomes phosphorylated. Phosphorylation of CREB results in the expression of IL-6 and IL-8 [24]. Mutation in TLR4 in murine models revealed its role on bacterial pathogenesis. There are other receptors related to UTI pathogenesis. One of such is CXCR1, but there are both types of evidences that demonstrate the positive and “no correlation” of CXCR1 with recurrent UTIs. Polymorphisms in IL-8 genes were found to have a correlation with pyelonephritis in the case of no correlation with CXCR1 mutation [19, 64]. TLR4 can be activated by the presence of type 1 fimbriae and P fimbriae.
As there are enough studies to evidence the activation of immune response against UPEC strains, there must be some ways that are used by these bacteria to overcome unfavorable situations early in the infection. Incubation of human urothelial cells with type 1-fimbriated UPEC strains resulted in increased apoptosis. In the case of a nonpathogenic type 1-fimbriated strain (HB101) of E. coli, rate of apoptosis was approximately 50% of that of pathogenic strains of UPEC [65]. UPEC blocks NF-ĸB, and this results in apoptosis and a decreased cytokine secretion.
Another indispensable way is the expression of toll/IL-1 receptor domain-containing protein (TcpC), which was discovered in UPEC strain CFT073. TcpC interacts with myeloid differentiation primary response 88 (MyD88), a protein that, in human, is encoded by MYD88 gene. Interaction of TcpC and MyD88 subsequently stops downstream signaling pathways mediated by TLRs.
Modification of capsular lipopolysaccharides specific to the pathogenic strain can cause the failure of TLR4 to recognize the pathogen. However, LPS biosynthetic genes encoded by rfa, rfb operons, and surA are the factors responsible for the suppression of TLR-initiated signaling cascades. Biosynthesis of a number of outer membrane proteins and fimbriae is facilitated by the protein encoded by surA, which is a periplasmic cis-trans prolyl isomerase [66, 67].
Several epidemiological, serological, and bacteriological studies revealed that uropathogenic E. coli is the pathogen most frequently associated with UTIs. In recent years, our understanding of virulence factors and behavior of this pathogen is increased remarkably. Several studies showed that E. coli colonizes the urinary tract and may ascend toward the bladder to cause cystitis. If it is left untreated, UPEC may ascend the ureters to the kidney and establish a secondary infection. Our increased understanding of its virulence factors can uncover novel approaches to control UPEC-mediated UTIs. However, accumulation of theoretical knowledge through virulence studies allows practical applications and may facilitate the application of more precise approaches in phenotypic or molecular diagnosis and epidemiology.
Ion channels and transporters (ICTs) are emerging as potential cancer biomarkers. Indeed, ICTs are aberrantly expressed in several types of human cancers, and exert a relevant role in mediating interactions between tumor cells and tumor microenvironment. Such interactions drive different functions which in turn regulate neoplastic progression, such as cell proliferation and survival, cell invasiveness and pro-angiogenetic programs [1, 2, 3]. Moreover, due to their prevalent expression at the cell surface, ICTs represent good targets for antibodies, to be exploited for diagnostic purposes. Finally, being highly druggable molecules, ICTs may represent novel molecular targets for antineoplastic therapy [4, 5].
The expression and role of different ion channels in tumor cells and their different contribution to tumor progression has been thoroughly described elsewhere [6]. In this chapter, we will focus on the possibility of exploiting ICTs as cancer biomarkers, for diagnostic, prognostic or predictive purposes. Some examples, relative to either solid cancers or hematologic malignancies are provided. We will analyze the possibility of using ICT-targeting antibodies for either in vitro or in vivo cancer diagnosis.
The technologies available to help physicians to detect and diagnose cancer has changed dramatically in recent years. In particular, the use of biomarkers has greatly improved diagnosis through their application for either in vitro diagnosis (on tumor specimens or in blood samples) or in vivo molecular imaging. According to the National Cancer Institute (NCI) definition (NCI Dictionary of Cancer Terms,
For the purposes of this chapter, we will briefly summarize the main techniques, either in vitro or in vivo, which take advantage of the use of biomarkers to obtain diagnostic, prognostic and predictive data on the cancer under study. Notably, most, although not all, of these techniques are based on the use of antibodies, targeting specific cancer-related biomarkers.
