Development Of Solid Tumors Research Articles

Pro-atherogenic high fat diet accelerates tumor growth in mice through activation of innate immunity

Inflammation is a physiologic protective process triggered in response to injury or infection. When unresolved, inflammation often promotes the development of chronic pathologies such as cancer or atherosclerosis. In atherosclerosis, hypercholesterolemia-associated monocytosis drives plaque formation in mice. Epidemiologic and experimental studies have shown the involvement of dyslipidiemia and low-grade inflammation on the development of multiple cancers. Surprisingly, the link between atherosclerosis and cancer has not been studied in details. The objective of our study was to question whether a pro-atherogenic high fat diet (HFD) would modify the development of solid tumors. Our experimental approach was to feed mice susceptible to atherosclerosis with a classical HFD (15% fat, 1.25% cholesterol) or a chow diet for 2 weeks before induction of tumor development. We monitored tumor development every two days and analyzed the mechanistic events by in vitro and in vivo experiments. We found that the proatherogenic HFD accelerated the growth of several solid tumors (B16F10 and TC1) in C57Bl6 mice, independently of cholesterol levels. In contrast, the HFD induced a significant increase of myeloid cells number in circulation and in the tumor microenvironment (flow cytometry). We isolated (Miltenyi) and analyzed the phenotype (qPCR and ELISA) of tumor-infiltrating leukocytes (TILs). We found a rapid upregulation of IL-1beta and VEGFa expression and a downregulation of several inflammatory cytokines. The supernatant of TILs isolated from mice under HFD and cultured for 48 hours, failed to reduce tumor cell proliferation in vitro (tritiated thymidine) and absence of IL-1beta, or selective depletion of neutrophils protected mice against tumor acceleration under HFD. These data show that in the context of a proaterogenic HFD, neutrophils accumulate in the tumor microenvironment and switch toward an immunosuppressive phenotype, thus promoting the fast growing of tumors.

Genomic hotspots but few recurrent fusion genes in breast cancer.

The advent of next generation sequencing technologies has boosted the interest in exploring the role of fusion genes in the development and progression of solid tumors. In breast cancer, most of the detected gene fusions seem to be "passenger" events while the presence of recurrent and driver fusions is still under study. We performed RNA sequencing in 55 well-characterized breast cancer samples and 10 adjacent normal breast tissues, complemented by an analysis of SNP array data. We explored the presence of fusion genes and defined their association with breast cancer subtypes, clinical-pathologic characteristics and copy number aberrations. Overall, 370 fusions were detected across the majority of the samples. HER2+ samples had significantly more fusions than triple negative and luminal subtypes. The number of fusions was correlated with histological grade, Ki67 and tumor size. Clusters of fusion genes were observed across the genome and a significant correlation of fusions with copy number aberrations and more specifically amplifications was also revealed. Despite the large number of fusion events, only a few were recurrent, while recurrent individual genes forming fusions with different partners were also detected including the estrogen receptor 1 gene in the previously detected ESR1-CCDC170 fusion. Overall we detected novel gene fusion events while we confirmed previously reported fusions. Genomic hotspots of fusion genes, differences between subtypes and small number of recurrent fusions are the most relevant characteristics of these events in breast cancer. Further investigation is necessary to comprehend the biological significance of these fusions.

Hepatocellular carcinoma in Gaucher disease: an international case series

Gaucher disease (GD) is associated with an increased risk for malignancies. Next to hematological malignancies, the development of solid tumors in several organs has been described. The liver is one of the major storage sites involved in GD pathogenesis, and is also affected by liver-specific complications. In this case series, we describe 16 GD type 1 (GD1) patients from eight different referral centers around the world who developed hepatocellular carcinoma (HCC). Potential factors contributing to the increased HCC risk in GD patients are studied. Eleven patients had undergone a splenectomy in the past. Liver cirrhosis, one of the main risk factors for the development of HCC, was present in nine out of 14 patients for whom data was available. Three out of seven examined patients showed a transferrin saturation > 45%. In these three patients the presence of iron overload after histopathological examination of the liver was shown. Chronic hepatitis C infection was present in three of 14 examined cases. We summarized all findings and made a comparison to the literature. We recommend that GD patients, especially those with prior splenectomy or iron overload, be evaluated for signs of liver fibrosis and if found to be monitored for HCC development.

