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Sample records for aggressive tumor phenotype

  1. Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype1

    PubMed Central

    Bergström, Sofia Halin; Rudolfsson, Stina H; Bergh, Anders

    2016-01-01

    Prostate cancer generally metastasizes to bone, and most patients have tumor cells in their bone marrow already at diagnosis. Tumor cells at the metastatic site may therefore progress in parallel with those in the primary tumor. Androgen deprivation therapy is often the first-line treatment for clinically detectable prostate cancer bone metastases. Although the treatment is effective, most metastases progress to a castration-resistant and lethal state. To examine metastatic progression in the bone microenvironment, we implanted androgen-sensitive, androgen receptor–positive, and relatively slow-growing Dunning G (G) rat prostate tumor cells into the tibial bone marrow of fully immune-competent Copenhagen rats. We show that tumor establishment in the bone marrow was reduced compared with the prostate, and whereas androgen deprivation did not affect tumor establishment or growth in the bone, this was markedly reduced in the prostate. Moreover, we found that, with time, G tumor cells in the bone microenvironment progress to a more aggressive phenotype with increased growth rate, reduced androgen sensitivity, and increased metastatic capacity. Tumor cells in the bone marrow encounter lower androgen levels and a higher degree of hypoxia than at the primary site, which may cause high selective pressures and eventually contribute to the development of a new and highly aggressive tumor cell phenotype. It is therefore important to specifically study progression in bone metastases. This tumor model could be used to increase our understanding of how tumor cells adapt in the bone microenvironment and may subsequently improve therapy strategies for prostate metastases in bone. PMID:26992916

  2. Phenotypic changes of acid adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment.

    PubMed

    Damaghi, Mehdi; Gillies, Robert

    2016-09-16

    The inter- and intra-tumoral metabolic phenotypes of tumors are heterogeneous, and this is related to microenvironments that select for increased glycolysis. Increased glycolysis leads to decreased pH, and these local microenvironment effects lead to further selection. Hence, heterogeneity of phenotypes is an indirect consequence of altering microenvironments during carcinogenesis. In early stages of growth, tumors are stratified, with the most aggressive cells developing within the acidic interior of the tumor. However, these cells eventually find themselves at the tumor edge, where they invade into the normal tissue via acid-mediated invasion. We believe acid adaptation during the evolution of cancer cells in their niche is a Rubicon that, once crossed, allows cells to invade into and outcompete normal stromal tissue. In this study, we illustrate some acid-induced phenotypic changes due to acidosis resulting in more aggressiveness and invasiveness of cancer cells.

  3. RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer.

    PubMed

    Knudsen, Erik S; McClendon, A Kathleen; Franco, Jorge; Ertel, Adam; Fortina, Paolo; Witkiewicz, Agnieszka K

    2015-01-01

    Triple negative breast cancer (TNBC) is characterized by multiple genetic events occurring in concert to drive pathogenic features of the disease. Here we interrogated the coordinate impact of p53, RB, and MYC in a genetic model of TNBC, in parallel with the analysis of clinical specimens. Primary mouse mammary epithelial cells (mMEC) with defined genetic features were used to delineate the combined action of RB and/or p53 in the genesis of TNBC. In this context, the deletion of either RB or p53 alone and in combination increased the proliferation of mMEC; however, the cells did not have the capacity to invade in matrigel. Gene expression profiling revealed that loss of each tumor suppressor has effects related to proliferation, but RB loss in particular leads to alterations in gene expression associated with the epithelial-to-mesenchymal transition. The overexpression of MYC in combination with p53 loss or combined RB/p53 loss drove rapid cell growth. While the effects of MYC overexpression had a dominant impact on gene expression, loss of RB further enhanced the deregulation of a gene expression signature associated with invasion. Specific RB loss lead to enhanced invasion in boyden chambers assays and gave rise to tumors with minimal epithelial characteristics relative to RB-proficient models. Therapeutic screening revealed that RB-deficient cells were particularly resistant to agents targeting PI3K and MEK pathway. Consistent with the aggressive behavior of the preclinical models of MYC overexpression and RB loss, human TNBC tumors that express high levels of MYC and are devoid of RB have a particularly poor outcome. Together these results underscore the potency of tumor suppressor pathways in specifying the biology of breast cancer. Further, they demonstrate that MYC overexpression in concert with RB can promote a particularly aggressive form of TNBC.

  4. Nuclear maspin expression correlates with the CpG island methylator phenotype and tumor aggressiveness in colorectal cancer.

    PubMed

    Kim, Jung Ho; Cho, Nam-Yun; Bae, Jeong Mo; Kim, Kyung-Ju; Rhee, Ye-Young; Lee, Hye Seung; Kang, Gyeong Hoon

    2015-01-01

    It has been suggested that nuclear expression of maspin (mammary serine protease inhibitor; also known as SERPINB5) in colorectal cancer (CRC) is associated with proximal colonic tumor location, mucinous and poorly differentiated histology, microsatellite instability-high (MSI-H), and poor prognosis. Based on these findings, there may be a potential association between nuclear maspin expression and the CpG island methylator phenotype (CIMP) in CRC, but no study has elucidated this issue. Here, we evaluated maspin protein expression status by immunohistochemistry in 216 MSI-H CRCs. CIMP status was also determined by methylation-specific quantitative PCR method (MethyLight) using eight CIMP markers (MLH1, NEUROG1, CRABP1, CACNA1G, CDKN2A (p16), IGF2, SOCS1, and RUNX3) in 216 MSI-H CRCs. Associations between maspin expression status and various pathological, molecular, and survival data were statistically analyzed. Among the 216 MSI-H CRCs, 111 (51%) cases presented nuclear maspin-positive tumors. Nuclear maspin-positive MSI-H CRCs were significantly associated with proximal tumor location (P = 0.003), tumor budding (P < 0.001), lymphovascular invasion (P = 0.001), perineural invasion (P = 0.008), absence of peritumoral lymphoid reaction (P = 0.045), lymph node metastasis (P = 0.003), distant metastasis (P = 0.005), advanced AJCC/UICC stage (stage III/IV) (P = 0.001), and CIMP-high (CIMP-H) status (P < 0.001). Patients with nuclear maspin-positive tumors showed worse disease-free survival than patients with nuclear maspin-negative tumors (log-rank P = 0.025). In conclusion, nuclear maspin expression is molecularly associated with CIMP-H rather than MSI-H, and clinicopathologically correlates with tumor aggressiveness in CRC.

  5. Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype*

    PubMed Central

    Purushothaman, Anurag; Hurst, Douglas R.; Pisano, Claudio; Mizumoto, Shuji; Sugahara, Kazuyuki; Sanderson, Ralph D.

    2011-01-01

    Heparanase acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins known to drive tumor progression (e.g. VEGF, MMP-9, hepatocyte growth factor (HGF), and RANKL). However, the mechanism whereby this enzyme regulates gene expression remains unknown. We previously reported that elevation of heparanase levels in myeloma cells causes a dramatic reduction in the amount of syndecan-1 in the nucleus. Because syndecan-1 has heparan sulfate chains and because exogenous heparan sulfate has been shown to inhibit the activity of histone acetyltransferase (HAT) enzymes in vitro, we hypothesized that the reduction in nuclear syndecan-1 in cells expressing high levels of heparanase would result in increased HAT activity leading to stimulation of protein transcription. We found that myeloma cells or tumors expressing high levels of heparanase and low levels of nuclear syndecan-1 had significantly higher levels of HAT activity when compared with cells or tumors expressing low levels of heparanase. High levels of HAT activity in heparanase-high cells were blocked by SST0001, an inhibitor of heparanase. Restoration of high syndecan-1 levels in heparanase-high cells diminished nuclear HAT activity, establishing syndecan-1 as a potent inhibitor of HAT. Exposure of heparanase-high cells to anacardic acid, an inhibitor of HAT activity, significantly suppressed their expression of VEGF and MMP-9, two genes known to be up-regulated following elevation of heparanase. These results reveal a novel mechanistic pathway driven by heparanase expression, which leads to decreased nuclear syndecan-1, increased HAT activity, and up-regulation of transcription of multiple genes that drive an aggressive tumor phenotype. PMID:21757697

  6. Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer

    PubMed Central

    Gupta, Shilpi; Kumar, Prabhat; Kaur, Harsimrut; Sharma, Nishi; Saluja, Daman; Bharti, Alok C.; Das, Bhudev C.

    2015-01-01

    Tongue squamous cell carcinoma (TSCC) is most aggressive head and neck cancer often associated with HR-HPV infection. The role of AP-1 which is an essential regulator of HPV oncogene expression and tumorigenesis is not reported in tongue cancer. One hundred tongue tissue biopsies comprising precancer, cancer and adjacent controls including two tongue cancer cell lines were employed to study the role of HPV infection and AP-1 family proteins. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tongue carcinomas (78.5%). A higher expression and DNA binding activity of AP-1 was observed in tongue tumors and cancer cell lines with c-Fos and Fra-2 as the major binding partners forming the functional AP-1 complex but c-Jun participated only in HPV negative and poorly differentiated carcinoma. Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated. The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis only in HPV negative cases while HPV infection leads to well differentiation and better prognosis preferably in nonsmokers. PMID:26581505

  7. A Multiplex Cancer/Testis Antigen-Based Biomarker Panel to Predict Aggressive Phenotype of Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-12-1-0535 TITLE: A Multiplex Cancer/Testis Antigen-Based Biomarker Panel to Predict Aggressive Phenotype of Prostate...30Sep2014 - 29Sep2015 4. TITLE AND SUBTITLE: A Multiplex Cancer/Testis Antigen-Based Biomarker Panel to Predict Aggressive Phenotype of Prostate...different between aggressive and indolent tumors. For the third year of the grant, we evaluated the gene expression of these 8 CTAs in PCa and benign

  8. Predictors of aggressive clinical phenotype among immunohistochemically confirmed atypical adenomas.

    PubMed

    Zaidi, Hasan A; Cote, David J; Dunn, Ian F; Laws, Edward R

    2016-12-01

    Despite formal pathological criteria, not all atypical pituitary adenomas display clinically aggressive behavior. We set out to determine which factors predict a clinically aggressive phenotype among a cohort of atypical pituitary adenomas. Medical records were retrospectively reviewed from April 2008 to July 2015. Of 569 pituitary adenomas, 47 (8.3%) patients were surgically treated for atypical adenomas as defined by the WHO criteria. Clinically aggressive adenomas were defined as occurring in those patients who necessitated additional therapeutic intervention after the index (first) surgery, including additional surgery, medical therapy, or radiosurgery. Forty-seven patients with histopathological and immunohistochemical confirmation of atypical adenomas were identified and of these, 23 were noted to have a clinically aggressive course. Among the remaining 24 patients, the disease remained quiescent after the index surgery. On univariate analysis, clinically aggressive lesions were more likely to have a larger axial diameter on MRI (2.9±1.9cm vs. 1.9±0.7cm, p=0.02), greater incidence of cavernous sinus invasion (65.2% vs. 20.8%, p<0.01), and greater incidence of clival extension (60.9% vs. 0, p<0.01) on preoperative imaging. The two groups were equivalent with regard to immunohistochemical staining for ACTH, HGH, LH, FSH, PRL, and TSH. Clinically aggressive lesions, however, trended towards a greater average MIB-1 proliferative index (7.5%±4.9 vs. 6.0%±3.6, p=0.03). On multivariate analysis, the MIB-1 proliferative index trended towards statistical significance (p=0.06) as an independent predictor of clinical aggressiveness. Atypical pituitary adenomas are defined by a rigid set of immunohistochemical markers, but not all necessarily demonstrate an aggressive clinical phenotype.

  9. Tumor Tension Induces Persistent Inflammation and Promotes Breast Cancer Aggression

    DTIC Science & Technology

    2015-10-01

    Award Number: W81XWH-14-1-0056 TITLE: Tumor Tension Induces Persistent Inflammation and Promotes Breast Cancer Aggression PRINCIPAL INVESTIGATOR...Breast Cancer Aggression 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Ori Maller and Valerie M. Weaver email...ECM stiffening cooperate with inflammatory signaling to facilitate immune evasion and promote breast cancer aggression . In this progress report, I

  10. Novel roles of the unfolded protein response in the control of tumor development and aggressiveness.

    PubMed

    Dejeans, Nicolas; Barroso, Kim; Fernandez-Zapico, Martin E; Samali, Afshin; Chevet, Eric

    2015-08-01

    The hallmarks of cancer currently define the molecular mechanisms responsible for conferring specific tumor phenotypes. Recently, these characteristics were also connected to the status of the secretory pathway, thereby linking the functionality of this cellular machinery to the acquisition of cancer cell features. The secretory pathway ensures the biogenesis of proteins that are membrane-bound or secreted into the extracellular milieu and can control its own homeostasis through an adaptive signaling pathway named the unfolded protein response (UPR). In the present review, we discuss the specific features of the UPR in various tumor types and the impact of the selective activation of this pathway on cell transformation, tumor development and aggressiveness.

  11. Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor.

    PubMed

    Thearle, Marie S; Freda, Pamela U; Bruce, Jeffrey N; Isaacson, Steven R; Lee, Yoomi; Fine, Robert L

    2011-12-01

    Only rarely do corticotroph pituitary tumors become invasive leading to symptoms caused by compression of cranial nerves and other local structures. When aggressive pituitary neuroendocrine tumors do develop, conventional treatment options are of limited success. A 50-year-old man developed a giant invasive corticotroph pituitary tumor 2 years after initial presentation. His tumor and symptoms failed to respond to maximal surgical, radio-surgical, radiation and medical therapy and a bilateral adrenalectomy was done. He subsequently developed rapid growth of his tumor leading to multiple cranial nerve deficits. He was administered salvage chemotherapy with capecitabine and temozolomide (CAPTEM), a novel oral chemotherapy regimen developed at our institution for treatment of neuroendocrine tumors. After two cycles of CAPTEM, his tumor markedly decreased in size and ACTH levels fell by almost 90%. Despite further decreases in ACTH levels, his tumor recurred after 5 months with increased avidity on PET scan suggesting a transformation to a more aggressive phenotype. Temozolomide had been reported to be effective against other pituitary tumors and this case adds to this literature demonstrating its use along with capecitabine (CAPTEM) against a corticotroph tumor. Further evaluation of the CAPTEM regimen in patients with pituitary neuroendocrine tumors which fail to respond to classic treatments is warranted.

  12. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    DTIC Science & Technology

    2008-07-01

    component involved application and further refinement of optical tomographic imaging using independent component analysis ( OPTICA ) for locating and cross...section imaging of a tumor in a model cancerous breast assembled using ex vivo breast tissue specimens. The OPTICA approach was able to detect...infrared imaging, optical tomography using independent component analysis ( OPTICA ), training, molecular imaging, cancer biology 16. SECURITY

  13. Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

    PubMed Central

    Brodsky, Alexander S.; Fischer, Andrew; Miller, Daniel H.; Vang, Souriya; MacLaughlan, Shannon; Wu, Hsin-Ta; Yu, Jovian; Steinhoff, Margaret; Collins, Colin; Smith, Peter J. S.; Raphael, Benjamin J.; Brard, Laurent

    2014-01-01

    The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development. PMID:24732363

  14. Phenotyping of aggressive behavior in golden retriever dogs with a questionnaire.

    PubMed

    van den Berg, L; Schilder, M B H; de Vries, H; Leegwater, P A J; van Oost, B A

    2006-11-01

    Reliable and valid phenotyping is crucial for our study of genetic factors underlying aggression in Golden Retriever dogs. A mail questionnaire based on the Canine Behavioral Assessment and Research Questionnaire (CBARQ; Hsu and Serpell, 2003, JAVMA 223(9):1293-1300) was used to assess behavioral phenotypes. Owners of 228 Golden Retrievers completed the questionnaire. These dogs had been referred to our clinic for aggression problems several years earlier or they were related to aggressive dogs. In this paper, three sets of results are presented, which indicate that behavior scores from the CBARQ can be applied to genetic studies. First, factor analysis demonstrated that CBARQ items can be grouped into 10 behavioral traits, including three types of aggression: stranger-directed aggression, owner-directed aggression, and dog-directed aggression. The results were remarkably similar to those reported by Hsu and Serpell. The aggression scores showed considerable variation in our dog families, which is a prerequisite for genetic studies. Second, retrospective questions enabled us to study changes in the aggressive behavior of the dogs in the course of time. After an average time interval of 4.3 years, over 50% of the dogs had become less aggressive. Third, we analyzed data obtained with an aggression test of 83 dogs. Two out of the three CBARQ aggression factors were also found in the aggression test data.

  15. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    DTIC Science & Technology

    2013-09-01

    Magnetic Resonance Spectroscopic Imaging Optical Techniques for Actuation, Sensing , and Imaging of Biological Systems Multi-functional tumor...Time Reversal Optical Tomography Non-negative Matrix Factorization- based Optical Tomography Optical Tomography based on Principal Component...of the two targets 3.9. Estimated size and absorption coefficient of the targets 4.1. Positions and optical strengths retrieved using ICA, PCA and

  16. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    DTIC Science & Technology

    2012-07-01

    approaches for detection of breast tumors in early stages of growth when those are more amenable to treatment; and (b) training of CCNY researchers at...classification method of Multiple Signal Classification ( MUSIC ). It provided the locations of small absorptive and scattering targets within a turbid...targets, the locations are determined using the MUSIC pseudo spectrum [11]     2 22 ( ) ( ) j T s p s p s p j s pP g g v g    X X X X

  17. Aggressive tumor recurrence after radiofrequency ablation for hepatocellular carcinoma.

    PubMed

    Kang, Tae Wook; Lim, Hyo Keun; Cha, Dong Ik

    2017-03-01

    Image-guided radiofrequency ablation (RFA) is an evolving and growing treatment option for patients with hepatocellular carcinoma (HCC) and hepatic metastasis. RFA offers significant advantages as it is less invasive than surgery and carries a low risk of major complications. However, serious complications, including aggressive tumor recurrence, may be observed during follow-up, and recently, mechanical or thermal damage during RFA has been proposed to be one of the causes of this kind of recurrence. Although the exact mechanism of this still remains unclear, physicians should be familiar with the imaging features of aggressive tumor recurrence after RFA for HCC and its risk factors. In addition, in order to prevent or minimize this newly recognized tumor recurrence, a modified RFA technique, combined RFA treatments with transarterial chemoembolization, and cryoablation can be used as alternative treatments. Ultimately, combining an understanding of this potential complication of RFA with an understanding of the possible risk factors for aggressive tumor recurrence and choosing alternative treatments are crucial to optimize clinical outcomes in each patient with HCC.

  18. Aggressive tumor recurrence after radiofrequency ablation for hepatocellular carcinoma

    PubMed Central

    Kang, Tae Wook; Lim, Hyo Keun; Cha, Dong Ik

    2017-01-01

    Image-guided radiofrequency ablation (RFA) is an evolving and growing treatment option for patients with hepatocellular carcinoma (HCC) and hepatic metastasis. RFA offers significant advantages as it is less invasive than surgery and carries a low risk of major complications. However, serious complications, including aggressive tumor recurrence, may be observed during follow-up, and recently, mechanical or thermal damage during RFA has been proposed to be one of the causes of this kind of recurrence. Although the exact mechanism of this still remains unclear, physicians should be familiar with the imaging features of aggressive tumor recurrence after RFA for HCC and its risk factors. In addition, in order to prevent or minimize this newly recognized tumor recurrence, a modified RFA technique, combined RFA treatments with transarterial chemoembolization, and cryoablation can be used as alternative treatments. Ultimately, combining an understanding of this potential complication of RFA with an understanding of the possible risk factors for aggressive tumor recurrence and choosing alternative treatments are crucial to optimize clinical outcomes in each patient with HCC. PMID:28349677

  19. Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

    PubMed

    Zhang-James, Yanli; Faraone, Stephen V

    2016-07-01

    Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc.

  20. MMSET is overexpressed in cancers: Link with tumor aggressiveness

    SciTech Connect

    Kassambara, Alboukadel; Klein, Bernard Moreaux, Jerome

    2009-02-20

    MMSET is expressed ubiquitously in early development and its deletion is associated with the malformation syndrome called Wolf-Hirschhorn syndrome. It is involved in the t(4; 14) (p16; q32) chromosomal translocation, which is the second most common translocation in multiple myeloma (MM) and is associated with the worst prognosis. MMSET expression has been shown to promote cellular adhesion, clonogenic growth and tumorigenicity in multiple myeloma. MMSET expression has been recently shown to increase with ascending tumor proliferation activity in glioblastoma multiforme. These data demonstrate that MMSET could be implicated in tumor emergence and/or progression. Therefore, we compared the expression of MMSET in 40 human tumor types - brain, epithelial, lymphoid - to that of their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. We found significant overexpression of MMSET in 15 cancers compared to their normal counterparts. Furthermore MMSET is associated with tumor aggressiveness or prognosis in many types of these aforementioned cancers. Taken together, these data suggest that MMSET potentially acts as a pathogenic agent in many cancers. The identification of the targets of MMSET and their role in cell growth and survival will be key to understand how MMSET is associated with tumor development.

  1. Tumor reactive stroma in cholangiocarcinoma: The fuel behind cancer aggressiveness

    PubMed Central

    Brivio, Simone; Cadamuro, Massimiliano; Strazzabosco, Mario; Fabris, Luca

    2017-01-01

    Cholangiocarcinoma (CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma (TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS (myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors (cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix (ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells (as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas.

  2. Lactate Activates HIF-1 in Oxidative but Not in Warburg-Phenotype Human Tumor Cells

    PubMed Central

    De Saedeleer, Christophe J.; Copetti, Tamara; Porporato, Paolo E.; Verrax, Julien

    2012-01-01

    Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness. Together with anaerobic glycolysis, the Warburg effect, formally corresponding to uncoupling glycolysis from oxidative phosphorylation, directly participates in cancer aggressiveness, supporting both tumor progression and dissemination. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key contributor to glycolysis. It stimulates the expression of glycolytic transporters and enzymes supporting high rate of glycolysis. In this study, we addressed the reverse possibility of a metabolic control of HIF-1 in tumor cells. We report that lactate, the end-product of glycolysis, inhibits prolylhydroxylase 2 activity and activates HIF-1 in normoxic oxidative tumor cells but not in Warburg-phenotype tumor cells which also expressed lower basal levels of HIF-1α. These data were confirmed using genotypically matched oxidative and mitochondria-depleted glycolytic tumor cells as well as several different wild-type human tumor cell lines of either metabolic phenotype. Lactate activates HIF-1 and triggers tumor angiogenesis and tumor growth in vivo, an activity that we found to be under the specific upstream control of the lactate transporter monocarboxylate transporter 1 (MCT1) expressed in tumor cells. Because MCT1 also gates lactate-fueled tumor cell respiration and mediates pro-angiogenic lactate signaling in endothelial cells, MCT1 inhibition is confirmed as an attractive anticancer strategy in which a single drug may target multiple tumor-promoting pathways. PMID:23082126

  3. Matrix stiffening promotes a tumor vasculature phenotype

    PubMed Central

    Bordeleau, Francois; Mason, Brooke N.; Lollis, Emmanuel Macklin; Mazzola, Michael; Zanotelli, Matthew R.; Somasegar, Sahana; Califano, Joseph P.; Montague, Christine; LaValley, Danielle J.; Huynh, John; Mencia-Trinchant, Nuria; Negrón Abril, Yashira L.; Hassane, Duane C.; Bonassar, Lawrence J.; Butcher, Jonathan T.; Weiss, Robert S.; Reinhart-King, Cynthia A.

    2017-01-01

    Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell–cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery. PMID:28034921

  4. [Radiation-induces increased tumor cell aggressiveness of tumors of the glioblastomas?].

    PubMed

    Falk, Alexander T; Moncharmont, Coralie; Guilbert, Matthieu; Guy, Jean-Baptiste; Alphonse, Gersende; Trone, Jane-Chloé; Rivoirard, Romain; Gilormini, Marion; Toillon, Robert-Alain; Rodriguez-Lafrasse, Claire; Magné, Nicolas

    2014-09-01

    Glioblastoma multiform is the most common and aggressive brain tumor with a worse prognostic. Ionizing radiation is a cornerstone in the treatment of glioblastome with chemo-radiation association being the actual standard. As a paradoxal effect, it has been suggested that radiotherapy could have a deleterious effect on local recurrence of cancer. In vivo studies have studied the effect of radiotherapy on biological modification and pathogenous effect of cancer cells. It seems that ionizing radiations with photon could activate oncogenic pathways in glioblastoma cell lines. We realized a review of the literature of photon-enhanced effect on invasion and migration of glioblastoma cells by radiotherapy.

  5. Genetic and phenotypic diversity in breast tumor metastases

    PubMed Central

    Almendro, Vanessa; Kim, Hee Jung; Cheng, Yu-Kang; Gönen, Mithat; Itzkovitz, Shalev; Argani, Pedram; van Oudenaarden, Alexander; Sukumar, Saraswati; Michor, Franziska; Polyak, Kornelia

    2014-01-01

    Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance our knowledge of how cancer cell populations change during metastatic progression is limited. Here we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immuno-FISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected prior to systemic therapy. We calculated Shannon index of intratumor diversity in all cancer cells and within phneotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naïve primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2+ tumors compared to other subtypes and in metastases of triple negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples, could be used for the improved prognostication of cancer patients and for the design of more effective therapies for progressive disease. Major findings By defining quantitative measures of intratumor cellular genetic and phenotypic heterogeneity in primary and metastatic breast tumors and by assessing tumor topology, we determined that distant metastatic tumors are the most diverse, which

  6. Hyperpolarized 13C MR Markers of Renal Tumor Aggressiveness

    DTIC Science & Technology

    2013-10-01

    reliably distinguish renal cancer aggressiveness for optimal triage of therapies . Hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI...reliably distinguish renal cancer aggressiveness for optimal triage of therapies . Hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) is... cancer and normal tissues were obtained from nephrectomy specimens and sliced using Krumdieck slicer. With a precision gauge micrometer, the slice

  7. Aberrant PGE₂ metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells.

    PubMed

    Eruslanov, Evgeniy; Daurkin, Irina; Vieweg, Johannes; Daaka, Yehia; Kusmartsev, Sergei

    2011-07-01

    Bladder cancer is associated with enhanced inflammation and characterized by deregulated prostanoid metabolism. Here we examined prostaglandin E₂ (PGE₂) metabolism and myeloid cell subsets that infiltrate tumor tissue using two xenograft models of human bladder cancer. Human bladder tumor xenografts implanted into athymic nude mice become highly infiltrated with host CD11b myeloid cells of bone marrow origin. Fast growing SW780 bladder tumor xenografts were infiltrated with heterogeneous CD11b myeloid cell subsets including tumor-associated macrophages and myeloid-derived suppressor cells. In contrast, majority of myeloid cells in tumor tissue from slow growing bladder cancer Urothel 11 displayed more immature, homogenous phenotype and comprised mostly MHC II class-negative myeloid-derived suppressor cells. We demonstrate that human bladder tumors secrete substantial amounts of PGE₂. Normal bone marrow myeloid cell progenitors cultured in the presence of a bladder tumor-conditioned medium, which is enriched for PGE₂, failed to differentiate into mature APCs and acquired phenotype of the myeloid-derived suppressor cells or inflammatory macrophages with up-regulated chemokine receptor CXCR4. Collectively our data demonstrate that enhanced cancer-related inflammation and deregulated PGE₂ metabolism in tumor microenvironment promote immunosuppressive pro-tumoral phenotype of myeloid cells in bladder cancer. These data also suggest that not only local tumor microenvironment but other factors such as stage of cancer disease and pace of tumor growth could markedly influence the phenotype, differentiation and immune function of myeloid cells in tumor tissue.

  8. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness

    PubMed Central

    Bao, Bin; Azmi, Asfar S.; Ali, Shadan; Ahmad, Aamir; Li, Yiwei; Banerjee, Sanjeev; Kong, Dejuan; Sarkar, Fazlul H.

    2013-01-01

    Hypoxia is one of the fundamental biological phenomena that are intricately associated with the development and aggressiveness of a variety of solid tumors. Hypoxia-inducible factors (HIF) function as a master transcription factor, which regulates hypoxia responsive genes and has been recognized to play critical roles in tumor invasion, metastasis, and chemo-radiation resistance, and contributes to increased cell proliferation, survival, angiogenesis and metastasis. Therefore, tumor hypoxia with deregulated expression of HIF and its biological consequence lead to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. It has been well recognized that cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) phenotypic cells are associated with therapeutic resistance and contribute to aggressive tumor growth, invasion, metastasis and believed to be the cause of tumor recurrence. Interestingly, hypoxia and HIF signaling pathway are known to play an important role in the regulation and sustenance of CSCs and EMT phenotype. However, the molecular relationship between HIF signaling pathway with the biology of CSCs and EMT remains unclear although NF-κB, PI3K/Akt/mTOR, Notch, Wnt/β-catenin, and Hedgehog signaling pathways have been recognized as important regulators of CSCs and EMT. In this article, we will discuss the state of our knowledge on the role of HIF-hypoxia signaling pathway and its kinship with CSCs and EMT within the tumor microenvironment. We will also discuss the potential role of hypoxia-induced microRNAs (miRNAs) in tumor development and aggressiveness, and finally discuss the potential effects of nutraceuticals on the biology of CSCs and EMT in the context of tumor hypoxia. PMID:22579961

  9. 5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors*

    PubMed Central

    Laderoute, Keith R.; Calaoagan, Joy M.; Chao, Wan-ru; Dinh, Dominc; Denko, Nicholas; Duellman, Sarah; Kalra, Jessica; Liu, Xiaohe; Papandreou, Ioanna; Sambucetti, Lidia; Boros, Laszlo G.

