Mannan-binding lectin in malignancy

Molecular Immunology 55 (2013) 16–21

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Review

Mannan-binding lectin in malignancy Anna S. Swierzko a , David C. Kilpatrick b , Maciej Cedzynski a,∗ a b

Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland Scottish National Blood Transfusion Service, National Science Laboratory, Ellen’s Glen Road, Edinburgh EH17 7QT, Scotland, UK

a r t i c l e

i n f o

Article history: Received 19 June 2012 Received in revised form 12 September 2012 Accepted 19 September 2012 Available online 11 October 2012 Keywords: Mannan-binding lectin MBL2 Innate immunity Cancer

a b s t r a c t Complement may play a dual role in cancer: it may contribute either to the development or to the inhibition of tumour growth. Its components may be candidate biomarkers facilitating the disease detection, its progress or effectiveness of therapy. Additionally, complement deficiencies may increase the risk of infections and contribute to the higher mortality, especially in patients undergoing aggressive chemotherapy. In this paper, possible cancer associations of one of the factors activating complement via the lectin pathway, mannan-binding lectin (MBL), are discussed. © 2012 Elsevier Ltd. All rights reserved.

1. Introduction

2. Synthesis of MBL and its multimers

Mannan-binding lectin (mannose-binding lectin, MBL), belongs to the collectin group of the C-type lectin family. Like other collectins, it possesses a cysteine-rich domain, a collagen-like triple helical region, a neck region and a carbohydrate recognition domain. The native MBL molecule is an oligomer, consisting of up to six identical subunits, each built up from three polypeptide chains. It is a pattern-recognition molecule (PRM), binding with high affinity to microbial polysaccharides or glycoconjugates rich in d-mannose, N-acetyl-d-glucosamine or l-fucose, acting as a first line defense factor in various infections. Under certain conditions, it may recognize endogenous ligands contributing to the clearance of apoptotic/necrotic cells, or taking part in autoimmune processes. It is moreover thought to contribute to anti-cancer immunity. MBL has opsonic activity and, in co-operation with MBL-associated serine proteases (MASPs), the ability to activate complement via the lectin pathway. The latter property is shared with another collectin, CL-11, and three (M-, L-, and H-) ficolins. MBL insufficiency is believed to be the most common human immunodeficiency, having numerous clinical associations (reviewed by Thiel and Gadjeva, 2009; Heitzeneder et al., 2012). A schematic overview of MBL activity, involving various innate immune mechanisms and factors is presented in Fig. 1.

The gene responsible for MBL synthesis (MBL2) is localized to chromosome 10 (10q11.2-11) (Hansen and Holmskov, 1998). It contains four exons: the first encoding a 5 -untranslated region, a cysteine-rich region and part of the collagen-like domain; the second encoding the remaining part of the collagen domain; the third, the neck region; and the fourth encoding the carbohydrate recognition domain and 3 -untranslated region (Madsen et al., 1995). Single-nucleotide polymorphisms (SNPs) in exon 1 are responsible for altered MBL serum concentration and its impaired function. The dominant alleles D, B, and C (collectively designated O), corresponding to mutations in codons 52, 54, and 57, respectively, are associated with lower MBL levels compared to the A wild-type allele. Polymorphisms in the promoter and untranslated region of exon 1 (H/L, Y/X, and P/Q at positions −550, −221, and +4, respectively) influence the gene expression level and thus the serum protein concentration (Madsen et al., 1995; Bernig et al., 2005). Homozygotes or compound heterozygotes containing variant alleles as well as LXPA/O heterozygotes are considered to be MBL deficient. The promoter and structural gene mutations are in strong linkage disequilibrium, resulting in a relatively small number of haplotypes. Nevertheless, there are 7 or perhaps 8 common haplotypes: HYPA, LYPA, LYQA, LXPA, HYPD, LYPB, LYQC and LYPD. Moreover, several rare haplotypes (mostly corresponding to synonymous nucleotide substitutions or being a result of recombination, as LYQB or HXPA) have been reported (Boldt et al., 2010). Bernig et al. (2005) suggested an influence of the 3 -end haplotype block (Ex4-1483T>C; Ex4-1067G>A; Ex4-901G>A; Ex4-710G>A) on

∗ Corresponding author. Tel.: +48 42 2723607; fax: +48 42 2723630. E-mail address: [email protected] (M. Cedzynski). 0161-5890/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molimm.2012.09.005

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MBL-MASP COMPLEX PATTERN RECOGNITION

OPSONISATION

COMPLEMENT ACTIVATION

BINDING TO CELL RECEPTORS

PRODUCTION OF ANAPHYLATOXINS

DIRECT LYSIS

PHAGOCYTOSIS

CHEMOTAXIS

INFLAMMATION

Fig. 1. A schematic overview of the activity of mannan-binding lectin, complexed with associated-serine proteases (MASP).

