Single-cell analysis identified POSTN+ cells associated with the aggressive phenotype and risk of esophageal squamous cell carcinoma.

Tumors are intricate and heterogeneous systems characterized by mosaic cancer cell populations with diverse expression profiles. Leveraging single-cell technologies, we employed the Scissor algorithm to delineate an epithelial subpopulation associated with the aggressive phenotype in esophageal squamous cell carcinoma (ESCC). This identified subpopulation exhibited elevated expression of genes involved in critical pathways, such as epithelial-mesenchymal transition and PI3K-Akt. Key signature genes within this subpopulation, namely CAV1, COL3A1, COL6A1, POSTN, and TAGLN, demonstrated significant upregulation concomitant with both tumorigenesis and tumor progression across independent single-cell datasets. Furthermore, we selected 1,450 expression quantitative trait loci of the top 62 signature genes of this cell subpopulation to investigate their potential in predicting ESCC risk. The results showed that the POSTN loci were predominantly associated with ESCC susceptibility. Through functional annotation and replication analyses, we identified that the rs1028728 in the POSTN promoter was significantly associated with increased ESCC risk in 7,049 ESCC cases and 8,063 controls (odds ratio = 1.29, 95% confidence interval: 1.18-1.42, p = 4.03 × 10-8). Subsequent biochemical experiments showed that the rs1028728[T] allele enhanced POSTN expression by affecting the binding of PRRX1 in the POSTN promoter. In summary, our meticulous single-cell analysis delineates an invasive epithelial subpopulation in ESCC, with POSTN emerging as an important marker for the aggressive phenotype. These findings offer more insights into potential strategies for the prevention and intervention of ESCC, enriching our understanding of this complex cancer landscape.

Activation of oncogenic signaling kinase PAK1 by ionising radiation confers an aggressive phenotype in head and neck squamous cell carcinoma.

Head and neck squamous cancers are very aggressive tumors often diagnosed in late stages with poor prognosis. HNSCCs are usually treated by a course of radiation (IR) therapy and followed by surgery. These treatment regimens fail to bring a complete response. Molecular signatures in tumors are attributed to this response and an improved understanding of the signaling events could offer new avenues for therapy. Here, we show that P21 activated kinase-1 (PAK1) - an oncogenic signaling serine/threonine kinase, is activated upon exposure to IR and this leads to an accelerated tumorigenic character in HNSCC cells. Our results show that PAK1 is highly expressed in HNSCC cell lines, as compared to normal buccal mucosa cells and when HNSCC cells were exposed to IR, they show activated PAK1 and an aggressive phenotype as determined by in vitro functional assays. PAK1 levels were elevated in HNSCC as compared to adjacent normal oral tissues and our results also show convincing evidence of activated PAK1 in patient tumor samples of post- IR treatment as compared to pre-IR treatment and is associated with poor survival. Pak1 Knockout (KO) clones in HNSCC cells showed that they were more sensitive to IR as compared to wild type (wt) cells. This altered sensitivity to IR was attributed to enhanced DNA damage response modulated by PAK1 in cells. Overall, our results suggest that PAK1 expression in HNSCC could be a critical determinant in IR therapy response and silencing PAK1 is likely to be a treatment modality to improve clinical outcomes.

Pre-Exposure to Stress-Inducing Agents Increase the Anticancer Efficacy of Focused Ultrasound against Aggressive Prostate Cancer Cells.