    2014-01-01

    Rapid tumor growth can establish metabolically stressed microenvironments that activate 5′-AMP-activated protein kinase (AMPK), a ubiquitous regulator of ATP homeostasis. Previously, we investigated the importance of AMPK for the growth of experimental tumors prepared from HRAS-transformed mouse embryo fibroblasts and for primary brain tumor development in a rat model of neurocarcinogenesis. Here, we used triple-negative human breast cancer cells in which AMPK activity had been knocked down to investigate the contribution of AMPK to experimental tumor growth and core glucose metabolism. We found that AMPK supports the growth of fast-growing orthotopic tumors prepared from MDA-MB-231 and DU4475 breast cancer cells but had no effect on the proliferation or survival of these cells in culture. We used in vitro and in vivo metabolic profiling with [13C]glucose tracers to investigate the contribution of AMPK to core glucose metabolism in MDA-MB-231 cells, which have a Warburg metabolic phenotype; these experiments indicated that AMPK supports tumor glucose metabolism in part through positive regulation of glycolysis and the nonoxidative pentose phosphate cycle. We also found that AMPK activity in the MDA-MB-231 tumors could systemically perturb glucose homeostasis in sensitive normal tissues (liver and pancreas). Overall, our findings suggest that the contribution of AMPK to the growth of aggressive experimental tumors has a critical microenvironmental component that involves specific regulation of core glucose metabolism. PMID:24993821

  10. Parotid gland solitary fibrous tumor with mandibular bone destruction and aggressive behavior

    PubMed Central

    González-Otero, Teresa; Castro-Calvo, Alejandro; Ruiz-Bravo, Elena; Burgueño, Miguel

    2014-01-01

    Introduction: Solitary fibrous tumor is associated with serosal surfaces. Location in the salivary glands is extremely unusual. Extrathoracic tumors have an excellent prognosis associated with their benign clinical behavior. We report an aggressive and recurrent case of this tumor. We review the clinical presentation, inmunohistochemical profiles and therapeutic approaches. Case Report: A 73-years-old woman presented a mass in her right parotid gland. She had a past history of right superficial parotidectomy due to a neurilemoma. FNAB and magnetic resonance were non-specific. After a tumor resection, microscopic findings were spindled tumor cells with reactivity to CD34, bcl-2 and CD99 and the tumor was diagnosed as Solitary Fibrous Tumor. The patient suffered two recurrences and the tumor had a histological aggressive behavior and a destruction of the cortical bone of the mandible adjacent to the mass. A marginal mandibulectomy with an alveolar inferior nerve lateralization was performed. Conclusions: Solitary fibrous tumor is a very rare tumor. Usually, they are benign, but occasionally they can be aggressive. Complete resection is the most important prognostic factor and no evidence supports the efficacy of any therapy different to surgery. Due to the unknown prognosis and to the small number of cases reported, a long-term follow-up is guaranteed. Key words:Solitary fibrous tumor, parotid mass, parotid gland, salivary gland, rare tumors. PMID:25136435

  11. The nested variant of urothelial carcinoma: an aggressive tumor closely simulating benign lesions.

    PubMed

    Dundar, Emine; Acikalin, Mustafa Fuat; Can, Cavit

    2006-01-01

    The "nested" variant is a rare form of urothelial carcinoma and its biologic behavior is highly aggressive. Herein two new cases of nested variant of urothelial carcinoma with immunohistochemical examination are presented. In one of the cases, the tumor extended through the bladder wall into the perivesicular soft tissue, prostatic urethra and left vesicula seminalis, and metastasized to obturator lymph nodes. In the other case, invasion of muscular layer was observed and three recurrences were developed during a follow-up period of 23 months. Both tumors of our study demonstrated high p53 and Ki-67 indices, supporting the aggressive nature of such tumors.

  12. Abrupt transitions to tumor extinction: a phenotypic quasispecies model.

    PubMed

    Sardanyés, Josep; Martínez, Regina; Simó, Carles; Solé, Ricard

    2016-10-06

    The dynamics of heterogeneous tumor cell populations competing with healthy cells is an important topic in cancer research with deep implications in biomedicine. Multitude of theoretical and computational models have addressed this issue, especially focusing on the nature of the transitions governing tumor clearance as some relevant model parameters are tuned. In this contribution, we analyze a mathematical model of unstable tumor progression using the quasispecies framework. Our aim is to define a minimal model incorporating the dynamics of competition between healthy cells and a heterogeneous population of cancer cell phenotypes involving changes in replication-related genes (i.e., proto-oncogenes and tumor suppressor genes), in genes responsible for genomic stability, and in house-keeping genes. Such mutations or loss of genes result into different phenotypes with increased proliferation rates and/or increased genomic instabilities. Despite bifurcations in the classical deterministic quasispecies model are typically given by smooth, continuous shifts (i.e., transcritical bifurcations), we here identify a novel type of bifurcation causing an abrupt transition to tumor extinction. Such a bifurcation, named as trans-heteroclinic, is characterized by the exchange of stability between two distant fixed points (that do not collide) involving tumor persistence and tumor clearance. The increase of mutation and/or the decrease of the replication rate of tumor cells involves this catastrophic shift of tumor cell populations. The transient times near bifurcation thresholds are also characterized, showing a power law dependence of exponent [Formula: see text] of the transients as mutation is changed near the bifurcation value. These results are discussed in the context of targeted cancer therapy as a possible therapeutic strategy to force a catastrophic shift by simultaneously delivering mutagenic and cytotoxic drugs inside tumor cells.

  13. Human Tumor-Infiltrating Myeloid Cells: Phenotypic and Functional Diversity

    PubMed Central

    Elliott, Louise A.; Doherty, Glen A.; Sheahan, Kieran; Ryan, Elizabeth J.

    2017-01-01

    Our current understanding of human tumor-resident myeloid cells is, for the most part, based on a large body of work in murine models or studies enumerating myeloid cells in patient tumor samples using immunohistochemistry (IHC). This has led to the establishment of the theory that, by and large, tumor-resident myeloid cells are either “protumor” M2 macrophages or myeloid-derived suppressor cells (MDSC). This concept has accelerated our understanding of myeloid cells in tumor progression and enabled the elucidation of many key regulatory mechanisms involved in cell recruitment, polarization, and activation. On the other hand, this paradigm does not embrace the complexity of the tumor-resident myeloid cell phenotype (IHC can only measure 1 or 2 markers per sample) and their possible divergent function in the hostile tumor microenvironment. Here, we examine the criteria that define human tumor-infiltrating myeloid cell subsets and provide a comprehensive and critical review of human myeloid cell nomenclature in cancer. We also highlight new evidence characterizing their contribution to cancer pathogenesis based on evidence derived from clinical studies drawing comparisons with murine studies where necessary. We then review the mechanisms in which myeloid cells are regulated by tumors in humans and how these are being targeted therapeutically. PMID:28220123

  14. A Testosterone-Related Structural Brain Phenotype Predicts Aggressive Behavior From Childhood to Adulthood

    PubMed Central

    Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N.; Hudziak, James J; Ducharme, Simon

    2015-01-01

    Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6 to 22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. PMID:26431805

  15. ERK-dependent downregulation of the atypical chemokine receptor D6 drives tumor aggressiveness in Kaposi sarcoma.

    PubMed

    Savino, Benedetta; Caronni, Nicoletta; Anselmo, Achille; Pasqualini, Fabio; Borroni, Elena Monica; Basso, Gianluca; Celesti, Giuseppe; Laghi, Luigi; Tourlaki, Athanasia; Boneschi, Vinicio; Brambilla, Lucia; Nebuloni, Manuela; Vago, Gianluca; Mantovani, Alberto; Locati, Massimo; Bonecchi, Raffaella

    2014-07-01

    D6 is an atypical chemokine receptor acting as a decoy and scavenger for inflammatory CC chemokines expressed in lymphatic endothelial cells. Here, we report that D6 is expressed in Kaposi sarcoma (KS), a tumor ontogenetically related to the lymphatic endothelium. Both in human tumors and in an experimental model, D6 expression levels were inversely correlated with tumor aggressiveness and increased infiltration of proangiogenic macrophages. Inhibition of monocyte recruitment reduced the growth of tumors, while adoptive transfer of wild-type, but not CCR2(-/-) macrophages, increased the growth rate of D6-competent neoplasms. In the KS model with the B-Raf V600E-activating mutation, inhibition of B-Raf or the downstream ERK pathway induced D6 expression; in progressing human KS tumors, the activation of ERK correlates with reduced levels of D6 expression. These results indicate that activation of the K-Ras-B-Raf-ERK pathway during KS progression downregulates D6 expression, which unleashes chemokine-mediated macrophage recruitment and their acquisition of an M2-like phenotype supporting angiogenesis and tumor growth. Combined targeting of CCR2 and the ERK pathway should be considered as a therapeutic option for patients with KS.

  16. Mucinous micropapillary carcinoma of the breast: an aggressive counterpart to conventional pure mucinous tumors.

    PubMed

    Barbashina, Violetta; Corben, Adriana D; Akram, Muzaffar; Vallejo, Christina; Tan, Lee K

    2013-08-01

    Mucinous micropapillary carcinoma of the breast, also described as "pure mucinous carcinoma with micropapillary pattern," has recently come to attention as an unusual form of invasive breast cancer exhibiting dual mucinous and micropapillary differentiation. Despite increasing awareness of this morphologic variant, its clinical significance has not yet been elucidated. Here, we present 15 additional examples of these rare tumors to highlight some important differences between mucinous micropapillary carcinoma of the breast and ordinary pure mucinous carcinomas. The key features of mucinous micropapillary carcinoma of the breast included (a) largely or entirely mucinous appearance (>90% mucinous morphology), (b) distinctive micropapillary arrangement of the neoplastic cells, (c) intermediate to high nuclear grade, (d) "hobnail" cells, and (e) frequent psammomatous calcifications. In contrast to ordinary pure mucinous carcinomas, 20% of mucinous micropapillary carcinomas of the breast were characterized by human epidermal growth factor receptor 2 positivity, and 23% were p53 positive. More than half of mucinous micropapillary carcinomas of the breast (60%) demonstrated lymphovascular invasion, sometimes extensive. Synchronous axillary lymph node metastases were detected in 33% of patients and, on 2 occasions, involved more than 10 nodes. With a median follow-up of 4.5 years, we identified 1 patient (7%) with chest wall recurrence of mucinous micropapillary carcinoma of the breast after mastectomy. We conclude that mucinous micropapillary carcinomas of the breast constitute a clinically aggressive subset of mucin-producing breast carcinomas characterized by an increased capacity for lymphatic invasion and regional lymph node metastasis, reflective of their dual phenotype. Recognition of the morphologic and biologic heterogeneity within breast cancer subtypes should allow for a more accurate classification of the individual tumors and better patient stratification for

  17. Hyperpolarized 13C MR Markers of Renal Tumor Aggressiveness

    DTIC Science & Technology

    2014-10-01

    lactate in the media. We observed three fold higher rate of lactate secreted into the media by the ccRCC tissue compared to the normal kidney (figure...imaging sequences with higher spatial resolution as well as sensitivity to generate contrast between the mouse kidney and the tumor grafts. This will...signal in the tumor grafts compared to the high background signal arising from the mouse kidney , several optimizations were explored, such as diffusion

  18. Unusual aggressive breast cancer: metastatic malignant phyllodes tumor.

    PubMed

    Singer, Adam; Tresley, Jonathan; Velazquez-Vega, Jose; Yepes, Monica

    2013-02-01

    For the year of 2012, it has been estimated that breast cancer will account for the greatest number of newly diagnosed cancers and the second highest proportion of cancer related deaths among women. Breast cancer, while often lumped together as one disease, represents a diverse group of malignancies with different imaging findings, histological appearances and behavior. While most invasive primary breast cancers are epithelial derived adenocarcinomas, rare neoplasms such as the phyllodes tumor may arise from mesenchymal tissue. Compared to the breast adenocarcinoma, the phyllodes tumor tends to affect a younger population, follows a different clinical course, is associated with different imaging and histological findings and is managed distinctively. There may be difficulty in differentiating the phyllodes tumor from a large fibroadenoma, but the mammographer plays a key role in reviewing the clinical and imaging data in order to arrive at the correct diagnosis. Early diagnosis with proper surgical management can often cure non-metastatic phyllodes tumors. However, in rare cases where metastasis occurs, prognosis tends to be poor. This report describes the presentation, imaging findings and management of a metastatic malignant phyllodes tumor.

  19. 3D Silicon Microstructures: A New Tool for Evaluating Biological Aggressiveness of Tumor Cells.

    PubMed

    Mazzini, Giuliano; Carpignano, Francesca; Surdo, Salvatore; Aredia, Francesca; Panini, Nicolò; Torchio, Martina; Erba, Eugenio; Danova, Marco; Scovassi, Anna Ivana; Barillaro, Giuseppe; Merlo, Sabina

    2015-10-01

    In this work, silicon micromachined structures (SMS), consisting of arrays of 3- μ m-thick silicon walls separated by 50- μm-deep, 5- μ m-wide gaps, were applied to investigate the behavior of eight tumor cell lines, with different origins and biological aggressiveness, in a three-dimensional (3D) microenvironment. Several cell culture experiments were performed on 3D-SMS and cells grown on silicon were stained for fluorescence microscopy analyses. Most of the tumor cell lines recognized in the literature as highly aggressive (OVCAR-5, A375, MDA-MB-231, and RPMI-7951) exhibited a great ability to enter and colonize the narrow deep gaps of the SMS, whereas less aggressive cell lines (OVCAR-3, Capan-1, MCF7, and NCI-H2126) demonstrated less penetration capability and tended to remain on top of the SMS. Quantitative image analyses of several fluorescence microscopy fields of silicon samples were performed for automatic cell recognition and count, in order to quantify the fraction of cells inside the gaps, with respect to the total number of cells in the examined field. Our results show that higher fractions of cells in the gaps are obtained with more aggressive cell lines, thus supporting in a quantitative way the observation that the behavior of tumor cells on the 3D-SMS depends on their aggressiveness level.

  20. Vascular patterns provide therapeutic targets in aggressive neuroblastic tumors

    PubMed Central

    Tadeo, Irene; Bueno, Gloria; Berbegall, Ana P.; Fernández-Carrobles, M. Milagro; Castel, Victoria; García-Rojo, Marcial; Navarro, Samuel; Noguera, Rosa

    2016-01-01

    Angiogenesis is essential for tumor growth and metastasis, nevertheless, in NB, results between different studies on angiogenesis have yielded contradictory results. An image analysis tool was developed to characterize the density, size and shape of total blood vessels and vascular segments in 458 primary neuroblastic tumors contained in tissue microarrays. The results were correlated with clinical and biological features of known prognostic value and with risk of progression to establish histological vascular patterns associated with different degrees of malignancy. Total blood vessels were larger, more abundant and more irregularly-shaped in tumors of patients with associated poor prognostic factors than in the favorable cohort. Tumor capillaries were less abundant and sinusoids more abundant in the patient cohort with unfavorable prognostic factors. Additionally, size of post-capillaries & metarterioles as well as higher sinusoid density can be included as predictive factors for survival. These patterns may therefore help to provide more accurate pre-treatment risk stratification, and could provide candidate targets for novel therapies. PMID:26918726

  1. The role of temozolomide in the treatment of aggressive pituitary tumors.

    PubMed

    Liu, James K; Patel, Jimmy; Eloy, Jean Anderson

    2015-06-01

    Pituitary tumors are amongst the most common intracranial neoplasms and are generally benign. However, some pituitary tumors exhibit clinically aggressive behavior that is characterized by tumor recurrence and continued progression despite repeated treatments with conventional surgical, radiation and medical therapies. More recently, temozolomide, a second generation oral alkylating agent, has shown therapeutic promise for aggressive pituitary adenomas and carcinomas with favorable clinical and radiographic responses. Temozolomide causes DNA damage by methylation of the O(6) position of guanine, which results in potent cytotoxic DNA adducts and consequently, tumor cell apoptosis. The degree of MGMT expression appears to be inversely related to therapeutic responsiveness to temozolomide with a significant number of temozolomide-sensitive pituitary tumors exhibiting low MGMT expression. The presence of high MGMT expression appears to mitigate the effectiveness of temozolomide and this has been used as a marker in several studies to predict the efficacy of temozolomide. Recent evidence also suggests that mutations in mismatch repair proteins such as MSH6 could render pituitary tumors resistant to temozolomide. In this article, the authors review the development of temozolomide, its biochemistry and interaction with O(6)-methylguanine-DNA methyltransferase (MGMT), its role in adjuvant treatment of aggressive pituitary neoplasms, and future works that could influence the efficacy of temozolomide therapy.

  2. Shorter telomeres and high telomerase activity correlate with a highly aggressive phenotype in breast cancer cell lines.

    PubMed

    Ceja-Rangel, Hugo A; Sánchez-Suárez, Patricia; Castellanos-Juárez, Emilio; Peñaroja-Flores, Rubicelia; Arenas-Aranda, Diego J; Gariglio, Patricio; Benítez-Bribiesca, Luis

    2016-09-01

    Maintenance of telomere length is one function of human telomerase that is crucial for the survival of cancer cells and cancer progression. Both telomeres and telomerase have been proposed as possible biomarkers of cancer risk and cancer invasiveness; however, their clinical relevance is still under discussion. In order to improve our understanding of the relationship between telomere length and telomerase activity with cancer invasiveness, we studied telomere length as well as telomerase levels, activity, and intracellular localization in breast cancer cell lines with diverse invasive phenotypes. We found an apparently paradoxical coincidence of short telomeres and enhanced telomerase activity in the most invasive breast cancer cell lines. We also observed that hTERT intracellular localization could be correlated with its level of activity. There was no association between human telomerase reverse transcriptase (hTERT) protein expression levels and invasiveness. We propose that simultaneous evaluation of these two biomarkers-telomere length and telomerase activity-could be useful for the assessment of the invasive capacity and aggressiveness of tumor cells from breast cancer patients.

  3. HIF-1α mediates tumor hypoxia to confer a perpetual mesenchymal phenotype for malignant progression.

    PubMed

    Yoo, Young-Gun; Christensen, Jared; Gu, Jie; Huang, L Eric

    2011-06-21

    Although tumor progression involves genetic and epigenetic alterations to normal cellular biology, the underlying mechanisms of these changes remain obscure. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α) is overexpressed in many human cancers and up-regulates a host of hypoxia-responsive genes for cancer growth and survival. We recently identified an alternative mechanism of HIF-1α function that induces genetic alterations by suppressing DNA repair. Here, we show that long-term hypoxia, which mimics the tumor microenvironment, drives a perpetual epithelial-mesenchymal transition (EMT) through up-regulation of the zinc finger E-box binding homeobox protein ZEB2, whereas short-term hypoxia induces a reversible EMT that requires the transcription factor Twist1. Moreover, we show that the perpetual EMT driven by chronic hypoxia depends on HIF-1α induction of genetic alterations rather than its canonical transcriptional activator function. These mesenchymal tumor cells not only acquire tumorigenicity but also display characteristics of advanced cancers, including necrosis, aggressive invasion, and metastasis. Hence, these results reveal a mechanism by which HIF-1α promotes a perpetual mesenchymal phenotype, thereby advancing tumor progression.

  4. Tumor-initiating cell frequency is relevant for glioblastoma aggressiveness

    PubMed Central

    Richichi, Cristina; Osti, Daniela; Del Bene, Massimiliano; Fornasari, Lorenzo; Patanè, Monica; Pollo, Bianca; DiMeco, Francesco; Pelicci, Giuliana

    2016-01-01

    Glioblastoma (GBM) is maintained by a small subpopulation of tumor-initiating cells (TICs). The arduous assessment of TIC frequencies challenges the prognostic role of TICs in predicting the clinical outcome in GBM patients. We estimated the TIC frequency in human GBM injecting intracerebrally in mice dissociated cells without any passage in culture. All GBMs contained rare TICsand were tumorigenic in vivo but only 54% of them grew in vitro as neurospheres. We demonstrated that neurosphere formation in vitro did not foretell tumorigenic ability in vivo and frequencies calculated in vitro overestimated the TIC content. Our findings assert the pathological significance of GBM TICs. TIC number correlated positively with tumor incidence and inversely with survival of tumor-bearing mice. Stratification of GBM patients according to TIC content revealed that patients with low TIC frequency experienced a trend towards a longer progression free survival. The expression of either putative stem-cell markers or markers associated with different GBM molecular subtypes did not associate with either TIC content or neurosphere formation underlying the limitations of TIC identification based on the expression of some putative stem cell-markers. PMID:27582543

  5. Gene expression profiles of metabolic aggressiveness and tumor recurrence in benign meningioma.

    PubMed

    Serna, Eva; Morales, José Manuel; Mata, Manuel; Gonzalez-Darder, José; San Miguel, Teresa; Gil-Benso, Rosario; Lopez-Gines, Concha; Cerda-Nicolas, Miguel; Monleon, Daniel

    2013-01-01

    Around 20% of meningiomas histologically benign may be clinically aggressive and recur. This strongly affects management of meningioma patients. There is a need to evaluate the potential aggressiveness of an individual meningioma. Additional criteria for better classification of meningiomas will improve clinical decisions as well as patient follow up strategy after surgery. The aim of this study was to determine the relationship between gene expression profiles and new metabolic subgroups of benign meningioma with potential clinical relevance. Forty benign and fourteen atypical meningioma tissue samples were included in the study. We obtained metabolic profiles by NMR and recurrence after surgery information for all of them. We measured gene expression by oligonucleotide microarray measurements on 19 of them. To our knowledge, this is the first time that distinct gene expression profiles are reported for benign meningioma molecular subgroups with clinical correlation. Our results show that metabolic aggressiveness in otherwise histological benign meningioma proceeds mostly through alterations in the expression of genes involved in the regulation of transcription, mainly the LMO3 gene. Genes involved in tumor metabolism, like IGF1R, are also differentially expressed in those meningioma subgroups with higher rates of membrane turnover, higher energy demand and increased resistance to apoptosis. These new subgroups of benign meningiomas exhibit different rates of recurrence. This work shows that benign meningioma with metabolic aggressiveness constitute a subgroup of potentially recurrent tumors in which alterations in genes regulating critical features of aggressiveness, like increased angiogenesis or cell invasion, are still no predominant. The determination of these gene expression biosignatures may allow the early detection of clinically aggressive tumors.

  6. Resection replantation of the upper limb for aggressive malignant tumors.

    PubMed

    El-Gammal, Tarek Abdalla; El-Sayed, Amr; Kotb, Mohamed Mostafa

    2002-04-01

    Stage IIB malignant tumors of the upper limb have been traditionally treated by amputation or disarticulation. There have been isolated reports on the technique of segmental resection of the tumor-bearing segment complete with the skin, and replanting the distal arm or forearm with or without neurovascular repair. The present paper describes four cases in which a wide resection margin was achieved in all by resecting the affected cylinder of the limb. Functional reconstruction was performed by appropriate tendon transfer. The main vessels and nerves were dealt with according to the findings revealed by preoperative investigations. If they had to be sacrificed, end-to-end suture was performed, but if the main nerves could be spared, it greatly enhanced the functional outcome. Local and systemic recurrences occurred in one case, and systemic recurrence occurred in another case. The other two cases remained disease-free at more than 4 years' follow-up. This operation is as radical as amputation, while the esthetic and functional results are equivalent to those of resection-arthrodesis.

  7. Altered PTEN, ATRX, CHGA, CHGB & TP53 Expression are Associated with Aggressive VHL-Associated Pancreatic Neuroendocrine Tumors

    PubMed Central

    Weisbrod, Allison B.; Zhang, Lisa; Jain, Meenu; Barak, Stephanie; Quezado, Martha M.; Kebebew, Electron

    2013-01-01

    Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which 8-17% of germline mutation carriers develop pancreatic neuroendocrine tumors (PNETs). There is limited data on prognostic markers for PNETs other than Ki-67, which is included in the World Health Organization classification system. Recently, specific genes and pathways have been identified by whole exome sequencing which may be involved in the tumorigenesis of PNETs and may be markers of disease aggressiveness. The objective of this study was to identify molecular markers of aggressive disease in VHL-associated PNETs. The protein expression of 8 genes (PTEN, CHGA, CHGB, ATRX, DAXX, CC-3, VEGF, TP53) was analyzed in PNETs by immunohistochemistry and compared to clinical data, VHL genotype, functional imaging results, and pathologic findings. Subcellular distribution of PTEN, CHGA and ATRX were significantly different by WHO classifications (p<0.05). There was decreased PTEN nuclear to cytoplasmic ratio (p<0.01) and decreased CHGA nuclear expression (p=0.03) in malignant samples as compared to benign. Lower cytoplasmic CHGB expression (p=0.03) was associated with malignant tumors and metastasis. Higher nuclear expression of PTEN was associated with VHL mutations in exon 3 (p=0.04). Higher PTEN and CHGB expression was associated with higher FDG-PET avidity (p<0.05). Cytoplasmic expression of CC-3 was associated with higher serum Chromogranin A levels (σ=0.72, p= 0.02). Lastly, greater cytoplasmic expression of p53 was associated with metastasis. Our findings suggest that altered PTEN, ATRX, CHGA and CHGB expression are associated with aggressive PNET phenotype in VHL and may serve as useful adjunct prognostic markers to Ki-67 in PNETs. PMID:23361940

  8. Simulating Brain Tumor Heterogeneity with a Multiscale Agent-Based Model: Linking Molecular Signatures, Phenotypes and Expansion Rate

    PubMed Central

    Zhang, Le; Strouthos, Costas G.; Wang, Zhihui; Deisboeck, Thomas S.

    2008-01-01

    We have extended our previously developed 3D multi-scale agent-based brain tumor model to simulate cancer heterogeneity and to analyze its impact across the scales of interest. While our algorithm continues to employ an epidermal growth factor receptor (EGFR) gene-protein interaction network to determine the cells’ phenotype, it now adds an implicit treatment of tumor cell adhesion related to the model’s biochemical microenvironment. We simulate a simplified tumor progression pathway that leads to the emergence of five distinct glioma cell clones with different EGFR density and cell ‘search precisions’. The in silico results show that microscopic tumor heterogeneity can impact the tumor system’s multicellular growth patterns. Our findings further confirm that EGFR density results in the more aggressive clonal populations switching earlier from proliferation-dominated to a more migratory phenotype. Moreover, analyzing the dynamic molecular profile that triggers the phenotypic switch between proliferation and migration, our in silico oncogenomics data display spatial and temporal diversity in documenting the regional impact of tumorigenesis, and thus support the added value of multi-site and repeated assessments in vitro and in vivo. Potential implications from this in silico work for experimental and computational studies are discussed. PMID:20047002

  9. miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma.

    PubMed

    Lin, Chuyong; Liu, Aibin; Zhu, Jinrong; Zhang, Xin; Wu, Geyan; Ren, Pengli; Wu, Jueheng; Li, Mengfeng; Li, Jun; Song, Libing

    2014-08-06

    The strength and duration of phosphoinositide signalling from phosphatidylinositol-3-kinase (PI3K) activation to Akt is tightly balanced by phosphoinositide kinases and phosphatases. However, how phosphatase-mediated negative regulatory effects are concomitantly disrupted in cancers, which commonly exhibit constitutively activated PI3K/Akt signalling, remains undefined. Here we report that miR-508 directly suppresses multiple phosphatases, including inositol polyphosphate-5-phosphatase J (INPP5J), phosphatase and tensin homologue (PTEN) and inositol polyphosphate 4-phosphatase type I (INPP4A), resulting in constitutive activation of PI3K/Akt signalling. Furthermore, we find that overexpressing miR-508 promotes, while silencing miR-508 impairs, the aggressive phenotype of oesophageal squamous cell carcinoma (ESCC) both in vitro and in vivo. Importantly, the level of miR-508 correlates with poor survival and activated PI3K/Akt signalling in a large cohort of ESCC specimens. These findings uncover a mechanism for constitutive PI3K/Akt activation in ESCC, and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

  10. Inflammatory myofibroblastic tumor of the uterus: clinical and pathologic review of 10 cases including a subset with aggressive clinical course.