IHC represents an indispensable diagnostic tool to assess the presence or absence, as well as the amount, of a specific molecular tumor marker in a tissue. After appropriate assessment of categorical scoring system and proper validation of the immunohistochemical assay, a given marker can be proposed as a potential diagnostic or prognostic factor. Indeed, many of the cancer biomarkers routinely used in cancer diagnostics are based on this technique.
Using a multiparametric approach, FC immunophenotyping plays an indispensable role in the diagnosis and subclassification of leukemias, as well as for minimal residual disease detection. FC, in fact, provides a rapid and detailed determination of antigen expression profiles; these information along with morphologic assessment, allow to diagnose a particular type of leukemia and/or help in distinguishing from other subtypes. Also, the identification of specific antigens has prognostic and therapeutic relevance in acute leukemias. Moreover, FC immunophenotyping is useful to monitor response to therapy, recurrence and minimal residual disease.
While IHC and FC represent the standard of care in solid cancers and hematologic malignancies, respectively, some remarkable technological breakthroughs of the last 10 years have greatly contributed to improve cancer diagnostics through either the definition of “Omics profile” or the assessment of plasma-based cancer biomarkers:
The study of tumor genomes using high throughput profiling strategies including (but not limited to) DNA copy number, DNA methylation, and transcriptome and whole-genome sequencing—technologies that may collectively be defined as “omics”—has led to identifying genes and pathways deregulated in cancer, hence revealing those that may be useful for the detection and management of disease. In the near future, such discoveries will lead to the discovery of novel diagnostic, prognostic and predictive markers that will ultimately improve patient outcomes.
Besides ex vivo procedures (either on surgical/bioptic samples or blood), cancer diagnosis is mainly based on imaging procedures, such as computed tomography,magnetic resonance imaging and positron emission tomography. The advent of molecular imaging techniques has progressively allowed more accurate in vivo visualization of cancer, based on specific biological and pathological processes. Antibody-based imaging is of great utility since the combination of tumor specificity and different imaging methodologies might improve cancer diagnosis, monitoring and follow up [7, 8, 9, 10, 11]. The diagnostic imaging approaches currently used in cancer has been improved by the application of antibodies, thanks to the accuracy that allows antibodies to precisely identifying their targets. Some practical examples of mAbs recognizing cancer-specific biomarkers that are approved by the FDA and/or EMA and are currently used in the clinical setting have been described elsewhere [12]. Monoclonal antibodies (mAbs) have several features (big size, slow pharmacokinetics and blood clearance, not complete penetration and accumulation in tumor tissue) that can delay the time point for imaging. A different class of antibodies (single chain Fragment variable, scFv) might be useful to overcome such limitations and due to the possibility of conjugating the recombinant proteins with fluorescent dyes, scFv antibodies have been proposed for use in imaging applications, especially for cancer diagnostics [8, 11, 13].
An overview of the main ion channels and transporters expressed in different solid tumors is reported in Figure 1.
Schematic representation of the main ICTs expressed in solid tumors.
K+ channels are the class of ion channels mostly de-regulated in cancers. Among them, KCa 1.1 channels (also known as BK channels, encoded by the KCNMA1 gene) have shown a clinical relevance in breast (BC) and prostate cancer (PCa). In both tumor types, BK overexpression can be traced back to the amplification of the KCNMA1 gene located in 10q22: in BC, the amplification is restricted to invasive ductal tumors, and is associated with high stage, high grade and unfavorable prognosis [14]. In BC, KCa 1.1 positively correlates with the expression of estrogen receptors [15] and their levels are higher in BC metastatizing to brain [16]. In PCa, the KCNMA1 gene is frequently amplified in late-stage tumors [17] and can be considered a potential biomarker [18]. Another Ca2+-dependent K+ channel often overexpressed in human cancers is KCa3.1 (encoded by the KCNN4 gene). KCa3.1 channels are upregulated in BC, especially in high grade tumors [19], in pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) [20], in colorectal cancer (CRC) [21] as well as in small cell lung cancer (SCLC) [22]. While the clinical relevance of KCa3.1 was hypothesized in CRC [23], although not validated [24], KCNN4 hypomethylation turned out to be a negative prognostic factor in SCLC [22]. Kv channels are voltage-dependent K+ channels whose expression is often increased in cancer tissues [25]. For example, the