A built-in co-carcinogenic effect due to viruses involved in latent or persistent infections

A new hypothesis for some cancers, which combines the chromosomal instability theories with a co-carcinogenic effect of viruses causing latent or persistent infection, is presented. The hypothesis incorporates the multi-step model of cancer and that pre-cancerous cells reach a state of chromosomal instability. Because of chromosomal instability, the genome of these cell lines will lead to changes from generation to generation and will face a remarkable selection pressure both from lost traits, apoptosis, and from the immune system. Viruses causing latent or persistent infections have evolved many different genes capable to evade the immune system. If these viruses are harboured in the genome of pre-cancerous cells they could provide them with "superpowers" and with genes that may assist the cells to elude the immune system. The theory explains why cancer predominantly is a disease of old age. Upon aging, the immune system becomes reduced including the ability to control and suppress the viruses that cause latent or persistent infections. The risk of cancer could thereby increase as the immune functions decrease. The theory provides new insights to the genesis of cancers.     

Phenotypes of invasion in sporadic colorectal carcinomas related to aberrations of the adenomatous polyposis coli (APC ) gene

AIMS: To determine whether the dissociation of tumour cells from neoplastic glands in colorectal carcinomas is caused by disruption of the wnt-signalling pathway and whether the adenomatous polyposis coli (APC) protein is implicated in this. METHODS AND RESULTS: In a series of 99 clinically sporadic colorectal carcinomas, APC exon 15 mutations, loss of heterozygosity (LOH) and promoter methylation were found in 49, 20 and 23 cases, respectively. Singly, these APC aberrations were not associated with the degree of tumour cell dissociation, but dissociation was higher for the cases with combined APC mutation and LOH. Immunohistochemical beta-catenin translocation to the nucleus correlated with APC aberrations. Tumour growth pattern (expansive/infiltrative/diffuse) and tumour stroma (desmoplastic common-type versus keloid-like) showed a statistically significant association with tumour cell dissociation and with beta-catenin translocation. Of other molecular alterations tested (p53 mutation; LOH at 17p13, 18q, 9p21; CpG island methylator phenotype), only the highly microsatellite unstable status (n = 11) was negatively associated. CONCLUSIONS: In colorectal carcinomas, wnt dysregulation relates to APC aberrations, but wnt dysregulation and APC aberrations are not strictly required for tumour cell dissociation, and additional and/or alternative factors must play a role. Of these, outside-in signalling by cancer cell-matrix interactions, as partially mirrored in histomorphological features, could be important.     

肼苯哒嗪对宫颈癌细胞株APC基因表达和甲基化状况以及细胞增殖与凋亡的影响

目的观察宫颈癌细胞株HeLa、CaSki和SiHa中APC基因的表达及其与甲基化修饰之间的相关性,探讨肼苯哒嗪对APC基因的去甲基化作用及其对细胞生长和凋亡的影响。方法应用甲基化特异性聚合酶链反应（MSP）及逆转录聚合酶链反应（RT—PCR）、荧光定量聚合酶链反应（FQ—PCR）分析肼苯哒嗪处理前后宫颈癌细胞株APC基因的甲基化状态及表达情况;采用免疫组织化学SP法检测肼苯哒嗪对宫颈癌细胞株APC相关蛋白β-连环蛋白表达的影响;四甲基偶氮唑蓝（MTT）法及流式细胞术观察肼苯哒嗪对宫颈癌细胞增殖及凋亡的影响。结果（1）HeLa及CaSki细胞APC基因分别为甲基化及半甲基化,SiHa细胞APC基因无甲基化。（2）40μmol／L肼苯哒嗪处理72h后,HeLa、CaSki和SiHa细胞的生长抑制率分别为（52．12．4-3．78）％、（44．31．4-2．59）％、（47．73．4-4．73）％,正常细胞人脐静脉内皮细胞（HECV）表现为耐药;HeLa和CaSki细胞中APC基因呈去甲基化状态且APCmRNA均呈阳性表达;HeLa、CaSki和SiHa三种细胞中APCmRNA表达分别比处理前增加10．35、11．40及0．73倍。（3）40μmol／L肼苯哒嗪作用HeLa、CaSki细胞72h后,可将细胞阻滞于S期和G2-M期并诱导细胞凋亡;β-连环蛋白在细胞膜上有明显的表达。结论APC甲基化修饰是宫颈癌发生重要机制之一,肼苯哒嗪能使甲基化的APC基因去除甲基化修饰重新表达,且能抑制宫颈癌细胞生长。     

No difference in the occurrence of mismatch repair defects and APC and CTNNB1 genes mutation in a multi-racial colorectal carcinoma patient cohort

