Serum amyloid A and inflammasome activation: A link to breast cancer progression?

Breast cancer is the most frequently diagnosed cancer in women globally. Although there have been many significant advances made in the diagnosis and treatment of breast cancer, numerous unresolved challenges remain, which include prevention, early diagnosis, metastasis and recurrence. The role of inflammation in cancer development is well established and is believed to be one of the leading hallmarks of cancer progression. Recently, the role of the inflammasome, a cytosolic multiprotein complex, has received attention in different cancers. By contributing to the activation of inflammatory cytokines the inflammasome intensifies the inflammatory cascade. The inflammasome can be activated through several pathways, which include the binding of pattern associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) to toll-like receptors (TLRs). Serum amyloid A (SAA), a non-specific acute-phase protein, can function as an endogenous DAMP by binding to pattern recognition receptors like TLRs on both breast cancer cells and cancer associated fibroblasts (CAFs). SAA can thus stimulate the production of IL-1β, thereby creating a favourable inflammatory environment to support tumour growth. The aim of this review is to highlight the possible role of SAA as an endogenous DAMP in the tumour microenvironment (TME) thereby promoting breast cancer growth through the activation of the NLRP3 inflammasome.     

Claspin functions in cell homeostasis—A link to cancer?

Cancer remains one of the leading causes of mortality worldwide. Most cancers present high degrees of genomic instability. DNA damage and replication checkpoints function as barriers to halt cell cycle progression until damage is resolved, preventing the perpetuation of errors. Activation of these checkpoints is critically dependent on Claspin, an adaptor protein that mediates the phosphorylation of the effector kinase Chk1 by ATR. However, Claspin also performs other roles related to the protection and maintenance of cell and genome integrity. For instance, following DNA damage and checkpoint activation, Claspin bridges checkpoint responses to DNA repair or to apoptosis. During DNA replication, Claspin acts a sensor and couples DNA unwinding to strand polymerization, and may also indirectly regulate replication initiation at firing origins. As Claspin participates in several processes that are vital to maintenance of cell homeostasis, its function is tightly regulated at multiple levels. Nevertheless, little is known about its role in cancer. Accumulating evidence suggests that Claspin inactivation could be an essential event during carcinogenesis, indicating that Claspin may function as a tumour suppressor. In this review, we will examine the functions of Claspin and how its deregulation may contribute to cancer initiation and progression. To conclude, we will discuss means by which Claspin can be targeted for cancer therapy.     

Involvement of β-arrestins in cancer progression

β-arrestins, including β-arrestin1 and β-arrestin2, are ubiquitous cytosolic proteins which localize in the cytoplasm and plasma membrane, initially be regarded as an potential character in G protein-coupled receptors (GPCR) desensitization, sequestration, and internalization. Besides, recent many studies increasingly revealed that β-arrestins served widely as versatile adapter proteins for scaffolding many intracellular signaling networks to modulate the strength and duration of signaling by diverse types of receptors and downstream kinases. As we known, the biologic and clinical behaviors of many tumors are largely determined by multiple molecular signal pathways. More recently, accumulating evidences established that β-arrestins got widely involved in many cancer developmental signaling events which responsible for tumor viability and metastasis, suggesting an impressive role of β-arrestins in tumor progression. Because of the regulation and biological output of β-arrestins is so complex, the role of β-arrestins in cancer development still remains enigmatic. However, the further understanding with the clinical prognosis and oncogenic potential of β-arrestins might facilitate the identification of diagnosis biomarkers and development of drug targets in cancer. In this article, we reviewed a comprehensive summary of the β-arrestins-mediated functions in human cancers.     

Mitochondrial pyruvate carrier—A possible link between gluconeogenesis and ketogenesis in the liver

Effects of various ketogenic substrates on gluconeogenesis from lactate or alanine were compared. The results suggest that, in intact liver cells, cytoplasmic pyruvate is transported into mitochondria in exchange for intramitochondrially generated acetoacetate. An interrelationship between gluconeogenesis and ketogenesis may thus exist in the liver at the level of mitochondrial pyruvate carrier.     

Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression

Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.     