expression of Kv 1.3 (KCNA3), markedly increased in PCa in samples with Gleason score of 5–6 (GS5–6), but significantly decreased in the GS8–9 group. This malignancy grade-dependent K+-channel expression pattern may provide a convenient marker to understand PCa progression level [26]. In PCa, Kv1.3 is mainly expressed in early stages of progression and down-regulated in high grade cancers [27]. Kv1.3 expression is lower in cancer compared with healthy pancreas. Kv1.3 downregulation could be traced back to promoter’s methylation and was associated with the presence of metastases [28]. K2P9.1 (KCNK9) belongs to the K2P family and genomic amplification of the gene was shown in a small fraction of BC [29]. K2P5.1 (KCNK5) is a member of the same family and it was shown to be induced by estrogens in ER-positive BC cells; for this reason, it might represent a therapeutic target for ER-positive BCs [30]. The amplification of the KCNK9 gene at the 8q23.4 locus justifies the over expression of K2P9.1 channels in BC. The overexpression of another K2p channel K2p 2.1 has been demonstrated in PCa and it was shown that it regulates cell proliferation [31]. The expression of inward rectifiers K+ channels, in particular Kir3.1 (KCNJ3) channels positively correlated with lymph node metastases in BC [32]. The voltage-gated K+ channels (VGKC) appear to exert a pleiotropic role in colorectal cancer. In primary human samples, the transcripts of KCNA3, KCNA5, KCNC1, KCNH1 [33, 34, 35], KCNH2 [36] and KCNK9 [37] have been detected. A relevant family of VGKC, whose most important members are Kv 10.1 and Kv 11.1 was shown to be highly represented in human cancers. Kv10.1 (KCNH1) was expressed in esophageal squamous cell carcinoma (ESCC) compared with the corresponding normal tissue, it was associated with depth of invasion and represented an independent negative prognostic factor [38].
Kv11.1 (KCNH2) channels are expressed in gastric cancer (GC) cell lines and primary GCs. In GC cell lines, they regulate tumor proliferation [39]. Consistently, treatment with Kv11.1 blockers, like cisapride, and siRNA impairs tumor growth [40, 41]. It was also shown that the mean survival time was shorter in Kv11.1 positive patients thus Kv11.1 expression was proposed as an independent prognostic factor. We also showed that Kv11.1 regulates VEGF-A secretion, with a pathway similar to the one described in CRC [42]. In vivo analyses of xenografts obtained with GC cells demonstrated that the treatment with Bevacizumab and Kv11.1 blockers dramatically reduces greatly tumor growth. Kv11.1 is highly expressed in primary CRC and is associated with invasive phenotype [36]; moreover, along with Glut-1 absence, it represents a negative prognostic factor in TNM I and II CRC [43]. Kv11.1 expression is associated with chemosensitivity for several anti-tumor agents (such as vincristine, paclitaxel and hydroxy-camptothecin, doxorubicin). Such chemosensitivity is modulated by erythromycin that is also capable which, to inhibit Kv11.1 current [44]. Kv11.1 also regulates lung cancer (LC) cell proliferation [45]. Kv11.1 is expressed in precancerous and neoplastic lesions of the esophagus and it is associated with malignant progression [46]. Kv11.1 channel expression represents a negative prognostic factor in terms of ESCC patients’ survival [47]. Kv11.1 are also expressed in PDAC cell lines and primary samples and it negatively affects patients’ prognosis [48].
Voltage-gated sodium channels (VGSC) were among the first channels to be demonstrated mis-expressed in BC and PCa. In particular, the predominant VGSC in BC is the “neonatal” splice variant of SCN5A (nNaV1.5), whose activity promotes metastatization [49, 50, 51]; consistently, the nNAv1.5 was up-regulated in metastatic BC samples [49, 50, 52]. On the whole, VGSC and in particular nNav1.5 could represent a good specific target for BC treatment. In CRC [53, 54, 55], the clinical relevance of Nav 1.5 expression was established by IHC in CRC samples with respect to healthy colon. VGSC regulates invasiveness and it was shown that SCNA5 gene modulates genes mediating, among others, cell migration and cell cycle control. Both nNav 1.5 and its “adult” counterpart are expressed in CRC and the local anesthetic Ropivacaine, blocks Nav 1.5 variants [56]. PCa show an aberrant expression of Nav1.7 (SCN9A), associated with a strong metastatic potential and its activity potentiates cell migration, crucial for the metastatic cascade [57]. Hence, Nav1.7 could represent a useful diagnostic marker [58]. A recent paper [59] showed that EGFR and Nav1.7 are expressed in NSCLC cells and that EGFR-mediated upregulation of SCN9A is necessary for the invasiveness of such cells. Nav1.7 has clinical relevance and might represent a novel target for therapy and/or a prognostic biomarker in NSCLC [59]. A recent multicenter study identified two single nucleotide polymorphisms of VGSC genes (SCN4A-rs2302237 and SCN10A-rs12632942) that were associated with oxaliplatin-induced peripheral neuropathy development [60].
