Interferon-gamma plasma levels and presence of mouse mammary tumor virus-like env gene: Implications on the pathogenesis of breast cancer.

Mouse mammary tumor virus (MMTV) is a retrovirus that has been associated with the development of breast cancer (BC) in mice. The identification of a 95% homologous gene sequence to MMTV in human BC samples has increased interest in this hypothesis. This virus in humans received the name of mouse mammary tumor virus-like (MMTV-like). Several cytokines may be involved in the interactions between MMTV and the immune system, such as interferon-gamma (IFN-γ), which can enhance Th1-mediated antitumor immune response but it can also play a protumorigenic role by transmitting antiapoptotic and proliferative signals. Little is known about the antiviral immune response in a microenvironment with the presence of MMTV-like in BC patients. Therefore, the purpose of the present study was to quantify the plasma levels of IFN-γ in the peripheral blood of 123 neoplasia-free donors and 98 BC patients of different molecular subtypes, by enzyme-linked immunosorbent assay (ELISA), and evaluate the association of these plasma levels with the detection of the MMTV-like env gene in tumor tissue. Correlation analyzes involving IFN-γ plasma levels and clinical-pathological parameters were performed by Kendall Tau-c test. In our study, a decrease in IFN-γ levels was observed in the group of BC patients (30.85 ± 57.49 pg/ml) compared to the control group (115.00 ± 176.80 pg/ml) (p < 0.0001). In the analysis by stratified BC molecular subtypes, Luminal-A (30.79 ± 61.04 pg/ml; p < 0.0001), Luminal-B (24.74 ± 25.78 pg/ml; p = 0.0188) and triple-negative (23.95 ± 40.45 pg/ml; p = 0.0005) had a lower plasma level compared to control group. There was no significant difference between IFN-γ plasma levels of MMTV-like DNA positive samples compared to MMTV-negative samples (p = 0.2056). In general BC, patients with larger tumor size had higher IFN-γ plasma levels (Tau-c = 0.202; p = 0.019). By analyzing the MMTV-like env negative samples, we could identify that IFN-γ plasma levels were higher in larger tumor size (Tau-c = 0.222; p = 0.020) and with greater lymph node involvement (Tau-c = 0.258; p = 0.042). Also, higher IFN-γ plasma levels were observed in patients with higher histopathological grades (Tau-c = 0.384; p = 0.019) in MMTV-like env positive samples. For the first time, we assessed the association between plasma levels of IFN-γ and the presence of the MMTV-like env gene in BC samples. However, more studies are needed to clarify whether the high levels of IFN-γ in MMTV-like env positive samples are reflecting a possible antiviral immune response or whether this cytokine is promoting tumor growth.

The role of NFKB1/NFKBIA genetic variants in HPV infection: A cross-sectional cohort study.

Human Papillomavirus (HPV) is the most frequent etiological agent sexually transmitted. In the context of the immune response, NF-kB pathway plays an important role controlling the expression of several genes essential to cellular activity and structural and/or functional changes in components of this pathway can promote the development of several tumors. Thus, the study purpose was to evaluate the influence of NFKB1 rs28362491 and NFKBIA rs696 genetic variants on HPV infection and cervical lesions development. In this study 334 patients were recruited, of whom 48.8% (n = 163) were HPV infected, and considered our case group. HPV-DNA was detected by polymerase chain reaction (PCR) and the genetic variants were assessed in blood cells and tumor tissues paraffin embedded samples through restriction fragment length polymorphism analysis. Among women who were recruited for this study who were infected, 37.4% presented precursor lesions and 16.8% were diagnosed with cervical cancer (CC). The present study did not observe significant effects of the interaction between such genetic variants on HPV infection, nor on the development of lesions and progression to CC. Further studies will be important to investigate if under some circumstance the NFKB1 rs28362491 and NFKBIA rs696 genetic variants influence the progression of HPV-associated lesions.

Acute lymphoid leukemia etiopathogenesis.

Acute lymphoid leukemia (ALL) is a type of hematological neoplasm that affects the precursor cells of strains B, T  and NK, with a higher incidence in the pediatric range. The pathophysiology of ALL is characterized by chromosomal abnormalities and genetic alterations involved in the differentiation and proliferation of lymphoid precursor cells. Despite the lack of information in the literature, it is believed that leukemogenesis originates from a complex interaction between environmental and genetic factors, which combined lead to cellular modifications. Environmental factors have been evaluated as possible predisposing factors in the development of ALL but there are still conflicting results in the world literature. In this context, the aim of the present review is to discuss the major exogenous factors regarding ALL.