Despite the initial success in treatment of localized prostate cancer (PCa) using surgery, radiation or hormonal therapy, recurrence of aggressive tumors dictates morbidity and mortality. Focused ultrasound (FUS) is being tested as a targeted, noninvasive approach to eliminate the localized PCa foci, and strategies to enhance the anticancer potential of FUS have a high translational value. Since aggressive cancer cells utilize oxidative stress (Ox-stress) and endoplasmic reticulum stress (ER-stress) pathways for their survival and recurrence, we hypothesized that pre-treatment with drugs that disrupt stress-signaling pathways in tumor cells may increase FUS efficacy. Using four different PCa cell lines, i.e., LNCaP, C4-2B, 22Rv1 and DU145, we tested the in vitro effects of FUS, alone and in combination with two clinically tested drugs that increase Ox-stress (i.e., CDDO-me) or ER-stress (i.e., nelfinavir). As compared to standalone FUS, significant (p < 0.05) suppressions in both survival and recurrence of PCa cells were observed following pre-sensitization with low-dose CDDO-me (100 nM) and/or nelfinavir (2 µM). In drug pre-sensitized cells, significant anticancer effects were evident at a FUS intensity of as low as 0.7 kW/cm2. This combined mechanochemical disruption (MCD) approach decreased cell proliferation, migration and clonogenic ability and increased apoptosis/necrosis and reactive oxygen species (ROS) production. Furthermore, although activated in cells that survived standalone FUS, pre-sensitization with CDDO-me and/or nelfinavir suppressed both total and activated (phosphorylated) NF-κB and Akt protein levels. Thus, a combined MCD therapy may be a safe and effective approach towards the targeted elimination of aggressive PCa cells.

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.

In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High-grade (Gleason 8-10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95% CI 2.0-10.7, P = .0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy.

LncRNA TBX5-AS1 Regulates the Tumor Progression Through the PI3K/AKT Pathway in Non-Small Cell Lung Cancer.

PURPOSE: Long non-coding RNAs (lncRNAs) have been reported to play important roles in tumor biology. In this study, we aimed to investigate the effects of T-box transcription factor 5 antisense RNA 1 (TBX5-AS1) on aggressive phenotypes of non-small cell lung cancer (NSCLC) cells and explore its regulatory pathway. METHODS: The expression of TBX5-AS1 in tissues, plasma, and cells was determined by qRT-PCR. Cell viability, proliferation, migration, invasion, and apoptosis were assessed using MTT, colony formation, wound-healing, Transwell, and flow cytometry assay, respectively. Western blot analysis was performed to measure the expression of apoptosis-related proteins. Besides, transfected cells were exposed to PI3K activator (740Y-P) to verify the regulatory pathway. RESULTS: TBX5-AS1 expression was down-regulated in NSCLC tissues, plasma, and cells, and associated with lymph node metastasis and histological grade. Overexpression of TBX5-AS1 inhibited cell viability, colony formation, migration, and invasion, while it promoted apoptosis. Conversely, knockdown of TBX5-AS1 showed the completely opposite results. Additionally, western blot showed that the phosphorylation of PI3K and AKT was stimulated by TBX5-AS1 knockdown and suppressed by TBX5-AS1 overexpression. The addition of 740Y-P in transfected cells reversed the TBX5-AS1-induced inhibition of PI3K and AKT phosphorylation and effects on aggressive phenotypes of NSCLC cells. CONCLUSION: The study confirmed the down-regulation of TBX5-AS1 in patients with NSCLC and its association with the progression. We innovatively proposed a possible model of TBX5-AS1-mediated gene regulation in NSCLC progression that TBX5-AS1 inhibited the aggressive phenotypes of NSCLC cells through inactivating the PI3K/AKT pathway. This finding provided a novel insight into NSCLC pathogenesis.

Aggressive utilization of liver allografts: Improved outcomes over time.

BACKGROUND: Aggressive acceptance of liver allografts has driven utilization of marginal allografts. Our aim was to assess the impact of the aggressive phenotype on transplant center outcomes over time. METHODS: We used a cohort of 148 361 candidates from the Organ Procurement and Transplantation Network for liver transplantation between 2002 and 2016 in 134 centers. Using the Discard Risk Index, we designated high probability discard allografts by the top 10th percentile for likelihood of discard. Aggressive phenotype was defined by usage of high probability discard (HPD) allografts (top 10th percentile). Our analysis of survival on waitlist and graft survival after transplantation included a comprehensive list of center level covariates across three equal time periods (2002-2006, 2007-2011, and 2012-2016). RESULTS: After adjusting for recipient and center-level factors, aggressive centers had improving graft survival over time. Aggressive vs non-aggressive centers: 2002-2006 HR 1.12 (1.05-1.19), 2007-2011 HR 1.13 (1.05-1.22), 2012-2016 HR 0.99 (0.89-1.10). Aggressive centers had improved waitlist survival compared with non-aggressive centers after adjusting for allograft disparity. CONCLUSIONS: Aggressive phenotype had a positive impact on waitlist survival, and graft survival in aggressive centers have improved to benchmark levels over time. These findings serve as justification for aggressive utilization of allografts.