Calcium signal remodeling is one of the common features of proliferating cells, including cancer. Indeed many functional studies have provided different calcium signaling that can modulate cell proliferation and resistance to apoptosis [61, 62, 63]. Voltage-gated calcium channels (VGCC) that are involved in the regulation of BC cell proliferation. CACNA2D3 gene (encoding the α2δ3 subunit of the voltage gated Ca2+ channel) is frequently up-regulated in BC, but in some metastatic cases, its expression is reduced [64]. The mechanisms of CACNA2D3 contribution to the metastatic process has not being clarified yet. One possible mechanism for the overexpression of some calcium permeable ion channels is through the involvement of hormone receptors, such as ERα. Examples are ORAI3 [65]. CACNA2D3, is frequently downregulated in primary BCs, as a result of methylation in CpG islands [64]. The influence of calcium channels in PCa has been known for over 30 years. Later research identified additional classes of channel proteins having an important regulatory role and affecting malignant transformation (reviewed in [66]). The expression of VGCC (mainly L-type) has been detected in the androgen-responsive LNCaP cells. In these cells Ca2+ currents are activated by androgens and mediate the androgen-induced effects [67]. Part of the Ca2+ effects depend on K+ channels stimulation, for example, KCa3.1 blocking inhibits the proliferation of PCa cells [67]. An aberrant methylation of CACNA2D1/3 gene (encoding the voltage-dependent calcium channel 2 subunit) was demonstrated in GC samples. CACNA2D3 methylation is associated with diffuse type GC and shorter survival [68]. ORAI1 and STIM1, belonging to the store operated calcium channels (SOC) family, are up-regulated in BC of the basal-like molecular subtype [69]. Moreover, another member of the same family, STIM2, is expressed at low levels in BC. Patients with high STIM1 and low STIM2 have unfavorable prognosis, suggesting that the SOC family has a role in aggressiveness and in the metastatic process [69]. ORAI3 has recently been associated with ER-positive BC [65] and could represent a novel target for ER-positive BCs [70].
TRP channels are non-selective cation channels that can be activated by different stimuli such as pH variations, temperature and pressure among others [71, 72]. Since TRP channels are involved in migration and invasiveness, they contribute to the metastatic process in different tumors [73]. Ca2+ influx through TRPCs also occurs and promotes either cell proliferation or apoptosis, depending on TRPC subtype. TRPC1 whose levels are high in BCs with low proliferation capacity, may not be the optimal target for therapies against aggressive BCs [74]. Significantly elevated (up to 200-fold) mRNA levels of TRPC6 were shown in BC samples compared with paired control samples [74, 75], but no correlations with clinico-pathological features emerged [74]. A similar behavior characterizes TRPC1, whose expression levels decrease during the progression of PCa from androgen-dependent to androgen-independent phase [75]. TRPC6 is overexpressed in ESCC with respect to normal esophageal tissue at both protein and mRNA levels [76]. A recent report evidenced correlations of TRPC6 with T and staging and an association between TRPC6 mRNA and poor prognosis [77]. TRPV6 is up-regulated in PgR and ER-negative BCs [78]. Basal-like BCs with high TRPV6 mRNA levels are associated with poor survival [79]. In vitro data suggest that TRPV6 may be a potential therapeutic target [79]. TRPV6 is highly expressed in PCa and are associated with the Gleason score and metastatisation [80]. The expression of TRPV4 is decreased by progesterone [81]. TRPM7 is highly expressed in BC, and such over expression is associated with poor prognosis in terms of distant metastasis- and recurrence-free survival [82]. In accordance with these observation, TRPM7 mRNA levels are higher in BC metastases with respect to primary tumors. Also, TRPM7 are overexpressed in pancreatic ductal adenocarcinomas and are associated with lymph node metastases [83]. TRPM7 mRNA and protein are also overexpressed in bladder cancer with respect to normal tissue and are associated with poor prognosis [84]. TRPA1 is overexpressed also in SCLC patients compared with NSCLC and since it is associated with SCLC patients’ survival representing a potential therapeutic target [85].