Effects of GSTT1 and GSTM1 polymorphisms in glutathione levels and breast cancer development in Brazilian patients.

Polymorphisms in the glutathione transferase enzymes (GSTs) genes have been associated with susceptibility to develop breast cancer (BC), but few are known regarding its role on this disease prognosis and impact on antioxidant status. This study evaluated the polymorphisms of GSTM1 and GSTT1 genes and their relationship with BC susceptibility and prognostic, as well as its impact on plasma reduced glutathione (GSH) levels. The present study included 121 women with invasive ductal BC and 151 healthy controls. Polymorphisms analyses were performed using the polymerase chain reaction (PCR) technique and GSH levels were measured with the Ellman's reagent. GSTT1 (OR 1.29; p = 0.39) and GSTM1 (OR 1.03; p = 0.91) polymorphisms did not show any association with BC susceptibility. The mean concentration values in nmol/L of GSH were 20.37 ± 5.82 for patients with null genotypes for both genes, 19.75 ± 3.47 for null GSTT1, 17.22 ± 1.35 for active GSTT1, 18.82 ± 1.96 for absent GSTM1, and 16.59 ± 1.66 for active GSTM1, but no significance was found. Therefore, it can be concluded that the behavior of these polymorphisms concerning BC might be not only related to the absence of enzymatic expression but may also be related to the body's response with its antioxidant mechanisms and it should be further studied.

Transforming growth factor beta 1 (TGFß1) plasmatic levels and haplotype structures in obesity: a role for TGFß1 in steatosis development.

BACKGROUND: Obesity is considered a chronic inflammatory disease and transforming growth factor beta 1 (TGFß1) might exert important roles in disease pathogenesis regulating adipocyte differentiation and immune-inflammatory environment. However, the role of this cytokine as a biomarker in obesity is poorly addressed. Therefore, the present study aimed to evaluate the impact of TGFB1 polymorphisms and TGFß1 plasmatic levels in obesity METHODS AND RESULTS: TGFB1 promoter region polymorphisms (rs1800468, G-800A and rs1800469, C-509 T) were evaluated in 75 obese patients and 45 eutrophic patients through PCR-RFLP and plasmatic TGFß1 was quantified through ELISA from 37 of the obese patients, and correlations with clinical and biochemical parameters were tested. Despite no association was found between TGFB1 polymorphisms and obesity susceptibility, several correlations with clinical data were noted. Among others, AC haplotype negatively correlated with plasmatic TGFß1, while plasmatic TGFß1 negatively correlated with C-reactive protein and positively correlated with liver abnormalities on ultrasound and, specifically, with steatosis presence and degree. Conversely, GT haplotype, which associates with higher TGFß1 production, was also positively correlated with the same parameters of liver abnormalities. Further, plasmatic vitamin D negatively correlated with TGFß1, while positively correlated with AC haplotype. CONCLUSION: Overall, the results indicate that TGFß1 might exert important roles in obesity pathophysiology and correlate with biochemical and clinical parameters both at systemic protein as well as at genetic level. Importantly, the consistent positive correlation at both levels with steatosis might suggest this cytokine as a biomarker for this hepatic abnormality in obese patients.

COVID-19: The question of genetic diversity and therapeutic intervention approaches.

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China's Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients' overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability.

Transforming growth factor beta 1 (TGFß1) plasmatic levels in breast cancer and neoplasia-free women: Association with patients' characteristics and TGFB1 haplotypes.

Transforming growth factor beta 1 (TGFß1) is a pleiotropic cytokine that acts in a context-dependent manner. In breast cancer (BC) this cytokine exerts subtype- and stage-specific roles, inhibiting poorly aggressive tumors while enhances the invasive potential of highly aggressive cancers. Single-nucleotide polymorphisms (SNPs) affecting TGFß1 production largely reflect this pattern of association, but studies investigating systemic TGFß1 levels in BC patients and their association with clinical features or SNPs produced conflicting conclusions. Therefore, the present work investigated plasmatic TGFß1 levels through enzyme linked immunosorbent assay (ELISA) in 341 individuals previously genotyped for four TGFB1 SNPs [G-800A (rs1800468), C-509T (rs1800469), T29C (rs1800470) and G74C (rs1800471)], encompassing 184 neoplasia-free women with clinical information regarding health status, 113 treatment-free pre-surgery BC patients and 44 treated BC patients. Results have shown that TGFß1 levels varied greatly in function of health status in neoplasia-free women, and disease-free individuals had higher TGFß1 levels than both treatment-free or treated BC patients. There was no correlation between TGFß1 with clinicopathological features in treatment-free BC general group, but it was negatively correlated with tumor size in luminal-B-HER2+ patients and with histopathological grade in triple-negative group. Also, TGFB1 ACTG haplotype (from G-800A to G74C) was associated with decreased TGFß1 levels compared to the reference GCTG haplotype, and regression analyses showed that this association was independent of age, health status or BC diagnosis. In conclusion, several factors may influence TGFß1 levels, and ACTG haplotype seems to be an important factor regulating TGFß1 production.

