Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies

BackgroundLow-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain.ObjectivesWe conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses.MethodsSearches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned.ResultsFive reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79–0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76–0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available.

Conclusions and Implications

The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin.

Systematic Review Protocol Number

CRD42015014145     

Role of inflammasomes and their regulators in prostate cancer initiation, progression and metastasis

Prostate cancer is one of the main cancers that affect men, especially older men. Though there has been considerable progress in understanding the progression of prostate cancer, the drivers of its development need to be studied more comprehensively. The emergence of resistant forms has also increased the clinical challenges involved in the treatment of prostate cancer. Recent evidence has suggested that inflammation might play an important role at various stages of cancer development. This review focuses on inflammasome research that is relevant to prostate cancer and indicates future avenues of study into its effective prevention and treatment through inflammasome regulation. With regard to prostate cancer, such research is still in its early stages. Further study is certainly necessary to gain a broader understanding of prostate cancer development and to create successful therapy solutions.     

光动力技术治疗胃癌的进展及展望

近年来应用光动力技术治疗胃癌取得了可喜的进步,它对各个时期的胃癌均有比较满意的临床效果。本文通过对国内外近年来用光动力技术治疗胃癌方面的文献进行综述,系统阐述光动力运用于胃癌治疗这一项技术的原理、机制,光敏剂、光源及临床效果等方面,并总结了这项技术在治疗胃癌方面的优点和相关问题。     

Oxidative stress-induced DNA damage by particulate air pollution

Exposure to ambient air particulate matter (PM) is associated with pulmonary and cardiovascular diseases and cancer. The mechanisms of PM-induced health effects are believed to involve inflammation and oxidative stress. The oxidative stress mediated by PM may arise from direct generation of reactive oxygen species from the surface of particles, soluble compounds such as transition metals or organic compounds, altered function of mitochondria or NADPH-oxidase, and activation of inflammatory cells capable of generating ROS and reactive nitrogen species. Resulting oxidative DNA damage may be implicated in cancer risk and may serve as marker for oxidative stress relevant for other ailments caused by particulate air pollution. There is overwhelming evidence from animal experimental models, cell culture experiments, and cell free systems that exposure to diesel exhaust and diesel exhaust particles causes oxidative DNA damage. Similarly, various preparations of ambient air PM induce oxidative DNA damage in in vitro systems, whereas in vivo studies are scarce. Studies with various model/surrogate particle preparations, such as carbon black, suggest that the surface area is the most important determinant of effect for ultrafine particles (diameter less than 100 nm), whereas chemical composition may be more important for larger particles. The knowledge concerning mechanisms of action of PM has prompted the use of markers of oxidative stress and DNA damage for human biomonitoring in relation to ambient air. By means of personal monitoring and biomarkers a few studies have attempted to characterize individual exposure, explore mechanisms and identify significant sources to size fractions of ambient air PM with respect to relevant biological effects. In these studies guanine oxidation in DNA has been correlated with exposure to PM(2.5) and ultrafine particles outdoor and indoor. Oxidative stress-induced DNA damage appears to an important mechanism of action of urban particulate air pollution. Related biomarkers and personal monitoring may be useful tools for risk characterization.     

Genetic epidemiology of multistage carcinogenesis

It is commonly believed that cancer is a multistage, polygenic disease. Even though conceptually appealing, the evidence supporting the multistage theory remains limited. Most known tumor suppresser genes are associated with monogenic dominant cancers following a two-hit pathway. We review results from a recent twin study on 90000 individuals that give support to the multistage theory. Statistically significant heritability estimates were shown for cancers of the colorectum (35%), breast (27%), and prostate (42%). These estimates are much higher than those obtained from family studies in which parents and offspring, or sibs are compared. The difference can be accounted for by the involvement of many genes. A polygenic cancer would show small effects in family studies but large effects in twin studies. We present calculations on the decrease in familial risks when the number of genes involved increases or when the penetrance decreases. We test the apparent number of stages involved in the main cancers from the Swedish Family-Cancer Database. The logarithms of the slopes suggest large differences in the apparent numbers of mutations involved in different cancers. The number of mutations required appears to be less in familial breast cancer compared to sporadic breast cancer. Study designs for gene identification should be revised to accommodate polygenic cancers.     