Pediatric Solid Tumors of Infancy: An Overview.

1. Wendy Allen-Rhoades, MD, FAAP* 2. Sarah B. Whittle, MD, MS, FAAP* 3. Nino Rainusso, MD, FAAP* 1. *Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine and Texas Children's Hospital Cancer and Hematology Centers, Houston, TX * Abbreviations: AFP: : α-fetoprotein ASCT: : autologous stem cell transplant CT: : computed tomography FDA: : Food and Drug Administration MRI: : magnetic resonance imaging OMS: : opsoclonus myoclonus syndrome VIP: : vasoactive intestinal peptide 123I-MIBG: : 123I-meta-iodo-benzylguanidine Pediatricians should recognize the role of age, genetic factors, and syndromes that predispose to the development of certain pediatric solid tumors. Many symptoms of common childhood illnesses that progress or do not resolve in a timely manner should require a detailed evaluation and prompt referral to a cancer specialist. After completing this article, readers should be able to: 1. Recognize the presenting signs and symptoms of pediatric solid tumors (eg, abdominal mass, constipation, shortness of breath, back pain, bone pain, fever, and hypertension). 2. Identify the signs and symptoms of retinoblastoma, neuroblastoma, hepatoblastoma, and Wilms tumor. 3. Recommend genetic evaluation and close disease surveillance for patients with certain solid tumors or particular predisposing conditions. 4. Recognize general aspects of the multidisciplinary treatment approach in children with retinoblastoma, neuroblastoma, hepatoblastoma, and Wilms tumor. Pediatric solid tumors are a group of nonhematologic, extracranial cancers that occur during childhood. This heterogeneous group of tumors represents approximately 40% of all pediatric cancers (Fig 1). Many pediatric solid tumors are referred to as embryonal or developmental cancers because they arise in young children or adolescents as a result of alterations in the processes of organogenesis or normal growth. In this review, we address common symptoms developed in children diagnosed as having malignant solid tumors and offer a general description of the most common pediatric solid tumors in infants and young children. Common malignant solid tumors in adolescents will be addressed in a separate article. Figure 1. Percentage distribution of pediatric cancers and solid tumors in children …

Trefoil factor 1 gene alternations and expression in colorectal carcinomas.

Aberrant expression of the trefoil factor family (TFF) has been recognized to be involved in the development and/or progression of various solid tumors. Increased trefoil factor 1 (TFF1) expression is found associated with tumor progression in some tumors, and TFF1 missense mutations have been detected in gastric cancer. The aim of the study was to analyze TFF1 alternations and expression in colorectal carcinoma and their correlation with cancer progression and pathological aspects. TFF1 mutations were detected in colorectal carcinomas by DNA sequencing. TFF1 mRNA and protein levels in subsets of the primary tumors were determined using quantitative reverse transcription polymerase chain reaction and immunohistochemistry analyses. The serum level of TFF1 was also detected by enzyme-linked immunosorbent assay for patients with colorectal carcinoma. Five variants were detected in the 5'-untranslation region and intron 1 of TFF1. TFF1 expression was increased in colorectal carcinoma compared to paired distal colonic mucosa. Immunohistochemistry in primary colorectal carcinoma showed no significant differences in tumor TFF1 levels with respect to clinicopathological parameters such as the patient's sex, cancer differentiation, stage and lymph node metastasis. However, serum TFF1 levels were significantly elevated in patients with colorectal carcinoma compared to healthy individuals. The results indicate that TFF1 missense mutations seem to be a rare event in colorectal carcinogenesis. Serum TFF1 may be a potential useful marker for patients with colorectal carcinoma.