    PubMed

    Parra-Herran, Carlos; Quick, Charles M; Howitt, Brooke E; Dal Cin, Paola; Quade, Bradley J; Nucci, Marisa R

    2015-02-01

    Inflammatory myofibroblastic tumor is currently regarded as a neoplasm with intermediate biological potential and a wide anatomic distribution. Inflammatory myofibroblastic tumors of the female genital tract are rare, and to date reported cases behaved indolently. We describe, herein, 10 cases of uterine inflammatory myofibroblastic tumor, 3 of which had an aggressive clinical course. Subject age ranged from 29 to 73 years. Tumors were composed of spindle and epithelioid myofibroblastic cells admixed with lymphoplasmacytic infiltrates in a variably myxoid stroma. Two growth patterns, myxoid and fascicular (leiomyoma-like), were noted. All tumors were positive for ALK expression by immunohistochemistry, which was stronger in the myxoid areas. Smooth muscle marker and CD10 expression was variable in extent, but typically positive. Fluorescence in situ hybridization for ALK rearrangements was positive in both fascicular and myxoid areas in all 8 cases tested. Three subjects showed clinical evidence of tumor aggressiveness as defined by extrauterine spread, local recurrence, or distant metastasis. Aggressive tumors were larger, had a higher proportion of myxoid stroma, and higher mitotic activity than indolent tumors. Tumor cell necrosis was seen only in cases with adverse outcome. This is the first report to describe aggressive biological behavior in uterine inflammatory myofibroblastic tumor. This diagnosis is often underappreciated and merits inclusion in the differential diagnosis of myxoid mesenchymal lesions of the uterus, particularly because patients with an aggressive course may benefit from targeted therapy.

  11. 'Salvage Treatment' of Aggressive Giant Cell Tumor of Bones with Denosumab.

    PubMed

    Vaishya, Raju; Agarwal, Amit Kumar; Vijay, Vipul

    2015-07-01

    Giant cell tumor of the bone (GCTB) presents as a lytic lesion of epiphyseometaphyseal regions of the long bones usually during the second to the fourth decade with female predilection. Histologically, they are formed of neoplastic mononuclear cells with a higher receptor activator of nuclear factor kappa-B ligand (RANKL) expression responsible for the aggressive osteolytic nature of the tumour. RANKL helps in the formation and functioning of osteoclasts. A newer molecule, Denosumab, is a monoclonal antibody directed against RANKL and thus prevents the formation and function of osteoclasts. Management of refractory, multicentric, recurrent, or metastatic GCTB remains challenging as achieving a tumor-free margin surgically is not always possible. Denosumab may play a crucial role, especially in the management of such difficult lesions. We present three cases of locally aggressive GCTB (involving proximal humerus, sacrum, and proximal femur) that were treated and responded very well to Denosumab therapy.

  12. 'Salvage Treatment' of Aggressive Giant Cell Tumor of Bones with Denosumab

    PubMed Central

    Vaishya, Raju; Vijay, Vipul

    2015-01-01

    Giant cell tumor of the bone (GCTB) presents as a lytic lesion of epiphyseometaphyseal regions of the long bones usually during the second to the fourth decade with female predilection. Histologically, they are formed of neoplastic mononuclear cells with a higher receptor activator of nuclear factor kappa-B ligand (RANKL) expression responsible for the aggressive osteolytic nature of the tumour. RANKL helps in the formation and functioning of osteoclasts. A newer molecule, Denosumab, is a monoclonal antibody directed against RANKL and thus prevents the formation and function of osteoclasts. Management of refractory, multicentric, recurrent, or metastatic GCTB remains challenging as achieving a tumor-free margin surgically is not always possible. Denosumab may play a crucial role, especially in the management of such difficult lesions. We present three cases of locally aggressive GCTB (involving proximal humerus, sacrum, and proximal femur) that were treated and responded very well to Denosumab therapy. PMID:26251767

  13. Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness

    PubMed Central

    Afonso, Julieta; Santos, Lúcio L.; Morais, António; Amaro, Teresina; Longatto-Filho, Adhemar; Baltazar, Fátima

    2016-01-01

    abstract Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells’ compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance. PMID:26636903

  14. Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells.

    PubMed

    Jiang, L; Zhou, J; Zhong, D; Zhou, Y; Zhang, W; Wu, W; Zhao, Z; Wang, W; Xu, W; He, L; Ma, Y; Hu, Y; Zhang, W; Li, J

    2017-03-13

    Overexpression of structural maintenance of chromosomes 4 (SMC4) has been reported to be involved in tumor cell growth, migration and invasion, and to be correlated with poor prognosis of cancer patient. However, its clinical significance and biological role in glioma remain unknown. Herein, we found that SMC4 expression at both mRNA and protein level was markedly increased in glioma cells and clinical tissues and that it correlated with poor prognosis. SMC4 overexpression markedly promoted the glioma cell proliferation rate and migration and invasive capability in vitro and in vivo, whereas SMC4 downregulation reduced it. Moreover, the transforming growth factor β (TGFβ)/Smad signaling pathway, which was activated in SMC4-transduced glioma cells and inhibited in SMC4-silenced glioma cells, contributed to SMC4-mediated glioma cell aggressiveness. Our results provide new insight into the oncofunction of SMC4 and the mechanism by which the TGFβ/Smad pathway is hyperactivated in gliomas, indicating that SMC4 is a valuable prognostic factor and a potential therapeutic target in gliomas.

  15. Epigenetic states of cells of origin and tumor evolution drive tumor-initiating cell phenotype and tumor heterogeneity.

    PubMed

    Chow, Kin-Hoe; Shin, Dong-Mi; Jenkins, Molly H; Miller, Emily E; Shih, David J; Choi, Seungbum; Low, Benjamin E; Philip, Vivek; Rybinski, Brad; Bronson, Roderick T; Taylor, Michael D; Yun, Kyuson

    2014-09-01

    A central confounding factor in the development of targeted therapies is tumor cell heterogeneity, particularly in tumor-initiating cells (TIC), within clinically identical tumors. Here, we show how activation of the Sonic Hedgehog (SHH) pathway in neural stem and progenitor cells creates a foundation for tumor cell evolution to heterogeneous states that are histologically indistinguishable but molecularly distinct. In spontaneous medulloblastomas that arise in Patched (Ptch)(+/-) mice, we identified three distinct tumor subtypes. Through cell type-specific activation of the SHH pathway in vivo, we determined that different cells of origin evolved in unique ways to generate these subtypes. Moreover, TICs in each subtype had distinct molecular and cellular phenotypes. At the bulk tumor level, the three tumor subtypes could be distinguished by a 465-gene signature and by differential activation levels of the ERK and AKT pathways. Notably, TICs from different subtypes were differentially sensitive to SHH or AKT pathway inhibitors, highlighting new mechanisms of resistance to targeted therapies. In summary, our results show how evolutionary processes act on distinct cells of origin to contribute to tumoral heterogeneity, at both bulk tumor and TIC levels.

  16. Lentivirus-mediated RASSF1A expression suppresses aggressive phenotypes of gastric cancer cells in vitro and in vivo

    PubMed Central

    Zhou, P-H; Zheng, J-B; Wei, G-B; Wang, X-L; Wang, W; Chen, N-Z; Yu, J-H; Yao, J-F; Wang, H; Lu, S-Y; Sun, X-J

    2015-01-01

    Loss of Ras association domain family protein 1 isoform A (RASSF1A) expression is associated with the development of a variety of human cancers and the expression of carcinoembryonic antigen (CEA) frequently occurs in gastric cancer. This study investigated the effects of RASSF1A expression restoration using a hypoxia-inducible CEA promoter-driven vector on xenograft tumor growth in nude mice and on the in-vitro regulation of gastric cancer cell viability, cell cycle distribution, apoptosis, colony formation and invasion capacity. The data showed that the level of CEA mRNA and protein was much higher in gastric cancer SGC7901 cells than in a second gastric cancer cell line, MKN28, or in the MCF-10A normal epithelial breast cell line. RASSF1A expression was restored in SGC7901 cells compared with the negative control virus-infected SGC7910 cells. RASSF1A expression restoration significantly inhibited gastric cancer cell viability, colony formation and invasion capacity, but induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. At the gene level, restoration of RASSF1A expression under hypoxic culture conditions significantly suppressed matrix metalloproteinase-2 expression and prevented cyclinD1 expression. A nude mouse xenograft assay showed that the restoration of RASSF1A expression reduced gastric cancer xenograft formation and growth. In conclusion, the restoration of RASSF1A expression using a hypoxia-inducible and CEA promoter-driven vector suppressed aggressive phenotypes of gastric cancer cells in vitro and in vivo. These results suggest that LV-5HRE-CEAp-RASSF1A gene therapy may be a promising novel approach to treat advanced gastric cancer. PMID:26005859

  17. Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors

    PubMed Central

    Decker, Brennan; Karyadi, Danielle M.; Davis, Brian W.; Karlins, Eric; Tillmans, Lori S.; Stanford, Janet L.; Thibodeau, Stephen N.; Ostrander, Elaine A.

    2016-01-01

    To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8–10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations. PMID:27087322

  18. Decreased HoxD10 expression promotes a proliferative and aggressive phenotype in prostate cancer.

    PubMed

    Mo, R-J; Lu, J-M; Wan, Y-P; Hua, W; Liang, Y-X; Zhuo, Y-J; Kuang, Q-W; Liu, Y-L; He, H-C; Zhong, W-D

    2017-02-19

    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.

  19. Aberrant PGE2 metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells

    PubMed Central

    Eruslanov, Evgeniy; Daurkin, Irina; Vieweg, Johannes; Daaka, Yehia; Kusmartsev, Sergei

    2011-01-01

    Bladder cancer is associated with enhanced inflammation and characterized by deregulated prostanoid metabolism. Here we examined prostaglandin E2 (PGE2) metabolism and myeloid cell subsets that infiltrate tumor tissue using two xenograft models of human bladder cancer. Human bladder tumor xenografts implanted into athymic nude mice become highly infiltrated with host CD11b myeloid cells of bone marrow origin. Fast growing SW780 bladder tumor xenografts were infiltrated with heterogeneous CD11b myeloid cell subsets including tumor-associated macrophages and myeloid-derived suppressor cells. In contrast, majority of myeloid cells in tumor tissue from slow growing bladder cancer Urothel 11 displayed more immature, homogenous phenotype and comprised mostly MHC II class-negative myeloid-derived suppressor cells. We demonstrate that human bladder tumors secrete substantial amounts of PGE2. Normal bone marrow myeloid cell progenitors cultured in the presence of a bladder tumor-conditioned medium, which is enriched for PGE2, failed to differentiate into mature APCs and acquired phenotype of the myeloid-derived suppressor cells or inflammatory macrophages with up-regulated chemokine receptor CXCR4. Collectively our data demonstrate that enhanced cancer-related inflammation and deregulated PGE2 metabolism in tumor microenvironment promote immunosuppressive pro-tumoral phenotype of myeloid cells in bladder cancer. These data also suggest that not only local tumor microenvironment but other factors such as stage of cancer disease and pace of tumor growth could markedly influence the phenotype, differentiation and immune function of myeloid cells in tumor tissue. PMID:21315786

  20. Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

    PubMed Central

    Ford, Catriona A.; Petrova, Sofia; Pound, John D.; Voss, Jorine J.L.P.; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L.; Gallimore, Awen M.; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E.; Dunbar, Donald R.; Murray, Paul G.; Ruckerl, Dominik; Allen, Judith E.; Hume, David A.; van Rooijen, Nico; Goodlad, John R.; Freeman, Tom C.; Gregory, Christopher D.

    2015-01-01

    Summary Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. PMID:25702581

  1. The Aurora-A-Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma.

    PubMed

    Wang, Jing; Nikhil, Kumar; Viccaro, Keith; Chang, Lei; Jacobsen, Max; Sandusky, George; Shah, Kavita

    2017-03-15

    We uncovered a crucial role for the Aurora kinase A (AURKA)-Twist1 axis in promoting epithelial-to-mesenchymal transition (EMT) and chemoresistance in pancreatic cancer. Twist1 is the first EMT-specific target of AURKA that was identified using an innovative screen. AURKA phosphorylates Twist1 at three sites, which results in its multifaceted regulation - AURKA inhibits its ubiquitylation, increases its transcriptional activity and favors its homodimerization. Twist1 reciprocates and prevents AURKA degradation, thereby triggering a feedback loop. Ablation of either AURKA or Twist1 completely inhibits EMT, highlighting both proteins as central players in EMT progression. Phosphorylation-dead Twist1 serves as a dominant-negative and fully reverses the EMT phenotype induced by Twist1, underscoring the crucial role of AURKA-mediated phosphorylation in mediating Twist1-induced malignancy. Likewise, Twist1-overexpressing BxPC3 cells formed large tumors in vivo, whereas expression of phosphorylation-dead Twist1 fully abrogated this effect. Furthermore, immunohistochemical analysis of pancreatic cancer specimens revealed a 3-fold higher level of Twist1 compared to that seen in healthy normal tissues. This is the first study that links Twist1 in a feedback loop with its activating kinase, which indicates that concurrent inhibition of AURKA and Twist1 will be synergistic in inhibiting pancreatic tumorigenesis and metastasis.

  2. Nuclear Morphometry Identifies a Distinct Aggressive Cellular Phenotype in Cutaneous Squamous Cell Carcinoma

    PubMed Central

    Glazer, Evan S.; Bartels, Peter H.; Prasad, Anil R.; Yozwiak, Michael L.; Bartels, Hubert G.; Einspahr, Janine G.; Alberts, David S.; Krouse, Robert S.

    2011-01-01

    By identifying aggressive cutaneous squamous cell carcinoma (cSCC) in patients who are at high risk for recurrences or second primaries after resection, intensive surveillance and therapy may decrease morbidity and mortality. We investigated the role of nuclear morphometry (karyometry) in differentiating between aggressive and nonaggressive cSCC. We retrospectively analyzed cSCC lesions from 40 male patients. 22 patients had evidence of aggressive cSCC (local/regional recurrence or a second primary cSCC), and 18 patients were identified with similar ages and sites of disease as control patients with nonaggressive cSCC (no evidence of recurrence, metastasis, or second primary). We performed karyometric analysis to identify nuclear features that discriminate between aggressive and nonaggressive cSCC nuclei. We used statistically significant differences (Kruskal-Wallis test P < 0.0001) to compose a quantitative aggressive classification score (proportion of aggressive nuclei from 0% to 100%). For comparisons, we used Fisher’s exact test or Student t test. The mean age was 79 ± 7 years for aggressive cSCC and 80 ± 9 years for nonaggressive cSCC (P = 0.66). We analyzed a mean of 96 nuclei in each group. The mean classification score for aggressive cSCC was significantly higher (69% ± 6%) than for nonaggressive cSCC (28% ± 5%, P = 0.00002). Overall, the classification score accurately categorized 80% of our patients (P = 0.0004). In most patients, karyometry differentiated between aggressive and nonaggressive cSCC. We found that classification scores, which provide information on individual lesions, could be used for risk stratification. PMID:21636541

  3. May bone cement be used to treat benign aggressive bone tumors of the feet with confidence?

    PubMed

    Özer, Devrim; Er, Turgay; Aycan, Osman Emre; Öke, Ramadan; Coşkun, Mehmet; Kabukçuoğlu, Yavuz Selim

    2014-03-01

    Using bone cement for the reconstruction of defects created after curettage of benign aggressive bone tumors is among acceptable methods. The study aimed to assess the effect of bone cement used in aggressive bone tumors in the feet on the function of the feet. Five patients were reviewed. They were treated between 2004 and 2010. Three cases were female and two male. Their age ranged from 16 to 55 with an average of 34.8. Follow up period ranged from 14 to 86 months with an average of 34. Two cases were giant cell tumor of bone located in calcaneus and 3 were solid variant aneurysmal bone cyst located in talus, navicular and first proximal phalanx. None had any previous treatment. A biopsy was done in all cases. Treatment was curettage, high speed burring (except phalanx case), and filling the cavity with bone cement. The case located in talus recurred and re-operated 1 year later doing the same procedure. Final evaluation included physical examination, X-ray and Maryland Foot Score. No recurrence was present in the final evaluation. No problems were detected related to bone cement. Maryland Foot Scores ranged 84-100, average of 94. Cement integrity was not disturbed. The procedure is found not to effect foot functions adversely.

  4. Reproducibility of radiomics for deciphering tumor phenotype with imaging

    PubMed Central

    Zhao, Binsheng; Tan, Yongqiang; Tsai, Wei-Yann; Qi, Jing; Xie, Chuanmiao; Lu, Lin; Schwartz, Lawrence H.

    2016-01-01

    Radiomics (radiogenomics) characterizes tumor phenotypes based on quantitative image features derived from routine radiologic imaging to improve cancer diagnosis, prognosis, prediction and response to therapy. Although radiomic features must be reproducible to qualify as biomarkers for clinical care, little is known about how routine imaging acquisition techniques/parameters affect reproducibility. To begin to fill this knowledge gap, we assessed the reproducibility of a comprehensive, commonly-used set of radiomic features using a unique, same-day repeat computed tomography data set from lung cancer patients. Each scan was reconstructed at 6 imaging settings, varying slice thicknesses (1.25 mm, 2.5 mm and 5 mm) and reconstruction algorithms (sharp, smooth). Reproducibility was assessed using the repeat scans reconstructed at identical imaging setting (6 settings in total). In separate analyses, we explored differences in radiomic features due to different imaging parameters by assessing the agreement of these radiomic features extracted from the repeat scans reconstructed at the same slice thickness but different algorithms (3 settings in total). Our data suggest that radiomic features are reproducible over a wide range of imaging settings. However, smooth and sharp reconstruction algorithms should not be used interchangeably. These findings will raise awareness of the importance of properly setting imaging acquisition parameters in radiomics/radiogenomics research. PMID:27009765

  5. Reproducibility of radiomics for deciphering tumor phenotype with imaging.

    PubMed

    Zhao, Binsheng; Tan, Yongqiang; Tsai, Wei-Yann; Qi, Jing; Xie, Chuanmiao; Lu, Lin; Schwartz, Lawrence H

    2016-03-24

    Radiomics (radiogenomics) characterizes tumor phenotypes based on quantitative image features derived from routine radiologic imaging to improve cancer diagnosis, prognosis, prediction and response to therapy. Although radiomic features must be reproducible to qualify as biomarkers for clinical care, little is known about how routine imaging acquisition techniques/parameters affect reproducibility. To begin to fill this knowledge gap, we assessed the reproducibility of a comprehensive, commonly-used set of radiomic features using a unique, same-day repeat computed tomography data set from lung cancer patients. Each scan was reconstructed at 6 imaging settings, varying slice thicknesses (1.25 mm, 2.5 mm and 5 mm) and reconstruction algorithms (sharp, smooth). Reproducibility was assessed using the repeat scans reconstructed at identical imaging setting (6 settings in total). In separate analyses, we explored differences in radiomic features due to different imaging parameters by assessing the agreement of these radiomic features extracted from the repeat scans reconstructed at the same slice thickness but different algorithms (3 settings in total). Our data suggest that radiomic features are reproducible over a wide range of imaging settings. However, smooth and sharp reconstruction algorithms should not be used interchangeably. These findings will raise awareness of the importance of properly setting imaging acquisition parameters in radiomics/radiogenomics research.

  6. Reproducibility of radiomics for deciphering tumor phenotype with imaging

    NASA Astrophysics Data System (ADS)

    Zhao, Binsheng; Tan, Yongqiang; Tsai, Wei-Yann; Qi, Jing; Xie, Chuanmiao; Lu, Lin; Schwartz, Lawrence H.

    2016-03-01

    Radiomics (radiogenomics) characterizes tumor phenotypes based on quantitative image features derived from routine radiologic imaging to improve cancer diagnosis, prognosis, prediction and response to therapy. Although radiomic features must be reproducible to qualify as biomarkers for clinical care, little is known about how routine imaging acquisition techniques/parameters affect reproducibility. To begin to fill this knowledge gap, we assessed the reproducibility of a comprehensive, commonly-used set of radiomic features using a unique, same-day repeat computed tomography data set from lung cancer patients. Each scan was reconstructed at 6 imaging settings, varying slice thicknesses (1.25 mm, 2.5 mm and 5 mm) and reconstruction algorithms (sharp, smooth). Reproducibility was assessed using the repeat scans reconstructed at identical imaging setting (6 settings in total). In separate analyses, we explored differences in radiomic features due to different imaging parameters by assessing the agreement of these radiomic features extracted from the repeat scans reconstructed at the same slice thickness but different algorithms (3 settings in total). Our data suggest that radiomic features are reproducible over a wide range of imaging settings. However, smooth and sharp reconstruction algorithms should not be used interchangeably. These findings will raise awareness of the importance of properly setting imaging acquisition parameters in radiomics/radiogenomics research.

  7. Expression of EGFR Under Tumor Hypoxia: Identification of a Subpopulation of Tumor Cells Responsible for Aggressiveness and Treatment Resistance

    SciTech Connect

    Hoogsteen, Ilse J.; Marres, Henri A.M.; Hoogen, Franciscus J.A. van den

    2012-11-01

    Purpose: Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena. Methods and Materials: In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry. Results: Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome. Conclusions: Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance.

  8. Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers.

    PubMed

    Olsen, Sarah Naomi; Wronski, Ania; Castaño, Zafira; Dake, Benjamin; Malone, Clare; De Raedt, Thomas; Enos, Miriam; DeRose, Yoko S; Zhou, Wenhui; Guerra, Stephanie; Loda, Massimo; Welm, Alana; Partridge, Ann H; McAllister, Sandra S; Kuperwasser, Charlotte; Cichowski, Karen

    2017-02-01

    Luminal breast cancers are typically estrogen receptor-positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.

  9. Cannibalism as an interacting phenotype: precannibalistic aggression is influenced by social partners in the endangered Socorro Isopod (Thermosphaeroma thermophilum).

    PubMed

    Bleakley, B H; Welter, S M; McCauley-Cole, K; Shuster, S M; Moore, A J

    2013-04-01

    Models for the evolution of cannibalism highlight the importance of asymmetries between individuals in initiating cannibalistic attacks. Studies may include measures of body size but typically group individuals into size/age classes or compare populations. Such broad comparisons may obscure the details of interactions that ultimately determine how socially contingent characteristics evolve. We propose that understanding cannibalism is facilitated by using an interacting phenotypes perspective that includes the influences of the phenotype of a social partner on the behaviour of a focal individual and focuses on variation in individual pairwise interactions. We investigated how relative body size, a composite trait between a focal individual and its social partner, and the sex of the partners influenced precannibalistic aggression in the endangered Socorro isopod, Thermosphaeroma thermophilum. We also investigated whether differences in mating interest among males and females influenced cannibalism in mixed sex pairs. We studied these questions in three populations that differ markedly in range of body size and opportunities for interactions among individuals. We found that relative body size influences the probability of and latency to attack. We observed differences in the likelihood of and latency to attack based on both an individual's sex and the sex of its partner but found no evidence of sexual conflict. The instigation of precannibalistic aggression in these isopods is therefore a property of both an individual and its social partner. Our results suggest that interacting phenotype models would be improved by incorporating a new conditional ψ, which describes the strength of a social partner's influence on focal behaviour.

  10. Identification of microRNAs associated with invasive and aggressive phenotype in cutaneous melanoma by next-generation sequencing.

    PubMed

    Babapoor, Sankhiros; Wu, Rong; Kozubek, James; Auidi, Donna; Grant-Kels, Jane M; Dadras, Soheil S

    2017-02-20

    A comprehensive repertoire of human microRNAs (miRNAs) that could be involved in early melanoma invasion into the dermis remains unknown. To this end, we sequenced small RNAs (18-30 nucleotides) isolated from an annotated series of invasive melanomas (average invasive depth, 2.0 mm), common melanocytic nevi, and matched normal skin (n=28). Our previously established bioinformatics pipeline identified 765 distinct mature known miRNAs and defined a set of top 40 list that clearly segregated melanomas into thin (0.75 mm) and thick (2.7 mm) groups. Among the top, miR-21-5p, let-7b-5p, let-7a-5p, miR-424-5p, miR-423-5p, miR-21-3p, miR-199b-5p, miR-182-5p, and miR-205-5p were differentially expressed between thin and thick melanomas. In a validation cohort (n=167), measured expression of miR-21-5p and miR-424-5p, not previously reported in melanoma, were significantly increased in invasive compared with in situ melanomas (P<0.0001). Increased miR-21-5p levels were significantly associated with invasive depth (P=0.038), tumor mitotic index (P=0.038), lymphovascular invasion (P=0.0036), and AJCC stage (P=0.038). In contrast, let-7b levels were significantly decreased in invasive and in situ melanomas compared with common and dysplastic nevi (P<0.0001). Decreased let-7b levels were significantly associated with invasive depth (P=0.011), Clark's level (P=0.013), ulceration (P=0.0043), and AJCC stage (P=0.011). These results define a distinct set of miRNAs associated with invasive and aggressive melanoma phenotype.Laboratory Investigation advance online publication, 20 February 2017; doi:10.1038/labinvest.2017.5.

  11. Correlation of tumor-infiltrating lymphocytes to histopathological features and molecular phenotypes in canine mammary carcinoma: A morphologic and immunohistochemical morphometric study.

    PubMed

    Kim, Jong-Hyuk; Chon, Seung-Ki; Im, Keum-Soon; Kim, Na-Hyun; Sur, Jung-Hyang

    2013-04-01

    Abundant lymphocyte infiltration is frequently found in canine malignant mammary tumors, but the pathological features and immunophenotypes associated with the infiltration remain to be elucidated. The aim of the present study was to evaluate the relationship between lymphocyte infiltration, histopathological features, and molecular phenotype in canine mammary carcinoma (MC). The study was done with archived formalin-fixed, paraffin-embedded samples (n = 47) by histologic and immunohistochemical methods. The degree of lymphocyte infiltration was evaluated by morphologic analysis, and the T- and B-cell populations as well as the T/B-cell ratio were evaluated by morphometric analysis; results were compared with the histologic features and molecular phenotypes. The degree of lymphocyte infiltration was significantly higher in MCs with lymphatic invasion than in those without lymphatic invasion (P < 0.0001) and in tumors of high histologic grade compared with those of lower histologic grade (P = 0.045). Morphometric analysis showed a larger amount of T-cells and B-cells in MCs with a higher histologic grade and lymphatic invasion, but the T/B ratio did not change. Lymphocyte infiltration was not associated with histologic type or molecular phenotype, as assessed from the immunohistochemical expression of epidermal growth factor receptor 2, estrogen receptor, cytokeratin 14, and p63. Since intense lymphocyte infiltration was associated with aggressive histologic features, lymphocytes may be important for tumor aggressiveness and greater malignant behavior in the tumor microenvironment.

  12. Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice.

    PubMed

    Wang, Hongwei; Venkatesh, Madhukumar; Li, Hao; Goetz, Regina; Mukherjee, Subhajit; Biswas, Arunima; Zhu, Liang; Kaubisch, Andreas; Wang, Lei; Pullman, James; Whitney, Kathleen; Kuro-o, Makoto; Roig, Andres I; Shay, Jerry W; Mohammadi, Moosa; Mani, Sridhar

    2011-08-01

    The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and "normal" intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas.

  13. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors.

    PubMed

    Cooper, Odelia; Mamelak, Adam; Bannykh, Serguei; Carmichael, John; Bonert, Vivien; Lim, Stephen; Cook-Wiens, Galen; Ben-Shlomo, Anat

    2014-06-01

    As ErbB signaling is a determinant of prolactin synthesis, role of ErbB receptors was tested for prolactinoma outcomes and therapy. The objective of this study was to characterize ErbB receptor expression in prolactinomas and then perform a pilot study treating resistant prolactinomas with a targeted tyrosine kinase inhibitor (TKI). Retrospective analysis of prolactinomas and pilot study for dopamine agonist resistant prolactinomas in tertiary referral center. We performed immunofluorescent staining of a tissue array of 29 resected prolactinoma tissues for EGFR, ErbB2, ErbB3, and ErbB4 correlated with clinical features. Two patients with aggressive resistant prolactinomas enrolled and completed trial. They received lapatinib 1,250 mg daily for 6 months with tumor and hormone assessments. Main outcome measures were positive tumor staining of respective ErbB receptors, therapeutic reduction of prolactin levels and tumor shrinkage. Treated PRL levels and tumor volumes were suppressed in both subjects treated with TKI. EGFR expression was positive in 82 % of adenomas, ErbB2 in 92 %, ErbB3 in 25 %, and ErbB4 in 71 %, with ErbB2 score > EGFR > ErbB4 > ErbB3. Higher ErbB3 expression was associated with optic chiasm compression (p = 0.03), suprasellar extension (p = 0.04), and carotid artery encasement (p = 0.01). Higher DA response rates were observed in tumors with higher ErbB3 expression. Prolactinoma expression of specific ErbB receptors is associated with tumor invasion, symptoms, and response to dopamine agonists. Targeting ErbB receptors may be effective therapy in patients with resistant prolactinomas.