MBL serum concentration The common haplotypes TAAA, TGAA and CGGG were shown to be associated with high, medium and low MBL levels, respectively. 3. Human (or human-derived) cells as targets for mannan-binding lectin Mannan-binding lectin binds to numerous microorganisms and viruses (reviewed by Thiel and Gadjeva, 2009), via recognition of pathogen-associated molecular patterns (PAMPs), and contributes to their elimination. Additionally, in both physiological and pathological conditions MBL may recognize host cells with changed glycosylation of the surface structures. MBL was shown to bind to late apoptotic as well as necrotic cells, thus contributing to their clearance (Nauta et al., 2003). Recently Tomaiuolo et al. (2012) demonstrated MBL-dependent lysis of senescent fibroblasts. Interaction with the TLR4 receptor on the surface of monocytoid cells leads to the suppression of bacterial lipopolysaccharide-induced cytokine production. It is supposed that the target structures for MBL are both oligosaccharide and peptide portions of TLR4 (Wang et al., 2011). Ezekowitz et al. (1989) demonstrated binding of plasma-derived MBL to cells infected with HIV. Numerous authors have investigated the interaction of MBL with cancer cells. It is well-known that malignant transformation is accompanied by aberrant glycosylation of surface structures which may influence tumour invasion and metastasis (Hakomori, 2002). Binding of the MBL–MASP complex to glioma cells was found to be accompanied by complement activation (Fujita et al., 1995). Later, Muto et al. (1999, 2001) showed calcium-dependent MBL interaction with O-glycosylated surface structures of some cells of human colon adenocarcionoma lines. They suggested that overexpressed Lewis A and Lewis B antigens were MBL targets. Terada et al. (2005) observed an inhibition of MBL binding to human colorectal carcinoma SW1116 cells by the plant lectin, AAL. This led to the hypothesis that fucose rather than mannose-rich structures (like Lewis antigens) are involved. Indeed, MBL was shown to recognize tandem repeats of the Lea /Leb epitopes. Further, the same group (Kawasaki et al., 2009) provided evidence that MBL-ligand oligosaccharide (MLO) is attached to 110 kDa transmembrane glycoprotein CD26. An early report concerning the possible role of mannan-binding lectin in anti-cancer immunity or therapy was published by Ma et al. (1999). An injection of vaccinia virus carrying human wildtype MBL-specific cDNA (WT-MBL) into the tumour mass induced in athymic nude mice via subcutaneous injection of SW1116 cells,

resulted in local MBL synthesis leading to a marked reduction in the tumour size. Moreover, such a treatment prolonged the life span of tumour-bearing animals. Unexpectedly, mutant MBL with little ability to activate complement was almost equally effective. This cytotoxic property, by an unexplained mechanism, was called MBLdependent cell-mediated cytotoxicity (MDCC). Moreover, MBL was demonstrated to interact with meprins: membrane-bound or secreted, highly glycosylated zinc metalloproteases expressed in kidney and small intestinal epithelium, and up-regulated in cancer cells. MBL binding results in inhibition of the proteolytic activity of meprins and their ability to degrade the components of extracellular matrix (Hirano et al., 2005). 4. Mannan-binding lectin in oncology patients Complement may play a dual role in cancer: it may contribute either to the development or to the inhibition of tumour growth (Markiewski and Lambris, 2009). Complement components may be candidate biomarkers facilitating the disease detection, its progress or effectiveness of therapy. Additionally, complement deficiencies may increase the risk of infections and contribute to higher mortality, especially in patients undergoing aggressive chemotherapy. They may contribute to an enhanced susceptibility to infections with pathogens associated with cancer, as Helicobacter pylori, human papillomavirus or hepatitis viruses (not discussed in this review). 4.1. Alimentary tract malignancies Baccarelli et al. (2006) found a higher risk of stomach cancer associated with the H/H homozygous variant of the MBL2 gene promoter, compared to L/L genotype. Similar associations were found in the case of HYD haplotype (compared with HYA) as well as YA/D diplotype (against YA/YA). The highest risk (3.5-fold increase) of gastric cancer was connected to combined carriage of the HYD variant and homo- or heterozygous mutation of the IL-1ˇ gene, at position −511 (C>T). Similarly, Scudiero et al. (2006) found an increased frequency of HYPD allele in H. pylori-positive stomach cancer. No association with other MBL2 gene exon 1 mutations (B or C types), however, was found (Baccarelli et al., 2006; Scudiero et al., 2006). In contrast, Wang et al. (2008) found the MBL2 B allele to be more prevalent in younger (aged ≤65 years) patients as well as in those with an advanced disease stage. Eurich et al. (2011) found an association of the X variant with hepatocellular carcinoma (HCC) induced by hepatitis C virus