MALAT1 Promotes the Proliferation and Metastasis of Osteosarcoma Cells By Activating the Rac1/JNK Pathway Via Targeting MiR-509.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA (lncRNA) that contributes to the initiation and development of many solid tumors, including osteosarcoma (OS). In this study, we showed that MALAT1 was increased in human OS tissues and cell lines. MALAT1 knockdown suppressed OS cell growth and metastasis, induced OS cell apoptosis and delayed tumor growth in an OS xenograft model. We also detected downregulation of microRNA-509 (miR-509), a suppressor of OS growth, in OS tissues and cell lines. Then, we identified that miR-509 is a direct target of MALAT1 and Ras-related C3 botulinum toxin substrate 1 (Rac1) is a direct target of miR-509. MALAT1 may promote OS cell growth through inhibition of miR-509, leading to the activation of Rac1/JNK pathway. Our results suggest a MALAT1/miR-509/Rac1 axis that mediates OS cell proliferation and tumor progression.

The Angiogenic Chemokines Expression Profile of Myeloid Cell Lines Co-Cultured with Bone Marrow-Derived Mesenchymal Stem Cells.

Objective Angiogenesis, the process of formation of new blood vessels, is essential for development of solid tumors. At first, it was first assumed that angiogenesis is not implicated in the development of acute myeloid leukemia (AML) as a liquid tumor. One of the most important elements in bone marrow microenvironment is mesenchymal stem cells (MSCs). These cells possess an intrinsic tropism for sites of tumor in various types of cancers and have an impact on solid tumors growth by affecting the angiogenic process. But so far, our knowledge is limited about MSCs’ role in liquid tumors angiogenesis. By increasing our knowledge about the role of MSCs on angiogenesis, new therapeutic strategies can be used to improve the status of patients with leukemia. Materials and Methods In this experimental study, HL-60, K562 and U937 cells were separately co-cultured with bone marrow derived-MSCs and after 8, 16 and 24 hours, alterations in the expression of 10 chemokine genes involved in angiogenesis, were evaluated by quantitative real time-polymerase chain reaction (qRT-PCR). Mono-cultures of leukemia cell lines were used as controls. Results We observed that in HL-60 and K562 cells co-cultured with MSCs, the expression of CXCL10 and CXCL3 genes are increased, respectively as compared to the control cells. Also, in U937 cells co-cultured with MSCs, the expression of CXCL6 gene was upgraded. Moreover in U937 cells, CCL2 gene expression in the first 16 hours was lower than the control cells, while within 24 hours its expression augmented. ConclusionOur observations, for the first time, demonstrated that bone marrow (BM)-MSCs are able to alter the expression profile of chemokine genes involved in angiogenesis, in acute myeloid leukemia cell lines. MSCs cause different effects on angiogenesis in different leukemia cell lines; in some cases, MSCs promote angiogenesis, and in others, inhibit it.

Methods to Study Angiogenesis in a Mouse Model of Prostate Cancer.

Angiogenesis is one important hallmark of cancer progression which explains the relevance of developing methods to efficiently analyze the neo-angiogenic process. In this report we make use of the transgenic adenocarcinoma of the murine prostate (TRAMP) model, considered a good model for studying clinical prostate cancer progression, to describe in detail the methods used to study angiogenesis in this type of solid tumor development. In this report we provide step-by-step procedures on the basis of previous work in our laboratory for: the mouse urogenital sinus (UGS) collection; microdissection of the prostate; preparation of the prostatic samples for immunofluorescence (to analyze vascular density, morphology, maturation, functionality, hypoxia, and others); preparation of prostatic samples to histopathological analysis and/or immunohistochemistry; and endothelial and vascular mural cell sorting and isolation by fluorescent associated cell sorting (FACS) to further analysis (mRNA, protein, or other) or to maintain in culture.

Cancer and Sickle Cell Disease (SCD): Predictors of Incident Cancer and Survival Compared to Non-SCD Patients in California

