key: cord-254549-ev0oesu0
authors: Kutikhin, Anton G; Yuzhalin, Arseniy E
title: C-type lectin receptors and RIG-I-like receptors: new points on the oncogenomics map
date: 2012-02-24
journal: Cancer Manag Res
DOI: 10.2147/cmar.s28983
sha: 
doc_id: 254549
cord_uid: ev0oesu0

The group of pattern recognition receptors includes families of Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors. They are key sensors for a number of infectious agents, some of which are oncogenic, and they launch an immune response against them, normally promoting their eradication. Inherited variations in genes encoding these receptors and proteins and their signaling pathways may affect their function, possibly modulating cancer risk and features of cancer progression. There are numerous studies investigating the association of single nucleotide polymorphisms within or near genes encoding Toll-like receptors and NOD-like receptors, cancer risk, and features of cancer progression. However, there is an almost total absence of articles analyzing the correlation between polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk or progression. Nevertheless, there is some evidence supporting the hypothesis that inherited C-type lectin receptor and RIG-I-like receptor variants can be associated with increased cancer risk. Certain C-type lectin receptors and RIG-I-like receptors recognize pathogen-associated molecular patterns of potentially oncogenic infectious agents, and certain polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors may have functional consequences at the molecular level that can lead to association of such single nucleotide polymorphisms with risk or progression of some diseases that may modulate cancer risk, so these gene polymorphisms may affect cancer risk indirectly. Polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors thereby may be correlated with a risk of lung, oral, esophageal, gastric, colorectal, and liver cancer, as well as nasopharyngeal carcinoma, glioblastoma, multiple myeloma, and lymphoma. The list of the most promising polymorphisms for oncogenomic investigations may include rs1926736, rs2478577, rs2437257, rs691005, rs2287886, rs735239, rs4804803, rs16910526, rs36055726, rs11795404, and rs10813831.

of reactive oxygen species, pyroptosis, angiogenesis, and, consequently, tissue remodeling and repair. [1] [2] [3] [4] There are four main groups of pattern recognition receptors, ie, Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors, and genes encoding them are broadly expressed, eg, in epithelial cells, endothelial cells, keratinocytes, lymphocytes, granulocytes, fibroblasts, and neurons. [1] [2] [3] [4] A summary of the most modern conceptual data about members of these groups and about their structure and function can be obtained from recent comprehensive reviews by Kawai and Akira, 1 Elinav et al, 2 Osorio et al, 3 and Loo and Gale. 4 The completion of the human genome project and widespread distribution of genotyping technologies have led to an enormous number of studies devoted to associating inherited gene polymorphisms with various diseases. Single nucleotide polymorphisms may result in amino acid substitutions altering protein function or splicing, and they can also change the structure of enhancer sequences during splicing 5 and affect mRNA stability. 6 Single nucleotide polymorphisms may alter transcription factor binding motifs, change the efficacy of enhancer or repressor elements, 7 and alter the structure of translation initiation codons that may lead to downregulation of wild-type transcripts. 8 Gene polymorphisms located in leucine-rich repeats constituting ectodomains of many pattern recognition receptors may affect the ability of these receptors to bind pathogens they normally recognize, 9 single nucleotide polymorphisms in transmembrane domains can lead to defects of intracellular receptor transport that prevent receptors localizing to the cell membrane, 10 and, finally, polymorphisms in the cytosolic domains may result in altered interactions with adaptor proteins or in disrupted receptor dimerization. Therefore, there are many avenues by which single nucleotide polymorphisms may alter pattern recognition receptor expression and activity. Because pattern recognition receptors recognize a number of oncogenic infectious agents and launch an immune response against them, inherited variation in their structure may modulate cancer risk and, possibly, influence cancer progression. In addition, pattern recognition receptors bind a lot of endogenous ligands, 1-4 so polymorphisms of genes encoding them can affect risk and/or progression of some autoimmune disorders and, consequently, cancer risk and/or progression, given that there is a fundamental and epidemiological association between many autoimmune diseases and cancer risk.