Polymorphisms in GSTT1 and GSTM1 genes as possible risk factors for susceptibility to breast cancer development and their influence in chemotherapy response: a systematic review.

Breast cancer (BC) is a heterogeneous and multifactorial disease. The system formed by glutathione-S-transferases (GSTs) acts to protect the organism against the oxidative stress generated by xenobiotics and their active products. Glutathione transferase mu 1 (GSTM1) and glutathione transferase theta 1 (GSTT1) present null polymorphic variants by complete deletion. The absence of these enzymes may influence the susceptibility to several diseases such as BC. This study aimed to systematically review and investigate the existence of a possible correlation between the presence/absence of these genetic variants and the development of BC and their influence in chemotherapy response. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol was used, and the searches were performed in the portal of the Virtual Health Library (VHL) and the PubMed, resulting in 21 articles. It is clear that most studies revealed a risk association between the deletion of GSTM1 and/or GSTT1 and the development and/or prognosis of BC.Moreover, it should be noted that these results of risk association were found in large part in the populations of the Americas and Europe, followed by Asians. Regarding the response to treatment, protective associations were found in the presence of GSTM1 deletion. However, due to the inconclusive results of many studies, further analysis in this area is required.

Transforming growth factor beta receptor II (TGFBR2) promoter region polymorphism in Brazilian breast cancer patients: association with susceptibility, clinicopathological features, and interaction with TGFB1 haplotypes.

PURPOSE: Transforming growth factor beta (TGFß) has paradoxical effects in breast cancer (BC), inhibiting initial tumors while promoting aggressive ones. A polymorphism on TGFBR2 promoter region (G-875A, rs3087465) increases TGFß type II receptor expression and is protective against cancer. Previously, we have shown that TGFB1 variants have subtype-specific roles in BC. This work sought to investigate the association between TGFBR2 and susceptibility and clinicopathological features in BC subgroups. METHODS: TGFBR2 G-875A was analyzed through PCR-RFLP in 388 BC patients and 405 neoplasia-free women. Case-control analyses as well as interaction with TGFB1 haplotypes previously associated with BC were tested through age-adjusted logistic regression. Correlations between G-875A and clinicopathological parameters were assessed through Kendall's Tau-b test. All statistical tests were two-tailed (α = 0.05). RESULTS: TGFBR2 G-875A was protective against BC in additive, genotypic, and dominant models. In subgroup-stratified analyses, these effects were greater in hormonal receptor-positive and luminal-A tumors, but were not significant in other subgroups. Logistic models including TGFB1 variants showed that in luminal-A tumors, G-875A retained its significance while TGFB1 haplotype showed a trend towards significance; otherwise, in HER2+ tumors TGFB1 variants remained significant while TGFBR2 showed a trend for association. There was no interaction between these genes. In correlation analyses, G-875A positively correlated with histopathological grade in total sample, and a trend towards significance was observed in triple-negative BCs. CONCLUSION: These results indicate that G-875A is a protective factor against BC, especially from luminal-A subtype, but may promote anaplasia in established tumors, consistent with TGFß signaling roles in BC.

Involvement of a mouse mammary tumor virus (MMTV) homologue in human breast cancer: Evidence for, against and possible causes of controversies.

Breast cancer (BC) is a complex and heterogeneous disease whose evolution depends on the tumor-host interaction. This type of cancer occurs when the mammary cells begin to grow wildly and become able to invade nearby tissues and/or promote metastases. Mouse mammary tumor virus (MMTV) is the accepted etiological agent of mammary tumors in mice. The identification of MMTV-like sequences and antigens in human mammary carcinoma has supported the theory that a virus homologous to MMTV (namely, HMTV) may be involved in human BC, but the role of retroviral elements in this disease remains elusive, as results from different research groups were contradictory. In the present review we present works for and against the involvement of HMTV in BC and discuss possible causes of divergences among studies. In the final section we fit current data regarding this issue to stablished causality criteria. We conclude that there is convincing data supporting the association of HMTV with BC, however there is still a need for epidemiological and basic research studies focusing on carcinogenic mechanisms for this virus in humans to fully understand its role in BC. This knowledge may open the way for the development of new preventive and therapeutic approaches in human BC.