A learning curve in using orphan liver allografts for transplantation.

Given the critical shortage of donor livers, marginal liver allografts have potential to increase donor supply. We investigate trends and long-term outcomes of liver transplant using national share allografts transplanted after rejection at the local and regional levels. We studied a cohort of 75 050 candidates listed in the Organ Procurement and Transplantation Network for liver transplantation between 2002 and 2016. We compared patients receiving national share and regional/local share allografts from 2002-2006, 2007-2011, and 2012-2016, performing multivariate Cox regression for graft survival. Recipient and center-level covariates that were not significant (P < .05) were removed. Graft survival of national share allografts improved over time. National share allografts had a 26% increased risk for graft failure in 2002-2006 but no impact on graft survival in 2007-2011 and 2012-2016. The cold ischemia time (CIT) of national share allografts decreased from 10.4 to 8.0 hours. We demonstrate that CIT had significant impact on graft survival using national share allografts (CIT <6 hours: hazard ratio 0.75 and CIT >12 hours: hazard ratio 1.25). Despite a trend toward sicker recipients and poorer quality allografts, graft survival outcomes using national share allografts have improved to benchmark levels. Reduction in cold ischemia time is a possible explanation.

Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel.

BACKGROUND: Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis. OBJECTIVE: To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease. DESIGN, SETTING, AND PARTICIPANTS: We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60yr) and 1160 selected controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n=201) versus nonaggressive (Gleason score ≤7, n=1048) cases. RESULTS AND LIMITATIONS: We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR]=1.29, 95% confidence interval [CI] 1.01-1.64, p=0.036). Gene-level analyses selected NBN (pSKAT-O=2.4×10-4) for overall risk and XPC (pSKAT-O=1.6×10-4) for aggressive disease, both at candidate-level significance (p<3.1×10-4 and p<3.4×10-4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR=3.2, 95% CI 2.1-4.8, pADA=4.1×10-3) and four genes that increased risk of aggressive disease (OR=11.2, 95% CI 4.6-27.7, pADA=5.6×10-3), three of which overlap the predisposition gene set. CONCLUSIONS: The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential. PATIENT SUMMARY: This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice.

A short peptide reverses the aggressive phenotype of prostate cancer cells.

Previous studies have demonstrated that fibroblast growth factor 8b (FGF8b) is up-regulated in a large proportion of prostate cancer patients, and plays a key role in the aggressive progress of prostate cancer. Herein, we investigated the effects of a short peptide derived from the gN helix domain of FGF8b on the metastatic behaviors of prostate cancer cells. The results demonstrated that the synthetic peptide might reverse the effects of FGF8b on cell proliferation, migration and invasion by suppressing the activation of MAPK and Akt signaling cascades, and reducing the expressions of the metastasis-related proteins, resulting in suppression of the aggressive phenotype of the prostate cancer cells. Collectively, these results underline the therapeutic potential of the FGF8b mimic peptide in advanced prostate cancer.

Glucose-regulated protein of 94 kDa contributes to the development of an aggressive phenotype in breast cancer cells.

Grp94 plays an essential role in protein assembly. We previously suggested that Grp94 overexpression is involved in tumor aggressiveness. However, the underlying mechanisms remain unknown. Since many tumors display high Grp94 levels, we investigated the effects of tumor microenvironment on the regulation of this chaperone expression. First, we found out that hypoxia did not change Grp94 expression in the human tumor cell lines MCF-7 (breast cancer) and HepG2 (liver cancer). Second, glucose deprivation significantly increased Grp94 protein levels. Subsequently, we focused in the putative role of Grp94 in the acquisition of an aggressive phenotype by cancer cells. Using a more aggressive cancer cell model (MDA-MB-231 breast tumor cells), we found out that Grp94 knockdown using siRNA decreased the invasive capacity of cancer cells. Moreover, cells with decreased Grp94 levels displayed an enhanced sensitivity of tumor cells to doxorubicin, a standard drug in the treatment of breast cancer. Taken together, our results suggest that the expression of Grp94 is linked to tumor aggressiveness. Therefore, targeting Grp94 could be an effective way to inhibit tumor growth improving chemotherapy outcome.