▪Background: We recently reported a unique pattern of cancer incidence among sickle cell disease (SCD) patients compared to the general population, with SCD patients having a higher incidence of hematologic malignancies and lower incidence of solid tumors. As few studies have focused on cancer in SCD patients, we sought to identify risk factors for the development of cancer among SCD patients and assess cancer survival among those with SCD compared to a matched cohort of cancer patients without SCD.Methods: SCD patients were previously identified in California (1991-2014) using hospitalization and emergency department databases and linked to the California Cancer Registry to identify patients with cancer. Conditional multivariable logistic regression was used to identify risk factors for cancer development overall, and for hematologic and solid tumors separately. In these analyses, we matched each SCD cancer patient to 4 SCD patients without cancer on race/ethnicity, gender, age of SCD identification in the databases and follow-up time. Risk factors were evaluated prior to age at cancer diagnosis or matched age and included number of transfusions, SCD severity (severe SCD was defined as averaging ≥3 visits per year over the study period), and specific Elixhauser comorbidities (fluid and electrolyte disorders, deficiency anemias, coagulopathy, obesity, liver disease, renal disease, chronic pulmonary disease, rheumatoid arthritis/collagen vascular diseases, and HIV/AIDS). Univariate predictors with p<0.2 were included in the multivariable model. To determine the impact of SCD on overall and cancer-specific survival after a cancer diagnosis, conditional multivariable Cox proportional hazards regression was used, with each SCD cancer patient matched to 4 non-SCD cancer patients on age, year of diagnosis, gender, race/ethnicity, cancer site and histology. Survival models were stratified by chemotherapy and stage and adjusted for radiation treatment, neighborhood socioeconomic status, and health insurance at diagnosis/initial treatment. Results are presented as odds ratios (OR), hazard ratios (HR) and 95% confidence intervals (CI).Results: Among 6423 patients with SCD, 115 were diagnosed with a first primary cancer, with a median age of diagnosis of 46 years. In the matched analysis examining risk factors for cancer development, we included 552 SCD patients (n=112 with cancer; n=31 hematologic/n=81 solid, n=440 without cancer). Overall, deficiency anemias, coagulopathy, and liver disease were associated with an increased likelihood of cancer. In analyses by cancer type, we found that coagulopathy was associated with a 3-fold increased likelihood of developing a hematologic cancer (OR=3.09, 95% CI=1.11-8.61), and number of prior transfusions did not significantly increase the risk for hematologic cancers (Table). Deficiency anemias and coagulopathy was associated with a 2-3 fold increased likelihood of solid tumor development, but no association was observed with number of prior transfusions. In the matched analysis examining survival, we included 461 cancer patients (n=100 with SCD; n=361 without SCD). In multivariable models, SCD was associated with a 40% increased risk of all-cause mortality compared to similarly matched cancer patients without SCD; specifically, severe SCD patients were at 78% increased mortality (HR=1.78, 95% CI= 1.15-2.74), while less severe SCD patients were no different than non-SCD cancer patients (HR=1.12, 95% CI= 0.71-1.75) (Figure). However, cancer-specific mortality was not increased by SCD (HR=0.79, 95% CI=0.49-1.26).Conclusions: Deficiency anemias and coagulopathy, but not number of prior transfusions, were associated with an increased likelihood of developing cancer. In addition, SCD patients with severe disease had worse survival than a matched non-SCD cancer cohort. However, cancer-specific survival was not affected by SCD. These results suggest that cancer outcomes in patients with SCD may not differ from those without SCD, and SCD cancer patients should be treated with curative intent. [Display omitted] DisclosuresWun:Janssen: Other: Steering Committee for Cassini Study and Callisto Program, Research Funding; Pfizer: Other: Steering Committee: RESET study, Research Funding.

Overexpression of miR-19a inhibits colorectal cancer angiogenesis by suppressing KRAS expression

The microRNA miR-19a is closely related to tumor formation and development and is a key oncogene. Previous studies have demonstrated that miR-19a is upregulated in multiple cancer types, including colorectal cancer (CRC). However, most of these experiments were performed invitro, and consequently, the mechanisms underlying the effects of miR-19a on CRC are still unclear. Therefore, in the present study, we investigated the role of miR-19a in the development of solid CRC tumors. We generated KRAS 3'UTR-Mut by deleting the predicted binding site for miR-19a in KRAS, and observed that the expression of a reporter gene containing the KRAS 3'UTR in HCT116 cells was suppressed by miR-19a, while that of a reporter gene with mutant KRAS 3'UTR was unaffected by miR-19a. We observed that high miR-19a levels reduced KRAS expression. In the tube formation assay, overexpression of miR-19a exhibited anti-angiogenesis effects, which were rescued by KRAS expression. We established a nude mouse xenograft model to investigate the specific role of miR-19a in solid tumors. The results revealed that the sizes of xenograft tumors and density of blood vessels developed from HCT116 cells expressing miR-19a were smaller/lower compared with those of the control. KRAS and VEGFA levels were also reduced. In conclusion, our results revealed that miR-19a overexpression supressed KRAS expression and angiogenesis in CRC, indicating possibilities of using miR-19a in future therapeutic applications.