Although there are a lot of studies investigating the association between single nucleotide polymorphisms in genes encoding Toll-like receptors and NOD-like receptors and the risk and features of cancer progression, there is an almost complete absence of articles analyzing the correlation between polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk or progression. This can be explained by the fact that the first wave of studies devoted to the association of polymorphisms of genes encoding Toll-like receptors and NOD-like receptors with cancer risk appeared only in 2004, and the number of such papers was relatively small until 2008. In addition, known hypotheses about the infectious agents causing human cancer and their recognition by pattern recognition receptors suggested that Toll-like receptors and NOD-like receptors should play a major role in the immune response against biological carcinogens. However, more recent findings concerning specific potentially carcinogenic ligands of C-type lectin receptors and RIG-I-like receptors were only obtained in the last few years, 3,4 so there has not been enough time as yet to conduct comprehensive investigations between single nucleotide polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk.

However, there is some evidence supporting the hypothesis that inherited features of C-type lectin receptor and RIG-I-like receptor structure can be associated with increased cancer risk.

Certain C-type lectin receptors and RIG-I-like receptors recognize PAMPs of oncogenic infectious agents. 3, 4, 11, 12 C-type lectin receptors: On the basis of known associations between inherited structural variations in Toll-like receptors and NOD-like receptors and cancer risk, 1,2 and according to data about cancer types caused by carcinogenic infectious agents, 11, 12 it is possible to suggest that risk of lung cancer may be modulated by polymorphisms of the MRC1, CD209, CLEC7A, CLEC6A, and CLEC4E genes, oral cancer risk by single nucleotide polymorphisms of the MRC1, CD207, CD209, CLEC6A, and CLEC4E genes, risk of glioblastoma and colorectal cancer by polymorphisms of the CD209 gene, hepatocellular carcinoma risk by polymorphisms of the CD209 and RIG-I genes, and risk of lymphoma, multiple myeloma, nasopharyngeal carcinoma, and esophageal and gastric cancer by single nucleotide polymorphisms of the RIG-I gene. In addition, single nucleotide polymorphisms of MRC1, CD207, LY75, CD209, CLEC1B, and CLEC4A genes may correlate with cancer types associated with HIV-1 infection.

Certain polymorphisms of genes indicated above may have functional consequences on the molecular level that can lead to association of such single nucleotide polymorphisms with risk or progression of some diseases that may modulate cancer risk, so these gene polymorphisms may affect cancer risk indirectly. In addition, polymorphisms of these genes correlating with diseases that are not related to cancer risk may also be useful in oncogenomics because they may have functional consequences at the molecular level as well, although they have not been investigated in relation to association with cancer risk or progression.