TXNIP (VDUP-1, TBP-2): a major redox regulator commonly suppressed in cancer by epigenetic mechanisms

TXNIP (also named as VDUP-1 or TBP-2) was originally isolated in HL60 cells treated with Vitamin D3. Subsequently, it has been identified as a major redox regulator and a Tumor Suppressor Gene (TSG) in various solid tumors and hematological malignancies. In the present review, we will first provide an overview of TXNIP gene and protein structures, followed by a summary of the studies that have demonstrated its frequent repression in human cancers and relevant clinical significance, as well as functional characterization in animal models. We will then highlight our current knowledge of TXNIP signaling and biological functions. Next, we will discuss the evidence that clearly have demonstrated that the epigenetic silencing of TXNIP in cancer through various molecular mechanisms. The therapeutic use of small molecular inhibitors to reactivate TXNIP expression for cancer treatment will also be discussed in this review.     

Free Radicals and Carcinogenesis

The role of free radicals and active states of oxygen in human cancer is as yet unresolved. Various lines of evidence provide strong but inferential evidence that free radical reactions can be of crucial importance in certain carcinogenic mechanisms. A central point in considering free radical reactions in carcinogenesis is that human cancer is really a group of highly diverse diseases for which the initial causation and the progression to clinical disease occur through a wide variety of mechanisms. Furthermore, for many human cancers it appears that there are alternate pathways capable of tumor initiation and tumor progression. While for certain of these pathways free radical reactions appear necessary, it is unlikely that there are human cancers for which free radicals, or any other mechanism, are sufficient for the entire processbeginning with the genetic alteration leading to a somatic mutation and eventually resulting in clinically overt disease. It is crucial that we view free radical reactions as aong a panoply of mechanisms leading to human cancer, and consider research about the role of free radicals in cancer as opportunities to prevent the initiation or progression of human cancer.     

Free Radicals and Carcinogenesis

The role of free radicals and active states of oxygen in human cancer is as yet unresolved. Various lines of evidence provide strong but inferential evidence that free radical reactions can be of crucial importance in certain carcinogenic mechanisms. A central point in considering free radical reactions in carcinogenesis is that human cancer is really a group of highly diverse diseases for which the initial causation and the progression to clinical disease occur through a wide variety of mechanisms. Furthermore, for many human cancers it appears that there are alternate pathways capable of tumor initiation and tumor progression. While for certain of these pathways free radical reactions appear necessary, it is unlikely that there are human cancers for which free radicals, or any other mechanism, are sufficient for the entire processbeginning with the genetic alteration leading to a somatic mutation and eventually resulting in clinically overt disease. It is crucial that we view free radical reactions as aong a panoply of mechanisms leading to human cancer, and consider research about the role of free radicals in cancer as opportunities to prevent the initiation or progression of human cancer.     

The versatile emodin: A natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers

Cancers are generally recognized as the leading cause of death and a predominant barrier to prolonging life expectancy in both developed and developing countries. Emodin is a typical anthraquinone derivative from various plants that exhibits a wide spectrum of biological activities, such as anticancer, antibacterial, hepatoprotective and anti-inflammatory activities. Much previous preclinical evidence has demonstrated that emodin exhibits reliable effects on several cancer types, including lung cancer, liver cancer, colon cancer, breast cancer, pancreatic cancer, leukemia, cervical cancer, and ovarian cancer, etc. The related molecular mechanisms corresponding to the anticancer activities of emodin are involved in the induction of apoptosis, inhibition of cell proliferation, enhanced reactive oxygen species (ROS) accumulation, and induction of autophagy, etc. In the present review, we summarized the sources, anticancer properties in vitro and in vivo, molecular mechanisms, metabolic transformation and toxicities of emodin. In addition, we also discussed the limitations of the present investigations of emodin against cancers and gave some perspectives for them, which would be beneficial for the further exploration and development of this natural compound as a clinical cancer drug.     