Effect of ovarian cancer ascites on SKOV-3 cells proteome: new proteins associated with aggressive phenotype in epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer is the second most lethal gynecological cancer worldwide. Ascites can be found in all clinical stages, however in advanced disease stages IIIC and IV it is more frequent and could be massive, associated with worse prognosis. Due to the above, it was our interest to understanding how the ascites of ovarian cancer patients induces the mechanisms by which the cells present in it acquire a more aggressive phenotype and to know new proteins associated to this process. METHODS: A proteomic analysis of SKOV-3 cells treated with five different EOC ascites was performed by two-dimensional electrophoresis coupled to MALDI-TOF. The level of expression of the proteins of interest was validated by RT-PCR because several of these proteins have only been reported at the messenger level. RESULTS: Among the proteins identified that increased their expression in ascites-treated SKOV-3 cells, were Ran GTPase, ZNF268, and Synaptotagmin like-3. On the other hand, proteins that were negatively regulated by ascites were HLA-I, HSPB1, ARF1, Synaptotagmin 1, and hnRNPH1, among others. Furthermore, an interactome for every one of these proteins was done in order to identify biological processes, molecular actions, and cellular components in which they may participate. CONCLUSIONS: Identified proteins participate in cellular processes highly relevant to the aggressive phenotype such as nuclear transport, regulation of gene expression, vesicular trafficking, evasion of the immune response, invasion, metastasis, and in resistance to chemotherapy. These proteins may represent a source of information which has the potential to be evaluated for the design of therapies directed against these malignant cells that reside on ovarian cancer ascites.

Over-expression of oncigenic pesudogene DUXAP10 promotes cell proliferation and invasion by regulating LATS1 and ß-catenin in gastric cancer.

BACKGROUND: Recently, the pesudogenes have emerged as critical regulators in human cancers tumorigenesis and progression, and been identified as a key revelation in post-genomic biology. However, the expression pattern, biological function and mechanisms responsible for these molecules in human gastric cancer (GC) are not fully understood. METHODS: In this study, we globally assessed the transcriptomic differences of pesudogenes in gastric cancer using publicly available microarray data. DUXAP10 expression levels in GC tissues and cells was detected using quantitative real-time PCR (qPCR). DUXAP10 siRNAs and over-expression vector were transfected into GC cells to down-regulate or up-regulate DUXAP10 expression. Loss- and gain-of function assays were performed to investigate the role of DUXAP10 in GC cells cell proliferation, and invasion. RIP, RNA pulldown, and ChIP assays were used to determine the mechanism of DUXAP10's regulation of underlying targets. RESULTS: The pesudogene DUXAP10 is the only pseudogene that significantly over-expressed in all four GEO datasets, and frequently over-expressed in many other cancers including Liver Hepatocellular carcinoma, Bladder cancer, and Esophageal Cancer. High DUXAP10 expression is associated with GC patients poor prognosis, and knockdown of DUXAP10 significantly inhibits cells proliferation, migration and invasion in GC. Mechanistic investigation shows that DUXAP10 can interact with PRC2 and LSD1 to repress LATS1 expression at transcriptional level, and bind with HuR to maintain the stability of ß-catenin mRNA and increase its protein levels at post-transcriptional level. CONCLUSIONS: Overall, our findings illuminate how increased DUXAP10 confers an oncogenic function in GC development and progression that may serve as a candidate prognostic biomarker and target for clinical management of GC.

SOCS6 Functions as a Tumor Suppressor by Inducing Apoptosis and Inhibiting Angiogenesis in Human Prostate Cancer.