Screening for possible miRNA–mRNA associations in a colon cancer cell line

MicroRNAs (miRNAs) are small non-coding RNAs mediating the regulation of gene expression in various biological contexts, including carcinogenesis. Here, we screened putative associations between 34, 45, and 103 miRNAs and 164, 391, and 81 mRNAs via Argonaute1 (Ago1) or Ago2 immunoprecipitation (IP) experiments in a colon cancer cell line. We used a combination of RIP Seq analysis. RNAs that were co-immunoprecipitated with Ago1 or Ago2 were used for massively parallel small RNA and mRNA sequencing. The detected miRNAs and mRNAs were further associated with one another based on in silico target predictions. Analysis of the putative associations indicated that, although Ago1 and Ago2 shared a similar repertory of miRNAs, the mRNAs possibly regulated by those miRNAs seemed different. The mRNAs detected with Ago1 IP were indicated to be frequently associated with genes having constitutive cellular functions, regulated by a smaller number of miRNAs, and appeared to receive more stringent translational regulation. In contrast, putative miRNA-mRNA associations detected with Ago2 IP appeared to be related to signal transduction genes, which had a larger number of possible miRNA binding sites. We then conducted a similar analysis using the colon cancer cells cultured under hypoxia and identified potential hypoxia-induced miRNA-mRNA associations, which included several well-characterized cancer-related genes as novel putative miRNA targets.     

The presence of serotonin in cigarette smoke – a possible mechanistic link to 5-HT-induced airway inflammation

We previously reported the involvement of serotonin (5-HT) metabolism in cigarette smoke-induced oxidative stress in rat lung in vivo. Here, we report cigarette smoke as a source of serotonin (5-HT) to the airways and aim at investigating the effects of 5-HT on oxidative stress and inflammation in human bronchial epithelial cells (BEAS-2B). A 5-HT analog was identified to be present in aqueous phase cigarette smoke using the LC-MS/MS approach, which was later confirmed by a 5-HT enzyme-linked immune assay (EIA). Furthermore, exposure to 5-HT caused a time-dependent elevation of intracellular ROS level, which was blocked in the presence of apocynin (a NOX inhibitor). In support, the immunoblot analysis indicated that there was an increase in the expression of NOX2 time-dependently. 5-HT-induced elevation of IL-8 at both mRNA and protein levels was observed, which was inhibited by TEMPOL (a free radical scavenger), and inhibitors for p38 MAPK (SB203580) and ERK (U0126), in line with the time-dependent phosphorylation of p38 MAPK and ERK. In conclusion, our findings suggest that 5-HT presented in bronchial epithelium of smokers may be involved in cigarette smoke-induced oxidative stress and inflammation via activation of p38 MAPK and ERK pathway after the formation of free radicals.     

Factors associated with and risk factors for depression in cancer patients – A systematic literature review

ObjectiveThe prevalence of depression in oncological patients is 3, 4-fold compared to the general population. However, the specific risk factors for these prevalence rates are not fully understood.MethodsA systematic literature review was conducted in nine electronic databases between 2005 and 2020. The quality of the eligible studies was appraised by two persons using the adapted 11-items Downs and Black checklist.ResultsAmong 2010 potentially relevant articles, 40 studies were eligible, with 27 studies of high quality and 13 studies of moderate quality. A total of 156 factors associated with depression were identified which were clustered into somatic, psychological, social and sociodemographic factors. Pre-existing depression and personality factors were the most consistent associated factors with depression in cancer patients, while for most somatic and treatment-related factors only modest associations were found.ConclusionsGrouped as bio-psycho-social associated factors, somatic factors showed a modest influence, whereas social relationship (support) and previous depression are unequivocally significantly associated with depression.     