Anoctamin 1 (ANO1), the calcium-activated chloride channel, is highly expressed in BC cell lines and primary BCs [86] and the 11q13 region is frequently amplified in BC and it is associated with grading and unfavorable outcome [86].
ANO1 was also shown to play an important role in controlling PDAC cell proliferation [87]. It has been shown that chloride channel accessory 1 and 2 genes (CLCA1 and CLCA2) transcripts show widespread downregulation in CRC patients [88]. Therefore CLCA proteins could be tumor suppressors in CRC in analogy with what occurs in BC. CLC1 is expressed in GC cells where it impairs cell proliferation and stimulates apoptosis, invasion and migration in vitro [89]. CLC1 overexpression in primary GC correlates with clinico-pathological parameters (lymph node involvement, stage, lymphatic and perineural invasion) as well as with poor prognosis [90]. CLIC3 is not expressed in healthy pancreas while it is expressed in PanIN lesions [91] and in PDAC where it has a negative impact on patient survival.
The ligand-gated nicotinic acethylcholine receptors (nAChRs) are the channel type mostly studied in LC [92]. NSCLC shows altered expression of nicotinic subunits (mainly α1, α5 ανδ α7) compared with normal tissue. Moreover in NSCLC cells, nicotine has mitogenic effects of nicotine, mediated by α7-containing nAChRs [93]. Multiple genome-wide association studies (GWAS) have implicated the 15q25 nAChR gene cluster CHRNA5-A3-B4 in nicotine dependence and LC [94]. The expression of the CHRNA5 gene which encodes the α5-nAchR was increased in LC tissue and that the p.Asp398Asn polymorphism in the CHRNA5 gene is associated with LC risk [92] and altered receptor function [95]. Additionally, the p.Asp398Asn polymorphism may influence α5 (CHRNA5) expression as well [92]. A α5-nAChR/HIF-1α/VEGF axis exists in LC and is involved in nicotine-induced tumor cell proliferation. This fact suggests that α5-nAChR may serve as a potential anticancer target in nicotine-associated LC [96].
AQP1 is expressed in BC and positively correlates with grading, histology, CK14 expression, smooth muscle actin expression, basal-like group and poor outcome, whereas it has significant negative correlation with ER status [97]. AQP1, AQP3 and AQP5 are expressed in CRC cell lines. AQP1 and AQP5 are expressed the early steps of CRC progression but also in liver metastases [98]. Moreover, AQP5 expression is associated with grading, nodal involvement and TNM stage [99]. AQP5 is expressed at significant levels in Lauren’s intestinal type-GC, where it shows an apical localization [100], whereas AQP3 and AQP4 are not overexpressed in GC. Shen et al. [101] showed that both AQP3 and AQP5 were overexpressed in GC and were associated with lymph node involvement. Moreover, AQP3 expression was higher in well differentiated tumors. AQP3 is also over-expressed in primary CRC with respect to healthy tissue, and its expression is positively regulated by EGF and is associated with lymph node involvement, metastasis and differentiation [102]. AQP3 and AQP5 are expressed in ESCC, while absent in healthy esophagus [103, 104]: the presence of the two aquaporins is associated with clinico-pathological features and their co-expression represents an independent negative prognostic factor. A recent microarray-based study demonstrated that reduced AQP9 gene expression is related to absence of adjuvant chemotherapy response in CRC patients [38].
The monocarboxylate transporter SLC16A1 (encoded by the SLC16A1 gene) is associated to basal-like BC, high histological grade, CK5, CK14, vimentin and Ki67. AQP1 along with SLC16A1 were shown to be associated with tumor aggressiveness of BC [105]. The voltage-gated proton channel Hv1 (HVCN1) overexpression in metastatic BC is associated with progression and unfavorable outcome [106]. The same occurs in CRC in which it is associated also with tumor size, lymph node involvement and stage [107]. In stage CRC, a low expression of SLC7A1 (cationic amino-acid transporters-1, encoded by SLC7A1 gene) is associated with shorter metastases-free survival [108].