Polymorphisms in the TGFB1 signal peptide influence human papillomavirus infection and development of cervical lesions.

The main purpose was to assess the effect of c.29C>T and c.74G>C polymorphisms in the TGFB1 signal peptide on HPV infection and development of cervical lesions. Cervical swabs and blood samples were obtained from 349 outpatient women, along with socio-demographic and sexual behavioral data. The study population was stratified by absence or presence of HPV DNA, as tested by PCR, as well as by lesion grade. TGFB1 signal peptide polymorphisms were genotyped using PCR-restriction fragment length polymorphism. HPV DNA was detected in 172 (49.3%) patients. c.74GC and the combined c.29CC+CT/c.74GC genotype were more frequent in infected patients (35.1 and 15.7%) than in uninfected women (6.2 and 14.7%). Accordingly, these genotypes were associated with a higher risk of HPV infection, with odds ratio and 95% confidence interval of 2.81 and 1.35-5.86 (P = 0.004) for c.74GC and 3.14 and 1.42-6.94 (P = 0.004) for the combined genotype, respectively. High-grade lesions were also 2.48 times more likely to occur in c.29CC patients than in c.29TT patients, with a 95% confidence interval of 1.01-6.08 (P = 0.047). The data demonstrate that c.74G>C and c.29C>T polymorphisms are significantly associated with risk of HPV infection and high-grade squamous intraepithelial lesions, respectively. Thus, TGFB1 signal peptide polymorphisms are potential susceptibility markers.

CCL5 protein level: influence on breast cancer staging and lymph nodes commitment.

Many tumor cells express chemokines and chemokine receptors, and these molecules can contribute to distinct modes of metastasis processes. It is known that they play a crucial role in breast cancer (BC) tumorigenesis and progression. Considering this, it was investigated a possible role for C-Chemokine receptor type 5(CCR5) polymorphism (rs333/delta32) by conventional polymerase chain reaction (PCR) and CCL5 (C-C motif chemokine ligand 5) protein level by immunosorbent assay (ELISA) in 47 BC patients (resulting in 47 tumoral tissue samples and 47 adjacent normal tissue samples). There was a significant difference between CCL5 level in tumoral and adjacent normal tissues for the same BC patients (p < 0.0001). A significant association was also found for CCL5 level in relation to lymph nodes commitment (p = 0.03). Likewise, there was a significant difference in CCL5 level from tumor tissue of stage III in relation to stage I (p < 0.02). On the other hand, it was verified that CCR5-delta32 polymorphism presented no significant association in relation to CCL5 protein level. Considering the present findings, we suggest that CCL5 may be involved in BC staging and metastasis process.

Interleukin 7 receptor alpha Thr244Ile genetic polymorphism is associated with susceptibility and prognostic markers in breast cancer subgroups.

Interleukin-7 (IL-7) exerts crucial functions on lymphoid cells' development and maintenance. In breast cancer (BC), IL-7 promotes growth of tumor cells in culture through the activation of JAK1/3-STAT5 and PI3K/AKT pathways, and expression of IL-7 signaling components was associated with worst prognosis. AC>T polymorphism (rs6897932; Thr244Ile) at exon 6 of IL-7 receptor alpha (IL-7Rα) gene (IL7RA) shifts the balance between the membrane-bound and soluble IL-7Rα splicing variants and was previously associated with autoimmune diseases, but has not been studied in cancer, including BC, so far. Therefore, the present study aimed to investigate the possible association of this polymorphism with the susceptibility and clinicopathological parameters of BC subgroups. IL7RA Thr244Ile was genotyped through PCR-RFLP in 403 women without neoplasia, no personal history of malignancy or family history of BC and in 338 BC patients with clinicopathological data available. BC patients were stratified according to their positivity for estrogen (ER) and/or progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Age-adjusted logistic regression was performed for case-control analyses, and correlations with clinicopathological parameters were assessed through Kendall's Tau-b coefficient. All analyses were two-tailed and had 95% confidence interval. In ER-PR-HER2- BCs, TT genotype was associated with increased susceptibility both in genotypic (TT vs. CC: OR=3.07; CI=1.01-9.38; p=0.05) and recessive (TT vs. CC+CT: OR=3.59; CI=1.19-10.85; p=0.02) models and negatively correlated with disease stage (Tau-b=-0.27; p=0.05). Whereas T allele was positively correlated with histopathological grade (Tau-b=0.29; p=0.03) and lymph node metastasis (Tau-b=0.35; p=0.02) in ER/PR+HER2+BCs and with Ki67 (Tau-b=0.51; p=0.008) in ER-PR-HER2+ subgroup. These data indicate that IL-7Rα is involved in BC, and that IL7RA polymorphism may play distinct roles in breast carcinogenesis according to BC subtype, pointing this genetic variant as an interesting marker for breast carcinogenesis to be validated by further mechanistic and prospective studies with larger samples.