For instance, it was suggested that variant alleles of MRC1 rs2477637, rs2253120, rs2477664, rs692527, rs1926736, and rs691005 gene polymorphisms are associated with development of asthma 13 (eg, variant A allele of rs1926736 was connected with decreased asthma risk). In addition, Alter et al 14 found that the variant A allele (S396) of rs1926736 (G396S) polymorphism is associated with a lower leprosy risk and, conversely, G allele (G396) correlates with increased risk of this disease. Interestingly, G396 did not influence leprosy risk in combination with T399 and L407 (amino acids resulting from variant alleles of rs2478577 and rs2437257, respectively). 14 The authors noted that all three of these MRC1 gene single nucleotide polymorphisms map to the second C-type lectin domain (CTLD2) of the MRC1 protein, with their in vitro results suggesting that a direct interaction between CTLD2 and an accessory receptor molecule is necessary in order for microbial ligand recognition to occur. 14 It is logical to propose that such interaction would be sensitive to G396 only in the context of the A399-F407 haplotype, and not in the context of the T399-L407 haplotype. 14 Thus, rs1926736 may have substantial functional consequences at the molecular level, but this depends on its relationship with other single nucleotide polymorphisms in the same exon. Finally, Hattori et al 15 showed that a variant allele of rs691005 polymorphism, located within the 3′ untranslated region of the MRC1 gene, is associated with a higher risk of sarcoidosis. Because of its location, it is feasible that this single nucleotide polymorphism may alter the regulatory binding sequence and influence mRNA expression. 15 The only study investigating the association of polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors with cancer risk is a study by Xu et al. 16 They investigated single nucleotide polymorphisms of the CD209 gene and found that the GG genotype of the rs2287886, AA genotype of the −939 promoter polymorphism, and the G allele of the rs735239 single nucleotide polymorphism were connected with higher nasopharyngeal carcinoma risk. 16 Polymorphisms in the promoter of the CD209 gene and in the CD209 gene were also associated with hemorrhage in patients with dengue fever (G allele of rs4804803), 17,18 modulated tuberculosis risk (G allele of rs4804803, A allele of rs735239), [19] [20] [21] higher celiac disease risk in HLA-DQ2-negative cases (G allele of rs4804803), 22 increased ulcerative colitis risk in HLA-DR3-positive patients (G allele of rs4804803), 23 higher susceptibility to cytomegalovirus infection (G allele of rs735240 and C allele of rs2287886), 24 protection from lung cavitation 20 and fever during tuberculosis 25 (GG genotype and G allele of rs4804803), decreased HIV-1 infection risk (GG genotype of rs4804803), 21 accelerated progression to acquired immune deficiency syndrome in HIV-1-infected hemophiliacs (C allele of rs2287886), 26 decreased human T-lymphotropic virus type I infection risk (G allele of rs4804803, A allele of rs2287886), 27 increased severity of liver disease during hepatitis C virus infection (G allele of rs4804803), 28 and better prognosis following severe acute respiratory syndrome (G allele of rs4804803). 29, 30 It was shown that the A allele of the rs4804803 single nucleotide polymorphism may increase gene expression in vitro, 17 expression in subjects with the G allele may result in an impaired immune response against hepatitis C virus, 28 M. tuberculosis, 19, 21 and bacteria potentially causing celiac disease 22 and ulcerative colitis, 23 that elevates the risk of diseases caused by these infectious agents. Such a decreased immune response may protect from hemorrhage during dengue fever, 17 from lung cavitation, 20 from fever during tuberculosis, 25 and from lung injury during severe acute respiratory syndrome 29,30 as a result of less cytokine production and diminished activation of immune cells. However, from the point of view of Vannberg et al, 20 conversely, lower CD209 gene expression as a consequence of G allele of rs4804803 polymorphism may protect against tuberculosis because of decreased production of proinflammatory cytokines such as interleukin-4. Further fundamental, translational, and clinical studies are necessary to clarify these discrepancies. Nevertheless, although there are a number of reasons for the discrepancies between studies devoted to the association between CD209 single nucleotide polymorphisms and development of tuberculosis, but confounding host, bacterial, and submit your manuscript | www.dovepress.com Dovepress Dovepress environmental factors between different study populations should be taken into account. In addition, Mezger et al 24 demonstrated that alleles of rs735240 and rs2287886 polymorphisms may also influence CD209 gene expression and thus affect transcription factor binding. In relation to the CLEC7A (Dectin-1) gene, it was also found that a variant allele of rs16910526 polymorphism is associated with impaired cytokine production by macrophages 31, 32 and with a defective response to Aspergillus and Candida invasion. 33, 34 The variant S form of I223S polymorphism was characterized by a lower capacity of the receptor to bind zymosan. 35 Among polymorphisms of genes encoding RIG-Ilike receptors, RIG-I single nucleotide polymorphisms are the most investigated. Pothlichet et al 36 conducted a comprehensive study investigating the functional consequences of rs36055726 (P229fs) and rs11795404 (S183I) polymorphisms. They found that the variant allele of rs36055726 results in a truncated constitutively active RIG-I (that leads to permanent production of proinflammatory mediators, particularly antiviral), and, conversely, the variant allele of rs11795404 induces an abortive conformation of RIG-I, causing formation of unintended stable complexes between CARD modules of RIG-I and between RIG-I and its downstream adapter protein, MAVS, rendering RIG-I incapable of downstream signaling and further cytokine synthesis. 36 Moreover, Shigemoto et al identified a variant of rs11795404 as a loss-of-function allele. 37 Ovsyannikova et al 38, 39 showed that a minor allele of rs10813831 polymorphism is associated with a decrease in the rubella virus-specific granulocyte-macrophage colony-stimulating factor/interleukin-6/IgG response, whilst a variant allele of rs3824456 is connected with an increase in the rubella virusspecific tumor necrosis factor alpha response, and a variant allele of rs669260 correlates with an increase in the rubellaspecific antibody level. Hu et al 40 discovered that a variant allele of rs10813831 polymorphism leads to increased gene expression and, consequently, cytokine production due to an amino acid substitution in the CARD domain of RIG-I that results in functional alteration of this RIG-I-like receptor.