Correction to: Novel role of the Mu‑opioid receptor in pancreatic cancer: potential link between opioid use and cancer progression

Molecular and Cellular Biochemistry -     

Mortality in small bowel cancers and adenomas – A nationwide,population-based matched cohort study

BackgroundSmall bowel adenocarcinoma (SBA), neuroendocrine tumors (NET) and gastrointestinal stromal tumors (GIST) are neoplastic lesions of the small bowel while small bowel adenomas are precursors of SBA.AimTo examine mortality in patients diagnosed with SBA, small bowel adenomas, NET and GIST.MethodsWe performed a population-based matched cohort study encompassing all individuals with SBA (n = 2289), adenomas (n = 3700), NET (n = 1884) and GIST (n = 509) in the small bowel diagnosed at any of Sweden’s 28 pathology departments between 2000 and 2016 (the “ESPRESSO study”). Each case was matched by sex, age, calendar year and county of residence to up to 5 comparators from the general population. Through Cox regression we estimated hazard ratios (HRs) and 95% confidence intervals (95%CIs) for death and cause-specific death adjusting for education.ResultsDuring follow-up until December 31, 2017, 1836 (80%) deaths occurred in SBA patients, 1615 (44%) in adenoma, 866 (46%) in NET and 162 (32%) in GIST patients. This corresponded to incidence rates of 295, 74, 80 and 62/1000 person-years respectively and adjusted HRs of 7.60 (95%CI=6.95–8.31), 2.21 (2.07–2.36), 2.74 (2.50–3.01) and 2.33 (1.90–2.87). Adjustment for education had a substantial impact on the HR for death in SBA but not for other neoplasias. The predominant cause of excess death was cancer in all groups.ConclusionThis study confirms earlier findings of increased death rates in patients with SBA and NET in a modern study population. We also demonstrate a more than 2-fold increased risk of death in both GIST and the SBA precursor adenoma.     

Downregulation of CK2 induces apoptosis in cancer cells – A potential approach to cancer therapy

We have previously documented that naked antisense CK2α ODN can potently induce apoptosis in cancer cells in culture and in mouse xenograft human prostate cancer. The effects of the antisense CK2α are related to downregulation of CK2α message and rapid loss of the CK2 from the nuclear compartment. Here we demonstrate that downregulation of CK2 elicited by diverse methods leads to inhibition of cell growth and induction of apoptosis. The various approaches to downregulation of CK2 employed were transfection with kinase-inactive plasmid, use of CK2α siRNA, use of inhibitors of CK2 activity, and use of antisense CK2α ODN packaged in sub-50 nm nanocapsules made from tenascin. In all cases, the downregulation of CK2 is associated with loss in cell survival. We have also described preliminary observations on an approach to targeting CK2 in cancer cells. For this, sub-50 nm tenascin-based nanocapsules bearing the antisense CK2α ODN were employed to test that the antisense is delivered to the cancer cells in vivo. The results provide the first preliminary evidence that such an approach may be feasible for targeting CK2 in cancer cells. Together, our results suggest that CK2 is potentially a highly plausible target for cancer therapy.     

Tumor–stroma co-evolution in prostate cancer progression and metastasis

Cancer development is complex and involves several layers of interactions and pleotropic signaling mechanisms leading to progression. Cancer cells associate with resident stromal fibroblasts, smooth muscle cells, macrophages, endothelium, neurons and migrating cells at metastatic sites and phenotypically and genotypically activate them. These become an integral part of the cancer cell community through activated cell signaling mechanisms. During this process, the cancer cells and cells in the cancer microenvironment “co-evolve” in part due to oxidative stress, and acquire the ability to mimic other cell types (which can be termed osteomimicry, vasculomimicry, neuromimicry and stem cell mimicry), and undergo transition from epithelium to mesenchyme with definitive morphologic and behavioral modifications. In our laboratory, we demonstrated that prostate cancer cells co-evolve in their genotypic and phenotypic characters with stroma and acquire osteomimetic properties allowing them to proliferate and survive in the skeleton as bone metastasis. Several signaling interactions in the bone microenvironment, mediated by reactive oxygen species, soluble and membrane bound factors, such as superoxide, β2-microglobulin and RANKL have been described. Targeting the signaling pathways in the cancer-associated stromal microenvironment in combination with known conventional therapeutic modalities could have a synergistic effect on cancer treatment. Since cancer cells are constantly interacting and acquiring adaptive and survival changes primarily directed by their microenvironment, it is imperative to delineate these interactions and co-target both cancer and stroma to improve the treatment and overall survival of cancer patients.     

