Ricardo Ney Oliveira Cobucci

The Role of the Mediators of Inflammation in Cancer Development

Epigenetic disorders such as point mutations in cellular tumor suppressor genes, DNA methylation and post-translational modifications are needed to transformation of normal cells into cancer cells. These events result in alterations in critical pathways responsible for maintaining the normal cellular homeostasis, triggering to an inflammatory response which can lead the development of cancer. The inflammatory response is a universal defense mechanism activated in response to an injury tissue, of any nature, that involves both innate and adaptive immune responses, through the collective action of a variety of soluble mediators. Many inflammatory signaling pathways are activated in several types of cancer, linking chronic inflammation to tumorigenesis process. Thus, Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, growth, invasion, and metastasis, affecting also the immune surveillance. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. A range of inflammation mediators, including cytokines, chemokines, free radicals, prostaglandins, growth and transcription factors, microRNAs, and enzymes as, cyclooxygenase and matrix metalloproteinase, collectively acts to create a favorable microenvironment for the development of tumors. In this review are presented the main mediators of the inflammatory response and discussed the likely mechanisms through which, they interact with each other to create a condition favorable to development of cancer.

Assessing the impact of HAART on the incidence of defining and non-defining AIDS cancers among patients with HIV/AIDS: a systematic review.

After highly active antiretroviral therapy (HAART) became widespread, several studies demonstrated changes in the incidence of defining and non-defining AIDS cancers among HIV/AIDS patients. We conducted a systematic review of observational studies evaluating the incidence of malignancies before and after the introduction of HAART in people with HIV/AIDS. Eligible studies were searched up to December 2012 in the following databases: Pubmed, Embase, Scielo, Cancerlit and Google Scholar. In this study, we determined the cancer risk ratio by comparing the pre- and post-HAART eras. Twenty-one relevant articles were found, involving more than 600,000 people with HIV/AIDS and 10,891 new cases of cancers. The risk for the development of an AIDS-defining cancer decreased after the introduction of HAART: Kaposis sarcoma (RR=0.30, 95% CI: 0.28-0.33) and non-Hodgkins lymphoma (RR=0.52, 95% CI: 0.48-0.56), in contrast to invasive cervical cancer (RR=1.46, 95% CI: 1.09-1.94). Among the non-AIDS-defining cancers, the overall risk increased after the introduction of HAART (RR=2.00, 95% CI: 1.79-2.23). The incidence of AIDS-defining cancers decreased and the incidence of non-AIDS-defining cancers increased after the early use of HAART, probably due to better control of viral replication, increased immunity and increased survival provided by new drugs.

Effects of physical activity on breast cancer prevention: a systematic review.

BACKGROUND Observational studies have reported an association between physical activity and breast cancer risk reduction. This study aims to evaluate the effect of physical activity on breast cancer prevention. METHODS Articles were identified through literature available on Electronic databases (PubMed, Embase, Scielo, Cochrane, CINAHL, Cancerlit, and Google Scholar) and manual searches. Case control and cohort studies were assessed for methodological quality, using the Newcastle-Ottawa scale. RESULTS Size, population, components, and characteristics of physical activity, and menopausal status were documented. Review Manager 5.1 performed analysis using the statistical method of Mantel-Haenszel. Fixed-effect analysis with dichotomous data, testing subgroups and calculating odds ratio with a confidence interval of 95% were used. MAIN RESULTS 7 cohort studies and 14 case control studies were evaluated. Statistical evidence found that physical activity reduces the risk of breast cancer in case-control studies [OR = 0.84 (0.81-0.88)] (heterogeneity 72%) and cohort studies [OR = 0.61 (0.59-0.63)] (heterogeneity 100%). CONCLUSION Physical activity seems to prevent breast cancer mainly in postmenopausal women.

Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review)

Inflammation is a defense strategy against invading agents and harmful molecules that is activated immediately following a stimulus, and involves the release of cytokines and chemokines, which activate the innate immune response. These mediators act together to increase blood flow and vascular permeability, facilitating recruitment of effector cells to the site of injury. Following resolution of the injury and removal of the stimulus, inflammation is disabled, but if the stimulus persists, inflammation becomes chronic and is strongly associated with cancer. This is likely to be due to the fact that the inflammation leads to a wound that does not heal, requiring a constant renewal of cells, which increases the risk of neoplastic transformation. Debris from phagocytosis, including the reactive species of oxygen and nitrogen that cause damage to DNA already damaged by the leukotrienes and prostaglandins, has an impact on inflammation and various carcinogenic routes. There is an association between chronic inflammation, persistent infection and cancer, where oncogenic action is mediated by autocrine and paracrine signals, causing changes in somatic cells under the influence of the microbial genome or of epigenetic factors. Among the infectious agents associated with cancer, certain genotypes of human papillomavirus (HPV) stand out. HPV is responsible for virtually all cases of cervical cancer and a lower proportion of cancers of the vagina, vulva, anus, penis and a number of extragenital cancers. In the present review, recent advances in the mechanisms involved in the inflammatory response are presented with their participation in the process of carcinogenesis, emphasizing the role of chronic inflammation in the development of HPV-induced cervical cancer.

Safety, tolerability and side effects of human papillomavirus vaccines: a systematic quantitative review

Recently, many studies have evaluated HPV vaccine safety and adverse effects. Two vaccines have been recently evaluated in randomized controlled trials: the bivalent vaccine for HPV 16 and 18 (Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and the quadrivalent vaccine for HPV 6, 11, 16, and 18 (Gardasil, Merck and Co., Inc., Whitehouse Station, NJ). We have performed a systematic review of all randomized controlled trials in which HPV vaccines were compared with placebo regarding safety, tolerability and adverse effects. Studies were searched up to March 2013 in the databases: Pubmed, Embase, Scielo and Cancerlit. Odds Ratios (OR) of most incident adverse effects were obtained. Twelve reports, involving 29,540 subjects, were included. In the HPV 16/18 group, the most frequently reported events related to the vaccine were pain (OR 3.29; 95% CI: 3.00-3.60), swelling (OR 3.14; 95% CI: 2.79-3.53) and redness (OR 2.41; 95% CI: 2.17-2.68). For the HPV 6/11/16/18 group the events were pain (OR 2.88; 95% CI: 2.42-3.43) and swelling (OR 2.65; 95% CI: 2.0-3.44). Concerning the HPV 16/18 vaccine, pain was the most common outcome detected. These effects can be due to a possible VLP-related inflammation process. Fatigue was the most relevant general effect observed followed by fever, gastrointestinal symptoms, and headache. In the HPV 6/11/16/18 group, only general symptoms, pain and swelling were observed. Pain and swelling were the most frequent. Comparing HPV 16/18 to HPV 6/11/16/18 vaccines, the former presented more adverse effects, perhaps because there are many more trials evaluating the bivalent vaccine. Other studies are needed to clarify this issue.

Comparative incidence of cancer in HIV-AIDS patients and transplant recipients

BACKGROUND Studies have found a relationship between decreased immunity and increased incidence of cancer. METHODS A systematic review of observational studies evaluating the incidence of cancer in both organ recipients and people with HIV/AIDS compared with the general population. Eligible studies were searched up to March 2011 in the following databases: Pubmed, Embase, Scielo, Cancerlit and Google scholar. In this study, the standardized incidence ratios (SIR) of cancer in people with HIV/AIDS and of organ transplant recipients were compared with those found among the general population. RESULTS Twenty-five studies of transplant and HIV-associated cancer risk, involving 866776 people with HIV/AIDS or organ recipients and 21260 new cases of cancer, were included. The risk for the development of new cancer cases was higher among people with HIV/AIDS (SIR=4, IC95% 3.78-4.24) and who received organs (SIR=3.28, IC95% 3.06-3.52) when compared with the general population. CONCLUSION Similar SIR in both immunocompromised populations suggests that the weakened immune system is responsible for the increased risk of new cases of cancer among these groups. Research investments are needed to develop effective cancer prevention strategies in these populations.

Macrophage Migration Inhibitory Factor (MIF): Biological Activities and Relation with Cancer.