BACKGROUND: Our previous studies revealed that the downregulation of Suppressor of cytokine signaling 6 (SOCS6) was correlated with malignant progression of human prostate cancer (PCa). AIMS: In the current study, we aimed to investigate the tumor suppressive roles of SOCS6 and the underlying mechanisms in PCa. METHODS: SOCS6 expression in PCa and non-cancerous prostate tissues was compared by immunohistochemistry. Statistical associations of SOCS6 expression with various clinicopathological features and patients prognosis were evaluated. In addition, we investigated SOCS6's functions by overexpressing it in vitro (cell apoptosis, migration and invasion assays) and in vivo (tumor formation, angiogenesis and apoptosis). Moreover, SOCS6-regulated genes were identified by nextgeneration RNA-sequencing analysis, followed by pathway enrichment analysis and in vitro experimental validation. RESULTS: SOCS6 downregulation was significantly associated with advanced clinical stage (P=0.029) and positive lymph node metastasis (P=0.013) in PCa patients. We also identified SOCS6 as an independent prognostic factor for disease-free survival in PCa patients (P=0.045). Moreover, overexpression of SOCS6 inhibited PCa cell invasion, migration, tumor xenografts growth and angiogenesis, but induced PCa cell apoptosis (P values <0.05). Mechanically, we revealed that SOCS6 expression may induce cell apoptosis coincident with down-regulation of Bcl2 and Hspa1a, and may suppress tumor angiogenesis with downregulation of F7, Fak3 and Frzb. CONCLUSION: These findings suggest that the reduced expression of SOCS6 may be predictive of unfavorable prognosis in PCa. Thus, SOCS6 may serve as a tumor suppressor and a novel therapeutic target for this cancer.

PHLDA1 (pleckstrin homology-like domain, family A, member 1) knockdown promotes migration and invasion of MCF10A breast epithelial cells.

PHLDA1 (pleckstrin homology-like domain, family A, member 1) is a multifunctional protein that plays distinct roles in several biological processes including cell death and therefore its altered expression has been identified in different types of cancer. Progressively loss of PHLDA1 was found in primary and metastatic melanoma while its overexpression was reported in intestinal and pancreatic tumors. Previous work from our group showed that negative expression of PHLDA1 protein was a strong predictor of poor prognosis for breast cancer disease. However, the function of PHLDA1 in mammary epithelial cells and the tumorigenic process of the breast is unclear. To dissect PHLDA1 role in human breast epithelial cells, we generated a clone of MCF10A cells with stable knockdown of PHLDA1 and performed functional studies. To achieve reduced PHLDA1 expression we used shRNA plasmid transfection and then changes in cell morphology and biological behavior were assessed. We found that PHLDA1 downregulation induced marked morphological alterations in MCF10A cells, such as changes in cell-to-cell adhesion pattern and cytoskeleton reorganization. Regarding cell behavior, MCF10A cells with reduced expression of PHLDA1 showed higher proliferative rate and migration ability in comparison with control cells. We also found that MCF10A cells with PHLDA1 knockdown acquired invasive properties, as evaluated by transwell Matrigel invasion assay and showed enhanced colony-forming ability and irregular growth in low attachment condition. Altogether, our results indicate that PHLDA1 downregulation in MCF10A cells leads to morphological changes and a more aggressive behavior.

Ellipticine inhibits the proliferation and induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via the STAT3 pathway.

OBJECTIVE: Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is an alkaloid isolated from Apocyanaceae plants. This study was designed to investigate the effects of ellipticine on the proliferation and apoptosis of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). METHODS: RA-FLSs were exposed to different concentrations of ellipticine (i.e., 0.5, 1, 2, 4 and 8 µM) for 24-72h and measured for viability, proliferation and apoptosis. The involvement of signal transducer and activators of transcription 3 (STAT3) signaling in the action of ellipticine was determined by Western blot analysis, luciferase reporter assay and rescue experiments. RESULTS: Ellipticine treatment significantly inhibited the viability and proliferation of RA-FLSs in a concentration-dependent manner. In contrast, ellipticine exposure did not alter the viability of normal human FLSs. Moreover, ellipticine triggered significant apoptosis and increased caspase-3 activity in RA-FLSs. Mechanistically, ellipticine reduced the phosphorylation of STAT3 and downregulated the expression of Mcl-1, cyclin D1 and Bcl-2. Luciferase reporter assay demonstrated that ellipticine treatment led to a significant inhibition of STAT3-mediated transcriptional activity in RA-FLSs. Overexpression of constitutively active STAT3 reversed the suppressive effects of ellipticine on RA-FLSs, which was accompanied by restoration of Mcl-1, cyclin D1 and Bcl-2. DISCUSSION AND CONCLUSIONS: Ellipticine shows anti-proliferative and pro-apoptotic effects on RA-FLSs through inhibition of the STAT3 pathway and may have therapeutic potential in RA.