There are also a lot of studies investigating the role of IFIH1/MDA5 (the gene encoding MDA5 protein that is also a RIG-I-like receptor) single nucleotide polymorphisms in the etiology of autoimmune diseases, but almost all of them are devoted to type 1 diabetes and multiple sclerosis, and data about the association of these diseases with cancer risk are conflicting, in that some studies showed an increased risk in patients with type 1 diabetes and multiple sclerosis, 41, 42 and in other investigations no connection or decreased risk of cancer has been observed. [43] [44] [45] [46] [47] [48] [49] Taking into account that there are no carcinogenic infectious agents recognizing MDA5, it does not seem to be prudent to investigate IFIH1/MDA5 gene polymorphisms from the oncogenomic point of view. In addition, polymorphisms of genes coding for components of the Toll-like receptor signaling pathway may modulate cancer risk as single nucleotide polymorphisms of the TLR gene family. 1 The same statement can be true for C-type lectin receptor and RIG-I-like receptor signaling pathways. For instance, a variant allele of rs11905552, encoding MAVS/ VISA/IPS-1, a key downstream signaling molecule of RIG-I and MDA5, was associated with a particular systemic lupus erythematosus phenotype. 50 It was found that this single nucleotide polymorphism leads to reduced production of type I interferon and other proinflammatory mediators, and also to the absence of anti-RNA-binding protein autoantibodies. 50 In addition, variant alleles of rs17857295 and rs2326369 polymorphisms of the MAVS/VISA/IPS-1 gene were associated with nephritis and arthritis in patients suffering from systemic lupus erythematosus. 51 A variant allele of another single nucleotide polymorphism of this gene, rs7269320, showed associations with different clinical characteristics of this autoimmune disease. 51 All the population case-control studies mentioned above are summarized in Table 1 .

All polymorphisms of genes encoding C-type lectin receptors, RIG-I-like receptors, and proteins of their specific signaling pathways that have known functional consequences and may be relevant to oncogenomics are summarized in Table 2 . The fundamental basis for the association of the inherited coding variation in genes encoding C-type lectin receptors and RIG-I-like receptors with cancer is represented by the defects in the immune response (that are caused by various single nucleotide polymorphisms) against specific carcinogenic infectious agents. Some polymorphisms may be valued as the most promising for further oncogenomic investigations on the basis of their association with cancer risk or because of their substantial functional consequences on the molecular level according to the following concept:

Gene polymorphism may be included on the short list for further oncogenomic studies if: • The single nucleotide polymorphism leads to substantial functional consequences at the molecular level (for instance, it strongly affects transcription, splicing, translation, stability and transport of pre-mRNA, mRNA, noncoding RNA, or protein encoding by the gene, or it noticeably influences signaling of synthesized protein) • It is associated with risk of cancer in population studies • It has functional consequences at the molecular level and it is strongly associated with a condition that significantly increases the risk of cancer (threshold may vary for each cancer type) The gene polymorphism can be also included on the extended list if: • It is characterized by more subtle functional alterations in a gene that, nonetheless, result in qualitative or quantitative alterations of the encoding protein (or noncoding RNA) • It is associated with a condition that substantially increases the risk of cancer but has not specifically been identified to increase the risk of cancer. According to this concept, the indicated short list of polymorphisms includes rs1926736, rs2478577, rs2437257, rs691005 (all located in the MRC1 gene), rs2287886, -939 promoter polymorphism, rs735239, rs735240, rs4804803 (all located in the CD209 gene), rs16910526 (CLEC7A gene), and rs36055726, rs11795404, rs10813831 (all located in the RIG-I gene). Other polymorphisms mentioned in this article may be added to the extended list for further investigations. Polymorphisms with known functional effects (rs1926736, rs2437257, rs691005, rs2287886, rs735240, rs4804803, rs16910526) were associated with relatively significant modulation of risk of diseases (as shown in Table 1 ) which is logical and demonstrates the correctness of the studies in which functional consequences of such single nucleotide polymorphisms were analyzed. There are still no comprehensive functional investigations for other single nucleotide polymorphisms correlated with risk of disease, so it is difficult to conclude which of them have independent significance, and which of them are just in linkage disequilibrium with truly functional variants.