Down syndrome and microRNAs.

In recent years numerous studies have indicated the importance of microRNAs (miRNA/miRs) in human pathology. Down syndrome (DS) is the most prevalent survivable chromosomal disorder and is attributed to trisomy 21 and the subsequent alteration of the dosage of genes located on this chromosome. A number of miRNAs are overexpressed in down syndrome, including miR-155, miR-802, miR- 125b-2, let-7c and miR-99a. This overexpression may contribute to the neuropathology, congenital heart defects, leukemia and low rate of solid tumor development observed in patients with DS. MiRNAs located on other chromosomes and with associated target genes on or off chromosome 21 may also be involved in the DS phenotype. In the present review, an overview of miRNAs and the haploinsufficiency and protein translation of specific miRNA targets in DS are discussed. This aimed to aid understanding of the pathogenesis of DS, and may contribute to the development of novel strategies for the prevention and treatment of the pathologies of DS.

Assessment of electrochemotherapy effects on the development of Ehrlich solid tumor in swiss mice using a novel electroporator device

ABSTRACT Electrochemotherapy is a local anticancer treatment in which non-permeant chemotherapeutic drugs are associated with electric pulses of well-established parameters. The electric pulses cause pores to open on the plasma membrane and facilitate drug transport, enhancing cytotoxicity and reducing side effects. Assessment of electrochemotherapy effects on Ehrlich solid tumor development in this work aims to evaluate in vivo usage of the electroporator device developed by the Department of Electrical Engineering of Engineering School of UFMG. Therefore, 40 Swiss mice were inoculated with Ehrlich tumor cells, and developed the tumor in solid form. After 21 days, mice were subjected to specific treatment protocols (control, bleomycin, electric pulses and electrochemotherapy); 17 days later they were euthanized and the tumors collected for histopathology analysis. Electrochemotherapy induced discrete weight loss and an inflammatory response in the tumor, which was not seen on the other treatment groups. Bleomycin alone induced necrosis. Both groups showed lower cellular proliferation rates. From this study, it was concluded that the animals tolerated electrochemotherapy treatment under anesthesia and the electroporator device developed by the Engineering School of UFMG was adequate when used in an electrochemotherapy protocol.

POTENTIAL ANTI-TUMOR AND ANTI-INFLAMMATORY ACTIVITY OF SIX MISTLETOE PLANTS IN THE FAMILY VISCACEAE PRESENT IN WESTERN GHATS, INDIA

ABSTRACTObjectivesTo find out the cytotoxicity, anti-tumor and anti-inflammatory activities of six species of plants belongs to Viscaeceae family available in Western Ghats (India).MethodsIn vitro cytotoxicity of Viscum extracts was studied by trypan blue exclusion method and MTT assay using various cell lines. Anti-tumor activity was determined using Ehrlich ascites carcinoma (EAC) and Dalton’s lymphoma ascites (DLA) cells in mice. Anti-inflammatory activities of Viscum extracts were studied using carrageenan and dextran induced mouse paw edema models in mice.ResultsAll six Viscaeceae plant extracts studied were cytotoxic towards transformed cell lines like DLA and EAC as well as to MCF-7, MDA-MB-231 and SKBR3 cell lines. V.orientale, V.nepalense and V.ramosissimum, V.trilobatum were cytotoxic towards normal cells while V.angulatum and V.capitellatum were found to be nontoxic. Excepting V.angulatum all the other species selected here showed toxicity to animals. Administration of nontoxic concentration of extracts of Viscaeceae plants significantly (P&lt;0.001) increased the lifespan of ascites tumor bearing animals and reduced DLA cells induced solid tumor development. All these plants except V.capitallatum and V.trilobatum showed significant (P&lt;0.001) anti-inflammatory activity against carrageenan and dextran models and reduced pro-inflammatory cytokine levels.ConclusionOut of six species studied four species of Viscum species studied were cytotoxic to tumour cells and inhibited tumour development. Of the six species studied V. angulatum was non-toxic to animals and showed maximum efficiency as an antitumour agent. These plants showed significant anti-inflammatory activity and reduced inflammatory markers.