Dysadherin specific drug conjugates for the treatment of thyroid cancers with aggressive phenotypes.

BACKGROUND: EDC1 is a novel type of antibody-drug conjugate which binds and inhibits the Na,K-ATPase on the surface of cancer cells expressing dysadherin. The purpose of this study was to determine the expression of dysadherin in different types of thyroid carcinoma, and evaluate the therapeutic potential of EDC1 for thyroid carcinomas. METHODS: Thyroid tissues from 158 patients were examined for dysadherin expression and correlation with clinicopathological features. Thyroid cancer cell lines were examined for the expression of dysadherin and effective dose range of EDC1. RESULTS: One in 53 benign thyroid tissues and 62% of thyroid cancers expressed dysadherin. All anaplastic and a majority of papillary thyroid cancers overexpressed dysadherin, while 25% of follicular thyroid cancers was found to be positive for dysadherin. Dysadherin expression significantly correlated with extrathyroidal extension and lymph node metastases in papillary thyroid cancer. Five of six human thyroid cancer cell lines analyzed expressed high levels of dysadherin. Of those cells lines sensitive to EDC1, half maximal effective concentrations (EC50) were observed to be between 0.125 nM and 1 nM. CONCLUSIONS: EDC1 showed selective inhibition of growth in thyroid cancer cells with moderate to high expression of dysadherin, thus could be a specific and effective treatment.

Decreased HoxD10 Expression Promotes a Proliferative and Aggressive Phenotype in Prostate Cancer.

HoxD10 gene plays a critical role in cell proliferation in the process of tumor development. However, the protein expression level and the function of HoxD10 in prostate cancer remain unknown. Using tissue microarray, we demonstrate that the protein expression of HoxD10 is commonly decreased in prostate cancer tissues (n = 92) compared to adjacent benign prostate tissues (n = 77). Functionally, knockdown of HoxD10 resulted in significant promotion of prostate cancer cell proliferation. Moreover, knockdown of HoxD10 strikingly stimulated prostate tumor growth in a mouse xenograft model. We also found a significant association between decreased immunohistochemical staining of HoxD10 expression and higher Gleason score (P = 0.031) and advanced clinical pathological stage (P = 0.011). An analysis of the Taylor database revealed that decreased HoxD10 expression predicted worse biochemical recurrence (BCR)-free survival of PCa patients (P = 0.005) and the multivariate analyses further supported that HoxD10 might be an independent predictor for BCR-free survival (P = 0.027). Collectively, our data suggest that the loss of HoxD10 function is common and may thus result in a progressive phenotype in PCa. HoxD10 may function as a biomarker that differentiates patients with BCR disease from the ones that are not after radical prostatectomy, implicating its potential as a therapeutic target.

Índice de masa corporal y características clinicopatológicas de pacientes con cáncer de mama / Body mass index and clinical and pathological characteristics of breast cancer patients