  14. Role of miR-139 as a surrogate marker for tumor aggression in breast cancer.

    PubMed

    Dai, Hongyan; Gallagher, Dan; Schmitt, Sarah; Pessetto, Ziyan Y; Fan, Fang; Godwin, Andrew K; Tawfik, Ossama

    2017-03-01

    MicroRNAs are non-protein coding molecules that play a key role in oncogenesis, tumor progression, and metastasis in many types of malignancies including breast cancer. In the current study, we studied the expression of microRNA-139-5p (miR-139) in invasive ductal carcinoma (IDC) of the breast and correlated its expression with tumor grade, molecular subtype, hormonal status, human epidermal growth factor receptor 2 status, proliferation index, tumor size, lymph node status, patient's age, and overall survival in 74 IDC cases. In addition, we compared and correlated miR-139 expression in 18 paired serum and tissue samples from patients with IDC to assess its value as a serum marker. Our data showed that miR-139 was down-regulated in all tumor tissue samples compared with control. More pronounced down-regulation was seen in tumors that were higher grade, estrogen receptor negative, progesterone receptor negative, more proliferative, or larger in size (P < .05). Although not statistically significant, lower miR-139 level was frequently associated with human epidermal growth factor receptor 2 overexpression. In addition, significantly lower miR-139 tissue level was seen in patients who were deceased (P = .027), although older age (>50 years) and positive local nodal disease did not adversely affect miR-139 expression. In contrast, serum miR-139 profile of the patients appeared similar to that of normal control. In conclusion, our study demonstrated that down-regulation of miR-139 was associated with aggressive tumor behavior and disease progression in breast cancer. miR-139 may serve as a risk assessment biomarker in tailoring treatment options.

  15. Astrocyte Elevated Gene 1 Interacts with Acetyltransferase p300 and c-Jun To Promote Tumor Aggressiveness.

    PubMed

    Liu, Liping; Guan, Hongyu; Li, Yun; Ying, Zhe; Wu, Jueheng; Zhu, Xun; Song, Libing; Li, Jun; Li, Mengfeng

    2017-03-01

    Astrocyte elevated gene 1 (AEG-1) is an oncoprotein that strongly promotes the development and progression of cancers. However, the detailed underlying mechanisms through which AEG-1 enhances tumor development and progression remain to be determined. In this study, we identified c-Jun and p300 to be novel interacting partners of AEG-1 in gliomas. AEG-1 promoted c-Jun transcriptional activity by interacting with the c-Jun/p300 complex and inducing c-Jun acetylation. Furthermore, the AEG-1/c-Jun/p300 complex was found to bind the promoter of c-Jun downstream targeted genes, consequently establishing an acetylated chromatin state that favors transcriptional activation. Importantly, AEG-1/p300-mediated c-Jun acetylation resulted in the development of a more aggressive malignant phenotype in gliomas through a drastic increase in glioma cell proliferation and angiogenesis in vitro and in vivo Consistently, the AEG-1 expression levels in clinical glioma specimens correlated with the status of c-Jun activation. Taken together, our results suggest that AEG-1 mediates a novel epigenetic mechanism that enhances c-Jun transcriptional activity to induce glioma progression and that AEG-1 might be a novel, potential target for the treatment of gliomas.

  16. Giant cell tumor of the bone: aggressive case initially treated with denosumab and intralesional surgery.

    PubMed

    von Borstel, Donald; A Taguibao, Roberto; A Strle, Nicholas; E Burns, Joseph

    2017-04-01

    Giant cell tumor of the bone (GCTB) is a locally aggressive benign tumor, which has historically been treated with wide surgical excision. We report a case of a 29-year-old male with histology-proven GCTB of the distal ulna. The initial imaging study was a contrast-enhanced magnetic resonance imaging (MRI) examination of the left wrist, which was from an outside facility performed before presenting to our institution. On the initial MRI, the lesion had homogenous T2-hyperintense and T1-hypointense signal with expansive remodeling of the osseous contour. A radiographic study performed upon presentation to our institution 1 month later showed progression of the lesion with atypical imaging characteristics. After confirming the diagnosis, denosumab therapy was implemented allowing for reconstitution of bone and intralesional treatment. The patient was treated with five doses of denosumab over the duration of 7 weeks. Therapeutic changes of the GCTB were evaluated by radiography and a post-treatment MRI. This MRI was interpreted as suspicious for worsening disease due to the imaging appearance of intralesional signal heterogeneity, increased perilesional fluid-like signal, and circumferential cortical irregularity. However, on subsequent intralesional curettage and bone autografting 6 weeks later, no giant cells were seen on the specimen. Thus, the appearance on the MRI, rather than representing a manifestation of lesion aggressiveness or a non-responding tumor, conversely represented the imaging appearance of a positive response to denosumab therapy. On follow-up evaluation, 5 months after intralesional treatment, the patient had recurrent disease and is now scheduled for wide-excision with joint prosthesis.

  17. Elusive Identities and Overlapping Phenotypes of Proangiogenic Myeloid Cells in Tumors

    PubMed Central

    Coffelt, Seth B.; Lewis, Claire E.; Naldini, Luigi; Brown, J. Martin; Ferrara, Napoleone; De Palma, Michele

    2010-01-01

    It is now established that bone marrow–derived myeloid cells regulate tumor angiogenesis. This was originally inferred from studies of human tumor biopsies in which a positive correlation was seen between the number of tumor-infiltrating myeloid cells, such as macrophages and neutrophils, and tumor microvessel density. However, unequivocal evidence was only provided once mouse models were used to examine the effects on tumor angiogenesis by genetically or pharmacologically targeting myeloid cells. Since then, identifying the exact myeloid cell types involved in this process has proved challenging because of myeloid cell heterogeneity and the expression of overlapping phenotypic markers in tumors. As a result, investigators often simply refer to them now as “bone marrow–derived myeloid cells.” Here we review the findings of various attempts to phenotype the myeloid cells involved and discuss the therapeutic implications of correctly identifying—and thus being able to target—this proangiogenic force in tumors. PMID:20167863

  18. Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors.

    PubMed

    Coffelt, Seth B; Lewis, Claire E; Naldini, Luigi; Brown, J Martin; Ferrara, Napoleone; De Palma, Michele

    2010-04-01

    It is now established that bone marrow-derived myeloid cells regulate tumor angiogenesis. This was originally inferred from studies of human tumor biopsies in which a positive correlation was seen between the number of tumor-infiltrating myeloid cells, such as macrophages and neutrophils, and tumor microvessel density. However, unequivocal evidence was only provided once mouse models were used to examine the effects on tumor angiogenesis by genetically or pharmacologically targeting myeloid cells. Since then, identifying the exact myeloid cell types involved in this process has proved challenging because of myeloid cell heterogeneity and the expression of overlapping phenotypic markers in tumors. As a result, investigators often simply refer to them now as "bone marrow-derived myeloid cells." Here we review the findings of various attempts to phenotype the myeloid cells involved and discuss the therapeutic implications of correctly identifying-and thus being able to target-this proangiogenic force in tumors.

  19. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal.

    PubMed Central

    Kindblom, L. G.; Remotti, H. E.; Aldenborg, F.; Meis-Kindblom, J. M.

    1998-01-01

    The interstitial cells of Cajal (ICC) form a complex cell network within the gastrointestinal tract wall where they function as a pacemaker system. Expression of the kit proto-oncogene is essential for the development of this system. The aim of our study was to examine the hypothesis that gastrointestinal stromal tumors differentiate toward cells with an ICC phenotype. Ultrastructurally, 58 stromal tumors were characterized and found to share many features with ICC. Seventy-eight stromal tumors were immunophenotyped, particularly with regard to the kit receptor. All 78 tumors revealed strong, homogeneous immunoreactivity for the kit receptor as did ICC of adjacent and control gastrointestinal walls. Focal hyperplasia and hypertrophy of kit receptor positive cells were also observed in the gastrointestinal wall adjacent to the tumors. CD34 immunoreactivity observed in interstitial cells surrounding Auerbach's ganglia suggests that a subpopulation of ICC is CD34 positive and may explain why 56 of 78 stromal tumors were CD34 positive. Thirty control tumors, including gastrointestinal leiomyomas and leiomyosarcomas, were all negative for the kit receptor. We conclude that gastrointestinal stromal tumors show striking morphological and immunophenotypic similarities with ICC and that they may originate from stem cells that differentiate toward a pacemaker cell phenotype. We propose that the noncommittal name "gastrointestinal stromal tumor" be replaced by gastrointestinal pacemaker cell tumor. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:9588894

  20. BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions.

    PubMed

    Sinha, Abhilasha; Paul, Bibbin T; Sullivan, Lisa M; Sims, Hillary; El Bastawisy, Ahmed; Yousef, Hend F; Zekri, Abdel-Rahman N; Bahnassy, Abeer A; ElShamy, Wael M

    2017-02-07

    Tumor-initiating cells (TICs) are cancer cells endowed with self-renewal, multi-lineage differentiation, increased chemo-resistance, and in breast cancers the CD44+/CD24-/ALDH1+ phenotype. Triple negative breast cancers show lack of BRCA1 expression in addition to enhanced basal, epithelial-to-mesenchymal transition (EMT), and TIC phenotypes. BRCA1-IRIS (hereafter IRIS) is an oncogene produced by the alternative usage of the BRCA1 locus. IRIS is involved in induction of replication, transcription of selected oncogenes, and promoting breast cancer cells aggressiveness. Here, we demonstrate that IRIS overexpression (IRISOE) promotes TNBCs through suppressing BRCA1 expression, enhancing basal-biomarkers, EMT-inducers, and stemness-enforcers expression. IRISOE also activates the TIC phenotype in TNBC cells through elevating CD44 and ALDH1 expression/activity and preventing CD24 surface presentation by activating the internalization pathway EGFR→c-Src→cortactin. We show that the intrinsic sensitivity to an anti-CD24 cross-linking antibody-induced cell death in membranous CD24 expressing/luminal A cells could be acquired in cytoplasmic CD24 expressing IRISOE TNBC/TIC cells through IRIS silencing or inactivation. We show that fewer IRISOE TNBC/TICs cells form large tumors composed of TICs, resembling TNBCs early lesions in patients that contain metastatic precursors capable of disseminating and metastasizing at an early stage of the disease. IRIS-inhibitory peptide killed these IRISOE TNBC/TICs, in vivo and prevented their dissemination and metastasis. We propose IRIS inactivation could be pursued to prevent dissemination and metastasis from early TNBC tumor lesions in patients.

  1. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas.

    PubMed

    Qi, Wenqing; Liu, Xiaobing; Cooke, Laurence S; Persky, Daniel O; Miller, Thomas P; Squires, Matthew; Mahadevan, Daruka

    2012-06-15

    Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation.

  2. The CD44+/CD24- phenotype is enriched in basal-like breast tumors

    PubMed Central

    Honeth, Gabriella; Bendahl, Pär-Ola; Ringnér, Markus; Saal, Lao H; Gruvberger-Saal, Sofia K; Lövgren, Kristina; Grabau, Dorthe; Fernö, Mårten; Borg, Åke; Hegardt, Cecilia

    2008-01-01

    Introduction Human breast tumors are heterogeneous and consist of phenotypically diverse cells. Breast cancer cells with a CD44+/CD24- phenotype have been suggested to have tumor-initiating properties with stem cell-like and invasive features, although it is unclear whether their presence within a tumor has clinical implications. There is also a large heterogeneity between tumors, illustrated by reproducible stratification into various subtypes based on gene expression profiles or histopathological features. We have explored the prevalence of cells with different CD44/CD24 phenotypes within breast cancer subtypes. Methods Double-staining immunohistochemistry was used to quantify CD44 and CD24 expression in 240 human breast tumors for which information on other tumor markers and clinical characteristics was available. Gene expression data were also accessible for a cohort of the material. Results A considerable heterogeneity in CD44 and CD24 expression was seen both between and within tumors. A complete lack of both proteins was evident in 35% of the tumors, while 13% contained cells of more than one of the CD44+/CD24-, CD44-/CD24+ and CD44+/CD24+ phenotypes. CD44+/CD24- cells were detected in 31% of the tumors, ranging in proportion from only a few to close to 100% of tumor cells. The CD44+/CD24- phenotype was most common in the basal-like subgroup – characterized as negative for the estrogen and progesterone receptors as well as for HER2, and as positive for cytokeratin 5/14 and/or epidermal growth factor receptor, and particularly common in BRCA1 hereditary tumors, of which 94% contained CD44+/CD24- cells. The CD44+/CD24- phenotype was surprisingly scarce in HER2+ tumors, which had a predominantly CD24+ status. A CD44+/CD24- gene expression signature was generated, which included CD44 and α6-integrin (CD49f) among the top-ranked overexpressed genes. Conclusion We demonstrate an association between basal-like and particularly BRCA1 hereditary breast cancer and

  3. siRNA Knockdown of Ribosomal Protein Gene RPL19 Abrogates the Aggressive Phenotype of Human Prostate Cancer

    PubMed Central

    Bee, Alix; Brewer, Daniel; Beesley, Carol; Dodson, Andrew; Forootan, Shiva; Dickinson, Timothy; Gerard, Patricia; Lane, Brian; Yao, Sheng; Cooper, Colin S.; Djamgoz, Mustafa B. A.; Gosden, Christine M.; Ke, Youqiang; Foster, Christopher S.

    2011-01-01

    We provide novel functional data that posttranscriptional silencing of gene RPL19 using RNAi not only abrogates the malignant phenotype of PC-3M prostate cancer cells but is selective with respect to transcription and translation of other genes. Reducing RPL19 transcription modulates a subset of genes, evidenced by gene expression array analysis and Western blotting, but does not compromise cell proliferation or apoptosis in-vitro. However, growth of xenografted tumors containing the knocked-down RPL19 in-vivo is significantly reduced. Analysis of the modulated genes reveals induction of the non-malignant phenotype principally to involve perturbation of networks of transcription factors and cellular adhesion genes. The data provide evidence that extra-ribosomal regulatory functions of RPL19, beyond protein synthesis, are critical regulators of cellular phenotype. Targeting key members of affected networks identified by gene expression analysis raises the possibility of therapeutically stabilizing a benign phenotype generated by modulating the expression of an individual gene and thereafter constraining a malignant phenotype while leaving non-malignant tissues unaffected. PMID:21799931

  4. Role of Receptor Sialylation in the Ovarian Tumor Cell Phenotype

    DTIC Science & Technology

    2012-06-01

    blocks apoptosis induced by the mammalian lectin, galectin - 3 , which our studies show is expressed in human ovarian tumor tissues and in ascitic fluid...omental cultures. • Optimized immunoblotting protocol for galectin - 3 in ascites • Determination that sialylation of Fas and TNFR1 blocks apoptotic...REPORT DATE 2. REPORT TYPE Annual report 3 . DATES COVERED 4. TITLE AND SUBTITLE Role of receptor sialylation in the ovarian tumor cell

  5. The ETS family member GABPα modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer

    PubMed Central

    Sharma, Naomi L.; Massie, Charlie E.; Butter, Falk; Mann, Matthias; Bon, Helene; Ramos-Montoya, Antonio; Menon, Suraj; Stark, Rory; Lamb, Alastair D.; Scott, Helen E.; Warren, Anne Y.; Neal, David E.; Mills, Ian G.

    2014-01-01

    In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention. PMID:24753418

  6. Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15

    PubMed Central

    2013-01-01

    Introduction Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. Methods We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features. Results MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. Conclusion MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice. PMID:23663520

  7. An unusually large aggressive adenomatoid odontogenic tumor of maxilla involving the third molar: A clinical case report

    PubMed Central

    Dhupar, Vikas; Akkara, Francis; Khandelwal, Pulkit

    2016-01-01

    Adenomatoid odontogenic tumor (AOT) is a rare tumor comprising only 3% of all odontogenic tumors. It is a benign, encapsulated, noninvasive, nonaggressive, slowly growing odontogenic lesion associated with an impacted tooth. These lesions may go unnoticed for years. The usual treatment is enucleation and curettage, and the lesion does not recur. Here, we present a rare case of an unusually large aggressive AOT of maxilla associated with impacted third molar. The authors also discuss clinical, radiographic, histopathologic, and therapeutic features of the case. Subtotal maxillectomy with simultaneous reconstruction of the surgical defect with temporalis myofascial flap was planned and carried out. PMID:27095910

  8. Proposed therapeutic strategy for adult low-grade glioma based on aggressive tumor resection.

    PubMed

    Nitta, Masayuki; Muragaki, Yoshihiro; Maruyama, Takashi; Ikuta, Soko; Komori, Takashi; Maebayashi, Katsuya; Iseki, Hiroshi; Tamura, Manabu; Saito, Taiichi; Okamoto, Saori; Chernov, Mikhail; Hayashi, Motohiro; Okada, Yoshikazu

    2015-01-01

    significantly correlated with patient survival; thus, one should aim for maximum tumor resection. In addition, patients with a higher EOR can be safely observed without adjuvant therapy. For patients with partial resection, postoperative chemotherapy should be administered for those with oligodendroglial subtypes, and repeat resection should be considered for those with astrocytic tumors. More aggressive treatment with RT and chemotherapy may be required for patients with a poor prognosis, such as those with diffuse astrocytoma, 1p/19q nondeleted tumors, or IDH1 wild-type oligodendroglial tumors with partial resection.

  9. Phenotypes of murine leukemia virus-induced tumors: influence of 3' viral coding sequences.

    PubMed Central

    Ott, D E; Keller, J; Sill, K; Rein, A

    1992-01-01

    Murine leukemia viruses (MuLVs) induce leukemias and lymphomas in mice. We have used fluorescence-activated cell sorter analysis to determine the hematopoietic phenotypes of tumor cells induced by a number of MuLVs. Tumor cells induced by ecotropic Moloney, amphotropic 4070A, and 10A1 MuLVs and by two chimeric MuLVs, Mo(4070A) and Mo(10A1), were examined with antibodies to 13 lineage-specific cell surface markers found on myeloid cell, T-cell, and B-cell lineages. The chimeric Mo(4070A) and Mo(10A1) MuLVs, consisting of Moloney MuLV with the carboxy half of the Pol region and nearly all of the Env region of 4070A and 10A1, respectively, were constructed to examine the possible influence of these sequences on Moloney MuLV-induced tumor cell phenotypes. In some instances, these phenotypic analyses were supplemented by Southern blot analysis for lymphoid cell-specific genomic DNA rearrangements at the immunoglobulin heavy-chain, the T-cell receptor gamma, and the T-cell receptor beta loci. The results of our analysis showed that Moloney MuLV, 4070A, Mo(4070A), and Mo(10A1) induced mostly T-cell tumors. Moloney MuLV and Mo(4070A) induced a wide variety of T-cell phenotypes, ranging from immature to mature phenotypes, while 4070A induced mostly prothymocyte and double-negative (CD4- CD8-) T-cell tumors. The tumor phenotypes obtained with 10A1 and Mo(10A1) were each less variable than those obtained with the other MuLVs tested. 10A1 uniformly induced a tumor consisting of lineage marker-negative cells that lack lymphoid cell-specific DNA rearrangements and histologically appear to be early undifferentiated erythroid cell-like precursors. The Mo(10A1) chimera consistently induced an intermediate T-cell tumor. The chimeric constructions demonstrated that while 4070A 3' pol and env sequences apparently did not influence the observed tumor cell phenotypes, the 10A1 half of pol and env had a strong effect on the phenotypes induced by Mo(10A1) that resulted in a phenotypic

  10. GALNT6 expression enhances aggressive phenotypes of ovarian cancer cells by regulating EGFR activity.

    PubMed

    Lin, Tzu-Chi; Chen, Syue-Ting; Huang, Min-Chuan; Huang, John; Hsu, Chia-Lang; Juan, Hsueh-Fen; Lin, Ho-Hsiung; Chen, Chi-Hau

    2017-03-28

    Ovarian cancer is the most lethal of the gynecologic malignancies. N-acetylgalactosaminyltransferase 6 (GALNT6), an enzyme that mediates the initial step of mucin type-O glycosylation, has been reported to regulate mammary carcinogenesis. However, the expression and role of GALNT6 in ovarian cancer are still unclear. Here we showed that high GALNT6 expression correlates with increased recurrence, lymph node metastasis, and chemoresistance in ovarian endometrioid and clear cell carcinomas; and higher GALNT6 levels are significantly associated with poorer patient survivals. GALNT6 knockdown with two independent siRNAs significantly suppressed viability, migration, and invasion of ovarian cancer cells. Using phospho-RTK array and Western blot analyses, we identified EGFR as a critical target of GALNT6. GALNT6 knockdown decreased phosphorylation of EGFR, whereas GALNT6 overexpression increased the phosphorylation. Lectin pull-down assays with Vicia villosa agglutinin (VVA) indicated that GALNT6 was able to modify O-glycans on EGFR. Moreover, the GALNT6-enhanced invasive behavior was significantly reversed by erlotinib, an EGFR inhibitor. Our results suggest that GALNT6 expression is associated with poor prognosis of ovarian cancer and enhances the aggressive behavior of ovarian cancer cells by regulating EGFR activity.

  11. Computer-Aided Image Analysis and Fractal Synthesis in the Quantitative Evaluation of Tumor Aggressiveness in Prostate Carcinomas.

    PubMed

    Waliszewski, Przemyslaw

    2016-01-01

    The subjective evaluation of tumor aggressiveness is a cornerstone of the contemporary tumor pathology. A large intra- and interobserver variability is a known limiting factor of this approach. This fundamental weakness influences the statistical deterministic models of progression risk assessment. It is unlikely that the recent modification of tumor grading according to Gleason criteria for prostate carcinoma will cause a qualitative change and improve significantly the accuracy. The Gleason system does not allow the identification of low aggressive carcinomas by some precise criteria. The ontological dichotomy implies the application of an objective, quantitative approach for the evaluation of tumor aggressiveness as an alternative. That novel approach must be developed and validated in a manner that is independent of the results of any subjective evaluation. For example, computer-aided image analysis can provide information about geometry of the spatial distribution of cancer cell nuclei. A series of the interrelated complexity measures characterizes unequivocally the complex tumor images. Using those measures, carcinomas can be classified into the classes of equivalence and compared with each other. Furthermore, those measures define the quantitative criteria for the identification of low- and high-aggressive prostate carcinomas, the information that the subjective approach is not able to provide. The co-application of those complexity measures in cluster analysis leads to the conclusion that either the subjective or objective classification of tumor aggressiveness for prostate carcinomas should comprise maximal three grades (or classes). Finally, this set of the global fractal dimensions enables a look into dynamics of the underlying cellular system of interacting cells and the reconstruction of the temporal-spatial attractor based on the Taken's embedding theorem. Both computer-aided image analysis and the subsequent fractal synthesis could be performed

  12. Computer-Aided Image Analysis and Fractal Synthesis in the Quantitative Evaluation of Tumor Aggressiveness in Prostate Carcinomas

    PubMed Central

    Waliszewski, Przemyslaw

    2016-01-01

    The subjective evaluation of tumor aggressiveness is a cornerstone of the contemporary tumor pathology. A large intra- and interobserver variability is a known limiting factor of this approach. This fundamental weakness influences the statistical deterministic models of progression risk assessment. It is unlikely that the recent modification of tumor grading according to Gleason criteria for prostate carcinoma will cause a qualitative change and improve significantly the accuracy. The Gleason system does not allow the identification of low aggressive carcinomas by some precise criteria. The ontological dichotomy implies the application of an objective, quantitative approach for the evaluation of tumor aggressiveness as an alternative. That novel approach must be developed and validated in a manner that is independent of the results of any subjective evaluation. For example, computer-aided image analysis can provide information about geometry of the spatial distribution of cancer cell nuclei. A series of the interrelated complexity measures characterizes unequivocally the complex tumor images. Using those measures, carcinomas can be classified into the classes of equivalence and compared with each other. Furthermore, those measures define the quantitative criteria for the identification of low- and high-aggressive prostate carcinomas, the information that the subjective approach is not able to provide. The co-application of those complexity measures in cluster analysis leads to the conclusion that either the subjective or objective classification of tumor aggressiveness for prostate carcinomas should comprise maximal three grades (or classes). Finally, this set of the global fractal dimensions enables a look into dynamics of the underlying cellular system of interacting cells and the reconstruction of the temporal-spatial attractor based on the Taken’s embedding theorem. Both computer-aided image analysis and the subsequent fractal synthesis could be performed

  13. Characterization of Fusarium graminearum isolates recovered from wheat samples from Argentina by Fourier transform infrared spectroscopy: Phenotypic diversity and detection of specific markers of aggressiveness.

    PubMed

    Fígoli, Cecilia B; Rojo, Rodrigo; Gasoni, Laura A; Kikot, Gisele; Leguizamón, Mariana; Gamba, Raúl R; Bosch, Alejandra; Alconada, Teresa M

    2017-03-06

    Fusarium graminearum is the primary causal agent of Fusarium head blight of wheat in Argentina. This disease affects crop yields and grain quality also reducing the wheat end-use, and causing mycotoxin contamination. The aim of this work was to analyze the phenotypic characteristics associated with phenotypic diversity and aggressiveness of 34 F. graminearum sensu stricto isolates recovered from Argentinean fields in the 2008 growing season using the Fourier Transform Infrared (FTIR) dried film technology. We applied this technique also to search for spectral specific markers associated with aggressiveness. The combination of FTIR technology with hierarchical cluster analysis allowed us to determine that this population constitutes a highly diverse and heterogeneous group of fungi with significant phenotypic variance. Still, when the spectral features of a set of these isolates were compared against their aggressiveness, as measured by disease severity, thousand grains weight, and relative yield reduction, we found that the more aggressive isolates were richer in lipid content. Therefore, we could define several spectroscopic markers (>CH stretching modes in the 3000-2800 window, >CO and CO vibrational modes of esters at 1765-1707cm(-1) and 1474-900cm(-1), respectively), mostly assigned to lipid content that could be associated with F. graminearum aggressiveness. All together, by the application of FTIR techniques and simple multivariate analyses, it was possible to gain significant insights into the phenotypic characterization of F. graminearum local isolates, and to establish the existence of a direct relationship between lipid content and fungal aggressiveness. Considering that lipids have a major role as mediators in the interaction between plants and fungi our results could represent an attractive outcome in the study of Fusarium pathogenesis.

  14. Role of Receptor Sialylation in the Ovarian Tumor Cell Phenotype

    DTIC Science & Technology

    2014-08-01

    transit through the peritoneal cavity. Additionally, ST6Gal-I appears to contribute to metastatic targeting of omentum and resistance to cisplatin ...protection of tumor cells against cisplatin - mediated cell death (Task 3). Progress: We have by far made the most progress on Aim 3 and research...ovarian cancer resistance to cisplatin -mediated cell death, as well as death receptor signaling by ovarian cancer cells within the peritoneal cavity

  15. Gastric type endocervical adenocarcinoma: an aggressive tumor with unusual metastatic patterns and poor prognosis

    PubMed Central

    Karamurzin, Yevgeniy S.; Kiyokawa, Takako; Parkash, Vinita; Jotwani, Anjali R.; Patel, Prusha; Pike, Malcolm C.; Soslow, Robert A.; Park, Kay J.

    2016-01-01

    Gastric type adenocarcinoma of the uterine cervix (GAS) is a rare variant of mucinous endocervical adenocarcinoma not etiologically associated with human papillomavirus (HPV) infection, with minimal deviation adenocarcinoma (MDA) at the well-differentiated end of the morphologic spectrum. These tumors are reported to have worse prognosis than usual HPV-associated endocervical adenocarcinoma (UEA). A retrospective review of GAS was performed from the pathology databases of three institutions spanning 20 years. Stage, metastatic patterns, and overall survival were documented. Forty GAS cases were identified, with clinical follow-up data available for 38. The tumors were subclassified as MDA (n=13) and non-MDA GAS (n=27). Two patients were syndromic (one Li-Fraumeni, one Peutz-Jeghers). At presentation, 59% were advanced stage (FIGO II–IV), 50% had lymph node metastases, 35% had ovarian involvement, 20% had abdominal disease, 39% had at least one site of metastasis at the time of initial surgery, and 12% of patients experienced distant recurrence. The metastatic sites included lymph nodes, adnexa, omentum, bowel, peritoneum, diaphragm, abdominal wall, bladder, vagina, appendix, and brain. Follow-up ranged from 1.4 to 136.0 months (mean, 33.9 months); 20/38 (52.6%) had no evidence of disease, 3/38 (7.9%) were alive with disease, and 15/38 (39.5%) died of disease. Disease specific survival at 5 years was 42% for GAS vs. 91% for UEA. There were no survival differences between MDA and non-MDA GAS. GAS represents a distinct, biologically aggressive type of endocervical adenocarcinoma. The majority of patients present at advanced stage and pelvic, abdominal, and distant metastases are not uncommon. PMID:26457350

  16. Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data.