BANCR contributes to the growth and invasion of melanoma by functioning as a competing endogenous RNA to upregulate Notch2 expression by sponging miR‑204.

BRAF-activated non-coding RNA (BANCR) is a long non-coding RNA (lncRNA) that contributes to the initiation and development of many solid tumors, including melanoma. However, the BANCR functions and downstream mechanisms are largely unknown. In this study, we aim to investigate how BANCR participates in the proliferation and migration of malignant melanoma and elucidate the underlying mechanism in this process. We found that the expression of the BANCR was low in melanocytic nevus and human melanocytes but high in melanoma tissues and cell lines. Knockdown of BANCR inhibited melanoma cell proliferation and invasion, and induced cell apoptosis. The decreased expression of relative marker proteins further demonstrated the inhibitory effect of BANCR siRNA in cell growth and migration. Then, we detected downregulation of microRNA-204 (miR‑204), a suppressor of melanoma growth, in melanoma tissues and cell lines. We identified that miR‑204 was a direct target of BANCR and neurogenic locus notch homolog protein 2 (Notch2) was a direct target of miR‑204. BANCR may promote melanoma cell growth through inhibition of miR‑204, leading to the activation of Notch2 pathway. By tumorigenicity assay in BALB/c nude mice, we further demonstrated that BANCR knockdown inhibited tumor growth in vivo. Our results suggest the BANCR/miR‑204/Notch2 axis mediates melanoma cell proliferation and tumor progression.

Mitogen-activated Protein Kinase (MAPK) Interacting Kinases 1 and 2 (MNK1 and MNK2) as Targets for Cancer Therapy: Recent Progress in the Development of MNK Inhibitors.

MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development and progression of solid tumors and hematological malignancies has been widely discussed, particularly in the context of cap dependent translation, regulated by phosphorylation of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic, cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL, SMAD2, β-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation. MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor effects observed in genetic knockout and RNA interference experiments and at the same time lack of adverse effects in dual knockout animals. There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not only tools for further basic research studies but also potential drugs in diseases characterized by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive due to the absence of potent and selective probes. Moreover, in many instances, hypotheses have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently running at the preclinical stage. This review aims to provide an overview of recent progress in the development of MNK inhibitors.

Cellular senescence and colorectal cancer

Apart from proliferation and cell death, cellular senescence is an important response to numerous stress-associated stimuli. Originally described as an in vitro phenomenon, it is involved in various physiological and pathophysiological processes. For example, during the development of solid and generalized tumors, senescence induction poses an important barrier against disease progression. This could be demonstrated for malignant lymphomas, melanomas and various carcinomas using sophisticated animal models. However, senescent cells remain highly secretorically active and have aprofound effect on neighboring cells as well as the entire tissue network. This article tries to provide insight into the current literature and discusses clinical implications and future applications.

Identification of the S100 fused-type protein hornerin as a regulator of tumor vascularity

Sustained angiogenesis is essential for the development of solid tumors and metastatic disease. Disruption of signaling pathways that govern tumor vascularity provide a potential avenue to thwart cancer progression. Through phage display-based functional proteomics, immunohistochemical analysis of human pancreatic ductal carcinoma (PDAC) specimens, and in vitro validation, we reveal that hornerin, an S100 fused-type protein, is highly expressed on pancreatic tumor endothelium in a vascular endothelial growth factor (VEGF)-independent manner. Murine-specific hornerin knockdown in PDAC xenografts results in tumor vessels with decreased radii and tortuosity. Hornerin knockdown tumors have significantly reduced leakiness, increased oxygenation, and greater apoptosis. Additionally, these tumors show a significant reduction in growth, a response that is further heightened when therapeutic inhibition of VEGF receptor 2 (VEGFR2) is utilized in combination with hornerin knockdown. These results indicate that hornerin is highly expressed in pancreatic tumor endothelium and alters tumor vessel parameters through a VEGF-independent mechanism.