番茄红素与癌

番茄红素是主要的类胡萝卜素之一,最近的科学研究发现,它对人类健康有重要的作用。本文介绍了番茄红素的食物来源、生物合成、物理化学特性和生理活性,它的抗癌效果与其抗氧化活性有关。很多的流行病学研究证明,番茄红素对一些类型的癌有预防效果,如前列腺癌和消化道癌。体内和体外的癌细胞培养研究也支持这一结论。因此,具有广泛用途的番茄红素,将有希望成为最重要的一个化学防癌物质。     

Facilitative mechanisms of lead as a carcinogen

The carcinogenicity of lead compounds has received renewed attention because of continuing environmental and occupational sources of exposure in many countries. The epidemiological evidence for an association between lead exposures and human cancer risk has been strengthened by recent studies, and new data on mechanisms of action provide biological plausibility for assessing lead as a human carcinogen. Both epidemiological and mechanistic data are consistent with a facilitative role for lead in carcinogenesis, that is, lead by itself may not be both necessary and sufficient for the induction of cancer, but at a cellular and molecular level lead may permit or enhance carcinogenic events involved in DNA damage, DNA repair, and regulation of tumor suppressor and promoter genes. Some of these events may also be relevant to understanding mechanisms of lead-induced reproductive toxicity.     

Frequency-Risk and Duration-Risk Relationships between Aspirin Use and Gastric Cancer: A Systematic Review and Meta-Analysis

Background

Although previous meta-analyses have suggested an association between aspirin use and risk of gastric cancer, current evidence is inconsistent. Additionally, it remains unclear whether there are frequency-risk and duration-risk relationships and if a threshold of effect exists.

Methods

We identified studies by searching MEDLINE and PUBMED databases and reviewing relevant articles. We derived the summary risk estimates using fixed-effects or random-effects model based on homogeneity analysis. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Potential heterogeneity was tested using the Q statistic and quantified with the I ² statistic. Subgroup analyses and Galbraith plots were used to explore the potential sources of heterogeneity. Publication bias was evaluated with funnel plots and quantified by the Begg''s and Egger''s test.

Results

Fifteen studies were included in this meta-analysis. There was an overall 29% reduced risk of gastric cancer corresponding to aspirin use (RR  = 0.71, 95% CI 0.60–0.82). We found there are nonlinear frequency-risk and linear duration-risk relations between aspirin use and gastric cancer. A monotonically decreasing relation was observed only for low-frequency (≤4.5 times/week) aspirin intake (10% decreased risk for once/week, 19% for twice/week and 29% for 4.5 times/week), and the frequency threshold of aspirin use is 4.5 times per week. Regarding those with duration of aspirin use, there was a tendency towards stronger risk reduction of gastric cancer for longer aspirin use (10% decreased risk for 4 years, 19% for 8 years and 28% for 12 years), and no duration threshold was observed.

Conclusion

Our findings suggest that long-term (≥4 years) and low-frequency (1–4.5 times per week) aspirin use is associated with a statistically significant, dose-dependent reduction in the risk of gastric cancer.     

The potential utility of melatonin in the treatment of childhood cancer

Childhood cancer management has improved considerably, with the overall objective of preventing early-life cancers completely. However, cancer remains a major cause of death in children, with the survivors developing anticancer treatment-specific health problems. Therefore, the anticancer treatment needs further improvement. Melatonin is a effective antioxidant and circadian pacemaker. Through multiple mechanisms, melatonin has significant positive effects on multitude adult cancers by increasing survival and treatment response rates, and slowing disease progression. In addition, melatonin appears to be safe for children. As an appealing therapeutic agent, we herein address several key concerns regarding melatonin's potential for treating children with cancer.     

Biophysical mechanisms: a component in the weight of evidence for health effects of power-frequency electric and magnetic fields