    PubMed

    Wang, Edwin; Zaman, Naif; Mcgee, Shauna; Milanese, Jean-Sébastien; Masoudi-Nejad, Ali; O'Connor-McCourt, Maureen

    2015-02-01

    Tumor genome sequencing leads to documenting thousands of DNA mutations and other genomic alterations. At present, these data cannot be analyzed adequately to aid in the understanding of tumorigenesis and its evolution. Moreover, we have little insight into how to use these data to predict clinical phenotypes and tumor progression to better design patient treatment. To meet these challenges, we discuss a cancer hallmark network framework for modeling genome sequencing data to predict cancer clonal evolution and associated clinical phenotypes. The framework includes: (1) cancer hallmarks that can be represented by a few molecular/signaling networks. 'Network operational signatures' which represent gene regulatory logics/strengths enable to quantify state transitions and measures of hallmark traits. Thus, sets of genomic alterations which are associated with network operational signatures could be linked to the state/measure of hallmark traits. The network operational signature transforms genotypic data (i.e., genomic alterations) to regulatory phenotypic profiles (i.e., regulatory logics/strengths), to cellular phenotypic profiles (i.e., hallmark traits) which lead to clinical phenotypic profiles (i.e., a collection of hallmark traits). Furthermore, the framework considers regulatory logics of the hallmark networks under tumor evolutionary dynamics and therefore also includes: (2) a self-promoting positive feedback loop that is dominated by a genomic instability network and a cell survival/proliferation network is the main driver of tumor clonal evolution. Surrounding tumor stroma and its host immune systems shape the evolutionary paths; (3) cell motility initiating metastasis is a byproduct of the above self-promoting loop activity during tumorigenesis; (4) an emerging hallmark network which triggers genome duplication dominates a feed-forward loop which in turn could act as a rate-limiting step for tumor formation; (5) mutations and other genomic alterations have

  17. Nuclear survivin promoted by acetylation is associated with the aggressive phenotype of oral squamous cell carcinoma.

    PubMed

    Liu, Shuli; Shi, Lei; Yang, Xi; Ye, Dongxia; Wang, Tong; Dong, Cunshan; Guo, Wenzheng; Liao, Yueling; Song, Hongyong; Xu, Dongliang; Hu, Jingzhou; Zhang, Zhiyuan; Deng, Jiong

    2017-04-06

    Defects in apoptotic pathway contribute to development and progression of oral cancer. Survivin, a member of the inhibitors of apoptosis protein (IAP) family, is increased in many types of cancers. However, it is unclear whether increased survivin is associated with oral squamous cell carcinomas (OSCC), and what mechanisms may involve in. In this study, we examined survivin expression in OSCC compared to normal oral tissues via immunohistochemical staining. The results showed that, not only total survivin is increased in OSCCs, but also the subcellular location of survivin is changed in OSCCs compared to normal oral tissues. In most of normal oral tissues, survivin staining was either negative, or cytoplasmic positive/nuclear negative; whereas in most of OSCC tissues, survivin staining was nuclear positive. Statistic analysis indicates that nuclear survivin, rather than total or cytoplasmic one, correlates with tumor TNM stage and differentiation grade. Consistently, in vitro analysis showed that survivin is in cytoplasm in normal human oral kinotinocyte (HOK) cells; whereas it is in nucleus in OSCC HN6 cells. Importantly, treatment of HOK cells with HDAC inhibitor Trichostatin A (TSA) induces survivin acetylation and promotes its nuclear localization. Moreover, nuclear survivin in OSCC cells was acetylated at K129 in its C-terminal, suggesting that the acetylation is important for nuclear location of survivin. Our study demonstrates that it is nuclear survivin, rather than total or cytoplasmic one, associates with TNM stage and tumor grade of OSCC. Thus, we propose nuclear survivin as a prognostic marker for the progression of OSCC.

  18. Graded activation of the MEK1/MT1-MMP axis determines renal epithelial cell tumor phenotype

    PubMed Central

    Mahimkar, Rajeev; Alfonso-Jaume, Maria Alejandra; Cape, Leslie M.; Dahiya, Rajvir; Lovett, David H.

    2011-01-01

    Activation of Raf/Ras/mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase signaling and elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) are associated with von Hippel–Lindau gene alterations in renal cell carcinoma. We postulated that the degree of MEK activation was related to graded expression of MT1-MMP and the resultant phenotype of renal epithelial tumors. Madin Darby canine kidney epithelial cells transfected with a MEK1 expression plasmid yielded populations with morphologic phenotypes ranging from epithelial, mixed epithelial/mesenchymal to mesenchymal. Clones were analyzed for MEK1 activity, MT1-MMP expression and extent of epithelial–mesenchymal transition. Phenotypes of the MDCK-MEK1 clones were evaluated in vivo with nu/nu mice. Tissue microarray of renal cell cancers was quantitatively assessed for expression of phosphorylated MEK1 and MT1-MMP proteins and correlations drawn to Fuhrman nuclear grade. Graded increases in the MEK signaling module were associated with graded induction of epithelial–mesenchymal transition of the MDCK cells and induction of MT1-MMP transcription and synthesis. Inhibition of MEK1 and MT1-MMP activity reversed the epithelial–mesenchymal transition. Tumors generated by epithelial, mixed epithelial/mesenchymal and mesenchymal MDCK clones demonstrated a gradient of phenotypes extending from well-differentiated, fully encapsulated non-invasive tumors to tumors with an anaplastic morphology, high Fuhrman nuclear score, neoangiogenesis and invasion. Tumor microarray demonstrated a statistically significant association between the extent of phosphorylated MEK1, MT1-MMP expression and nuclear grade. We conclude that graded increases in the MEK1 signaling module are correlated with M1-MMP expression, renal epithelial cell tumor phenotype, invasive activity and nuclear grade. Phosphorylated MEK1 and MT1-MMP may represent novel, and mechanistic, biomarkers for the assessment of renal

  19. Graded activation of the MEK1/MT1-MMP axis determines renal epithelial cell tumor phenotype.

    PubMed

    Mahimkar, Rajeev; Alfonso-Jaume, Maria Alejandra; Cape, Leslie M; Dahiya, Rajvir; Lovett, David H

    2011-12-01

    Activation of Raf/Ras/mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase signaling and elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) are associated with von Hippel-Lindau gene alterations in renal cell carcinoma. We postulated that the degree of MEK activation was related to graded expression of MT1-MMP and the resultant phenotype of renal epithelial tumors. Madin Darby canine kidney epithelial cells transfected with a MEK1 expression plasmid yielded populations with morphologic phenotypes ranging from epithelial, mixed epithelial/mesenchymal to mesenchymal. Clones were analyzed for MEK1 activity, MT1-MMP expression and extent of epithelial-mesenchymal transition. Phenotypes of the MDCK-MEK1 clones were evaluated in vivo with nu/nu mice. Tissue microarray of renal cell cancers was quantitatively assessed for expression of phosphorylated MEK1 and MT1-MMP proteins and correlations drawn to Fuhrman nuclear grade. Graded increases in the MEK signaling module were associated with graded induction of epithelial-mesenchymal transition of the MDCK cells and induction of MT1-MMP transcription and synthesis. Inhibition of MEK1 and MT1-MMP activity reversed the epithelial-mesenchymal transition. Tumors generated by epithelial, mixed epithelial/mesenchymal and mesenchymal MDCK clones demonstrated a gradient of phenotypes extending from well-differentiated, fully encapsulated non-invasive tumors to tumors with an anaplastic morphology, high Fuhrman nuclear score, neoangiogenesis and invasion. Tumor microarray demonstrated a statistically significant association between the extent of phosphorylated MEK1, MT1-MMP expression and nuclear grade. We conclude that graded increases in the MEK1 signaling module are correlated with M1-MMP expression, renal epithelial cell tumor phenotype, invasive activity and nuclear grade. Phosphorylated MEK1 and MT1-MMP may represent novel, and mechanistic, biomarkers for the assessment of renal cell

  20. Conservation in Mammals of Genes Associated with Aggression-Related Behavioral Phenotypes in Honey Bees.

    PubMed

    Liu, Hui; Robinson, Gene E; Jakobsson, Eric

    2016-06-01

    The emerging field of sociogenomics explores the relations between social behavior and genome structure and function. An important question is the extent to which associations between social behavior and gene expression are conserved among the Metazoa. Prior experimental work in an invertebrate model of social behavior, the honey bee, revealed distinct brain gene expression patterns in African and European honey bees, and within European honey bees with different behavioral phenotypes. The present work is a computational study of these previous findings in which we analyze, by orthology determination, the extent to which genes that are socially regulated in honey bees are conserved across the Metazoa. We found that the differentially expressed gene sets associated with alarm pheromone response, the difference between old and young bees, and the colony influence on soldier bees, are enriched in widely conserved genes, indicating that these differences have genomic bases shared with many other metazoans. By contrast, the sets of differentially expressed genes associated with the differences between African and European forager and guard bees are depleted in widely conserved genes, indicating that the genomic basis for this social behavior is relatively specific to honey bees. For the alarm pheromone response gene set, we found a particularly high degree of conservation with mammals, even though the alarm pheromone itself is bee-specific. Gene Ontology identification of human orthologs to the strongly conserved honey bee genes associated with the alarm pheromone response shows overrepresentation of protein metabolism, regulation of protein complex formation, and protein folding, perhaps associated with remodeling of critical neural circuits in response to alarm pheromone. We hypothesize that such remodeling may be an adaptation of social animals to process and respond appropriately to the complex patterns of conspecific communication essential for social organization.

  1. Conservation in Mammals of Genes Associated with Aggression-Related Behavioral Phenotypes in Honey Bees

    PubMed Central

    Robinson, Gene E.; Jakobsson, Eric

    2016-01-01

    The emerging field of sociogenomics explores the relations between social behavior and genome structure and function. An important question is the extent to which associations between social behavior and gene expression are conserved among the Metazoa. Prior experimental work in an invertebrate model of social behavior, the honey bee, revealed distinct brain gene expression patterns in African and European honey bees, and within European honey bees with different behavioral phenotypes. The present work is a computational study of these previous findings in which we analyze, by orthology determination, the extent to which genes that are socially regulated in honey bees are conserved across the Metazoa. We found that the differentially expressed gene sets associated with alarm pheromone response, the difference between old and young bees, and the colony influence on soldier bees, are enriched in widely conserved genes, indicating that these differences have genomic bases shared with many other metazoans. By contrast, the sets of differentially expressed genes associated with the differences between African and European forager and guard bees are depleted in widely conserved genes, indicating that the genomic basis for this social behavior is relatively specific to honey bees. For the alarm pheromone response gene set, we found a particularly high degree of conservation with mammals, even though the alarm pheromone itself is bee-specific. Gene Ontology identification of human orthologs to the strongly conserved honey bee genes associated with the alarm pheromone response shows overrepresentation of protein metabolism, regulation of protein complex formation, and protein folding, perhaps associated with remodeling of critical neural circuits in response to alarm pheromone. We hypothesize that such remodeling may be an adaptation of social animals to process and respond appropriately to the complex patterns of conspecific communication essential for social organization

  2. Sub-100 nm Gold Nanomatryoshkas Improve Photo-thermal Therapy Efficacy in Large and Highly Aggressive Triple Negative Breast Tumors

    PubMed Central

    Bishnoi, Sandra; Urban, Alexander; Charron, Heather; Mitchell, Tamika; Shea, Martin; Nanda, Sarmistha; Schiff, Rachel; Halas, Naomi; Joshi, Amit

    2014-01-01

    There is an unmet need for efficient near-infrared photothermal transducers for the treatment of highly aggressive cancers and large tumors where the penetration of light can be substantially reduced, and the intra-tumoral nanoparticle transport is restricted due to the presence of hypoxic or nectrotic regions. We report the performance advantages obtained by sub 100 nm gold nanomatryushkas, comprising of concentric gold-silica-gold layers compared to conventional ~150 nm silica core gold nanoshells for photothermal therapy of triple negative breast cancer. We demonstrate that a 33% reduction in silica-core-gold-shell nanoparticle size, while retaining near-infrared plasmon resonance, and keeping the nanoparticle surface charge constant, results in a four to five fold tumor accumulation of nanoparticles following equal dose of injected gold for both sizes. The survival time of mice bearing large (>1000 mm3) and highly aggressive triple negative breast tumors is doubled for the nanomatryushka treatment group under identical photo-thermal therapy conditions. The higher absorption cross-section of a nanomatryoshka results in a higher efficiency of photonic to thermal energy conversion and coupled with 4-5X accumulation within large tumors results in superior therapy efficacy. PMID:25051221

  3. Sub-100nm gold nanomatryoshkas improve photo-thermal therapy efficacy in large and highly aggressive triple negative breast tumors.

    PubMed

    Ayala-Orozco, Ciceron; Urban, Cordula; Bishnoi, Sandra; Urban, Alexander; Charron, Heather; Mitchell, Tamika; Shea, Martin; Nanda, Sarmistha; Schiff, Rachel; Halas, Naomi; Joshi, Amit

    2014-10-10

    There is an unmet need for efficient near-infrared photothermal transducers for the treatment of highly aggressive cancers and large tumors where the penetration of light can be substantially reduced, and the intra-tumoral nanoparticle transport is restricted due to the presence of hypoxic or necrotic regions. We report the performance advantages obtained by sub 100nm gold nanomatryushkas, comprising concentric gold-silica-gold layers compared to conventional ~150nm silica core gold nanoshells for photothermal therapy of triple negative breast cancer. We demonstrate that a 33% reduction in silica-core-gold-shell nanoparticle size, while retaining near-infrared plasmon resonance, and keeping the nanoparticle surface charge constant, results in a four to five fold tumor accumulation of nanoparticles following equal dose of injected gold for both sizes. The survival time of mice bearing large (>1000mm(3)) and highly aggressive triple negative breast tumors is doubled for the nanomatryushka treatment group under identical photo-thermal therapy conditions. The higher absorption cross-section of a nanomatryoshka results in a higher efficiency of photonic to thermal energy conversion and coupled with 4-5× accumulation within large tumors results in superior therapy efficacy.

  4. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis).

    PubMed

    Kummar, Shivaani; O'Sullivan Coyne, Geraldine; Do, Khanh T; Turkbey, Baris; Meltzer, Paul S; Polley, Eric; Choyke, Peter L; Meehan, Robert; Vilimas, Rasa; Horneffer, Yvonne; Juwara, Lamin; Lih, Ann; Choudhary, Amul; Mitchell, Sandra A; Helman, Lee J; Doroshow, James H; Chen, Alice P

    2017-03-28

    Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

  5. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    SciTech Connect

    Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege  G.; Helland, Åslaug; Rye, Inga  H.; Borresen-Dale, Anne -Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin  L.; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

    2014-02-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

  6. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    DOE PAGES

    Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; ...

    2014-02-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatialmore » distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.« less

  7. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype

    PubMed Central

    Shrestha, Sanjeeb; Noh, Jae Myoung; Kim, Shin-Yeong; Ham, Hwa-Yong; Kim, Yeon-Ja; Yun, Young-Jin; Kim, Min-Ju; Kwon, Min-Soo; Song, Dong-Keun; Hong, Chang-Won

    2016-01-01

    ABSTRACT Tumor microenvironments polarize neutrophils to protumoral phenotypes. Here, we demonstrate that the angiotensin converting enzyme inhibitors (ACEis) and angiotensin II type 1 receptor (AGTR1) antagonist attenuate tumor growth via polarization of neutrophils toward an antitumoral phenotype. The ACEis or AGTR1 antagonist enhanced hypersegmentation of human neutrophils and increased neutrophil cytotoxicity against tumor cells. This neutrophil hypersegmentation was dependent on the mTOR pathway. In a murine tumor model, ACEis and AGTR1 antagonist attenuated tumor growth and enhanced neutrophil hypersegmentation. ACEis inhibited tumor-induced polarization of neutrophils to a protumoral phenotype. Neutrophil depletion reduced the antitumor effect of ACEi. Together, these data suggest that the modulation of Ang II pathway attenuates tumor growth via polarization of neutrophils to an antitumoral phenotype. PMID:26942086

  8. p16 overexpression and 9p21 deletion are linked to unfavorable tumor phenotype in breast cancer.

    PubMed

    Lebok, Patrick; Roming, Magdalena; Kluth, Martina; Koop, Christina; Özden, Cansu; Taskin, Berivan; Hussein, Khakan; Lebeau, Annette; Witzel, Isabell; Wölber, Linn; Geist, Stefan; Paluchowski, Peter; Wilke, Christian; Heilenkötter, Uwe; Müller, Volkmar; Schmalfeldt, Barbara; Simon, Ronald; Sauter, Guido; Terracciano, Luigi; Krech, Rainer Horst; von der Assen, Albert; Burandt, Eike

    2016-12-06

    Overexpression of the p16 tumor suppressor, but also deletion of its gene locus 9p21, is linked to unfavorable tumor phenotype and poor prognosis in breast cancer. To better understand these contradictory observations, and to clarify the prognostic impact of p16 expression and 9p21 deletion, a tissue microarray (TMA) with 2,197 breast cancers was analyzed by fluorescence in-situ hybridization and immunohistochemistry (FISH) for 9p21 deletion and p16 expression. p16 immunostaining was weak in 25.6%, moderate in 7.1%, and strong in 12.7% of 1,684 evaluable cancers. Strong p16 staining was linked to advanced tumor stage (p = 0.0003), high-grade (p < 0.0001), high tumor cell proliferation (p < 0.0001), negative hormone receptor (ER/PR) status (p < 0.0001 each), and shorter overall survival (p = 0.0038). 9p21 deletion was found in 15.3% of 1,089 analyzable breast cancers, including 1.7% homozygous and 13.6% heterozygous deletions. 9p21 deletion was linked to adverse tumor features, including high-grade (p < 0.0001) and nodal positive cancers (p = 0.0063), high cell proliferation (p < 0.0001), negative hormone receptor (ER/PR) status (p ≤ 0.0006), and HER2 amplification (p = 0.0078). Patient outcome was worse in 9p21 deleted than in undeleted cancers (p = 0.0720). p16 expression was absent in cancers harboring homozygous 9p21 deletions, but no difference in p16 expression was found between cancers with (59.2% p16 positive) and without heterozygous 9p21 deletion (51.3% p16 positive, p = 0.0256). In summary, p16 expression is unrelated to partial 9p21 deletion, but both alterations are linked to aggressive breast cancer phenotype. High-level p16 expression is a strong predictor of unfavorable disease course in breast cancer.

  9. The expression of P-glycoprotein is causally related to a less aggressive phenotype in human osteosarcoma cells.

    PubMed

    Scotlandi, K; Manara, M C; Serra, M; Benini, S; Maurici, D; Caputo, A; De Giovanni, C; Lollini, P L; Nanni, P; Picci, P; Campanacci, M; Baldini, N

    1999-01-21

    The relationship between P-glycoprotein expression and malignancy is controversial. We have recently found that, in osteosarcoma, multidrug resistance (MDR) is associated with a less aggressive behavior, both in vitro and in clinical settings. In this study, we evaluated whether P-glycoprotein overexpression has a cause-effect relationship with the reduced metastatic potential of MDR cells, or rather reflects a more complex phenotype. MDR1 gene-transfected osteosarcoma cell clones, showing different levels of P-glycoprotein expression, were analysed for their in vitro characteristics and their tumorigenic and metastatic ability in athymic mice. Apart from the different levels of P-glycoprotein, no significant change in the expression of surface antigens or in the differentiative features were observed in the MDR1 gene transfectants compared to the parental cell lines or control clones, obtained by transfection with neo gene alone. In contrast to controls, however, MDR1 transfectants showed a significantly lower ability to grow in semi-solid medium and were completely unable to grow and give lung metastases in athymic mice. These findings indicate that P-glycoprotein overexpression is causally associated with a low malignant potential of osteosarcoma cells, and open new insights on the role and functions of P-glycoprotein activity.

  10. Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression

    PubMed Central

    Mertens, Christina; Akam, Eman Abureida; Rehwald, Claudia; Brüne, Bernhard; Tomat, Elisa

    2016-01-01

    A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches. PMID:27806101

  11. Consensus micro RNAs governing the switch of dormant tumors to the fast-growing angiogenic phenotype.

    PubMed

    Almog, Nava; Ma, Lili; Schwager, Christian; Brinkmann, Bastian G; Beheshti, Afshin; Vajkoczy, Peter; Folkman, Judah; Hlatky, Lynn; Abdollahi, Amir

    2012-01-01

    Tumor dormancy refers to a critical stage in cancer development in which tumor cells remain occult for a prolonged period of time until they eventually progress and become clinically apparent. We previously showed that the switch of dormant tumors to fast-growth is angiogenesis dependent and requires a stable transcriptional reprogramming in tumor cells. Considering microRNAs (miRs) as master regulators of transcriptome, we sought to investigate their role in the control of tumor dormancy. We report here the identification of a consensus set of 19 miRs that govern the phenotypic switch of human dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors to fast-growth. Loss of expression of dormancy-associated miRs (DmiRs, 16/19) was the prevailing regulation pattern correlating with the switch of dormant tumors to fast-growth. The expression pattern of two DmiRs (miR-580 and 190) was confirmed to correlate with disease stage in human glioma specimens. Reconstitution of a single DmiR (miR-580, 588 or 190) led to phenotypic reversal of fast-growing angiogenic tumors towards prolonged tumor dormancy. Of note, 60% of angiogenic glioblastoma and 100% of angiogenic osteosarcoma over-expressing miR190 remained dormant during the entire observation period of ∼ 120 days. Next, the ability of DmiRs to regulate angiogenesis and dormancy-associated genes was evaluated. Transcriptional reprogramming of tumors via DmiR-580, 588 or 190 over-expression resulted in downregulation of pro-angiogenic factors such as TIMP-3, bFGF and TGFalpha. In addition, a G-CSF independent downregulation of Bv8 was found as a common target of all three DmiRs and correlated with decreased tumor recruitment of bone marrow-derived CD11b+ Gr-1+ myeloid cells. In contrast, antiangiogenic and dormancy promoting pathways such as EphA5 and Angiomotin were upregulated in DmiR over-expressing tumors. This work suggests novel means to reverse the malignant tumor phenotype into an

  12. The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location

    PubMed Central

    PAPAGIORGIS, PETROS C.; ZIZI, ADAMANTIA E.; TSELENI, SOPHIA; OIKONOMAKIS, IOANNIS N.; NIKITEAS, NIKOLAOS I.

    2012-01-01

    The role of epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) prognosis remains unclear despite the recent development of anti-EGFR treatments for metastatic disease. The heterogeneity of CRC may account for this discrepancy; proximal and distal CRC has been found to be genetically and clinicopathologically different. The aim of this study was to investigate the effect of tumor location on the association of EGFR with the conventional prognostic indicators (stage and grade) in CRC. Immunohistochemical assessment of EGFR was retrospectively performed in 119 primary CRC specimens and data were correlated with tumor stage and grade in the proximal and distal tumor subset. The molecular combination of EGFR with p53 (previously assessed in this sample) was similarly analyzed. EGFR positivity was detected in 34, 30 and 35% of the entire cohort, proximal and distal tumors, respectively. The pattern of EGFR clinicopathological correlation was found to differ by site. A reduction in the frequency of EGFR(+) with progression of stage and/or worsening of grade was observed proximally, whereas an opposite trend was recorded distally. Proximal tumors with stage I or with indolent features (stage I, well-differentiated) exhibited a significantly higher proportion of EGFR positivity than other tumors of this location (p=0.023 and p=0.022, respectively) or corresponding distal tumors (p=0.018 and p=0.035, respectively). Moreover, the co-existence of EGFR and high p53 staining (accounting for 11% of cases) was found in a significantly higher proportion of stage IV tumors compared to other stages (p=0.004), although only for the distal subset. Proximal and distal tumors showed various patterns of EGFR variation with disease progression and aggressiveness. This disparity provides further support to the hypothesis that these particular subsets of CRC are distinct tumor entities. It may also be suggestive of a potentially different therapeutic approach according to

  13. Receptor-Independent Ectopic Activity of Prolactin Predicts Aggressive Lung Tumors and Indicates HDACi-Based Therapeutic Strategies

    PubMed Central

    Le Bescont, Aurore; Vitte, Anne-Laure; Debernardi, Alexandra; Curtet, Sandrine; Buchou, Thierry; Vayr, Jessica; de Reyniès, Aurélien; Ito, Akihiro; Guardiola, Philippe; Brambilla, Christian; Yoshida, Minoru; Brambilla, Elisabeth

    2015-01-01

    Abstract Aims: Ectopic activation of tissue-specific genes accompanies malignant transformation in many cancers. Prolactin (PRL) aberrant activation in lung cancer was investigated here to highlight its value as a biomarker. Results: PRL is ectopically activated in a subset of very aggressive lung tumors, associated with a rapid fatal outcome, in our cohort of 293 lung tumor patients and in an external independent series of patients. Surprisingly PRL receptor expression was not detected in the vast majority of PRL-expressing lung tumors. Additionally, the analysis of the PRL transcripts in lung tumors and cell lines revealed systematic truncations of their 5′ regions, including the signal peptide-encoding portions. PRL expression was found to sustain cancer-specific gene expression circuits encompassing genes that are normally responsive to hypoxia. Interestingly, this analysis also indicated that histone deacetylase (HDAC) inhibitors could counteract the PRL-associated transcriptional activity. Innovation and Conclusion: Altogether, this work not only unravels a yet unknown oncogenic mechanism but also indicates that the specific category of PRL-expressing aggressive lung cancers could be particularly responsive to an HDAC inhibitor-based treatment. Antioxid. Redox Signal. 23, 1–14. PMID:24512221

  14. The in vitro and vivo effects of nuclear and cytosolic parafibromin expression on the aggressive phenotypes of colorectal cancer cells: a search of potential gene therapy target.

    PubMed

    Zheng, Hua-Chuan; Liu, Jia-Jie; Li, Jing; Wu, Ji-Cheng; Yang, Lei; Zhao, Gui-Feng; Zhao, Xin; Jiang, Hua-Mao; Huang, Ke-Qiang; Li, Zhi-Jie

    2017-02-16

    Down-regulated parafibromin is positively linked to the pathogenesis of parathyroid, lung, breast, ovarian, gastric and colorectal cancers. Here, we found that wild-type (WT) parafibromin overexpression suppressed proliferation, tumor growth, induced cell cycle arrest and apoptosis in colorectal cancer cells (p<0.05), but it was the converse for mutant-type (MT, mutation in nucleus localization sequence) parafibromin (p<0.05). Both WT and MT transfectants inhibited migration and invasion, and caused better differentiation (p<0.05) of cancer cells. WT parafibromin transfectants showed the overexpression of Cyclin B1, Cyclin D1, Cyclin E, p38, p53, and AIF in HCT-15 and HCT-116 cells, while MT parafibromin only up-regulated p38 expression. There was lower mRNA expression of bcl-2 in parafibromin transfectants than the control and mock, while higher expression of c-myc, Cyclin D1, mTOR, and Raptor. According to transcriptomic analysis, WT parafibromin suppressed PI3K-Akt and FoxO signaling pathways, while MT one promoted PI3K-Akt pathway, focal adhesion, and regulation of actin cytoskeleton. Parafibromin was less expressed in colorectal cancer than paired mucosa (p<0.05), and inversely correlated with its differentiation at both mRNA and protein levels (p<0.05). These findings indicated that WT parafibromin might reverse the aggressive phenotypes of colorectal cancer cells and be employed as a target for gene therapy. Down-regulated parafibromin expression might be closely linked to colorectal carcinogenesis and cancer differentiation.

  15. Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

    PubMed Central

    Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko

    2015-01-01

    CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP‐positive renal carcinogenesis. Genome (whole‐exome and copy number), transcriptome and proteome (two‐dimensional image converted analysis of liquid chromatography‐mass spectrometry) analyses were performed using tissue specimens of 87 CIMP‐negative and 14 CIMP‐positive clear cell RCCs and corresponding specimens of non‐cancerous renal cortex. Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non‐synonymous single‐nucleotide mutations and insertions/deletions) in CIMP‐positive RCCs, whereas CIMP‐negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP‐positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the “The metaphase checkpoint (p = 1.427 × 10−6),” “Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10−6)” and “Spindle assembly and chromosome separation (p = 9.260 × 10−6)” pathways. Quantitative RT‐PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP‐positive than in CIMP‐negative RCCs. All CIMP‐positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP‐positive renal carcinogenesis, and that AURKA and AURKB may be potential

  16. Identification of Tumor Endothelial Cells with High Aldehyde Dehydrogenase Activity and a Highly Angiogenic Phenotype

    PubMed Central

    Maishi, Nako; Ohga, Noritaka; Hida, Yasuhiro; Kawamoto, Taisuke; Iida, Junichiro; Shindoh, Masanobu; Tsuchiya, Kunihiko; Shinohara, Nobuo; Hida, Kyoko

    2014-01-01

    Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis. PMID:25437864

  17. Tumors with unmethylated MLH1 and the CpG island methylator phenotype are associated with a poor prognosis in stage II colorectal cancer patients

    PubMed Central

    Fu, Tao; Liu, Yanliang; Li, Kai; Wan, Weiwei; Pappou, Emmanouil P.; Iacobuzio-Donahue, Christine A.; Kerner, Zachary; Baylin, Stephen B.; Wolfgang, Christopher L.; Ahuja, Nita

    2016-01-01

    We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP−/MLH1-U, or CIMP−/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production. Kaplan-Meier analyses revealed differences in both disease-free survival (DFS) and overall survival (OS) among the four groups. In a multivariate analysis, CIMP/MLH1 methylation status was predictive of both DFS and OS, and DFS and OS were shortest in CIMP+/MLH1-U stage II CRC patients. These results suggest that tumor subtype classification based on the combination of CIMP and MLH1 methylation status is informative in stage II CRC patients, and that CIMP+/MLH1-U tumors exhibit aggressive features and are associated with poor clinical outcomes. PMID:27880934

  18. Loss of SOD3 (EcSOD) expression promotes an aggressive phenotype in human pancreatic ductal adenocarcinoma

    PubMed Central

    O’Leary, Brianne R.; Fath, Melissa A.; Bellizzi, Andrew M.; Hrabe, Jennifer E.; Button, Anna M.; Allen, Bryan G.; Case, Adam J.; Altekruse, Sean; Wagner, Brett A.; Buettner, Garry R.; Lynch, Charles F.; Hernandez, Brenda Y.; Cozen, Wendy; Beardsley, Robert A.; Keene, Jeffery; Henry, Michael D.; Domann, Frederick E.; Spitz, Douglas R.; Mezhir, James J.