The oncofetal Thomsen–Friedenreich carbohydrate antigen in cancer progression

The oncofetal Thomsen–Friedenreich carbohydrate antigen (Galβ1-3GalNAcα1-Ser/Thr TF or T antigen) is a pan-carcinoma antigen highly expressed by about 90% of all human carcinomas. Its broad expression and high specificity in cancer have attracted many investigations into its potential use in cancer diagnosis and immunotherapy. Over the past few years increasing evidence suggests that the increased TF occurrence in cancer cells may be functionally important in cancer progression by allowing increased interaction/communication of the cells with endogenous carbohydrate-binding proteins (lectins), particularly the members of the galactoside-binding galectin family. This review focuses on the recent progress in understanding of the regulation and functional significance of increased TF occurrence in cancer progression and metastasis.     

Expression of cancer testis antigens in human BRCA-associated breast cancers: potential targets for immunoprevention?

Introduction

Novel breast cancer risk-reducing strategies for individuals with germline mutations of the BRCA1 and/or BRCA2 genes are urgently needed. Identification of antigenic targets that are expressed in early cancers, but absent in normal breast epithelium of these high-risk individuals, could provide the basis for the development of effective immunoprophylactic strategies. Cancer testis (CT) antigens are potential candidates because their expression is restricted to tumors, and accumulating data suggest that they play important roles in cellular proliferation, stem cell function, and carcinogenesis. The objective of this study was to examine the expression of CT antigens and their frequency in BRCA-associated breast cancers.

Methods

Archived breast cancer tissues (n?=?26) as well as morphologically normal breast tissues (n?=?7) from women carrying deleterious BRCA 1 and/or 2 mutations were obtained for antigen expression analysis by immunohistochemistry. Expression of the following CT antigens was examined: MAGE-A1, MAGE-A3, MAGE-A4, MAGE-C1.CT7, NY-ESO-1, MAGE-C2/CT10, and GAGE.

Results

CT antigens were expressed in 16/26 (61.5%, 95% CI 43?C80%) of BRCA-associated cancers, including in situ tumors. Thirteen of twenty-six (50%) breast cancers expressed two or more CT antigens; three cancers expressed all seven CT antigens. MAGE-A was expressed in 13/26 (50%) of cancers, NY-ESO-1 was expressed in 10/26 (38%) of tumors. In contrast, none of the CT antigens were expressed in adjacent or contralateral normal breast epithelium (P?=?0.003).

Conclusions

We report a high CT antigen expression rate in BRCA-associated breast cancer as well as the lack of expression of these antigens in benign breast tissue of carriers, identifying CT antigens as potential vaccine targets for breast cancer prevention in these high-risk individuals.     

A possible rôle for microsomal oxidases in metamorphosis and reproduction in the housefly

Housefly larvae and adults of the Isolan-B strain, insecticide resistant because of high microsomal oxidase activity, and the susceptible WHO Standard Reference (SR) strain, were reared on diets containing phenobarbital or piperonyl butoxide. Periodically throughout the treatments groups of insects were assayed for microsomal aldrin epoxidase activity. This activity was compared with such growth and development parameters as pupation, adult emergence, and reproduction in similar groups of insects. At diet levels of 0·01 to 0·50 per cent both chemicals caused large increases, as much as elevenfold in microsomal oxidase activity in third instar larvae and 15 to 100 per cent inhibition of pupation and emergence. In the adult diet at 1 per cent, both compounds caused at least 50 per cent decrease in egg production. Phenobarbital enhanced the enzyme system in both larval and adult stages of both strains but piperonyl butoxide, while enhancing enzyme activity in larvae of the Isolan-B strain, was an inhibitor in the adult stage. The results are interpreted as an indication of a direct connexion between microsomal oxidase activity and the action of hormones in the housefly, probably through regulation of hormone titre by these enzymes.     