The expression of vasohibin-1 and its prognostic significance in bladder cancer.

Angiogenesis is important in the development of solid tumors. Vasohibin-1 (VASH-1) is an endothelium-derived protein that acts as an inhibitor of angiogenesis in many different types of cancer. However, the expression of VASH-1 and its clinical value in bladder cancer remain unknown. The current study analyzed the expression of VASH-1, as well as the expression of the angiogenesis-related factors vascular endothelial growth factor-A, hypoxia inducible factor-1α and cluster of differentiation 34 in bladder cancer tissues from 50 patients using immunohistochemistry. The associations between the expression of these factors and the clinicopathological characteristics of the patients were assessed. The current study demonstrated that VASH-1 is primarily expressed in the cytoplasm of bladder cancer cells and in a fraction of vascular endothelial cells. Furthermore, the expression of VASH-1 was positively associated with the tumor stage (P<0.01), pathological grade (P<0.01) and distant metastasis (P<0.05) but not with patient age or sex (P>0.05). Spearman rank correlation tests indicated that levels of those four factors were positively correlated with each other. Kaplan-Meier analysis indicated that high expression of these four factors was significantly associated with lower 5-year overall survival and progression-free survival rates. Collectively, the results of the current study suggest that VASH-1 is clinically significant in bladder cancer and its high expression may predict the progression and prognosis of patients with bladder cancer. The present study also implies that VASH-1 may be a novel target for vascular targeting therapy.

Inhibition of Human Class I vs Class III Phosphatidylinositol 3'-Kinases.

Most investigations of phosphatidylinositol 3'-kinase (PI3K) drug inhibition have been via assays based on ADP appearance or ATP consumption (e.g., Liu, Q., et al. ( 2011 ) J. Med. Chem. 54 , 1473 - 1480 ). However, at least some PI3K isoforms show basal ATPase activity in the absence of PI lipid substrate(s), which may complicate quantification of drug potency, isoform specificity of some drugs, and synergy for drug combinations. In this study, we probe the class I vs class III isoform specificity of a selected set of PI3K inhibitors using a simple, inexpensive, semi high-throughput assay that quantifies production of phosphatidylinositol 3'-phosphate (PI3P) from phosphatidylinositol. Results are compared to previous data largely generated using ATPase activity assays. Good agreement between EC50 values computed via ATPase assays vs the reported PI3P formation assay is found for most drugs, but with a few exceptions. Furthermore, for the first time, drug inhibition of class I vs class III enzymes is compared side-by-side with the same assay for the important class I-specific inhibitors GSK2126458 ("Omipalisib") and NVP-BGT226 ("BGT226") currently in clinical development for advanced solid tumors.

English

High levels of cyclooxygenase (COX) enzymes and its metabolites, especially prostaglandin E2 (PGE2) are generated in inflammatory conditions and, eventually, can contribute to neoplasms growth, justifying, in certain malignancies. COX occurs in two major isoforms, physiologically as isoform COX-1 and during inflammation as COX-2. In certain neoplasms, benefits are reported with the use of the selective COX-2 inhibitor drug, meloxicam. This study aimed to evaluate the effect of meloxicam on the development of solid Ehrlich tumor. Fourteen male Swiss mice, 30-45 days old, 35-45 g of weight, were inoculated with 107 of the tumor cells, and divided in two groups according to the treatment: Phys) 0.1 mL intraperitoneal injection (IP) of sterile 0.9% saline solution, and Mel) treated with meloxicam, 2 mg/kg, 0.1 mL, IP, both once a day. After 21 days, all the animals were euthanized and the tumor removed, weighed and prepared for histomorphometric and immunohistochemical evaluation for COX-2. Mel group presented significantly reduction of the tumor weight and COX-2 production, as well as an increase in stromal component, but did not interfere in tumor growth, in comparison to Phys group. From these results it was concluded that meloxicam did not restrain tumor growth in this experimental model. Reduction in tumor weight alone cannot be taken as a reliable criterion for evaluation of tumor progression. &nbsp; Key words: Ehrlich solid tumor, arachidonic acid, inflammation, Meloxicam.