    2015-01-01

    Purpose Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. The current work tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. Experimental Design We evaluated the prognostic significance of EcSOD in a human tissue microarray of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase inhibitor to determine the mechanism of action of EcSOD in PDA. Results Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Over-expression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. Conclusions These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. PMID:25634994

  19. Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients

    PubMed Central

    Lu, Janice; Fan, Tina; Zhao, Qiang; Zeng, Wei; Zaslavsky, Eva; Chen, John J.; Frohman, Michael A.; Golightly, Marc G.; Madajewicz, Stefan; Chen, Wen-Tien

    2009-01-01

    Recent research advances show that tumor cell intravasation (entry into the circulation) and metastasis occur very early in breast cancer progression. Clinical studies also illustrate the potential importance of detection of circulating tumor cells (CTCs) in outcomes of patients with metastatic breast cancer. Whether these cells exhibit the invasiveness and express tumor stem or progenitor markers, hallmark of the metastatic phenotype, is less well characterized. To detect CTCs with the invasive phenotype and to explore their molecular features, we applied a functional cell separation method, called collagen adhesion matrix (CAM) assay, as enrichment and identification steps. The CAM-coated device successfully recovered tumor cells spiked in one mL of blood with a 54%±9% (n=18) recovery rate and 0.5-35% purity, and detected invasive tumor cells in 10/10 blood samples (100% yield) from patients with metastatic breast cancer with a range of 18 to 256 CTCs/mL and average of 126±25 (mean±SD) CTCs/mL. CTCs were detected in blood samples of 28/54 (52%) stage I-III breast cancer patients with a mean count of 61 CTCs/mL. Furthermore, the relative frequency of these cells correlated to the staging, lymph node-status and survival of patients with early stage breast cancer. CAM-captured cells were capable of propagation in culture. Gene expression and multiplex flow cytometric analyses on CAM-captured cells demonstrated the existence of distinct populations of CTCs including these of epithelial lineage and stem or progenitor cells. Thus, CAM-initiated CTC detection provides advantages for examining invasiveness and tumor progenitor phenotypes. PMID:19662651

  20. Engagement of the Mannose Receptor by Tumoral Mucins Activates an Immune Suppressive Phenotype in Human Tumor-Associated Macrophages

    PubMed Central

    Allavena, P.; Chieppa, M.; Bianchi, G.; Solinas, G.; Fabbri, M.; Laskarin, G.; Mantovani, A.

    2010-01-01

    Tumor-Associated Macrophages (TAMs) are abundantly present in the stroma of solid tumors and modulate several important biological processes, such as neoangiogenesis, cancer cell proliferation and invasion, and suppression of adaptive immune responses. Myeloid C-type lectin receptors (CLRs) constitute a large family of transmembrane carbohydrate-binding receptors that recognize pathogens as well as endogenous glycoproteins. Several lines of evidence demonstrate that some CLRs can inhibit the immune response. In this study we investigated TAM-associated molecules potentially involved in their immune suppressive activity. We found that TAMs isolated from human ovarian carcinoma samples predominantly express the CLRs Dectin-1, MDL-1, MGL, DCIR, and most abundantly the Mannose Receptor (MR). Components of carcinomatous ascites and purified tumoral mucins (CA125 and TAG-72) bound the MR and induced its internalization. MR engagement by tumoral mucins and by an agonist anti-MR antibody modulated cytokine production by TAM toward an immune-suppressive profile: increase of IL-10, absence of IL-12, and decrease of the Th1-attracting chemokine CCL3. This study highlights that tumoral mucin-mediated ligation of the MR on infiltrating TAM may contribute to their immune suppressive phenotype. PMID:21331365

  1. Genomic and phenotypic profiles of two Brazilian breast cancer cell lines derived from primary human tumors

    PubMed Central

    CORRÊA, NATÁSSIA C.R.; KUASNE, HELLEN; FARIA, JERUSA A.Q.A.; SEIXAS, CIÇA C.S.; SANTOS, IRIA G.D.; ABREU, FRANCINE B.; NONOGAKI, SUELY; ROCHA, RAFAEL M.; SILVA, GERLUZA APARECIDA BORGES; GOBBI, HELENICE; ROGATTO, SILVIA R.; GOES, ALFREDO M.; GOMES, DAWIDSON A.

    2013-01-01

    Breast cancer is the most common type of cancer among women worldwide. Research using breast cancer cell lines derived from primary tumors may provide valuable additional knowledge regarding this type of cancer. Therefore, the aim of this study was to investigate the phenotypic profiles of MACL-1 and MGSO-3, the only Brazilian breast cancer cell lines available for comparative studies. We evaluated the presence of hormone receptors, proliferation, differentiation and stem cell markers, using immunohistochemical staining of the primary tumor, cultured cells and xenografts implanted in immunodeficient mice. We also investigated the ability of the cell lines to form colonies and copy number alterations by array comparative genomic hybridization. Histopathological analysis showed that the invasive primary tumor from which the MACL-1 cell line was derived, was a luminal A subtype carcinoma, while the ductal carcinoma in situ (DCIS) that gave rise to the MGSO-3 cell line was a HER2 subtype tumor, both showing different proliferation levels. The cell lines and the tumor xenografts in mice preserved their high proliferative potential, but did not maintain the expression of the other markers assessed. This shift in expression may be due to the selection of an ‘establishment’ phenotype in vitro. Whole-genome DNA evaluation showed a large amount of copy number alterations (CNAs) in the two cell lines. These findings render MACL-1 and MGSO-3 the first characterized Brazilian breast cancer cell lines to be potentially used for comparative research. PMID:23404580

  2. βIII-tubulin overexpression is linked to aggressive tumor features and genetic instability in urinary bladder cancer.

    PubMed

    Hinsch, Andrea; Chaker, Aref; Burdelski, Christian; Koop, Christina; Tsourlakis, Maria Christina; Steurer, Stefan; Rink, Michael; Eichenauer, Till Simon; Wilczak, Waldemar; Wittmer, Corinna; Fisch, Margit; Simon, Ronald; Sauter, Guido; Büschek, Franziska; Clauditz, Till; Minner, Sarah; Jacobsen, Frank

    2017-03-01

    Development of genetic instability is a hallmark of tumor progression. Type III β-tubulin (TUBB3) is a component of microtubules involved in chromosome segregation. Its overexpression has been linked to adverse features of urinary bladder cancer. To investigate the role of TUBB3 for development of genetic instability, we compared TUBB3 expression with histopathological features and surrogate markers of genetic instability and tumor aggressiveness; copy number changes of HER2, TOP2A, CCND1, RAF1, and FGFR1; nuclear accumulation of p53, and cell proliferation in a tissue microarray (TMA) with more than 700 bladder cancers. TUBB3 expression was linked to high-grade and advanced-stage cancers (P<.0001), rapid cell proliferation (P<.0001), presence of multiple gene copy number alterations (P=.0008), and nuclear accumulation of p53 (P=.0008). Strong TUBB3 staining was found in 43% of urothelial cancers harboring copy number alterations as compared with 28% of genetically stable cancers, and in 50% of p53-positive cancers as compared with 30% of p53-negative tumors. The fraction of tumors with concomitant TUBB3 and p53 positivity increased with tumor stage and grade: 2% in pTaG1-2, 11% in pTaG3, 17% in pT1G2, 23% in pT1G3, and 32% in pT2-4 cancers (P<.0001). Importantly, strong TUBB3 overexpression was detectable in about 20% of low-grade, noninvasive cancers. In summary, our study demonstrates that TUBB3 overexpression is linked to an aggressive subtype of urinary bladder cancers, which is characterized by increased genetic instability, p53 alterations, and rapid cell proliferation. Detection of TUBB3 overexpression in genetically stable, low-grade, and noninvasive bladder cancers may be clinically useful to identify patients requiring particular close monitoring.

  3. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation

    PubMed Central

    Diedrich, Jonathan D.; Rajagurubandara, Erandi; Herroon, Mackenzie K.; Mahapatra, Gargi; Hüttemann, Maik; Podgorski, Izabela

    2016-01-01

    Metabolic adaptation is increasingly recognized as a key factor in tumor progression, yet its involvement in metastatic bone disease is not understood. Bone is as an adipocyte-rich organ, and a major site of metastasis from prostate cancer. Bone marrow adipocytes are metabolically active cells capable of shaping tumor metabolism via lipolysis and lipid transfer. In this study, using in vitro and in vivo models of marrow adiposity, we demonstrate that marrow fat cells promote Warburg phenotype in metastatic prostate cancer cells. We show increased expression of glycolytic enzymes, increased lactate production, and decreased mitochondrial oxidative phosphorylation in tumor cells exposed to adipocytes that require paracrine signaling between the two cell types. We also reveal that prostate cancer cells are capable of inducing adipocyte lipolysis as a postulated mechanism of sustenance. We provide evidence that adipocytes drive metabolic reprogramming of tumor cells via oxygen-independent mechanism of HIF-1α activation that can be reversed by HIF-1α downregulation. Importantly, we also demonstrate that the observed metabolic signature in tumor cells exposed to adipocytes mimics the expression patterns seen in patients with metastatic disease. Together, our data provide evidence for a functional relationship between marrow adipocytes and tumor cells in bone that has likely implications for tumor growth and survival within the metastatic niche. PMID:27588494

  4. Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype.

    PubMed

    Garrido, Federico; Romero, Irene; Aptsiauri, Natalia; Garcia-Lora, Angel M

    2016-01-15

    Intratumor heterogeneity among cancer cells is promoted by reversible or irreversible genetic alterations and by different microenvironmental factors. There is considerable experimental evidence of the presence of a variety of malignant cell clones with a wide diversity of major histocompatibility class I (MHC-I) expression during early stages of tumor development. This variety of MHC-I phenotypes may define the evolution of a particular tumor. Loss of MHC-I molecules frequently results in immune escape of MHC-negative or -deficient tumor cells from the host T cell-mediated immune response. We review here the results obtained by our group and other researchers in animal models and humans, showing how MHC-I intratumor heterogeneity may affect local oncogenicity and metastatic progression. In particular, we summarize the data obtained in an experimental mouse cancer model of a methylcholanthrene-induced fibrosarcoma (GR9), in which isolated clones with different MHC-I expression patterns demonstrated distinct local tumor growth rates and metastatic capacities. The observed "explosion of diversity" of MHC-I phenotypes in primary tumor clones and the molecular mechanism ("hard"/irreversible or "soft"/reversible) responsible for a given MHC-I alteration might determine not only the metastatic capacity of the cells but also their response to immunotherapy. We also illustrate the generation of further MHC heterogeneity during metastatic colonization and discuss different strategies to favor tumor rejection by counteracting MHC-I loss. Finally, we highlight the role of MHC-I genes in tumor dormancy and cell cycle control.

  5. Enriched CD44(+)/CD24(-) population drives the aggressive phenotypes presented in triple-negative breast cancer (TNBC).

    PubMed

    Ma, Fei; Li, Huihui; Wang, Haijuan; Shi, Xiuqing; Fan, Ying; Ding, Xiaoyan; Lin, Chen; Zhan, Qimin; Qian, Haili; Xu, Binghe

    2014-10-28

    The mechanism underlying the aggressive behaviors of triple negative breast cancer (TNBC) is not well characterized yet. The association between cancer stem cell (CSC) population and the aggressive behaviors of TNBC has not been established. We found the CD44(+)/CD24(-) cell population was enriched in TNBC tissues and cell lines, with a higher capacity of proliferation, migration, invasion and tumorigenicity as well as lower adhesion ability. The CD44(+)/CD24(-) cell population with cancer stem cell-like properties may play an important role in the aggressive behaviors of TNBC. This discovery may lead to new therapeutic strategies targeting CD44(+)/CD24(-) cell population in TNBC.

  6. Phenotypically distinct helper NK cells are required for gp96-mediated anti-tumor immunity

    PubMed Central

    Sedlacek, Abigail L.; Kinner-Bibeau, Lauren B.; Binder, Robert J.

    2016-01-01

    A number of Heat Shock Proteins (HSPs), in the extracellular environment, are immunogenic. Following cross-presentation of HSP-chaperoned peptides by CD91+ antigen presenting cells (APCs), T cells are primed with specificity for the derivative antigen-bearing cell. Accordingly, tumor-derived HSPs are in clinical trials for cancer immunotherapy. We investigate the role of NK cells in gp96-mediated anti-tumor immune responses given their propensity to lyse tumor cells. We show that gp96-mediated rejection of tumors requires a unique and necessary helper role in NK cells. This helper role occurs during the effector phase of the anti-tumor immune response and is required for T cell and APC function. Gp96 activates NK cells indirectly via APCs to a phenotype distinct from NK cells activated by other mechanisms such as IL-2. While NK cells have both lytic and cytokine producing properties, we show that gp96 selectively activates cytokine production in NK cells, which is important in the HSP anti-tumor immune response, and leaves their cytotoxic capacity unchanged. PMID:27431727

  7. Linking of mPGES-1 and iNOS activates stem-like phenotype in EGFR-driven epithelial tumor cells.

    PubMed

    Terzuoli, Erika; Finetti, Federica; Costanza, Filomena; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2017-03-01

    Inflammatory prostaglandin E-2 (PGE-2) favors cancer progression in epithelial tumors characterized by persistent oncogene input. However, its effects on tumor cell stemness are poorly understood at molecular level. Here we describe two epithelial tumor cells A431 and A459, originating from human lung and skin tumors, in which epithelial growth factor (EGF) induces sequential up-regulation of mPGES-1 and iNOS enzymes, producing an inflammatory intracellular milieu. We demonstrated that concerted action of EGF, mPGES-1 and iNOS causes sharp changes in cell phenotype demonstrated by acquisition of stem-cell features and activation of the epithelial-mesenchymal transition (EMT). When primed with EGF, epithelial tumor cells transfected with mPGES-1 or iNOS to ensure steady enzyme levels display major stem-like and EMT markers, such as reduction in E-cadherin with a concomitant rise in vimentin, ALDH-1, CD133 and ALDH activity. Tumorsphere studies with these cells show increased sphere number and size, enhanced migratory and clonogenic capacity and sharp changes in EMT markers, indicating activation of this process. The concerted action of the enzymes forms a well-orchestrated cascade where expression of iNOS depends on overexpression of mPGES-1. Indeed, we show that through its downstream effectors (PGE-2, PKA, PI3K/Akt), mPGES-1 recruits non-canonical transcription factors, thus facilitating iNOS production. In conclusion, we propose that the initial event leading to tumor stem-cell activation may be a leveraged intrinsic mechanism in which all players are either inherent constituents (EGF) or highly inducible proteins (mPGES-1, iNOS) of tumor cells. We suggest that incipient tumor aggressiveness may be moderated by reducing pivotal input of mPGES-1.

  8. SU-E-J-248: Contributions of Tumor and Stroma Phenotyping in Computer-Aided Diagnosis

    SciTech Connect

    Li, H; Lan, L; Sennett, C; Giger, M

    2015-06-15

    Purpose: To gain insight into the role of parenchyma stroma in the characterization of breast tumors by incorporating computerized mammographic parenchyma assessment into breast CADx in the task of distinguishing between malignant and benign lesions. Methods: This study was performed on 182 biopsy-proven breast mass lesions, including 76 benign and 106 malignant lesions. For each full-field digital mammogram (FFDM) case, our quantitative imaging analysis was performed on both the tumor and a region-of-interest (ROI) from the normal contralateral breast. The lesion characterization includes automatic lesion segmentation and feature extraction. Radiographic texture analysis (RTA) was applied on the normal ROIs to assess the mammographic parenchymal patterns of these contralateral normal breasts. Classification performance of both individual computer extracted features and the output from a Bayesian artificial neural network (BANN) were evaluated with a leave-one-lesion-out method using receiver operating characteristic (ROC) analysis with area under the curve (AUC) as the figure of merit. Results: Lesion characterization included computer-extracted phenotypes of spiculation, size, shape, and margin. For parenchymal pattern characterization, five texture features were selected, including power law beta, contrast, and edge gradient. Merging of these computer-selected features using BANN classifiers yielded AUC values of 0.79 (SE=0.03) and 0.67 (SE=0.04) in the task of distinguishing between malignant and benign lesions using only tumor phenotypes and texture features from the contralateral breasts, respectively. Incorporation of tumor phenotypes with parenchyma texture features into the BANN yielded improved classification performance with an AUC value of 0.83 (SE=0.03) in the task of differentiating malignant from benign lesions. Conclusion: Combining computerized tumor and parenchyma phenotyping was found to significantly improve breast cancer diagnostic accuracy

  9. V3 vasopressin receptor and corticotropic phenotype in pituitary and nonpituitary tumors.

    PubMed

    de Keyzer, Y; René, P; Lenne, F; Auzan, C; Clauser, E; Bertagna, X

    1997-01-01

    Pituitary corticotropic cells express a specific vasopressin receptor, called V1b or V3, through which vasopressin stimulates corticotropin secretion. We recently cloned a cDNA coding for this receptor and showed that it belongs to the G protein-coupled receptor family. V3 mRNA is readily detected by RT-PCR in normal human pituitaries and corticotropic pituitary adenomas but not in PRL or GH-secreting adenomas, thus demonstrating that, like POMC itself and the CRH receptor, V3 is a marker of the corticotropic phenotype. Nuclease protection experiments suggest that V3 is overexpressed in some corticotropic adenomas, and thus may play a role in tumor development by activating the phospholipase C-signalling pathway. In addition analysis of its expression in nonpituitary neuroendocrine tumors showed a striking association with carcinoids of the lung responsible for the ectopic ACTH syndrome.

  10. Clinical value of digital image analysis in the diagnosis of urinary bladder cancer, particularly in aggressive tumors: a preliminary report.

    PubMed

    Borkowski, T; Monika Dulewicz, A; Borkowski, A; Piętka, D; Radziszewski, P

    2016-06-01

    The aim of the project was to evaluate the clinical value of a computer analysis of cytological specimen images obtained from urine and bladder washing samples. Three sample types (voided urine, catheterized urine and bladder washing) from 59 patients with primary or recurrent tumor were analyzed. All patients underwent cystoscopy and biopsy or resection. The histological results were compared with the results of the image analyzing computer system of collected urine samples. The consistency between the computer diagnosis and the clinical or histological diagnosis both in the presence and absence of cancer was as follows: 77% for voided urine samples, 72.5% for catheterized urine samples and 78% for bladder washing samples. The specificity of the method at the standard pathology level was 71%, and the sensitivity was 83%. The positive and negative predictive values (PPV and NPV) were 87.5% and 63% respectively. The sensitivity for G3 or CIS or T2 or T3 tumors reached nearly 100%. Computer analysis of urine provided correct diagnoses in cancer and control patients with the sensitivity of 83% and specificity of 71% and gave excellent results in aggressive tumors such as T2, T3, G3 and in CIS.

  11. Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report

    PubMed Central

    UMEDA, KATSUTSUGU; SAIDA, SATOSHI; YAMAGUCHI, HIDEKI; OKAMOTO, SHINYA; OKAMOTO, TAKESHI; KATO, ITARU; HIRAMATSU, HIDEFUMI; IMAI, TSUYOSHI; KODAIRA, TAKESHI; HEIKE, TOSHIO; ADACHI, SOUICHI; WATANABE, KEN-ICHIRO

    2016-01-01

    Patients with desmoplastic small round cell tumors (DSRCTs) have an extremely poor outcome despite the use of aggressive therapy. The current study presents the case of 16-year-old male with metastatic DSRCT, in which multimodal therapy, including intensive chemotherapies using frequent autologous stem cell support, gross resection of primary and metastatic lesions, and whole abdominopelvic intensity-modulated radiation therapy, was administered. Subsequent to these treatments, there was no evidence of active disease. However, cerebellar and pineal body lesions, and bone metastasis to the left humerus were detected 1 year and 2 months after the initial diagnosis. Combination chemotherapy with irinotecan and temozolomide was initially effective against the central nervous system (CNS) metastatic lesions; however, the patient succumbed due to progressive CNS disease after seven courses of combination chemotherapy. Additional studies are required to accumulate information regarding CNS recurrence of DSRCT. PMID:26870296

  12. Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.

    PubMed

    Naves, Luciana A; Daly, Adrian F; Dias, Luiz Augusto; Yuan, Bo; Zakir, Juliano Coelho Oliveira; Barra, Gustavo Barcellos; Palmeira, Leonor; Villa, Chiara; Trivellin, Giampaolo; Júnior, Armindo Jreige; Neto, Florêncio Figueiredo Cavalcante; Liu, Pengfei; Pellegata, Natalia S; Stratakis, Constantine A; Lupski, James R; Beckers, Albert

    2016-02-01

    X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

  13. Immunostimulatory early phenotype of tumor-associated macrophages does not predict tumor growth outcome in an HLA-DR mouse model of prostate cancer.

    PubMed

    Riabov, Vladimir; Kim, David; Chhina, Surmeet; Alexander, Richard B; Klyushnenkova, Elena N

    2015-07-01

    Tumor-associated macrophages (TAM) were shown to support the progression of many solid tumors. However, anti-tumor properties of TAM were also reported in several types of cancer. Here, we investigated the phenotype and functions of TAM in two transgenic mouse models of prostate cancer that display striking differences in tumor growth outcome. Mice expressing prostate-specific antigen (PSA) as a self-antigen specifically in prostate (PSAtg mice) rejected PSA-expressing transgenic adenocarcinoma of mouse prostate (TRAMP) tumors. However, the introduction of HLA-DRB1*1501 (DR2b) transgene presenting PSA-derived peptides in a MHC class II-restricted manner exacerbated the growth of TRAMP-PSA tumors in DR2bxPSA F 1 mice. Despite the difference in tumor growth outcome, tumors in both strains were equally and intensively infiltrated by macrophages on the first week after tumor challenge. TAM exhibited mixed M1/M2 polarization and simultaneously produced pro-inflammatory (TNFα, IL1β) and anti-inflammatory (IL10) cytokines. TAM from both mouse strains demonstrated antigen-presenting potential and pronounced immunostimulatory activity. Moreover, they equally induced apoptosis of tumor cells. In vivo depletion of macrophages in DR2bxPSA F 1 but not PSAtg mice aggravated tumor growth suggesting that macrophages more strongly contribute to anti-tumor immunity when specific presentation of PSA to CD4+ T cells is possible. In summary, we conclude that in the early stages of tumor progression, the phenotype and functional properties of TAM did not predict tumor growth outcome in two transgenic prostate cancer models. Furthermore, we demonstrated that during the initial stage of prostate cancer development, TAM have the potential to activate T cell immunity and mediate anti-tumor effects.

  14. Sphere-derived tumor cells exhibit impaired metastasis by a host-mediated quiescent phenotype

    PubMed Central

    Bleau, Anne-Marie; Zandueta, Carolina; Redrado, Miriam; Martínez-Canarias, Susana; Larzábal, Leyre; Montuenga, Luis M.

    2015-01-01

    The spread of lung cancer cells to distant sites represents a common event associated with poor prognosis. A fraction of tumor cells named cancer stem cells (CSCs) have the ability to overcome therapeutic stress and remain quiescent. However, whether these CSCs have also the capacity to initiate and sustain metastasis remains unclear. Here, we used tumor sphere cultures (TSC) isolated from mouse and human lung cancer models to enrich for CSCs, and assessed their metastatic potential as compared to non-CSCs. As expected, TSC overexpressed a variety of stem cell markers and displayed chemoresistance. The CSC phenotype of TSC was confirmed by their higher growth ability in soft agar and tumorigenic potential in vivo, despite their reduced in vitro cell growth kinetics. Surprisingly, the appearance of spontaneous lung metastases was strongly delayed in mice injected with TSC as compared to non-TSC cells. Similarly, this finding was confirmed in several other models of metastasis, an effect associated with a retarded colonization activity. Interestingly, such delay correlated with a quiescent phenotype whose underlined mechanisms included an increase in p27 protein and lower phospho-ERK1/2 levels. Thus, these data suggest that cells enriched for CSC properties display an impaired metastatic activity, a finding with potential clinical implications. PMID:26318423

  15. Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells

    PubMed Central

    2013-01-01

    Background Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells. Methods To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system. Results Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines. Conclusions Our findings suggest that chronic

  16. Functional interaction between acyl-CoA synthetase 4, lipooxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells.

    PubMed

    Maloberti, Paula M; Duarte, Alejandra B; Orlando, Ulises D; Pasqualini, María E; Solano, Angela R; López-Otín, Carlos; Podestá, Ernesto J

    2010-11-11

    The acyl-CoA synthetase 4 (ACSL4) is increased in breast cancer, colon and hepatocellular carcinoma. ACSL4 mainly esterifies arachidonic acid (AA) into arachidonoyl-CoA, reducing free AA intracellular levels, which is in contradiction with the need for AA metabolites in tumorigenesis. Therefore, the causal role of ACSL4 is still not established. This study was undertaken to determine the role of ACSL4 in AA metabolic pathway in breast cancer cells. The first novel finding is that ACSL4 regulates the expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin in MDA-MB-231 cells. We also found that ACSL4 is significantly up-regulated in the highly aggressive MDA-MB-231 breast cancer cells. In terms of its overexpression and inhibition, ACSL4 plays a causal role in the control of the aggressive phenotype. These results were confirmed by the increase in the aggressive behaviour of MCF-7 cells stably transfected with a Tet-off ACSL4 vector. Concomitantly, another significant finding was that intramitochondrial AA levels are significantly higher in the aggressive cells. Thus, the esterification of AA by ACSL4 compartmentalizes the release of AA in mitochondria, a mechanism that serves to drive the specific lipooxygenase metabolization of the fatty acid. To our knowledge, this is the first report that ACSL4 expression controls both lipooxygenase and cyclooxygenase metabolism of AA. Thus, this functional interaction represents an integrated system that regulates the proliferating and metastatic potential of cancer cells. Therefore, the development of combinatory therapies that profit from the ACSL4, lipooxygenase and COX-2 synergistic action may allow for lower medication doses and avoidance of side effects.

  17. Metabolomics profiling in plasma samples from glioma patients correlates with tumor phenotypes

    PubMed Central

    Zhao, Hua; Heimberger, Amy B.; Lu, Zhimin; Wu, Xifeng; Hodges, Tiffany R.; Song, Renduo; Shen, Jie

    2016-01-01

    Background Tumor-based molecular biomarkers have redefined in the classification gliomas. However, the association of systemic metabolomics with glioma phenotype has not been explored yet. Methods In this study, we conducted two-step (discovery and validation) metabolomic profiling in plasma samples from 87 glioma patients. The metabolomics data were tested for correlation with glioma grade (high vs low), glioblastoma (GBM) versus malignant gliomas, and IDH mutation status. Results Five metabolites, namely uracil, arginine, lactate, cystamine, and ornithine, significantly differed between high- and low-grade glioma patients in both the discovery and validation cohorts. When the discovery and validation cohorts were combined, we identified 29 significant metabolites with 18 remaining significant after adjusting for multiple comparisons. Those 18 significant metabolites separated high- from low-grade glioma patients with 91.1% accuracy. In the pathway analysis, a total of 18 significantly metabolic pathways were identified. Similarly, we identified 2 and 6 metabolites that significantly differed between GBM and non-GBM, and IDH mutation positive and negative patients after multiple comparison adjusting. Those 6 significant metabolites separated IDH1 mutation positive from negative glioma patients with 94.4% accuracy. Three pathways were identified to be associated with IDH mutation status. Within arginine and proline metabolism, levels of intermediate metabolites in creatine pathway were all significantly lower in IDH mutation positive than in negative patients, suggesting an increased activity of creatine pathway in IDH mutation positive tumors. Conclusion Our findings identified metabolites and metabolic pathways that differentiated tumor phenotypes. These may be useful as host biomarker candidates to further help glioma molecular classification. PMID:26967252

  18. Phenotype and function of tumor-associated neutrophils and their subsets in early-stage human lung cancer.

    PubMed

    Eruslanov, Evgeniy B

    2017-03-10

    Neutrophils accumulate in many types of human and murine tumors and represent a significant portion of tumor-infiltrating myeloid cells. Our current understanding of the role of neutrophils in tumor development has depended primarily on murine models of cancer. However, there are crucial species differences in the evolution of tumors, genetic diversity, immune and inflammatory responses, and intrinsic biology of neutrophils that might have a profound impact on the tumor development and function of neutrophils in mouse versus human tumors. To date, the majority of experimental approaches to study neutrophils in cancer patients have been limited to the examination of circulating blood neutrophils. The phenotype and function of tumor-associated neutrophils (TANs) in humans, particularly in the early stages of tumor development, have not been extensively investigated. Thus, the long-term goal of our work has been to characterize human TANs and determine their specific role in tumor development. Here, we summarize our findings on human TANs obtained from human early stage lung cancer patients. We will describe the phenotypes of different TAN subsets identified in early stage lung tumors, as well as their functional dialog with T cells.