The sodium proton exchanger 1 (NHE1, SLC9A1) interacts with EGFR and is involved in PDAC cell invasiveness [109]. It was shown that the Glucose Transporter 1 (SLC2A1, GLUT1) is expressed in BE-derived tumors in the late events of tumor progression [110]. SLC2A1 expression described also occurs in ESCC, where it represents a marker of poor prognosis [111]. Moreover, SLC2A1 expression increased after radiotherapy in ESCC patients [112]. The apical sodium-dependent bile acid transporters (SLC10A2), which mediate bile acid transport [113], are not expressed in the normal squamous epithelium of the esophagus [114], whereas their expression increases in Barrett’s Esophagus, to decline in EA [115]. Divalent metal transporter1 (DMT1, SLC11A2) overexpression was associated with metastatization in EC [116]. One of the main causes of chemotherapy failure is drug efflux mediated by ATP-binding cassette transporters (ABC) [117]. It was recently shown that ABCG2 together with V-ATPase are overexpressed in ESCC and are associated with grading, TNM stage and metastatization. ABCB1 and ABCG2 are expressed in primary GC and GC cell lines [118] in which their expression is associated with tumor differentiation. ABCB1 expression is higher in diffuse type GC [119]. ABCG2 represents a target for a several chemotherapy drugs [120]: for example, cisplatin increases ABCG2 mRNA in vitro and this is associated with patients’ outcome [121]. In PDAC, ABCB4, ABCB11, ABCC1, ABCC3, ABCC5, ABCC10 and ABCG2 are up-regulated, while ABCA3, ABCC6, CFTR (ABCC7) and ABCC8 are down-regulated: such deregulation contributes to PDAC poor response to therapy [122]. The Solute Carrier transporters (SLC) is a family of transporters frequently deregulated in PDAC. SLC7A5 (the L-type aminoacid transporter 1) are overexpressed in PDAC and are associated with molecular and clinico-pathological features (such as Ki-67, p53, CD34, CD98, VEGF size, stage) and prognosis [122]. SLC22A3 and SLC22A18 are up-regulated in PDAC with respect to healthy pancreas while SLC22A1, SLC22A2, SLC22A11, SLC28A1, SLC28A3 and SLC29A1 are down-regulated [122]. In particular, SLC28A1 overexpression was associated with poor overall survival whereas SLC22A3 and SLC29A3 overexpression was observed in patients treated with Gemcitabine with longer overall survival. PC patients with low expression of SMCT1 (SLC5A8) have poorer survival with respect to patients with high SLC5A8 levels [123]. The human equilibrative nucleoside transporter 1 (SLC29A1) is associated to longer time to progression and it was shown that it could predict gemcitabine effects in non-resectable PDAC patients, if evaluated in samples obtained by fine-needle aspiration [124]. Different conclusions were drawn when analyzing SLC29A1 expression in patients treated with chemo-radiotherapy [125]. In GC, SLC7A5 overexpression was detected and it was found to be associated with clinico-pathological features such as size, lymph node involvement, TNM stage and local invasion [126]. SLC16A1 was found to be expressed both in healthy stomach and GC, and it could be hypothesized a role in gastric physiology for this transporter [119]. In metastatic GC, SLC16A3 is down-regulated [119] and is associated with intestinal type. 4F2hc (SLC3A2) was found to be over-expressed in GC cell lines and in primary GC, with no significant correlation with clinico-pathological features. Since the study was conducted on a small number of samples, it could not allow definitive conclusions [127].