Genetic variant in CXCL12 gene raises susceptibility to HPV infection and squamous intraepithelial lesions development: a case-control study.

BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted virus in women worldwide. The persistence of the virus may cause warts that are considered benign lesions and low or high grade intraepithelial lesions (LSIL/HSIL). Immunological system plays an important role in the resolution of infections. In this context, we highlight the chemokines, which are important regulators in the development of viral infections and inflammation. Among which CXCL12 stands out, due to its pro-inflammatory features, acting as chemoattractant recruiting immune cells. Several polymorphisms were identified in CXCL12 gene including rs1801157 in the 3'-untranslated region, which is characterized by a substitution of a guanine for an adenine. METHODS: In this study, 195 women were classified as HPV non-infected and 169 as HPV-infected. HPV-DNA was detected by polymerase chain reaction (PCR) and the polymorphism was assessed in blood cells through restriction fragment length polymorphism analysis. RESULTS: HPV infection was more incident in women who had more than 4 sexual partners during lifetime (p = 0.007), among those who presented lower number of pregnancies (p = 0.017). HPV was more prevalent among allele A carriers confirmed by logistic regression analysis adjusted for several confounding factors [ORADJ = 4.985; CI95% (2.85-8.72), p < 0.001]. An association between allele A carriers and HSIL development (p = 0.003) was also observed. CONCLUSIONS: In the present study, we demonstrated that CXCL12 rs1801157 is independently associated with HPV infection and exerts influence in HSIL development, suggesting it as a promising susceptibility biomarker for HPV infection and lesions development.

Potential use of CXCL12/CXCR4 and sonic hedgehog pathways as therapeutic targets in medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor occurring in children, and although high long-term survival rates have been reached with current therapeutic protocols, several neurological injuries are still observed among survivors. It has been shown that the development of MB is highly dependent on the microenvironment surrounding it and that the CXCL12 chemokine and its receptor, CXCR4 and the Sonic Hedgehog (SHH) pathway are crucial for cerebellar development, coordinating proliferation and migration of embryonic cells and malfunctions in these axes can lead to MB development. Indeed, the concomitant overactivation of these axes was suggested to define a new MB molecular subgroup. New molecules are being studied, aiming to inhibit either CXCR4 or the SHH pathways and have been tested in preclinical settings for the treatment of cancers. The use of these molecules could improve MB treatment and save patients from aggressive surgery, chemotherapy and radiotherapy regimens, which are responsible for severe neurological consequences. This review aims to summarize current data about the experimental inhibition of CXCR4 and SHH pathways in MB and its potential implications in treatment of this cancer.

CXCL12 chemokine and CXCR4 receptor: association with susceptibility and prognostic markers in triple negative breast cancer.

CXCL12/CXCR4 signaling has been implicated in breast carcinogenesis, and genetic polymorphisms in these molecules have been associated with different types of cancer. The present study analyzed genetic polymorphisms in CXCL12 (rs1801157, G > A) and CXCR4 (rs2228014, C > T) and CXCR4 immunostaining in tumor tissues from patients with triple negative breast cancer (TNBC) aiming to evaluate their possible role in its' susceptibility and prognosis. Genetic polymorphisms were analyzed in 59 TNBC patients and 150 control women; age-adjusted logistic regression showed no association when variants were considered in isolation; however, a statistically significant interaction was noted for heterozygosis for both allelic variants increasing the odds for TNBC (CXCL12-GA by CXCR4-CT: OR 7.23; 95% CI 1.15-45.41; p = 0.035). CXCL12 polymorphism was correlated negatively with proliferation index (Ki67) (Tau-b = - 0.406; p = 0.006). CXCR4 immunostaining was evaluated in 37 TNBC patients (22 with paired tumor-normal adjacent tissue). CXCR4 was detected more intensely in cell cytoplasm than in membrane, and was more expressed in tumor than in normal adjacent tissues, although not statistically significant. CXCR4 expression on the membrane of tumor cells was correlated positively with histopathological grade (Tau-b = 0.271; p = 0.036) and negatively with lymph node metastasis (Tau-b = - 0.478; p = 0.036). The present study indicates that CXCL12 and CXCR4 polymorphisms and CXCR4 immunostaining might have susceptibility and prognostic roles in TNBC pathogenesis.