  19. Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism

    PubMed Central

    Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Lamb, Rebecca; Hulit, James; Howell, Anthony; Sotgia, Federica; Rubin, Emanuel; Lisanti, Michael P.

    2013-01-01

    Little is known about how alcohol consumption promotes the onset of human breast cancer(s). One hypothesis is that ethanol induces metabolic changes in the tumor microenvironment, which then enhances epithelial tumor growth. To experimentally test this hypothesis, we used a co-culture system consisting of human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts. Here, we show that ethanol treatment (100 mM) promotes ROS production and oxidative stress in cancer-associated fibroblasts, which is sufficient to induce myofibroblastic differentiation. Oxidative stress in stromal fibroblasts also results in the onset of autophagy/mitophagy, driving the induction of ketone body production in the tumor microenvironment. Interestingly, ethanol has just the opposite effect in epithelial cancer cells, where it confers autophagy resistance, elevates mitochondrial biogenesis and induces key enzymes associated with ketone re-utilization (ACAT1/OXCT1). During co-culture, ethanol treatment also converts MCF7 cells from an ER(+) to an ER(-) status, which is thought to be associated with “stemness,” more aggressive behavior and a worse prognosis. Thus, ethanol treatment induces ketone production in cancer-associated fibroblasts and ketone re-utilization in epithelial cancer cells, fueling tumor cell growth via oxidative mitochondrial metabolism (OXPHOS). This “two-compartment” metabolic model is consistent with previous historical observations that ethanol is first converted to acetaldehyde (which induces oxidative stress) and then ultimately to acetyl-CoA (a high-energy mitochondrial fuel), or can be used to synthesize ketone bodies. As such, our results provide a novel mechanism by which alcohol consumption could metabolically convert “low-risk” breast cancer patients to “high-risk” status, explaining tumor recurrence or disease progression. Hence, our findings have clear implications for both breast cancer prevention and therapy. Remarkably, our results

  20. Versatile in vivo regulation of tumor phenotypes by dCas9-mediated transcriptional perturbation

    PubMed Central

    Braun, Christian J.; Bruno, Peter M.; Horlbeck, Max A.; Gilbert, Luke A.; Weissman, Jonathan S.; Hemann, Michael T.

    2016-01-01

    Targeted transcriptional regulation is a powerful tool to study genetic mediators of cellular behavior. Here, we show that catalytically dead Cas9 (dCas9) targeted to genomic regions upstream or downstream of the transcription start site allows for specific and sustainable gene-expression level alterations in tumor cells in vitro and in syngeneic immune-competent mouse models. We used this approach for a high-coverage pooled gene-activation screen in vivo and discovered previously unidentified modulators of tumor growth and therapeutic response. Moreover, by using dCas9 linked to an activation domain, we can either enhance or suppress target gene expression simply by changing the genetic location of dCas9 binding relative to the transcription start site. We demonstrate that these directed changes in gene-transcription levels occur with minimal off-target effects. Our findings highlight the use of dCas9-mediated transcriptional regulation as a versatile tool to reproducibly interrogate tumor phenotypes in vivo. PMID:27325776

  1. Dissection of Ras-Dependent Signaling Pathways Controlling Aggressive Tumor Growth of Human Fibrosarcoma Cells: Evidence for a Potential Novel Pathway

    PubMed Central

    Gupta, Swati; Plattner, Rina; Der, Channing J.; Stanbridge, Eric J.

    2000-01-01

    Activation of multiple signaling pathways is required to trigger the full spectrum of in vitro and in vivo phenotypic traits associated with neoplastic transformation by oncogenic Ras. To determine which of these pathways are important for N-ras tumorigenesis in human cancer cells and also to investigate the possibility of cross talk among the pathways, we have utilized a human fibrosarcoma cell line (HT1080), which contains an endogenous mutated allele of the N-ras gene, and its derivative (MCH603c8), which lacks the mutant N-ras allele. We have stably transfected MCH603c8 and HT1080 cells with activating or dominant-negative mutant cDNAs, respectively, of various components of the Raf, Rac, and RhoA pathways. In previous studies with these cell lines we showed that loss of mutant Ras function results in dramatic changes in the in vitro phenotypic traits and conversion to a weakly tumorigenic phenotype in vivo. We report here that only overexpression of activated MEK contributed significantly to the conversion of MCH603c8 cells to an aggressive tumorigenic phenotype. Furthermore, we have demonstrated that blocking the constitutive activation of the Raf-MEK, Rac, or RhoA pathway alone is not sufficient to block the aggressive tumorigenic phenotype of HT1080, despite affecting a number of in vitro-transformed phenotypic traits. We have also demonstrated the possibility of bidirectional cross talk between the Raf-MEK-ERK pathway and the Rac-JNK or RhoA pathway. Finally, overexpression of activated MEK in MCH603c8 cells appears to result in the activation of an as-yet-unidentified target(s) that is critical for the aggressive tumorigenic phenotype. PMID:11094080

  2. Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival.

    PubMed

    Kim, Joo Young; Brosnan-Cashman, Jacqueline A; An, Soyeon; Kim, Sung Joo; Song, Ki-Byung; Kim, Min-Sun; Kim, Mi-Ju; Hwang, Dae Wook; Meeker, Alan K; Yu, Eunsil; Kim, Song Cheol; Hruban, Ralph H; Heaphy, Christopher M; Hong, Seung-Mo

    2017-03-15

    Purpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET).Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors.Results: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, P < 0.001). ALT also strongly correlated with lymphovascular (P < 0.001) and perineural invasion (P = 0.001) and the presence of lymph node (P < 0.001) and distant metastases (P = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83-6.27; P < 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08-0.68; P = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (P < 0.001), aggressive clinical behavior, and reduced recurrence-free survival (P < 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (P = 0.003).Conclusions: Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of

  3. The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype

    PubMed Central

    Marsden, Carolyn G.; Jensen, Ryan B.; Zagelbaum, Jennifer; Rothenberg, Eli; Morrical, Scott W.; Wallace, Susan S.; Sweasy, Joann B.

    2016-01-01

    The RAD51 protein plays a key role in the homology-directed repair of DNA double-strand breaks and is important for maintaining genome stability. Here we report on a novel human RAD51 variant found in an aggressive and therapy-refractive breast carcinoma. Expression of the RAD51 G151D variant in human breast epithelial cells increases the levels of homology-directed repair. Expression of RAD51 G151D in cells also promotes high levels of chromosomal aberrations and sister chromatid exchanges. In vitro, the purified RAD51 G151D protein directly and significantly enhances DNA strand exchange activity in the presence of RPA. In concordance with this result, co-incubation of G151D with BRCA2 resulted in a much higher level of strand-exchange activity compared to WT RAD51. Strikingly, the RAD51 G151D variant confers resistance to multiple DNA damaging agents, including ionizing radiation, mitomycin C, and doxorubicin. Our findings demonstrate that the RAD51 G151D somatic variant has a novel hyper-recombination phenotype and suggest that this property of the protein is important for the repair of DNA damage, leading to drug resistance. PMID:27513445

  4. The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype.

    PubMed

    Marsden, Carolyn G; Jensen, Ryan B; Zagelbaum, Jennifer; Rothenberg, Eli; Morrical, Scott W; Wallace, Susan S; Sweasy, Joann B

    2016-08-01

    The RAD51 protein plays a key role in the homology-directed repair of DNA double-strand breaks and is important for maintaining genome stability. Here we report on a novel human RAD51 variant found in an aggressive and therapy-refractive breast carcinoma. Expression of the RAD51 G151D variant in human breast epithelial cells increases the levels of homology-directed repair. Expression of RAD51 G151D in cells also promotes high levels of chromosomal aberrations and sister chromatid exchanges. In vitro, the purified RAD51 G151D protein directly and significantly enhances DNA strand exchange activity in the presence of RPA. In concordance with this result, co-incubation of G151D with BRCA2 resulted in a much higher level of strand-exchange activity compared to WT RAD51. Strikingly, the RAD51 G151D variant confers resistance to multiple DNA damaging agents, including ionizing radiation, mitomycin C, and doxorubicin. Our findings demonstrate that the RAD51 G151D somatic variant has a novel hyper-recombination phenotype and suggest that this property of the protein is important for the repair of DNA damage, leading to drug resistance.

  5. NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype.

    PubMed

    Ames, Erik; Canter, Robert J; Grossenbacher, Steven K; Mac, Stephanie; Chen, Mingyi; Smith, Rachel C; Hagino, Takeshi; Perez-Cunningham, Jessica; Sckisel, Gail D; Urayama, Shiro; Monjazeb, Arta M; Fragoso, Ruben C; Sayers, Thomas J; Murphy, William J

    2015-10-15

    Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, including NK coculture (autologous and allogeneic) with multiple human cancer cell lines and dissociated primary cancer specimens and NK transfer in NSG mice harboring orthotopic pancreatic cancer xenografts, we assessed CSC viability, CSC frequency, expression of death receptor ligands, and tumor burden. We demonstrate that activated NK cells are capable of preferentially killing CSCs identified by multiple CSC markers (CD24(+)/CD44(+), CD133(+), and aldehyde dehydrogenase(bright)) from a wide variety of human cancer cell lines in vitro and dissociated primary cancer specimens ex vivo. We observed comparable effector function of allogeneic and autologous NK cells. We also observed preferential upregulation of NK activation ligands MICA/B, Fas, and DR5 on CSCs. Blocking studies further implicated an NKG2D-dependent mechanism for NK killing of CSCs. Treatment of orthotopic human pancreatic cancer tumor-bearing NSG mice with activated NK cells led to significant reductions in both intratumoral CSCs and tumor burden. Taken together, these data from multiple preclinical models, including a strong reliance on primary human cancer specimens, provide compelling preclinical evidence that activated NK cells preferentially target cancer cells with a CSC phenotype, highlighting the translational potential of NK immunotherapy as part of a combined modality approach for refractory solid malignancies.

  6. Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma

    PubMed Central

    Lee, Jee San; Yoo, Jeong Eun; Kim, Haeryoung; Rhee, Hyungjin; Koh, Myoung Ju; Nahm, Ji Hae; Choi, Jin Sub; Lee, Kee-Ho; Park, Young Nyun

    2017-01-01

    Senescence secretome was recently reported to promote liver cancer in an obese mouse model. Steatohepatitic hepatocellular carcinoma (SH-HCC), a new variant of HCC, has been found in metabolic syndrome patients, and pericellular fibrosis, a characteristic feature of SH-HCC, suggests that alteration of the tumor stroma might play an important role in SH-HCC development. Clinicopathological characteristics and tumor stroma showing senescence and senescence-associated secretory phenotype (SASP) were investigated in 21 SH-HCCs and 34 conventional HCCs (C-HCCs). The expression of α-smooth muscle actin (α-SMA), p21Waf1/Cif1, γ-H2AX, and IL-6 was investigated by immunohistochemistry or immunofluorescence. SH-HCCs were associated with older age, higher body mass index, and a higher incidence of metabolic syndrome, compared to C-HCC (P <0.05, all). The numbers of α-SMA-positive cancer-associated fibroblasts (CAFs) (P = 0.049) and α-SMA-positive CAFs co-expressing p21Waf1/Cif1 (P = 0.038), γ-H2AX (P = 0.065), and IL-6 (P = 0.048) were greater for SH-HCCs than C-HCCs. Additionally, non-tumoral liver from SH-HCCs showed a higher incidence of non-alcoholic fatty liver disease and a higher number of α-SMA-positive stellate cells expressing γ-H2AX and p21Waf1/Cif1 than that from C-HCCs (P <0.05, all). In conclusion, SH-HCCs are considered to occur more frequently in metabolic syndrome patients. Therein, senescent and damaged CAFs, as well as non-tumoral stellate cells, expressing SASP including IL-6 may contribute to the development of SH-HCC. PMID:28273155

  7. Conditional inactivation of the mouse Wwox tumor suppressor gene recapitulates the null phenotype.

    PubMed

    Abdeen, Suhaib K; Del Mare, Sara; Hussain, Sadeeq; Abu-Remaileh, Muhannad; Salah, Zaidoun; Hagan, John; Rawahneh, Maysoon; Pu, Xin-An; Russell, Stacey; Stein, Janet L; Stein, Gary S; Lian, Jane B; Aqeilan, Rami I

    2013-07-01

    WW domain-containing oxidoreductase (WWOX) is highly conserved in both human and murine. WWOX spans the second most common human chromosomal fragile site, FRA16D, and is commonly inactivated in multiple human cancers. Modeling WWOX inactivation in mice revealed a complex phenotype including postnatal lethality, defects in bone metabolism and steroidogenesis and tumor suppressor function resulting in osteosarcomas. For better understanding of WWOX roles in different tissues at distinct stages of development and in pathological conditions, Wwox conditional knockout mice were generated in which loxp sites flank exon 1 in the Wwox allele. We demonstrated that Cre-mediated recombination using EIIA-Cre, a Cre line expressed in germline, results in postnatal lethality by age of 3 weeks and decreased bone mineralization resembling total ablation of WWOX as in conventional null mice. This animal model will be useful to study distinct roles of WWOX in multiple tissues at different ages.

  8. Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma

    PubMed Central

    Poruk, Katherine E.; Valero, Vicente; Saunders, Tyler; Blackford, Amanda L.; Griffin, James F.; Poling, Justin; Hruban, Ralph H.; Anders, Robert A.; Herman, Joseph; Zheng, Lei; Rasheed, Zeshaan A.; Laheru, Daniel A.; Ahuja, Nita; Weiss, Matthew J.; Cameron, John L.; Goggins, Michael; Iacobuzio-Donahue, Christine A.; Wood, Laura D.; Wolfgang, Christopher L.

    2016-01-01

    Objective We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC). Background PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification. Methods Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45. Results Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal-like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multi-variable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02). Conclusions CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers. PMID:26756760

  9. A 3D tension bioreactor platform to study the interplay between ECM stiffness and tumor phenotype.

    PubMed

    Cassereau, Luke; Miroshnikova, Yekaterina A; Ou, Guanqing; Lakins, Johnathon; Weaver, Valerie M

    2015-01-10

    Extracellular matrix (ECM) structure, composition, and stiffness have profound effects on tissue development and pathologies such as cardiovascular disease and cancer. Accordingly, a variety of synthetic hydrogel systems have been designed to study the impact of ECM composition, density, mechanics, and topography on cell and tissue phenotype. However, these synthetic systems fail to accurately recapitulate the biological properties and structure of the native tissue ECM. Natural three dimensional (3D) ECM hydrogels, such as collagen or hyaluronic acid, feature many of the chemical and physical properties of tissue, yet, these systems have limitations including the inability to independently control biophysical properties such as stiffness and pore size. Here, we present a 3D tension bioreactor system that permits precise mechanical tuning of collagen hydrogel stiffness, while maintaining consistent composition and pore size. We achieve this by mechanically loading collagen hydrogels covalently-conjugated to a polydimethylsiloxane (PDMS) membrane to induce hydrogel stiffening. We validated the biological application of this system with oncogenically transformed mammary epithelial cell organoids embedded in a 3D collagen I hydrogel, either uniformly stiffened or calibrated to create a gradient of ECM stiffening, to visually demonstrate the impact of ECM stiffening on transformation and tumor cell invasion. As such, this bioreactor presents the first tunable 3D natural hydrogel system that is capable of independently assessing the role of ECM stiffness on tissue phenotype.

  10. Out on a LIM: chronic kidney disease, podocyte phenotype and the Wilm's tumor interacting protein (WTIP).

    PubMed

    Sedor, John R; Madhavan, Sethu M; Kim, Jane H; Konieczkowski, Martha

    2011-01-01

    Normal function of the glomerular filtration barrier requires wild-type differentiation of the highly specialized glomerular epithelial cell, the podocyte. Podocytes express three distinct domains, consisting of a cell body, primary processes, and secondary foot processes (FP). These FP express slit diaphragms, which are highly specialized cell-cell contacts critical for filtration-barrier function. Foot processes are dynamic structures that reorganize within minutes through actin cytoskeletal rearrangement. Glomerular diseases are characterized by a persistent simplification in podocyte domain structure with loss of FP, a phenotype described as FP effacement. The generation of such phenotypic plasticity requires that signaling pathways in subcellular compartments be integrated dynamically for a cell to respond appropriately to information flow from its microenvironment. We have identified a LIM-domain-containing protein, Wilm's tumor interacting protein (WTIP), that regulates podocyte actin dynamics to maintain stable cell contacts. After glomerular injury, the WTIP molecule shuttles to the podocyte nucleus in response to changes in slit-diaphragm assembly, and changes gene transcription to permit podocyte remodeling. Defining regulatory pathways of podocyte differentiation identifies novel, druggable targets for chronic kidney diseases characterized by glomerular scarring.

  11. Decoding Tumor Phenotypes for ALK, ROS1, and RET Fusions in Lung Adenocarcinoma Using a Radiomics Approach

    PubMed Central

    Yoon, Hyun Jung; Sohn, Insuk; Cho, Jong Ho; Lee, Ho Yun; Kim, Jae-Hun; Choi, Yoon-La; Kim, Hyeseung; Lee, Genehee; Lee, Kyung Soo; Kim, Jhingook

    2015-01-01

    Abstract Quantitative imaging using radiomics can capture distinct phenotypic differences between tumors and may have predictive power for certain phenotypes according to specific genetic mutations. We aimed to identify the clinicoradiologic predictors of tumors with ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) fusions in patients with lung adenocarcinoma. A total of 539 pathologically confirmed lung adenocarcinomas were included in this retrospective study. The baseline clinicopathologic characteristics were retrieved from the patients’ medical records and the ALK/ROS1/RET fusion status was reviewed. Quantitative computed tomography (CT) and positron emission tomography imaging characteristics were evaluated using a radiomics approach. Significant features for the fusion-positive tumor prediction model were extracted from all of the clinicoradiologic features, and were used to calculate diagnostic performance for predicting 3 fusions’ positivity. The clinicoradiologic features were compared between ALK versus ROS1/RET fusion-positive tumors to identify the clinicoradiologic similarity between the 2 groups. The fusion-positive tumor prediction model was a combination of younger age, advanced tumor stage, solid tumor on CT, higher values for SUVmax and tumor mass, lower values for kurtosis and inverse variance on 3-voxel distance than those of fusion-negative tumors (sensitivity and specificity, 0.73 and 0.70, respectively). ALK fusion-positive tumors were significantly different in tumor stage, central location, SUVmax, homogeneity on 1-, 2-, and 3-voxel distances, and sum mean on 2-voxel distance compared with ROS1/RET fusion-positive tumors. ALK/ROS1/RET fusion-positive lung adenocarcinomas possess certain clinical and imaging features that enable good discrimination of fusion-positive from fusion-negative lung adenocarcinomas. PMID:26469915

  12. Decoding Tumor Phenotypes for ALK, ROS1, and RET Fusions in Lung Adenocarcinoma Using a Radiomics Approach.

    PubMed

    Yoon, Hyun Jung; Sohn, Insuk; Cho, Jong Ho; Lee, Ho Yun; Kim, Jae-Hun; Choi, Yoon-La; Kim, Hyeseung; Lee, Genehee; Lee, Kyung Soo; Kim, Jhingook

    2015-10-01

    Quantitative imaging using radiomics can capture distinct phenotypic differences between tumors and may have predictive power for certain phenotypes according to specific genetic mutations. We aimed to identify the clinicoradiologic predictors of tumors with ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) fusions in patients with lung adenocarcinoma.A total of 539 pathologically confirmed lung adenocarcinomas were included in this retrospective study. The baseline clinicopathologic characteristics were retrieved from the patients' medical records and the ALK/ROS1/RET fusion status was reviewed. Quantitative computed tomography (CT) and positron emission tomography imaging characteristics were evaluated using a radiomics approach. Significant features for the fusion-positive tumor prediction model were extracted from all of the clinicoradiologic features, and were used to calculate diagnostic performance for predicting 3 fusions' positivity. The clinicoradiologic features were compared between ALK versus ROS1/RET fusion-positive tumors to identify the clinicoradiologic similarity between the 2 groups.The fusion-positive tumor prediction model was a combination of younger age, advanced tumor stage, solid tumor on CT, higher values for SUV(max) and tumor mass, lower values for kurtosis and inverse variance on 3-voxel distance than those of fusion-negative tumors (sensitivity and specificity, 0.73 and 0.70, respectively). ALK fusion-positive tumors were significantly different in tumor stage, central location, SUV(max), homogeneity on 1-, 2-, and 3-voxel distances, and sum mean on 2-voxel distance compared with ROS1/RET fusion-positive tumors.ALK/ROS1/RET fusion-positive lung adenocarcinomas possess certain clinical and imaging features that enable good discrimination of fusion-positive from fusion-negative lung adenocarcinomas.

  13. Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

    PubMed Central

    Morandi, Andrea; Taddei, Maria Letizia; Chiarugi, Paola; Giannoni, Elisa

    2017-01-01

    The epithelial-to-mesenchymal transition (EMT) process allows the trans-differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention. PMID:28352611

  14. NTPDase5/PCPH as a New Target in Highly Aggressive Tumors: A Systematic Review

    PubMed Central

    Bracco, Paula Andreghetto; Bertoni, Ana Paula Santin; Wink, Márcia Rosângela

    2014-01-01

    The protooncogene PCPH was recently identified as being the ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5). This protooncogene is converted into an oncogene by a single base pair deletion, resulting in frame change and producing a premature stop codon, leading to a mutated protein (mt-PCPH) with only 27 kDa, which is much smaller than the original 47 kDa protein. Overexpression of the PCPH as well as the mutated PCPH increases the cellular resistance to stress and apoptosis. This is intriguing considering that the active form, that is, the oncogene, is the mutated PCPH. Several studies analyzed the expression of NTPDase5/mt-PCPH in a wide range of tumor cells and evaluated its role and mechanisms in cancer and other pathogenic processes. The main point of this review is to integrate the findings and proposed theories about the role played by NTPDase5/mt-PCPH in cancer progression, considering that these proteins have been suggested as potential early diagnostic tools and therapy targets. PMID:25045656

  15. Social networking in tumor cell communities is associated with increased aggressiveness

    PubMed Central

    Lodillinsky, Catalina; Podsypanina, Katrina; Chavrier, Philippe

    2016-01-01

    ABSTRACT Extracellular vesicles (EVs) are lipid-bilayer-enclosed vesicles that contain proteins, lipids and nucleic acids. EVs produced by cells from healthy tissues circulate in the blood and body fluids, and can be taken up by unrelated cells. As they have the capacity to transfer cargo proteins, lipids and nucleic acids (mostly mRNAs and miRNAs) between different cells in the body, EVs are emerging as mediators of intercellular communication that could modulate cell behavior, tissue homeostasis and regulation of physiological functions. EV-mediated cell-cell communications are also proposed to play a role in disease, for example, cancer, where they could contribute to transfer of traits required for tumor progression and metastasis. However, direct evidence for EV-mediated mRNA transfer to individual cells and for its biological consequences in vivo has been missing until recently. Recent studies have reported elegant experiments using genetic tracing with the Cre recombinase system and intravital imaging that visualize and quantify functional transfer of mRNA mediated by EVs in the context of cancer and metastasis. PMID:28243516

  16. Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors.

    PubMed

    Morandi, Andrea; Taddei, Maria Letizia; Chiarugi, Paola; Giannoni, Elisa

    2017-01-01

    The epithelial-to-mesenchymal transition (EMT) process allows the trans-differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention.

  17. Overexpression of TMPRSS4 promotes tumor proliferation and aggressiveness in breast cancer

    PubMed Central

    Li, Xiao-Mei; Liu, Wen-Lou; Chen, Xu; Wang, Ya-Wen; Shi, Duan-Bo; Zhang, Hui; Ma, Ran-Ran; Liu, Hai-Ting; Guo, Xiang-Yu; Hou, Feng; Li, Ming; Gao, Peng

    2017-01-01

    Transmembrane protease serine 4 (TMPRSS4) is a novel type II transmembrane serine protease that is overexpressed in various types of human cancers and has an important function in cancer progression. However, there is a paucity of data available regarding the biological effects of TMPRSS4 on breast cancer (BC) cells and the underlying mechanisms. In this study, expression of TMPRSS4 in BC tissues was detected by immunohistochemistry. The relationship between TMPRSS4 expression and clinicopathological characteristics as well as prognosis was evaluated. The effects of TMPRSS4 on cell proliferation, migration and invasion were investigated in BC cell lines in vitro. Additionally, RT-qPCR and western blot analysis were used to determine the expressions of epithelial-mesenchymal transition (EMT) biomarkers and TMPRSS4 in BC cell lines. We found that TMPRSS4 was overexpressed in BC tissues and its expression level was closely correlated with tumor size, histological grade, lymph node metastasis, clinical stage as well as poor survival (all P<0.05) and could be recognized as an independent prognostic factor for BC patients. Overexpression of TMPRSS4 promoted the proliferation, migration and invasion of BC cells in vitro. Moreover, TMPRSS4 knockdown significantly enhanced the expression of E-cadherin and claudin-1 and inhibited the expression of vimentin and Slug, indicating suppression of EMT. Our results suggest that TMPRSS4 plays a crucial role in the progression of BC. Moreover, TMPRSS4 overexpression promoted the proliferation, invasion and migration of BC cells by possibly inducing EMT. To conclude, TMPRSS4 may be a potential therapeutic target for cancer treatment. PMID:28259959

  18. Multi-modality imaging of tumor phenotype and response to therapy

    NASA Astrophysics Data System (ADS)

    Nyflot, Matthew J.

    2011-12-01

    Imaging and radiation oncology have historically been closely linked. However, the vast majority of techniques used in the clinic involve anatomical imaging. Biological imaging offers the potential for innovation in the areas of cancer diagnosis and staging, radiotherapy target definition, and treatment response assessment. Some relevant imaging techniques are FDG PET (for imaging cellular metabolism), FLT PET (proliferation), CuATSM PET (hypoxia), and contrast-enhanced CT (vasculature and perfusion). Here, a technique for quantitative spatial correlation of tumor phenotype is presented for FDG PET, FLT PET, and CuATSM PET images. Additionally, multimodality imaging of treatment response with FLT PET, CuATSM, and dynamic contrast-enhanced CT is presented, in a trial of patients receiving an antiangiogenic agent (Avastin) combined with cisplatin and radiotherapy. Results are also presented for translational applications in animal models, including quantitative assessment of proliferative response to cetuximab with FLT PET and quantification of vascular volume with a blood-pool contrast agent (Fenestra). These techniques have clear applications to radiobiological research and optimized treatment strategies, and may eventually be used for personalized therapy for patients.