Introducción: estudios previos han sugerido la relación del índice de masa corporal elevado con una mayor incidencia y un peor pronóstico del cáncer de mama. Objetivo: identificar la relación entre el índice de masa corporal en el momento del diagnóstico, y las características clinicopatológicas de pacientes con cáncer de mama de acuerdo con la presencia o no de menopausia. Métodos: estudio transversal y descriptivo de 47 mujeres, entre 36 y 84 años, con carcinoma ductal invasivo. Se midieron el peso y la estatura. Se calculó el índice de masa corporal para la clasificación de las pacientes en tres categorías: peso normal, sobrepeso y obesa. Se determinaron las características clinicopatológicas: tamaño del tumor, presencia de ganglios linfáticos metastásicos, etapa clínica, grado histológico y estado de los receptores de estrógeno, progesterona y receptor 2 para el factor de crecimiento epidérmico. Resultados: el índice de masa corporal varió en el rango de 18,54 a 44,92 kg/m2. No se observaron diferencias estadísticamente significativas entre los valores promedio globales de esta variable en las mujeres premenopáusicas y posmenopáusicas (26,76 kg/m2 ± 5,26 vs. 28,11 ± 5,61 kg/m2; p= 0,450), ni en el análisis realizado por categorías. La obesidad y el sobrepeso fueron asociados con un alto grado histológico, tanto en mujeres premenopáusicas (p= 0,038) como posmenopáusicas (p= 0,037). Adicionalmente, una asociación significativa entre el índice de masa corporal y el subtipo positivo al receptor de estrógenos o progesterona/receptor 2 para el factor de crecimiento epidérmico, se observó solo para las mujeres posmenopáusicas (p= 0,032). Conclusiones: estos resultados muestran que las mujeres obesas y con sobrepeso desarrollan fenotipos agresivos de cáncer de mama, independientemente de la presencia o no de menopausia. Además, entre las mujeres posmenopáusicas con índice de masa corporal elevado predominó el subtipo positivo al receptor de estrógenos o progesterona/receptor 2 para el factor de crecimiento epidérmico. Estudios futuros deberán realizarse para comprender los factores relevantes del hospedero y del tumor, para la prevención y el manejo clínico de las pacientes obesas con cáncer de mama(AU)

Introduction: previous studies have suggested the relationship of the high body mass index with higher incidence and bad prognosis of the breast cancer. Objective: to determine the relationship between the body mass index at the time of diagnosis of cancer, and the clinical-pathological characteristics of menopausal or non-menopausal breast cancer patients. Methods: descriptive and cross-sectional study of 47 women aged 36 to 84 years, with invasive duct carcinoma. Their weight and height were taken. Body mass index calculation served to classify the patients into 3 categories: normoweighed, overweighed and obese. The studied clinical-pathological characteristics were size of tumor, presence of metastatic lymph nodes, clinical staging, histological grade and state of estrogen receptor, progesterone receptor and 2 receptor for the epidermal growth factor. Results: the body mass index changed from 18.54 to 44.92 kg/m2. There were no statistically significant differences among the average overall values of this variable either in premenopausal and postmenopausal women ((26.76 kg/m2 ± 5.26 vs. 28.11 ± 5.61 kg/m2; p= 0.450) or in the analysis by categories. Obesity and overweight were associated to high histological grade both in premenopausal (p= 0.035) and postmenopausal women (p= 0.037). Additionally, a significant association was found between the body mass index and the estrogen or progesterone receptor /receptor 2-positive subtype (for the epidermal growth factor) in postmenopausal women (p= 0.032). Conclusions: these results show that obese and overweighed women may develop aggressive breast cancer phenotypes regardless of menopause. Moreover, the estrogen or progesterone receptor/receptor 2-positive subtype for the epidermal growth factor prevailed in postmenopausal women with high body mass index. Further studies should be conducted to better understand the relevant factors in the host and the tumor for the prevention and the clinical management of obese patients with breast cancer(AU)

Índice de masa corporal y características clinicopatológicas de pacientes con cáncer de mama / Body mass index and clinical and pathological characteristics of breast cancer patients