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(HCV) infection. In its carriers, larger tumour size and higher pretransplant ␣-fetoprotein (AFP) levels were noted. X/X homozygotes were, however, more frequently AFP-negative. Both X/X and Y/X genotypes were moreover significantly associated with bilobar tumour growth. Earlier, Segat et al. (2008) did not find any difference in the frequency of exon 1 mutations (B, C or D) in HCC patients in comparison to healthy subjects. In that study, various groups of patients were investigated (infected with HBV, HCV, coinfected with both or with no infection). Segat et al., however, did not analyse the Y/X dimorphism. As promoter X variant is in linkage disequilibrium with A variant of exon 1 (see Section 1), the results presented by Eurich et al. and Segat et al. are not necessarily discrepant. The proteomics and Western blot analysis of sera revealed upregulation of MBL in patients suffering from pancreatic cancer (Rong et al., 2010). Ytting et al. (2004, 2011) investigated serum MBL concentrations, MBL-dependent lectin pathway activity and MBL2 gene polymorphism in colorectal cancer. In their first report, they demonstrated both MBL level and its activity to be higher in patients than in controls, independently of age, sex, tumour location or disease stage according to Dukes’s classification. Moreover, no impact of genotype on patient survival, disease recurrence or incidence of post-operative infections was found. Numbers of MBLdeficient individuals (based on serum level or genotype) did not differ significantly between colorectal cancer patients and healthy persons (Ytting et al., 2005, 2011). Recently, Zanetti et al. (2012) reported an association of LYPA and LYQC haplotypes (as well as CGGT haplotype corresponding to 3 -end SNPs: Ex4-1483 T>C, Ex4901 A>G, Ex4-710 A>G and 3283 bp STP C>T) with an increased risk of colon cancer in African Americans, but not Caucasians. Since Ytting et al. investigated a Danish population, it may be supposed that their results are not inconsistent with these published by Zanetti et al. 4.2. Gynaecological malignancies Although Guimaraes et al. (2008) as well as Segat et al. (2009) found an association between MBL2 gene functional polymorphisms and risk of HPV infection, no effect on incidence of uterine cervical cancer was observed. Swierzko et al. (2007) demonstrated a higher incidence of both exon 1 mutations (O/O and A/O genotypes) and XA/XA promoter region variant in ovarian cancer patients in comparison with the control group. Additionally, the serum MBL levels and MBL–MASP2 complex activities were significantly higher in women with cancer carrying MBL-sufficient genotypes (YA/YA, YA/XA) than in corresponding controls. Moreover, MBL2-specific mRNA was detected in both normal as well in malignant ovaries. Similarly, Nevadunsky et al. (2012) reported that the MBL2 B variant and accompanying low local (vaginal) MBL concentrations may be risk factors for ovarian cancer. In Afro-American women (but not in Caucasians), a 3 -end block haplotype TATAAC (corresponding to SNPs: Ex4-1483 T>C, Ex41067 G>A, Ex4-1047 T>C, Ex4-901 G>A, Ex4-710 A>G, 3238 bp 3 STP C>T) was postulated to be protective against breast cancer Bernig et al. (2007). Thus, as with colon cancer, ethnic background might be important. 4.3. Lung cancer Similarly, in lung cancer, a possible protective effect of certain MBL2 gene variants seems to depend on ethnicity. Pine et al. (2007) found improved survival among Caucasian (but not AfricanAmerican) patients carrying the X allele. Such associations were apparent for X/X and Y/X genotypes (compared to Y/Y) as well