HER2 Ile655Val polymorphism is negatively associated with breast cancer susceptibility.

BACKGROUND: The HER2 (human epidermal growth factor receptor-2) Ile655Val (rs1136201) genetic polymorphism can alter the receptor structure and its auto-activation, which can modify the signal transduction and, consequently, the cell cycle regulation. For this reason, this polymorphism has been extensively investigated as a candidate marker for breast cancer (BC). In this context, the aim of this study was to evaluate the possible influence of HER2 Ile655Val in BC susceptibility and prognostic factors in a Brazilian population. METHODS: Polymorphism genotype was assessed through RFLP-PCR in 107 BC patients with clinicopathological data available and in 150 women with no evidence of neoplasia and with no familial history of BC as control group. Association between this polymorphism and BC susceptibility and clinical parameters was evaluated through odds ratio (OR) and chi-squared or Fisher's exact test, respectively. RESULTS: A significant negative association between valine allele and BC susceptibility in dominant model was found (OR 0.5; 95% CI 0.27-0.93, P = .036). No significant association was found in relation to BC clinicopathological features (tumor size, lymph nodes commitment, histological grade, HER2 overexpression, hormonal receptors, p53, and Ki-67). CONCLUSION: Although this polymorphism did not demonstrate potential as a prognostic marker, it may be a suitable susceptibility marker for BC.

Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma.

Chemokines and its receptors have significant impact on physiological and pathological processes and studies concerning their association with tumor biology are subject of great interest in scientific community. CXCL12/CXCR4 axis has been widely studied due to its significant role in tumor microenvironment, but it is also important to development and maintenance of tissues and organs, for example, in the brain and cerebellum. Studies have demonstrated that CXCL12 and CXCR4 are required for normal cerebellar development and that dysfunction in this pathway may be involved with medulloblastoma pathogenesis. In this context, a new molecular subgroup has been suggested based on the importance of the association between CXCR4 overexpression and sonic hedgehog subgroup. Treatment using CXCR4 antagonists showed significant results, evidencing the important role and possible therapeutic capacity of CXCR4 in MB. This review summarizes studies on MB cell biology, focusing on a chemokine-receptor axis, CXCL12/CXCR4, that may have implications for treatment strategies once it can improve life expectancy and reduce neurocognitive sequelae of patients with this neoplasia.

CXCL12/CXCR4 axis in the pathogenesis of acute lymphoblastic leukemia (ALL): a possible therapeutic target.

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, accounting for approximately 80 % of leukemia in the pediatric group, and its etiology is unknown. This neoplasia is characterized by male predominance, high-risk features and poor outcome, mainly in recurrence patients and adults. In recent years, advances in the success of childhood ALL treatment were verified, and the rate of cure is over 80 % of individuals. However, there is a considerable scope for improving therapeutic outcome in this neoplasia. Improvements in ALL therapy might readily be achieved by developing additional biomarkers that can predict and refine prognosis in patients with ALL. In normal hematopoietic cells, cytokines provide the stimulus for proliferation, survival, self-renewal, differentiation and functional activation. Abnormalities of cytokines are characteristic in all forms of leukemia, including ALL. The stromal cell-derived factor-1 (SDF-1 or CXCL12) is a member of the CXC chemokine family that binds to CXC chemokine receptor 4 (CXCR4). The CXCL12/CXCR4 axis appears to play a role in dissemination of solid tumors and hematopoietic diseases. Understanding the mechanisms by which ALL cells are disseminated will provide additional information to expand therapeutic approach. Therefore, this review summarizes information relating to ALL cell biology, focusing specifically in a cytokine receptor important axis, CXCL12/CXCR4, that may have implications for novel treatment strategies to improve life expectancy of patients with this neoplasia.