BACKGROUND AND AIMS: Colorectal cancers of different subtypes involve different pathogenic pathways like the Wnt and the mutator pathways. In this study, we screened 73 colorectal cancer cases from a multi-racial group for genetic and expression profile defects with the aim of correlating these with patients' clinicopathological characteristics. METHODS: Mutation screening of the entire coding region of APC and exon 3 of CTNNB1, loss of heterozygosity (LOH) of APC, and microsatellite instability (MSI) status were assessed for 44 patients with available paired frozen normal and tumour tissues. In addition, 29 cases with available paraffin embedded tumour blocks were screened for mutation in exon 3 of CTNNB1, the APC mutation cluster region (codon 1286-1513), and hMLH1, hMSH2, hMSH6 protein expressions by immunohistochemistry method. RESULTS: In our study, 15/73 cases showed APC mutations (20.5%), 1/73 cases had CTNNB1 mutation (1.4%), 5/32 cases had APC LOH (15.6%), and 16/70 (22.9%) cases revealed at least some form of mismatch repair (MMR) defect. Tumour grade (poor differentiation) was found to correlate significantly with right-sided tumour and mucinous histology (p = 0.01879 and 0.00320, respectively). Patients of younger age (below 45 years) more often had tumours of mucinous histology (p = 0.00014), while patients of older age (above 75 years) more often had tumours on the right side of the colon (p = 0.02448). Tumours of the mucinous histology subtype often had MMR defects (p = 0.02686). There was no difference in the occurrence of APC and CTNNB1 mutations and MMR defects found within our multi-racial colorectal cancer patient cohort. CONCLUSION: Our findings support the notion that racial factor may not be related to the occurrence of MMR defects and APC and CTNNB1 mutations in our multi-racial patient cohort.     

Co-delivery of a CD4 T cell helper epitope via covalent liposome attachment with a surface-arrayed B cell target antigen fosters higher affinity antibody responses

Liposomal vaccines incorporating adjuvant and CD4 T cell helper peptides enhance antibody responses against weakly immunogenic B cell epitopes such as found in the membrane proximal external region (MPER) of the HIV-1 gp41 subunit. While the inclusion of exogenous helper peptides in vaccine formulations facilitates stronger and more durable antibody responses, the helper peptide incorporation strategy per se may influence the overall magnitude and quality of B cell target antigen immunogenicity. Both variability in individual peptide encapsulation as well as the potential for liposome surface-associated helper peptides to misdirect the humoral response are potential parameters impacting outcome. In this study, we used MPER/liposome vaccines as a model system to examine how the mode of the potent LACK T helper peptide formulation modulates antibody responses against the MPER antigen. We directly compared liposome surface-arrayed palmitoyl LACK (pLACK) versus soluble LACK (sLACK) encapsulated in the liposomes and free in solution. Independent of LACK formulation methods, dendritic cell activation and LACK presentation were equivalent in vivo. The frequency of MPER-specific GC B cells promoted by sLACK was higher than that stimulated by pLACK formulation, a finding associated with a significantly greater frequency of LACK-specific GC B cells induced by pLACK. While there were no significant differences in the quantity of MPER-specific serological responses, the MPER-specific antibody titer trended higher with sLACK formulated vaccines at the lower dose of LACK. However, pLACK generated relatively greater MPER-specific antibody affinities than those induced by sLACK-formulated vaccines. Overall, the results suggest that liposomal surface-associated LACK enhances immunogenicity of LACK through better engagement of LACK-specific B cells. Of note, this is not detrimental to the induction of MPER-specific immune responses; rather, the elicitation of higher affinity anti-MPER antibodies benefits from augmented help delivered via covalent linkage of the pLACK CD4 T cell epitope in conjunction with MPER/liposome presentation.     

Mechanisms of Disease: Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBDs), represented by Crohn disease and ulcerative colitis, are associated with major morbidity in Western countries and with increasing incidence in the developing world. Although analysis of the genome of patients with IBD, especially through genome-wide association studies, has unraveled multiple pathways involved in IBD pathogenesis, only part of IBD heritability has been explained by genetic studies. This finding has revealed that environmental factors also play a major role in promoting intestinal inflammation, mostly through their effects in the composition of the microbiome. However, in order for microbial dysbiosis to result in uncontrolled intestinal inflammation, the intestinal barrier formed by intestinal epithelial cells and the innate immune system should also be compromised. Finally, activation of the immune system depends on the working balance between effector and regulatory cells present in the intestinal mucosa, which have also been found to be dysregulated in this patient population. Therefore, IBD pathogenesis is a result of the interplay of genetic susceptibility and environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation. In this article, we will review the mechanisms proposed to cause IBD from the genetic, environmental, intestinal barrier, and immunologic perspectives.     

Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9

BACKGROUND: The phenotypic spectrum of familial adenomatous polyposis (FAP) varies from the classic appearance of hundreds of adenomatous colonic polyps in the young adult and early onset colorectal cancer, to the occurrence of sparse adenomas in the older adult, "attenuated" FAP, due to mutations at the 5' or 3' ends of the APC gene. AIMS: To investigate marked intrafamilial phenotypic variation occurring in a family with an APC gene mutation in exon 9. PATIENTS: An extended kindred of 22 people of whom 16 had colorectal neoplasia and/or were APC mutation carriers. RESULTS: Phenotypic manifestation varied from classic FAP to a complete lack of clinical or endoscopic, or bioptic disease in five people in three different generations. This occurred in four of them over two generations, in spite of having a confirmed 11 bp insertion causing a frame shift and stop codon (363) in exon 9 of the APC gene. CONCLUSIONS: At present, it is assumed that in this family there is alternative splicing of the APC gene, and/or unidentified modifying genetic factors. The family illustrates the importance of genetic testing in evaluating carrier status and not just clinical examination. This clinical observation also high- lights the dilemma in recognising the possible contribution of low penetrance germline APC mutations to what has been considered "sporadic" colorectal neoplasia.     

Thymoquinone (2-Isopropyl-5-methyl-1, 4-benzoquinone) as a chemopreventive/anticancer agent: Chemistry and biological effects

Cancer remains the topmost disorder of the mankind and number of cases is unceasingly growing at unprecedented rates. Although the synthetic anti-cancer compounds still hold the largest market in the modern treatment of cancer, natural agents have always been tried and tested for potential anti-cancer properties. Thymoquinone (TQ), a monoterpene and main ingredient in the essential oil of Nigella sativa L. has got very eminent rankings in the traditional systems of medicine for its anti-cancer pharmacological properties. In this review we summarized the diverse aspects of TQ including its chemistry, biosynthesis, sources and pharmacological properties with a major concern being attributed to its anti-cancer efficacies. The role of TQ in different aspects involved in the pathogenesis of cancer like inflammation, angiogenesis, apoptosis, cell cycle regulation, proliferation, invasion and migration have been described. The mechanism of action of TQ in different cancer types has been briefly accounted. Other safety and toxicological aspects and some combination therapies involving TQ have also been touched. A detailed literature search was carried out using various online search engines like google scholar and pubmed regarding the available research and review accounts on thymoquinone upto may 2019. All the articles reporting significant addition to the activities of thymoquinone were selected. Additional information was acquired from ethno botanical literature focusing on thymoquinone. The compound has been the centre of attention for a long time period and researched regularly in quite considerable numbers for its various physicochemical, medicinal, biological and pharmacological perspectives. Thymoquinone is studied for various chemical and pharmacological activities and demonstrated promising anti-cancer potential. The reviewed reports confirmed the strong anti-cancer efficacy of thymoquinone. Further in-vitro and in-vivo research is strongly warranted regarding the complete exploration of thymoquinone in ethnopharmacological context.     

TLR2- and 4-independent immunomodulatory effect of high molecular weight components from Ascaris suum

Components of high molecular-weight (PI) obtained from Ascaris suum extract down-regulate the Th1/Th2-related immune responses induced by ovalbumin (OVA)-immunization in mice. Furthermore, the PI down-modulates the ability of dendritic cells (DCs) to activate T lymphocytes by an IL-10-mediated mechanism. Here, we evaluated the role of toll like receptors 2 and 4 (TLR2 and 4) in the modulatory effect of PI on OVA-specific immune response and the PI interference on DC full activation. An inhibition of OVA-specific cellular and humoral responses were observed in wild type (WT) or in deficient in TLR2 (TLR2^−/−) or 4 (TLR4^−/−) mice immunized with OVA plus PI when compared with OVA-immunized mice. Low expression of class II MHC, CD40, CD80 and CD86 molecules was observed in lymph node (LN) cells from WT, TLR2^−/− or TLR4^−/− mice immunized with OVA plus PI compared with OVA-primed cells. We also verified that PI was able to modulate the activation of DCs derived from bone marrow of WT, TLR2^−/− or TLR4^−/− mice induced in vitro by agonists of TLRs, as observed by a decreased expression of class II MHC and costimulatory molecules and by low secretion of pro-inflammatory cytokines. Its effect was accompanied by IL-10 synthesis. In this sense, the modulatory effect of PI on specific-immune response and DC activation is independent of TLR2 or TLR4.