as the XA haplotype and the XA/B variant. The influence of the X allele was strongest in heavy smokers (more than 64.8 pack-years), independently of age, sex, disease stage, weight loss, tumour grade or histological subtype. Moreover, no association with chronic obstructive pulmonary disease, or risk of cardiac- or sepsis-related death was noticed. The authors hypothesized that the tumour may be less aggressive due to a weaker inflammatory reaction in its environment, related to low MBL. Olivo-Marston et al. (2009), taking into account two independent case–control studies, found that the HYPA haplotype (associated with the highest MBL concentration/activity) is a risk factor for lung cancer development in never-smokers exposed to second hand smoke during childhood). In contrast, the low MBL-associated LYQC variant appeared to be protective. Interestingly, Maffei et al. (2005) reported significantly higher MBL concentrations in heavy smokers (more than 10 cigarettes per day) in comparison with non-smokers and light smokers. On the other hand, Hodge et al. (2010) (although presenting data from an animal model), postulated therapeutic benefit from MBL in smoking-related lung inflammation. 4.4. Other malignancies Schmiegelow et al. (2002), reported MBL2-deficient genotypes (XA/O and O/O) to be a risk factor for childhood acute lymphoblastic leukaemia (ALL), especially with early age at onset. Recently, Fisch et al. (2011) did not observe significant differences in MBL concentrations in children with ALL, acute myeloid leukaemia (AML), Hodgkin’s disease, non-Hodgkin lymphoma or tumours of the central nervous system (CNS) compared to age-matched controls. In contrast, median MBL levels were significantly higher in patients with solid tumours outside the CNS. 4.5. Chemotherapy- or post-surgery-related complications MBL as a first-line defense antimicrobial factor has been considered in the context of chemotherapy-related infections in both paediatric and adult patients. More than decade ago, Neth et al. (2001) found that the duration of febrile neutropenic (FN) episodes in children with cancer is longer in carriers of MBL2 gene exon 1 mutation (O variants), compared to wild-type homozygotes. Moreover, patients with lower (<1 ␮g/ml) protein levels had a higher number of days with febrile neutropenia. Recently, Ghazi et al. (2012) confirmed such a cut-off level to be associated with the risk of infection. In contrast, Schlapbach et al. (2007) reported that children with cancer and normal serum MBL concentration (>1 ␮g/ml) had more frequent FN episodes than those with moderately low levels. However, MBL-deficient (<100 ng/ml) patients much more frequently experienced FN associated with severe bacterial infections. Frakking et al. (2011a) observed shorter eventfree survival in MBL-deficient (concentration <200 ng/ml) children with malignancies. They suggested also that low MBL may be associated with increased disease severity in paediatric intensive care units for the reason of FN (in the absence of microbiological findings). Moreover, higher MBL levels were found in A/A genotype-carrying patients, compared to controls. Earlier, the same group (Frakking et al., 2006) did not note more frequent infections among MBL-deficient paediatric oncology patients, however the majority of them were severely neutropenic. On the other hand, MBL-sufficient children with cancer were more commonly admitted to the intensive care unit. In several reports (Lehrnbecher et al., 1999; Laursen et al., 2006; Rubnitz et al., 2008), a lack of association of MBL deficiency (defined by genotype or serum concentration) with chemotherapy-related infections in children with haematological malignancies was reported. Therefore, the role of MBL in susceptibility to infection during anti-cancer chemotherapy is still controversial. Although MBL substitution therapy may

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Table 1 Associations of mannan-binding lectin and MBL2 gene polymorphism with cancer. Disease

Gastric cancer

Parameter

Postulated clinical associations

Population; number of cases/controls

References

H/H promoter variant HYD haplotype YA/D genotype HYD haplotype

Increased risk

Polish 305 cases/405 controls

Baccarelli et al. (2006)

Higher frequency in H. pylori-positive patients Higher prevalence in patients aged ≤65 years

Italian 145 cases/553 controls Japanese 388 cases/144 controls

Scudiero et al. (2006) Wang et al. (2008)