Comparatively high exposures to power-frequency electric and magnetic fields produce established biological effects that are explained by accepted mechanisms and that form the basis of exposure guidelines. Lower exposures to magnetic fields (< 1 microT average in the home) are classified as "possibly carcinogenic" on the basis of epidemiological studies of childhood leukemia. This classification takes into consideration largely negative laboratory data. Lack of biophysical mechanisms operating at such low levels also argues against causality. We survey around 20 biophysical mechanisms that have been proposed to explain effects at such low levels, with particular emphasis on plausibility: the principle that to produce biological effects, a mechanism must produce a "signal" larger than the "noise" that exists naturally. Some of the mechanisms are impossible, and some require specific conditions for which there is limited or no evidence as to their existence in a way that would make them relevant to human exposure. Others are predicted to become plausible above some level of field. We conclude that effects below 5 microT are implausible. At about 50 microT, no specific mechanism has been identified, but the basic problem of implausibility is removed. Above about 500 microT, there are established or likely effects from accepted mechanisms. The absence of a plausible biophysical mechanism at lower fields cannot be taken as proof that health effects of environmental electric and magnetic fields are impossible. Nevertheless, it is a relevant consideration in assessing the overall evidence on these fields.     

A New Trick of an Old Molecule: Androgen Receptor Splice Variants Taking the Stage?!

Prostate cancer is the second leading cause of cancer-related death in American men. Although most prostate cancers are initially androgen-dependent and respond to androgen ablation therapy, majority of them eventually relapse and progress into incurable castration-resistant (or hormone refractory) prostate cancer. The underlying mechanisms are the focus of intensive investigation for development of more effective treatment. Mounting evidence from both clinical and basic research has demonstrated that the activity of the androgen receptor (AR) is still required for castration-resistant prostate cancer. Multiple mechanisms by which AR is re-activated under androgen-depleted conditions may be involved in the development of castration resistance. The recent identification of AR splicing variants may add another layer of complexity in AR biology. The present review summarizes recent progress in study of AR splicing variants in prostate cancer.     

The long non‐coding RNA SPRY4‐IT1: An emerging player in tumorigenesis and osteosarcoma

Accumulating evidence from genome‐wide analysis and functional studies has begun to unveil the important role of long non‐coding RNAs (lncRNAs) in cancer development. The lncRNA SPRY4‐IT1 is derived from an intron of SPRY4 gene and was originally reported to be upregulated in melanoma in which it functioned as an oncogene. Since this discovery, an increasing number of studies have investigated the expression and function of SPRY4‐IT1 in human cancers. Aberrant expression of SPRY4‐IT1 has now been documented in different cancer types, including osteosarcoma, breast, renal, oesophageal and prostate cancers. However, its deregulation and function in lung and gastric cancers remain controversial. Pertinent to clinical practice, SPRY4‐IT1 expression has been shown to predict survival of cancer patients. In this review, we summarize recent evidence concerning SPRY4‐IT1 deregulation and the associated mechanisms in human cancers. We also discuss the potential clinical utilization of this lncRNA as a diagnostic and prognostic biomarker for cancer patients.     

Homeostatic chemokine receptors and organ-specific metastasis

It has been 10 years since the role of a chemokine receptor, CXCR4, in breast cancer metastasis was first documented. Since then, the field of chemokines and cancer has grown significantly, so it is timely to review the progress, analyse the studies to date and identify future challenges facing this field. Metastasis is the major factor that limits survival in most patients with cancer. Therefore, understanding the molecular mechanisms that control the metastatic behaviour of tumour cells is pivotal for treating cancer successfully. Substantial experimental and clinical evidence supports the conclusion that molecular mechanisms control organ-specific metastasis. One of the most important mechanisms operating in metastasis involves homeostatic chemokines and their receptors. Here, we review this field and propose a model of 'cellular highways' to explain the effects of homeostatic chemokines on cancer cells and how they influence metastasis.     

Cisplatin resistance: Preclinical findings and clinical implications

Cisplatin is used for the treatment of many types of solid cancers. While testicular cancers respond remarkably well to cisplatin, the therapeutic efficacy of cisplatin for other solid cancers is limited because of intrinsic or acquired drug resistance. Our understanding about the mechanisms underlying cisplatin resistance has largely arisen from studies carried out with cancer cell lines in vitro. The process of cisplatin resistance appears to be multifactorial and includes changes in drug transport leading to decreased drug accumulation, increased drug detoxification, changes in DNA repair and damage bypass and/or alterations in the apoptotic cell death pathways. Translation of these preclinical findings to the clinic is emerging, but still scarce. The present review describes and discusses the clinical relevance of in vitro models by comparing the preclinical findings to data obtained in clinical studies.