As reported for solid tumors, a schematic overview of ion channels and transporters expressed in hematologic tumors is reported in Figure 2. Early evidence for the implication of K+ channels in leukemia cell proliferation was obtained in the myeloblastic leukemia cell line ML-1 [128]. In leukemias, it was shown that KCa3.1 might represent a useful target since its blockade impairs leukemic cells proliferation [129] while KCNN4 overexpression was detected in follicular lymphomas [130]. A significant Kv10.1 expression was detected in myelodysplastic syndromes, CML and almost half of a cohort of AML samples and blocking the channel results in the inhibition of both cell proliferation and migration. Smith and colleagues [131] carried out an extensive study of the K+ channel transcripts in primary lymphocytes, leukemias (B-cell CLL) and several leukemic cell lines and they found only Kv11.1 was significantly up-regulated. In AML cell lines (FLG 29.1, HL-60 and K562), it was shown that specific block of IKv11.1 led to G1 arrest and impaired their migration on fibronectin-containing ECM [132]. Kv11.1 was also overexpressed in circulating blasts from human AML, in which the block of the channel significantly decreased cell growth [132]. The hsloBK splice variant of gBK has been detected in gliomas [133] and the herg1b alternative transcript of Kv11.1 is overexpressed in human leukemias and neuroblastomas [134, 135]. TWIK-related spinal cord K+ (TRESK) channels, members of the double-pore domain K+ channel family, are expressed in Jurkat cells [136] that also express TRPV5 and TRPV6, which were also detected in K562 cells. TRP channels control Ca2+ homeostasis in the context of malignant transformation [137] and it was shown that of TRPV5/TRPV6-like channels’ activation mediate Ca2+ entry and the activation of Ca2+/Calmodulin-dependent kinase II in irradiated K562 cells [138].
Cartoon showing the main ICTs expressed in leukemias and lymphomas.
During the oxidative burst following activation of K562 cells non-selective cation channel TRPM2 are activated, thus activating SK4 KCa channels. In parallel, the voltage-gated Cl-channel ClC-3 is also activated. The overall effect is cell shrinkage because of the osmotic water loss determined KCl outflow [139, 140]. A similar volume-dependent regulation of leukemia cell apoptosis can be operated by volume-regulated chloride currents (VRCC). The volume-dependent regulatory mechanisms are accompanied by control of water levels suggesting it could represent an additional modulatory mechanism in the apoptotic cascade [141]. AQPs control osmotic fluxes in a variety of physiological conditions. For instance, AQP5 is overexpressed in CML cells, where it promotes cell proliferation and inhibits apoptosis, perhaps through an effect on cell volume control [142]. Expression of AQP5 increases in parallel with the development of resistance to imatinib mesylate [142].
Recently, an antibody directed to a cancer-related ion channel (the purinergic receptor P2X7) was introduced into the clinical settings: it is a polyclonal antibody targeting a conformational epitope of the non-functional channel and it is likely to be approved as a first-generation therapy. Antibodies targeting ORAI1 were obtained using U2OS cells overexpressing human ORAI1 as immunogens. One of such antibodies impaired cell proliferation of T lymphocytes in peripheral blood [143, 144]. In 2014, a method for the isolation of functional antibodies against Nav1.7 was published [145].
In a recent paper [146], an ICT molecular profile was defined for BC thus opening interesting perspectives in this field. In particular, the expression of 30 ion channel genes was shown to be associated with tumor grade. The authors were able of identifying a “IC30 gene signature” composed of 30 ion channel genes and demonstrated that IC30 might represent a prognostic biomarker predicting clinical outcome in BC, independently from clinical and pathological prognostic factors. The same approach was applied to LC and 37 ion channels genes were identified as differentially expressed in LC in comparison to healthy lung [147]. Moreover, 31 ion channel genes were identified as differentially expressed between lung adenocarcinoma and squamous-cell carcinoma samples, therefore the expression of such genes could be used for NSCLC molecular classification [147]. In NSCLC, it was shown that VDAC1 is an independent prognostic factor and it is associated with shorter overall survival [147]. VDAC1 was also found to be up-regulated in different types of carcinomas [148]. More recently, a paper describing gene expression profile in lymphomas demonstrated that KCNN4 and SLC2A1 genes are overexpressed in follicular lymphomas (FL) [130]. In particular, SLC2A1 was proposed to be the hub of a functional network, connecting channels and transporters in FL. Moreover, relapsed FL had 38 differentially expressed ICT genes, among which ATP9A, SLC2A1 and KCNN4 were under-expressed. In the same paper, it was shown that diffuse large B Cell lymphoma (DLBCL) have a completely different pattern of K+ channel encoding genes expression along with the overexpression of the fatty acid transporter-encoding gene SLC27A1.
The authors declare no conflict of interest.
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