In addition, PAMPs of specific infectious agents recognized by each C-type lectin receptor or RIG-I-like receptor define cancer types which can be primarily associated with inherited structural variation in the receptors discussed earlier. Furthermore, if a single nucleotide polymorphism of a gene encoding a specific C-type lectin receptor or RIG-I-like receptor is associated with risk or progression features of certain malignancies, polymorphisms in genes encoding specific signaling molecules constituting pathways of these receptors should correlate with similar neoplasms, if they have substantial functional consequences at the molecular level. The issue of an association of single nucleotide polymorphisms of genes encoding C-type lectin receptors, RIG-I-like receptors, and proteins of pattern recognition receptor pathways with various features of cancer progression is open, and only further population studies would be likely to give a definite answer. submit your manuscript | www.dovepress.com

Reasons for discrepancies in different investigations analyzing the association of polymorphisms in genes encoding C-type lectin receptors, RIG-I-like receptors, and the proteins of their signaling pathways with various aspects of cancer development may include confounding host, bacterial, or environmental factors in different ethnicities modulating penetrance of variant alleles and affecting the risk of conditions increasing cancer risk (such as autoimmune diseases, precancerous gastric lesions, tuberculosis, recurrent pneumonia), different bacterial impact on the etiology of such conditions in different populations (that will be reflected in different features of C-type lectin receptor/ RIG-I-like receptor-mediated immune response because of specific C-type lectin receptor/RIG-I-like receptor-ligand interaction), differences in sample size, in clinicopathological characteristics between study samples, in prevalence of infectious agents in case and control groups, diagnostics, stratification, genotyping methods, and chance.

Another interesting issue is that associations between single nucleotide polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk can be skewed by differences between cohorts in various immune responses and infections that may not influence cancer development. The problem is that the design in an epidemiological study having a large sample is very seldom ideal. Stratification by status of chronic infection is rather difficult because of their extreme diversity and because of the very high cost of such testing. Stratification by an immune response is even more complex because of innumerable peculiarities in functioning of the immune system. Therefore, if the study has a perfect funding source, stratification by infection status can be possible, but stratification by immune response status will be far from ideal.

Unfortunately, to the best of the authors' knowledge, no genome-wide association studies of the connection between polymorphisms of genes encoding the C-type lectin receptor and RIG-I-like receptors and cancer risk or progression have been performed, and this can be explained by the relative newness of the problem or perhaps by another unknown reason.

Summing up, polymorphisms of genes encoding C-type lectin receptors, RIG-I-like receptors, and proteins of their signaling pathways may be promising targets for oncogenomics and possibly could be used in programs of cancer prevention and early cancer diagnostics in the future. Population and further fundamental studies devoted to their association with cancer risk of progression should shed light on this issue.

The authors report no conflicts of interest in this work.

Toll-like receptors and their crosstalk with other innate receptors in infection and immunity

Regulation of the antimicrobial response by NLR proteins

Myeloid C-type lectin receptors in pathogen recognition and host defense

Immune signaling by RIG-I-like receptors

Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression

Plasminogen activator inhibitor type 2 contains mRNA instability elements within exon 4 of the coding region. Sequence homology to coding region instability determinants in other mRNAs

Single nucleotide polymorphism in 5′-flanking region reduces transcription of surfactant protein B gene in H441 cells

C/T polymorphism in the 5′ untranslated region of the apolipoprotein(a) gene introduces an upstream ATG and reduces in vitro translation