Introducción: estudios previos han sugerido la relación del índice de masa corporal elevado con una mayor incidencia y un peor pronóstico del cáncer de mama.Objetivo: identificar la relación entre el índice de masa corporal en el momento del diagnóstico, y las características clinicopatológicas de pacientes con cáncer de mama de acuerdo con la presencia o no de menopausia. Métodos: estudio transversal y descriptivo de 47 mujeres, entre 36 y 84 años, con carcinoma ductal invasivo. Se midieron el peso y la estatura. Se calculó el índice de masa corporal para la clasificación de las pacientes en tres categorías: peso normal, sobrepeso y obesa. Se determinaron las características clinicopatológicas: tamaño del tumor, presencia de ganglios linfáticos metastásicos, etapa clínica, grado histológico y estado de los receptores de estrógeno, progesterona y receptor 2 para el factor de crecimiento epidérmico.Resultados: el índice de masa corporal varió en el rango de 18,54 a 44,92 kg/m2. No se observaron diferencias estadísticamente significativas entre los valores promedio globales de esta variable en las mujeres premenopáusicas y posmenopáusicas (26,76 kg/m2 ± 5,26 vs. 28,11 ± 5,61 kg/m2; p= 0,450), ni en el análisis realizado por categorías. La obesidad y el sobrepeso fueron asociados con un alto grado histológico, tanto en mujeres premenopáusicas (p= 0,038) como posmenopáusicas (p= 0,037). Adicionalmente, una asociación significativa entre el índice de masa corporal y el subtipo positivo al receptor de estrógenos o progesterona/receptor 2 para el factor de crecimiento epidérmico, se observó solo para las mujeres posmenopáusicas (p= 0,032). Conclusiones: estos resultados muestran que las mujeres obesas y con sobrepeso desarrollan fenotipos agresivos de cáncer de mama, independientemente de la presencia o no de menopausia. Además, entre las mujeres posmenopáusicas con índice de masa corporal elevado predominó el subtipo positivo al receptor de estró....(AU)

Introduction: previous studies have suggested the relationship of the high body mass index with higher incidence and bad prognosis of the breast cancer.Objective: to determine the relationship between the body mass index at the time of diagnosis of cancer, and the clinical-pathological characteristics of menopausal or non-menopausal breast cancer patients.Methods: descriptive and cross-sectional study of 47 women aged 36 to 84 years, with invasive duct carcinoma. Their weight and height were taken. Body mass index calculation served to classify the patients into 3 categories: normoweighed, overweighed and obese. The studied clinical-pathological characteristics were size of tumor, presence of metastatic lymph nodes, clinical staging, histological grade and state of estrogen receptor, progesterone receptor and 2 receptor for the epidermal growth factor. Results: the body mass index changed from 18.54 to 44.92 kg/m2. There were no statistically significant differences among the average overall values of this variable either in premenopausal and postmenopausal women ((26.76 kg/m2 ± 5.26 vs. 28.11 ± 5.61 kg/m2; p= 0.450) or in the analysis by categories. Obesity and overweight were associated to high histological grade both in premenopausal (p= 0.035) and postmenopausal women (p= 0.037). Additionally, a significant association was found between the body mass index and the estrogen or progesterone receptor /receptor 2-positive subtype (for the epidermal growth factor) in postmenopausal women (p= 0.032). Conclusions: these results show that obese and overweighed women may develop aggressive breast cancer phenotypes regardless of menopause. Moreover, the estrogen or progesterone receptor/receptor 2-positive subtype for the epidermal growth factor prevailed in postmenopausal women with high body mass index. Further studies should be conducted to... (AU)

Telomerase activity in breast cancer patients: association with poor prognosis and more aggressive phenotype.

Telomerase expression is an important mechanism of tumor unlimited replicative potential. The aim of this study was to evaluate prognostic impact of telomerase activity in breast cancer patients and to correlate telomerase activity with established prognostic factors. We analyzed tissue of 102 malignant breast lesions and 20 healthy breast tissues. Telomerase activity was determined by telomeric repeat amplification protocol assay. Telomerase activity was present in 77 (75.49 %) of 102 breast cancers. Telomerase activity in breast cancers was statistically significantly higher in comparison with the activity in normal breast tissue. The levels of telomerase activity were significantly positively correlated with tumor size, axillary nodal status, histological grade, HER-2/neu protein expression in tumor tissue and expression of the nuclear antigen Ki-67. A statistically significant negative correlation was found between the presence of ER and telomerase activity. There was no correlation between telomerase activity and concentration of PR or the age of patients. Kaplan-Meier analysis showed that patients with higher telomerase activity had significantly shorter 10-year disease-free survival (p < 0.0001) and 10-year overall survival (p < 0.0001) than those with lower telomerase activity. These results were confirmed by logistic regression analysis. Our results support the prognostic role of telomerase activity and its relationship with the more aggressive phenotype of breast cancer.