Macrophage migration inhibitory factor (MIF) emerged in recent years as an important inflammation mediator, playing a prominent role in the pathogenesis of various types of malignant neoplasm. MIF is a glycoprotein that presents a wide spectrum of biological activities and exerts a complex interaction with various cellular signaling pathways, causing imbalance of homeostasis. Experimental and clinical studies show that high levels of MIF are found in almost all types of human cancers and are implicated in seemingly all stages of development of the tumors. The production of MIF is triggered through an autocrine signal emitted by tumor cells, and stimulates the production of cytokines, chemokines, and growth as well as angiogenic factors that lead to growth of the tumor, increasing its aggressiveness and metastatic potential. MIF is produced by virtually all types of human body cells, in response to stress caused by different factors, leading to pathological conditions such as chronic inflammation and immunomodulation with suppression of immune surveillance and of immune response against tumors, angiogenesis, and carcinogenesis. In this review, we present recent advances on the biological activity of MIF, the signaling pathways with which it is involved and their role in tumorigenesis.

Immunohistochemical expression of p16, Ki-67 and p53 in cervical lesions – A systematic review

This study evaluated the immunohistochemical (IHC) expression of p16, p53 and Ki-67 in precancerous lesions and in cervical cancer (CC). Identification and review of publications assessing IHC expression in cervical intraepithelial neoplasia (CIN) and CC until February 15, 2017. Systematic review of studies in women with and without cervical lesions in order to evaluate whether there is overexpression of these biomarkers. A total of 28 publications met the criteria which included 6005 patients. The analysis showed that there is higher IHC expression of these biomarkers associated with the more severe lesions. Nineteen out of 22 evaluated studies have shown that there is a higher p16 expression in more severe lesions (CC), while in p53 expression only 4 out of the 9 studies showed a higher expression among more severe cases. Regarding the Ki-67 expression, it was observed that 9 out of 14 studies showed higher expression in more severe lesions. A complete absence of or just minimal IHC expression was observed in the normal cervical epithelium, whilst a significant increase in the expression of these biomarkers was detected according to the severity of lesions. Results suggest that these biomarkers can be considered useful tools for discriminating between the stages of the progressive cervical disease.

Safety of Human Papillomavirus 9-Valent Vaccine: A Meta-Analysis of Randomized Trials

Vaccination against human papillomavirus (HPV) has been progressively implemented in most developed countries for approximately 10 years. In order to increase the protection of the vaccines, a 9-valent vaccine (HPV9) was developed, which provides protection against nine types of the virus. Studies evaluating its safety are rare. Thus, we performed a meta-analysis of three clinical trials assessing adverse effects on women randomly vaccinated with HPV9 or tetravalent vaccine (HPV4), with the objective of analyzing whether the HPV9 is as safe as HPV4. An electronic data search was performed through the PubMed, Embase, Scopus, Web of Science, and SciELO databases. The studies selected 27,465 women who received one of the two vaccines. Pain (OR 1.72; 95% CI 1.62–1.82) and erythema (OR 1.29; 95% CI 1.21–1.36) occurred significantly more in the HPV9 group. However, there was no significant difference between the groups for the following adverse effects: headache (OR 1.07; 95% CI 0.99–1.15), dizziness (OR 1.09; 95% CI 0.93–1.27), and fatigue (OR 1.09; 95% CI 0.91–1.30), and the occurrence of serious events related to vaccination was similarly rare among those vaccinated. Therefore, our findings demonstrate that HPV9 in female patients is as safe as the tetravalent vaccine.

Th17 response in patients with cervical cancer (Review)

Persistent infection by high-risk human papillomavirus (HR-HPV) is the main risk factor for uterine cervical cancer (UCC). However, viral infection alone is not sufficient for the development and progression of premalignant cervical lesions for cancer. In previous years it has been suggested that the adaptive immune response triggered by the differentiation of naïve helper T cells in Th17 cells may serve an important role in disease development. It has been hypothesized that Th17 cells may be involved in the promotion of UCC, as high levels of interleukin 17 (IL17) expression have been detected in the mucosa of the uterine cervix of patients affected by the disease. However, the role of Th17 cells in the tumor development and progression remains unclear. It is believed that the immune response of the Th17 type during persistent infection of the genital tract with HR-HPV triggers chronic inflammation with a long duration with the production of IL17 and other pro-inflammatory cytokines, creating a favorable environment for tumor development. These cytokines are produced by immune system cells in addition to tumor cells and appear to function by modulating the host immune system, resulting in an immunosuppressive response as opposed to inducing an effective protective immune response, thus contributing to the growth and progression of the tumor. In the present review, the latest advances are presented about the function of Th17 cells and the cytokines produced by them in the development and progression of UCC.