Leucine-rich repeats and pathogen recognition in toll-like receptors

Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy

Role of bacteria in oncogenesis

Infections and cancer: established associations and new hypotheses

Genetic variants in the mannose receptor gene (MRC1) are associated with asthma in two independent populations

Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis

Sequencing of DC-SIGN promoter indicates an association between promoter variation and risk of nasopharyngeal carcinoma in cantonese

A variant in the CD209 promoter is associated with severity of dengue disease

DC-SIGN (CD209) Promoter -336 A/G polymorphism is associated with dengue hemorrhagic fever and correlated to DC-SIGN expression and immune augmentation

Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis

CD209 genetic polymorphism and tuberculosis disease

CD209 gene polymorphisms in South Indian HIV and HIV-TB patients

A functional variant in the CD209 promoter is associated with DQ2-negative celiac disease in the Spanish population

CD209 in inflammatory bowel disease: a case-control study in the Spanish population

Investigation of promoter variations in dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) (CD209) and their relevance for human cytomegalovirus reactivation and disease after allogeneic stem-cell transplantation

Relationship between polymorphism of DC-SIGN (CD209) gene and the susceptibility to pulmonary tuberculosis in an eastern Chinese population

RANTES -28G delays and DC-SIGN -139C enhances AIDS progression in HIV type 1-infected Japanese hemophiliacs

DC-SIGN (CD209) gene promoter polymorphisms in a Brazilian population and their association with human T-cell lymphotropic virus type 1 infection

Variant in CD209 promoter is associated with severity of liver disease in chronic hepatitis C virus infection

DC-SIGN) -336 A . G promoter polymorphism and severe acute respiratory syndrome in Hong Kong Chinese

Association of a single nucleotide polymorphism in the CD209 (DC-SIGN) promoter with SARS severity

Functional consequences of DECTIN-1 early stop codon polymorphism Y238X in rheumatoid arthritis

Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient-and donordependent mechanisms of antifungal immunity

The Y238X stop codon polymorphism in the human β-glucan receptor Dectin-1 and susceptibility to invasive aspergillosis

Early stop polymorphism in human Dectin-1 is associated with increased candida colonization in hematopoietic stem cell transplant recipients

Genetic variation of innate immune genes in HIV-infected african patients with or without oropharyngeal candidiasis

Study of human RIG-I polymorphisms identifies two variants with an opposite impact on the antiviral immune response

Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes

Rubella vaccineinduced cellular immunity: evidence of associations with polymorphisms in the Toll-like, vitamin A and D receptors, and innate immune response genes

Polymorphisms in the vitamin A receptor and innate immunity genes influence the antibody response to rubella vaccination

A common polymorphism in the caspase recruitment domain of RIG-I modifies the innate immune response of human dendritic cells

Cancer risk among patients hospitalized for Type 1 diabetes mellitus: a populationbased cohort study in Sweden

Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden

Cancer incidence and mortality in patients with insulin-treated diabetes: a UK cohort study

Cancer and diabetes -a follow-up study of two population-based cohorts of diabetic patients

Cancer risk among patients with multiple sclerosis and their parents

Cancer risk among patients with multiple sclerosis: a population-based register study

Cancer incidence in multiple sclerosis: a 35-year follow-up

Multiple sclerosis and cancer in Norway. A retrospective cohort study

Cancer in patients with motor neuron disease, multiple sclerosis and Parkinson's disease: record linkage studies

A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients

Possible association of VISA gene polymorphisms with susceptibility to systemic lupus erythematosus in Chinese population

Publish your work in this journal Submit your manuscript here: http://www.dovepress.com/cancer-management-and-research-journal Cancer Management and Research is an international, peer-reviewed open access journal focusing on cancer research and the optimal use of preventative and integrated treatment interventions to achieve improved outcomes, enhanced survival and quality of life for the cancer patient. The journal welcomes original research, clinical & epidemiological studies, reviews & evaluations, guidelines, expert opinion & commentary, case reports & extended reports. The manuscript management system is completely online and includes a very quick and fair peerreview system, which is all easy to use. Visit http://www.dovepress.com/ testimonials.php to read real quotes from published authors.