A possible rôle for acid phosphatase in γ-amino-n-butyrate uptake in Aspergillus nidulans

Previously published work from another laboratory has shown that the mutation pacC-5 in the ascomycete Aspergillus nidulans leads to loss of an acid phosphatase (EC 3.1.3.2) activity and is probably located in the structural gene for this enzyme. Here, we show that, pleiotropically, pacC-5 considerably reduces -amino-n-butyrate transport levels as shown both by direct uptake measurements and two kinds of growth tests. A reduction in expression of the permease specified by the gabA gene is almost certainly reponsible for the -amino-n-butyrate uptake defect in pacC-5 strains. pacC-5 does not reduce l-proline uptake, mainly mediated by the prnB permease, or -alanine uptake. This work and our previously published results suggest that, although it does not uniquely reduce -amino-n-butyrate uptake, pacC-5 is highly selective in its effects on transport processes. It is therefore probable that the acid phosphatase specified by the pacC gene plays some rôle in the synthesis, membrane integration or functioning of a particular class of permeases. A rôle for acid phosphatases in membrane processes casts an intriguing new light on the fact that these enzymes are periplasmic and extracellular in many micro-organisms including A. nidulans.Non-Standard Abbreviations GABA -amino-n-butyrate - P5C l-¹pyrroline-5-carboxylate     

Escalated hyperfractionation in radiotherapy for head and neck cancer – 5-year results

PurposeTo evaluate 5-year results of escalated hyperfractionation schedule in aspect of local tumour control (LTC) and late radiation toxicity.Material and methodsForty eight patients with squamous cell carcinoma of oral cavity (34 pts), oropharynx (11 pts) and larynx (3) in stage T1-4N0-1 have been treated at Centre of Oncology in Gliwice, between the years 1988–92. There were four patients with T1 primary tumour, 27 with T2, 11 with T3 and 2 with T4; in 4 patients the tumour stage remains unknown (TX). All the patients were treated by radiation therapy alone, using the technique of two opposed parallel fields and hyperfractionation with escalation of the dose per fraction during the second part of the treatment schedule. The total dose ranged between 62,2 and 74 Gy. The median follow-up was 62 months.ResultsDespite of the relative high proportion of complete local regressions (75%), the 5-year LTC rate of 54% was noted in the whole group of patients. Stage-related LTC rates were as follows: 100% for TX tumours, 50% for T1, 55% for T2, 45% for T3 and 0% for T4. Acute radiation reactions were more intensive than those usually observed during conventional radiotherapy; all patients experienced a confluent mucositis and two waves of acute mucosal reaction because of treatment gap were observed during the radiation course. Severe late radiation toxicity (grade IV) was noted in two patients (4%).ConclusionsLong-term tumour control results of escalated hyperfractionation radiotherapy may suggest that there is no benefit of a such regimen. However, in the majority of patients the treatment course differed markedly from protocol assumptions.     

Sex in the PAC: A hidden affair in dark septate endophytes?

Background

Fungi are asexually and sexually reproducing organisms that can combine the evolutionary advantages of the two reproductive modes. However, for many fungi the sexual cycle has never been observed in the field or in vitro and it remains unclear whether sexual reproduction is absent or cryptic. Nevertheless, there are indirect approaches to assess the occurrence of sex in a species, such as population studies, expression analysis of genes involved in mating processes and analysis of their selective constraints. The members of the Phialocephala fortinii s. l. - Acephala applanata species complex (PAC) are ascomycetes and the predominant dark septate endophytes that colonize woody plant roots. Despite their abundance in many ecosystems of the northern hemisphere, no sexual state has been identified to date and little is known about their reproductive biology, and how it shaped their evolutionary history and contributes to their ecological role in forest ecosystems. We therefore aimed at assessing the importance of sexual reproduction by indirect approaches that included molecular analyses of the mating type (MAT) genes involved in reproductive processes.

Results

The study included 19 PAC species and > 3, 000 strains that represented populations from different hosts, continents and ecosystems. Whereas A. applanata had a homothallic (self-fertile) MAT locus structure, all other species were structurally heterothallic (self-sterile). Compatible mating types were observed to co-occur more frequently than expected by chance. Moreover, in > 80% of the populations a 1:1 mating type ratio and gametic equilibrium were found. MAT genes were shown to evolve under strong purifying selection.

Conclusions

The signature of sex was found in worldwide populations of PAC species and functionality of MAT genes is likely preserved by purifying selection. We hypothesize that cryptic sex regularely occurs in the PAC and that further field studies and in vitro crosses will lead to the discovery of the sexual state. Although structurally heterothallic species prevail, it cannot be excluded that homothallism represents the ancestral breeding system in the PAC.