B allele Hepatic cancer

X promoter haplotype

Larger tumour size

European 177 patients with HCV-induced liver disease, including 62 with and 115 without carcinoma

Eurich et al. (2011)

Pancreatic cancer

Serum MBL

Up-regulation in patients

Chinese 5 cases/5 controls

Rong et al. (2010)

Colon/colorectal cancer

MBL concentration MBL–MASP-2 activity

Higher in patients

Ytting et al. (2004 (a), 2011 (b))

LYPA and LYQC haplotypes CGGT haplotype (3 -end)a

Increased risk

Danish 193 cases/150 controls (a) 593 cases/348 controls (b) African-American 103 cases/201 controls

A/O and O/O genotypes X/X promoter variant B allele low vaginal MBL concentration

Higher frequency in patients Increased risk

Polish 117 cases/87 controls Ethnicity not stated 70 cases/126 controls

Swierzko et al. (2007) Nevadunsky et al. (2012)

TATAAC haplotype (3 -end)a

Protection

African-American 166 cases/180 controls

Bernig et al. (2007)

X promoter haplotype

Improved survival

Pine et al. (2007)

HYPA haplotype LYQC haplotype

Risk factor in never-smokers protection in never-smokers

Caucasian-American 558 cases American 624 cases/348 controls

XA/O and O/O genotypes

Risk factor in children

Ovarian cancer

Breast cancer

Lung cancer

Acute lymphoblastic leukaemia

a

Mixed (mainly Danish Caucasians) 137 cases/250 controls

Zanetti et al. (2012)

Olivo-Marston et al. (2009) Schmiegelow et al. (2002)

Details in text.

be beneficial in paediatric oncology patients (Neth et al., 2001; Frakking et al., 2009), its usefulness has to be established. As it was recently suggested by Frakking et al. (2011b) in a comprehensive review, the contradictory results may arise from the heterogeneity of investigated groups, differences in numbers of patients recruited, chemotherapy regimens, definitions of outcome and MBL deficiency as well as in the length of the follow-up. Similarly, discrepant results were published from adult cancer patients. Peterslund et al. (2001) found an association of low (<500 ng/ml) MBL levels and risk of severe infections in patients undergoing chemotherapy due to haematological malignancies. Later, Kilpatrick et al. (2003) noted more major infections only when MBL serum concentration did not exceed 100 ng/ml. These results seemed to be confirmed by Vekemans et al. (2007) who found commoner severe infections (although not infections in general or more prolonged FN episodes) in MBL-deficient patients. An association of LXA/B and B/B genotypes was found to be associated with major bacterial infections in patients receiving high-dose chemotherapy and autologous stem cell transplantation (Horiuchi et al., 2005). Moreover, Molle et al. (2006a,b) reported a significantly lower risk of developing septicaemia in multiple myeloma patients bearing A/A genotypes. Regarding solid tumours, Ytting et al. (2005) and Svendsen et al. (2006) suggested that low pre-operative MBL levels in patients suffering from colorectal cancer are predictive of pneumonia and thus

connected to poor survival. However, Van der Bol et al. (2010) found high MBL-producing haplo- and diplotypes in patients with various solid tumours treated with irinotecan to be associated with higher risk of febrile neutropenia. Such a finding was particularly evident in HYA/HYA and HYA/LYA homo-/heterozygotes. Recently, successful treatment with MBL replacement has been reported in a case of healing of radiotherapy-induced chronic ulcer after mastectomy and plastic surgery due to breast cancer (Maaloe et al., 2011). In several reports, a lack of impact of MBL deficiency on incidence of febrile neutropenia or infections during anti-cancer chemotherapy was found (Bergmann et al., 2003; Martinez-Lopez et al., 2009; Klostergaard et al., 2010; Wong et al., 2012). 5. Final remarks As reviewed, MBL may play various roles, depending on the type of cancer, age or ethnicity of patients (summarized in Table 1) as well as mode of treatment. There are some possible indications for replacement therapy in deficient patients, and paradoxically, suggestions that MBL deficiency might be beneficial. Therefore, as proposed by Frakking et al. (2011a), multicentre studies with precisely defined groups, treatment regimens, follow-up periods and methods for determining MBL levels and MBL2 genotypes are necessary.

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