  19. Circulating Tumor Cells: A Review of Present Methods and the Need to Identify Heterogeneous Phenotypes

    PubMed Central

    Millner, Lori M.; Linder, Mark W.; Valdes, Roland

    2016-01-01

    The measurement and characterization of circulating tumor cells (CTCs) hold promise for advancing personalized therapeutics. CTCs are the precursor to metastatic cancer and thus have the potential to radically alter patient treatment and outcome. Currently, clinical information provided by the enumeration of CTCs is limited to predicting clinical outcome. Other areas of interest in advancing the practice of pathology include: using CTCs for early detection of potential metastasis, determining and monitoring the efficacy of individualized treatment regimens, and predicting site-specific metastasis. Important hurdles to overcome in obtaining this type of clinical information involve present limitations in defining, detecting, and isolating CTCs. Currently, CTCs are detected using epithelial markers. The definition of what distinguishes a CTC should be expanded to include CTCs with heterogeneous phenotypes, and markers should be identified to enable a more comprehensive capture. Additionally, most methods available for detecting CTCs do not capture functionally viable CTCs. Retaining functional viability would provide a significant advantage in characterizing CTC-subtypes that may predict the site of metastatic invasion and thus assist in selecting effective treatment regimens. In this review we describe areas of clinical interest followed by a summary of current circulating cell-separation technologies and present limitations. Lastly, we provide insight into what is required to overcome these limitations as they relate to applications in advancing the practice of pathology and laboratory medicine. PMID:23884225

  20. Tumor and reproductive traits are linked by RNA metabolism genes in the mouse ovary: a transcriptome-phenotype association analysis

    PubMed Central

    2010-01-01

    Background The link between reproductive life history and incidence of ovarian tumors is well known. Periods of reduced ovulations may confer protection against ovarian cancer. Using phenotypic data available for mouse, a possible association between the ovarian transcriptome, reproductive records and spontaneous ovarian tumor rates was investigated in four mouse inbred strains. NIA15k-DNA microarrays were employed to obtain expression profiles of BalbC, C57BL6, FVB and SWR adult ovaries. Results Linear regression analysis with multiple-test control (adjusted p ≤ 0.05) resulted in ovarian tumor frequency (OTF) and number of litters (NL) as the top-correlated among five tested phenotypes. Moreover, nearly one-hundred genes were coincident between these two traits and were decomposed in 76 OTF(–) NL(+) and 20 OTF(+) NL(–) genes, where the plus/minus signs indicate the direction of correlation. Enriched functional categories were RNA-binding/mRNA-processing and protein folding in the OTF(–) NL(+) and the OTF(+) NL(–) subsets, respectively. In contrast, no associations were detected between OTF and litter size (LS), the latter a measure of ovulation events in a single estrous cycle. Conclusion Literature text-mining pointed to post-transcriptional control of ovarian processes including oocyte maturation, folliculogenesis and angiogenesis as possible causal relationships of observed tumor and reproductive phenotypes. We speculate that repetitive cycling instead of repetitive ovulations represent the actual link between ovarian tumorigenesis and reproductive records. PMID:21210965

  1. The mitotic checkpoint regulator RAE1 induces aggressive breast cancer cell phenotypes by mediating epithelial-mesenchymal transition

    PubMed Central

    Oh, Ji Hoon; Hur, Ho; Lee, Ji-Yeon; Kim, Yeejeong; Seo, Younsoo; Kim, Myoung Hee

    2017-01-01

    The gene RAE1 encodes ribonucleic acid export 1 (RAE1), which is involved in mRNA export and is known to serve as a mitotic checkpoint regulator. In addition, RAE1 haplo-insufficiency leads to chromosome missegregation and early aging-associated phenotypes. In humans, a positive correlation has been found between RAE1 copy number abnormalities and gene amplification in breast cancer cells. However, the precise functional role of RAE1 in breast cancer remains to be determined. An in silico analysis of data retrieved from GENT and cBio-Portal identified RAE1 upregulation in breast cancer tissues relative to normal breast cells. Functional studies of various cell lines showed that RAE1 induced invasive and migratory abilities by regulating epithelial-mesenchymal transition signals. A tissue microarray was constructed to demonstrate the interrelationship between clinicopathological features and RAE1 expression. Immunohistochemistry revealed a positive correlation between RAE1 expression and a high histologic grade. Furthermore, RAE1 overexpression was associated with considerably poorer disease-free survival and distant metastasis-free survival, especially in patients with oestrogen receptor-positive tumours. In summary, RAE1 may be a prognostic marker and therapeutic intervention target in malignant breast cancers. PMID:28181567

  2. The mitotic checkpoint regulator RAE1 induces aggressive breast cancer cell phenotypes by mediating epithelial-mesenchymal transition.

    PubMed

    Oh, Ji Hoon; Hur, Ho; Lee, Ji-Yeon; Kim, Yeejeong; Seo, Younsoo; Kim, Myoung Hee

    2017-02-09

    The gene RAE1 encodes ribonucleic acid export 1 (RAE1), which is involved in mRNA export and is known to serve as a mitotic checkpoint regulator. In addition, RAE1 haplo-insufficiency leads to chromosome missegregation and early aging-associated phenotypes. In humans, a positive correlation has been found between RAE1 copy number abnormalities and gene amplification in breast cancer cells. However, the precise functional role of RAE1 in breast cancer remains to be determined. An in silico analysis of data retrieved from GENT and cBio-Portal identified RAE1 upregulation in breast cancer tissues relative to normal breast cells. Functional studies of various cell lines showed that RAE1 induced invasive and migratory abilities by regulating epithelial-mesenchymal transition signals. A tissue microarray was constructed to demonstrate the interrelationship between clinicopathological features and RAE1 expression. Immunohistochemistry revealed a positive correlation between RAE1 expression and a high histologic grade. Furthermore, RAE1 overexpression was associated with considerably poorer disease-free survival and distant metastasis-free survival, especially in patients with oestrogen receptor-positive tumours. In summary, RAE1 may be a prognostic marker and therapeutic intervention target in malignant breast cancers.

  3. Overexpression of the growth-hormone-releasing hormone gene in acromegaly-associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior.

    PubMed Central

    Thapar, K.; Kovacs, K.; Stefaneanu, L.; Scheithauer, B.; Killinger, D. W.; Lioyd, R. V.; Smyth, H. S.; Barr, A.; Thorner, M. O.; Gaylinn, B.; Laws, E. R.

    1997-01-01

    The clinical behavior of growth hormone (GH)-producing pituitary tumors is known to vary greatly; however, the events underlying this variability remain poorly understood. Herein we demonstrate that tumor overexpression of the GH-releasing hormone (GHRH) gene is one prognostically informative event associated with the clinical aggressiveness of somatotroph pituitary tumors. Accumulation of GHRH mRNA transcripts was demonstrated in 91 of a consecutive series of 100 somatotroph tumors by in situ hybridization; these findings were corroborated by Northern analysis and reverse transcriptase polymerase chain reaction, and protein translation was confirmed by Western blotting. By comparison, transcript accumulation was absent or negligibly low in 30 normal pituitary glands. GHRH transcripts were found to preferentially accumulate among clinically aggressive tumors. Specifically, GHRH mRNA signal intensity was 1) linearly correlated with Ki-67 tumor growth fractions (r = 0.71; P < 0.001), 2) linearly correlated with preoperative serum GH levels (r = 0.56; p = 0.01), 3) higher among invasive tumors (P < 0.001), and 4) highest in those tumors in which post-operative remission was not achieved (P < 0.001). Using multivariate logistic regression, a model of postoperative remission likelihood was derived wherein remission was defined by the single criterion of suppressibility of GH levels to less than 2 ng/ml during an oral glucose tolerance test. In this outcome model, GHRH mRNA signal intensity proved to be the most important explanatory variable overall, eclipsing any and all conventional clinicopathological predictors as the single most significant predictor of postoperative remission; increases in GHRH mRNA signal were associated with marked declines in remission likelihood. The generalizability of this outcome model was further validated by the model's significant performance in predicting postoperative remission in a random sample of 30 somatotroph tumors treated at

  4. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters.

    PubMed

    Luque, Raul M; Sampedro-Nuñez, Miguel; Gahete, Manuel D; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D; Castaño, Justo P; Marazuela, Mónica

    2015-08-14

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value.

  5. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters

    PubMed Central

    Gahete, Manuel D.; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D.; Castaño, Justo P.; Marazuela, Mónica

    2015-01-01

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

  6. Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome

    PubMed Central

    Yamanoi, Kazuhiro; Arai, Eri; Tian, Ying; Takahashi, Yoriko; Miyata, Sayaka; Sasaki, Hiroki; Chiwaki, Fumiko; Ichikawa, Hitoshi; Sakamoto, Hiromi; Kushima, Ryoji; Katai, Hitoshi; Yoshida, Teruhiko; Sakamoto, Michiie; Kanai, Yae

    2015-01-01

    The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non-cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (βN) using the 3861 probes. This divided the 109 patients into three clusters: A (n = 20), B1 (n = 20), and B2 (n = 69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which βN characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (βT) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, βT was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that βT was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome. PMID:25740824

  7. Spontaneous occurrence of a distinctive renal tubule tumor phenotype in rat carcinogenicity studies conducted by the national toxicology program.

    PubMed

    Hard, Gordon C; Seely, John Curtis; Kissling, Grace E; Betz, Laura J

    2008-04-01

    The Toxicology Data Management System (TDMS) of the National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health, was surveyed for occurrence and distribution of a distinctive renal tubule tumor type in rats. The hallmark features of this tumor included eosinophilic/amphophilic staining, large finely granular cells, and numerous vacuoles and/or minilumens. It is referred to here as the amphophilic-vacuolar (AV) variant of renal tubule tumor. Of 154 studies in which renal tubule tumors had been recorded in the standard single sections of kidney in the TDMS, there were collectively 1012 rats with renal adenomas, carcinomas, or adenocarcinomas, and of these, 100 displayed the distinctive AV morphology, representing 74 studies involving mostly the F344 rat, but also the Sprague-Dawley and Wistar strains. The AV tumors (mainly adenomas but also some carcinomas) occurred usually as solitary lesions in the affected animals. However, they were multiple and bilateral in a few cases. They were equally distributed between the sexes, did not metastasize (at least to the lung), and were not associated with chronic progressive nephropathy. The distribution of this renal tumor type was random across studies and dose groups, underscoring the likelihood that it was of spontaneous origin and not chemically induced. Accordingly, it is suggested that this distinctive renal tumor phenotype be recorded as a separate category from conventional RTT when assessing the carcinogenic potential of a test compound.

  8. Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer.

    PubMed

    Theodoropoulos, Panayiotis A; Polioudaki, Hara; Agelaki, Sofia; Kallergi, Galatea; Saridaki, Zacharenia; Mavroudis, Dimitris; Georgoulias, Vassilis

    2010-02-01

    The CD44(+)/CD24(-/low) and ALDH1(+) cell phenotypes are associated with stemness and enhanced tumorigenic potential in breast cancer. We assessed the expression of CD44, CD24 and ALDH1 on tumor cells circulating in the peripheral blood (CTCs) of patients with metastatic breast cancer using triple-marker immunofluorescence microscopy. Among a total of 1439 CTCs identified in 20 (66.7%) out of 30 patients, 35.2% had the stem-like/tumorigenic phenotype CD44(+)/CD24(-/low), whereas 17.7% of the CTCs analyzed in seven patients, were ALDH1(high)/CD24(-/low). In conclusion, we report the existence of a subpopulation of CTCs with putative stem cell progenitor phenotypes in patients with metastatic breast cancer.

  9. Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity.

    PubMed

    Kaimala, Suneesh; Mohamed, Yassir A; Nader, Nancy; Issac, Jincy; Elkord, Eyad; Chouaib, Salem; Fernandez-Cabezudo, Maria J; Al-Ramadi, Basel K

    2014-06-01

    The effectiveness of attenuated Salmonella in inhibiting tumor growth has been demonstrated in many therapeutic models, but the precise mechanisms remain incompletely understood. In this study, we show that the anti-tumor capacity of Salmonella depends on a functional MyD88-TLR pathway and is independent of adaptive immune responses. Since myeloid suppressor cells play a critical role in tumor growth, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics, and functional activation in spleen and tumor tissue of B16.F1 melanoma-bearing mice. Salmonella treatment led to increased accumulation of splenic and intratumoral CD11b(+)Gr-1(+) myeloid cells, exhibiting significantly increased expression of various activation markers such as MHC class II, costimulatory molecules, and Sca-1/Ly6A proteins. Gene expression analysis showed that Salmonella treatment induced expression of iNOS, arginase-1 (ARG1), and IFN-γ in the spleen, but down-regulated IL-4 and TGF-β. Within the tumor, expression of iNOS, IFN-γ, and S100A9 was markedly increased, but ARG1, IL-4, TGF-β, and VEGF were inhibited. Functionally, splenic CD11b(+) cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.

  10. Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.

    PubMed

    Misemer, Benjamin S; Skubitz, Amy P N; Carlos Manivel, J; Schmechel, Stephen C; Cheng, Edward Y; Henriksen, Jonathan C; Koopmeiners, Joseph S; Corless, Christopher L; Skubitz, Keith M

    2014-02-01

    Aggressive fibromatosis (AF) represents a group of tumors with a variable and unpredictable clinical course, characterized by a monoclonal proliferation of myofibroblastic cells. The optimal treatment for AF remains unclear. Identification and validation of genes whose expression patterns are associated with AF may elucidate biological mechanisms in AF, and aid treatment selection. This study was designed to examine the protein expression by immunohistochemistry (IHC) of four genes, ADAM12, FAP, SOX11, and WISP1, that were found in an earlier study to be uniquely overexpressed in AF compared with normal tissues. Digital image analysis was performed to evaluate inter- and intratumor heterogeneity, and correlate protein expression with histologic features, including a histopathologic assessment of tumor activity, defined by nuclear chromatin density ratio (CDR). AF tumors exhibited marked inter- and intratumor histologic heterogeneity. Pathologic assessment of tumor activity and digital assessment of average nuclear size and CDR were all significantly correlated. IHC revealed protein expression of all four genes. IHC staining for ADAM12, FAP, and WISP1 correlated with CDR and was higher, whereas SOX11 staining was lower in tumors with earlier recurrence following excision. All four proteins were expressed, and the regional variation in tumor activity within and among AF cases was demonstrated. A spatial correlation between protein expression and nuclear morphology was observed. IHC also correlated with the probability of recurrence following excision. These proteins may be involved in AF pathogenesis and the corresponding pathways could serve as potential targets of therapy.

  11. Using Computer-extracted Image Phenotypes from Tumors on Breast MRI to Predict Breast Cancer Pathologic Stage

    PubMed Central

    Burnside, Elizabeth S.; Drukker, Karen; Li, Hui; Bonaccio, Ermelinda; Zuley, Margarita; Ganott, Marie; Net, Jose M.; Sutton, Elizabeth; Brandt, Kathleen R.; Whitman, Gary; Conzen, Suzanne; Lan, Li; Ji, Yuan; Zhu, Yitan; Jaffe, Carl; Huang, Erich; Freymann, John; Kirby, Justin; Morris, Elizabeth; Giger, Maryellen

    2015-01-01

    Background To demonstrate that computer-extracted image phenotypes (CEIPs) of biopsy-proven breast cancer on MRI can accurately predict pathologic stage. Methods We used a dataset of de-identified breast MRIs organized by the National Cancer Institute in The Cancer Imaging Archive. We analyzed 91 biopsy-proven breast cancer cases with pathologic stage (stage I = 22; stage II = 58; stage III = 11) and surgically proven nodal status (negative nodes = 46, ≥ 1 positive node = 44, no nodes examined = 1). We characterized tumors by (a) radiologist measured size, and (b) CEIP. We built models combining two CEIPs to predict tumor pathologic stage and lymph node involvement, evaluated them in leave-one-out cross-validation with area under the ROC curve (AUC) as figure of merit. Results Tumor size was the most powerful predictor of pathologic stage but CEIPs capturing biologic behavior also emerged as predictive (e.g. stage I+II vs. III demonstrated AUC = 0.83). No size measure was successful in the prediction of positive lymph nodes but adding a CEIP describing tumor “homogeneity,” significantly improved this discrimination (AUC = 0.62, p=.003) over chance. Conclusions Our results indicate that MRI phenotypes show promise for predicting breast cancer pathologic stage and lymph node status. PMID:26619259

  12. Gastrointestinal stromal tumors with KIT exon 9 mutations: Update on genotype-phenotype correlation and validation of a high-resolution melting assay for mutational testing.

    PubMed

    Künstlinger, Helen; Huss, Sebastian; Merkelbach-Bruse, Sabine; Binot, Elke; Kleine, Michaela Angelika; Loeser, Heike; Mittler, Jens; Hartmann, Wolfgang; Hohenberger, Peter; Reichardt, Peter; Büttner, Reinhard; Wardelmann, Eva; Schildhaus, Hans-Ulrich

    2013-11-01

    KIT exon 9 mutations in gastrointestinal stromal tumors (GISTs) are highly relevant and have direct therapeutic implications. In this context, we established and validated a fast and sensitive high-resolution melting assay. Analyzing 126 primary and 18 metastatic KIT exon 9-mutated cases from our registry, we demonstrate that the mutational spectrum of exon 9 is broader than previously thought and describe 3 novel mutations. Including these cases and the common p.A502_Y503dup mutation, we provide a comprehensive list of all known KIT exon 9 mutations according to the Human Genome Variation Society nomenclature. Two of the newly described mutations were associated with an aggressive phenotype and tumor progression while being treated with 400 mg imatinib, indicating that also GIST with rare exon 9 mutations could be treated with increased imatinib dosage. On the basis of >1500 GISTs from our registry, we have determined the frequency of KIT exon 9 mutations to be 9.2% among all GISTs and 22.5% among small-bowel cases. We describe for the first time that nearly 20% of exon 9-mutated GIST occur in the stomach or rectum. Furthermore, we provide first evidence that exon 9-mutated GISTs metastasize significantly more often to the peritoneum than to the liver. Performing extensive statistical analyses on data from our registry and from the literature, we demonstrate that KIT exon 9 mutations are neither associated with intermediate-risk/high-risk status nor overrepresented among metastatic lesions. Thus, we conclude that exon 9 mutations per se do not have prognostic relevance.

  13. Anti-thymocyte globulin could improve the outcome of allogeneic hematopoietic stem cell transplantation in patients with highly aggressive T-cell tumors

    PubMed Central

    Yang, J; Cai, Y; Jiang, J L; Wan, L P; Yan, S K; Wang, C

    2015-01-01

    The early experiment result in our hospital showed that anti-thymocyte globulin (ATG) inhibited the proliferation of lymphoid tumor cells in the T-cell tumors. We used the ATG as the part of the conditioning regimen and to evaluate the long-term anti-leukemia effect, the safety and complication in the patients with highly aggressive T-cell lymphomas. Twenty-three patients were enrolled into this study. At the time of transplant, six patients reached first or subsequent complete response, three patients had a partial remission and 14 patients had relapsed or primary refractory disease. The conditioning regimen consisted of ATG, total body irradiation, toposide and cyclophosphamide. The complete remission rate after transplant was 95.7%. At a median follow-up time of 25 months, 16 (69.6%) patients are alive and free from diseases, including nine patients in refractory and progressive disease. Seven patients died after transplant, five from relapse and two from treatment-related complications. The incidence of grades II–IV acute graft-vs-host disease (GvHD) was 39.1%. The maximum cumulative incidence of chronic GvHD was 30%. The most frequent and severe conditioning-related toxicities observed in 8 out of 23 patients were grades III/IV infections during cytopenia. Thus, ATG-based conditioning is a feasible and effective alternative for patients with highly aggressive T-cell tumors. PMID:26230956

  14. Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype.

    PubMed

    Sato, Shingo; Tang, Yuning J; Wei, Qingxia; Hirata, Makoto; Weng, Angela; Han, Ilkyu; Okawa, Atsushi; Takeda, Shu; Whetstone, Heather; Nadesan, Puvindran; Kirsch, David G; Wunder, Jay S; Alman, Benjamin A

    2016-07-26

    The cell of origin for most mesenchymal tumors is unclear. One cell type that contributes to this lineages is the pericyte, a cell expressing Ng2/Cspg4. Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4. Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing β-catenin in this same cell type caused desmoid tumors. Comparing expression between Ng2/Cspg4-expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53 showed inhibition of β-catenin signaling in the sarcomas. Activation of β-catenin inhibited the formation and growth of sarcomas. Thus, pericytes can be a cell of origin for mesenchymal tumors, and β-catenin dysregulation plays an important role in the neoplastic phenotype.

  15. A phenotype from tumor stroma based on the expression of metalloproteases and their inhibitors, associated with prognosis in breast cancer

    PubMed Central

    Eiró, Noemí; Fernandez-Garcia, Belen; Vázquez, Julio; del Casar, José M; González, Luis O; Vizoso, Francisco J

    2015-01-01

    The objective of the present work was to evaluate the impact of the phenotype of both mononuclear inflammatory cells (MICs) and cancer-associated fibroblast (CAFs) in early breast cancer patients, specifically assessed as to their expression of MMP/TIMP relative to their position within the tumor (i.e., localization at the tumor center or invasive front) and the occurrence of distant metastases.. An immunohistochemical study was performed using tissue arrays and specific antibodies against matrix metalloproteinase (MMP)−1, −2, −7, −9, −11, −13 and −14, tissue inhibitors of metalloproteinase (TIMP)−1, −2 and −3, both at tumor center and at invasive front, in 107 patients with primary ductal invasive breast tumors. Data were analyzed by unsupervised hierarchical clustering analysis. Our results indicated that MMP-11 expression by MICs, and TIMP-2 expression by CAFs at either the tumor center or the invasive front, were the most potent independent prognostic factors for predicting the clinical outcome of patients. Using the unsupervised hierarchical clustering analysis, we found well-defined clusters of cases identifying subgroups of tumors showing a high molecular profile of MMPs/TIMPs expression by stromal cells (CAFs and MICs), both at the tumor center and at the invasive front, which were strongly associated with a higher prevalence of distant metastasis. In addition, we found combinations of these clusters defining subpopulations of breast carcinomas differing widely in their clinical outcome. The results presented here identify biologic markers useful to categorize patients into different subgroups based on their tumor stroma, which may contribute to improved understanding of the prognosis of breast cancer patients. PMID:26140253

  16. ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: study in African-American and Caucasian prostate cancer models.

    PubMed

    Parray, Aijaz; Siddique, Hifzur R; Kuriger, Jacquelyn K; Mishra, Shrawan K; Rhim, Johng S; Nelson, Heather H; Aburatani, Hiroyuki; Konety, Badrinath R; Koochekpour, Shahriar; Saleem, Mohammad

    2014-12-01

    High-risk populations exhibit early transformation of localized prostate cancer (CaP) disease to metastasis which results in the mortality of such patients. The paucity of knowledge about the molecular mechanism involved in acquiring of metastatic behavior by primary tumor cells and non-availability of reliable phenotype-discriminating biomarkers are stumbling blocks in the management of CaP disease. Here, we determine the role and translational relevance of ROBO1 (an organogenesis-associated gene) in human CaP. Employing CaP-progression models and prostatic tissues of Caucasian and African-American patients, we show that ROBO1 expression is localized to cell-membrane and significantly lost in primary and metastatic tumors. While Caucasians exhibited similar ROBO1 levels in primary and metastatic phenotype, a significant difference was observed between tumor phenotypes in African-Americans. Epigenetic assays identified promoter methylation of ROBO1 specific to African-American metastatic CaP cells. Using African-American CaP models for further studies, we show that ROBO1 negatively regulates motility and invasiveness of primary CaP cells, and its loss causes these cells to acquire invasive trait. To understand the underlying mechanism, we employed ROBO1-expressing/ROBO1-C2C3-mutant constructs, immunoprecipitation, confocal-microscopy and luciferase-reporter techniques. We show that ROBO1 through its interaction with DOCK1 (at SH3-SH2-domain) controls the Rac-activation. However, loss of ROBO1 results in Rac1-activation which in turn causes E-Cadherin/β-catenin cytoskeleton destabilization and induction of cell migration. We suggest that ROBO1 is a predictive biomarker that has potential to discriminate among CaP types, and could be exploited as a molecular target to inhibit the progression of disease as well as treat metastasis in high-risk populations such as African-Americans.

  17. ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: Study in African-American and Caucasian prostate cancer models

    PubMed Central

    Parray, Aijaz; Siddique, Hifzur R.; Kuriger, Jacquelyn K.; Mishra, Shrawan K.; Rhim, Johng S.; Nelson, Heather H.; Aburatani, Hiroyuki; Konety, Badrinath R.; Koochekpour, Shahriar; Saleem, Mohammad

    2015-01-01

    High-risk populations exhibit early transformation of localized prostate cancer (CaP) disease to metastasis which results in the mortality of such patients. The paucity of knowledge about the molecular mechanism involved in acquiring of metastatic behavior by primary tumor cells and non-availability of reliable phenotype-discriminating biomarkers are stumbling blocks in the management of CaP disease. Here, we determine the role and translational relevance of ROBO1 (an organogenesis-associated gene) in human CaP. Employing CaP-progression models and prostatic tissues of Caucasian and African-American patients, we show that ROBO1 expression is localized to cell-membrane and significantly lost in primary and metastatic tumors. While Caucasians exhibited similar ROBO1 levels in primary and metastatic phenotype, a significant difference was observed between tumor phenotypes in African-Americans. Epigenetic assays identified promoter methylation of ROBO1 specific to African-American metastatic CaP cells. Using African-American CaP models for further studies, we show that ROBO1 negatively regulates motility and invasiveness of primary CaP cells, and its loss causes these cells to acquire invasive trait. To understand the underlying mechanism, we employed ROBO1-expressing/ROBO1-C2C3-mutant constructs, immunoprecipitation, confocal-microscopy and luciferase-reporter techniques. We show that ROBO1 through its interaction with DOCK1 (at SH3-SH2-domain) controls the Rac-activation. However, loss of ROBO1 results in Rac1-activation which in turn causes E-Cadherin/β-catenin cytoskeleton destabilization and induction of cell migration. We suggest that ROBO1 is a predictive biomarker that has potential to discriminate among CaP types, and could be exploited as a molecular target to inhibit the progression of disease as well as treat metastasis in high-risk populations such as African-Americans. PMID:24752651

  18. Enhanced detection and comprehensive in situ phenotypic characterization of circulating and disseminated heteroploid epithelial and glioma tumor cells

    PubMed Central

    Wang, Daisy Dandan; Li, Linda; Lin, Peter Ping

    2015-01-01

    Conventional strategy of anti-EpCAM capture and immunostaining of cytokeratins (CKs) to detect circulating tumor cells (CTCs) is limited by highly heterogeneous and dynamic expression or absence of EpCAM and/or CKs in CTCs. In this study, a novel integrated cellular and molecular approach of subtraction enrichment (SE) and immunostaining-FISH (iFISH) was successfully developed. Both large or small size CTCs and circulating tumor microemboli (CTM) in various biofluid samples including cerebrospinal fluid (CSF) of cancer patients and patient-derived-xenograft (PDX) mouse models were efficiently enriched and comprehensively identified and characterized by SE-iFISH. Non-hematopoietic CTCs with heteroploid chromosome 8 were detected in 87–92% of lung, esophageal and gastric cancer patients. Characterization of CTCs performed by CK18-iFISH showed that CK18, the dual epithelial marker and tumor biomarker, was strong positive in only 14% of lung and 24% of esophageal CTCs, respectively. Unlike conventional methodologies restricted only to the large and/or both EpCAM and CK positive CTCs, SE-iFISH enables efficient enrichment and performing in situ phenotypic and karyotypic identification and characterization of the highly heterogeneous CTC subtypes classified by both chromosome ploidy and the expression of various tumor biomarkers. Each CTC subtype may possess distinct clinical significance relative to tumor metastasis, relapse, therapeutic drug sensitivity or resistance, etc. PMID:26267323

  19. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castrationresistant prostate cancer: a report from the PETRUS prospective study

    PubMed Central

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-01-01

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. PMID:27391263

  20. Ovatodiolide sensitizes aggressive breast cancer cells to doxorubicin, eliminates their cancer stem cell-like phenotype, and reduces doxorubicin-associated toxicity.

    PubMed

    Bamodu, Oluwaseun Adebayo; Huang, Wen-Chien; Tzeng, David T W; Wu, Alexander; Wang, Liang Shun; Yeh, Chi-Tai; Chao, Tsu-Yi

    2015-08-10

    Triple-negative breast cancer (TNBC) is chemotherapy-refractory and associated with poor clinical prognosis. Doxorubicin (Doxo), a class I anthracycline and first-line anticancer agent, effective against a wide spectrum of neoplasms including breast carcinoma, is associated with several cumulative dose-dependent adverse effects, including cardiomyopathy, typhilitis, and acute myelotoxicity. This study evaluated the usability of Ovatodiolide (Ova) in sensitizing TNBC cells to Doxo cytotoxicity, so as to reduce Doxo effective dose and consequently its adverse effects. TNBC cell lines MDA-MB-231 and HS578T were used. Pre-treatment of the TNBC cells with 10 µM Ova 24 h before Doxo administration increased the Doxo anticancer effect (IC50 1.4 µM) compared to simultaneous treatment with Doxo ( IC50 1.8 µM), or Doxo alone (IC50 9.2 µM). Intracellular accumulation of Doxo was lowest in Ova pre-treated cells at all Doxo concentrations, when compared with Doxo or simultaneously treated cells. In comparison to the Doxo-only group, cell cycle analysis of MDA-MB-231 cells treated concurrently with 2.5 µM Ova and 1.25 µM Doxo showed increased percentage of cells arrested at G0/G1; however, pre-treatment with the same concentration of Ova 24 h before Doxo showed greater tumor growth inhibition, with a 2.4-fold increased percentage of cells in G0/G1 arrest, greater Doxo-induced apoptosis, and significantly reduced intracellular Doxo accumulation. Additionally, Ova-sensitized TNBC cells also lost their cancer stem cell-like phenotype evidenced by significant dissolution, necrosis of formed mammospheres. Taken together, these findings indicate that Ova sensitizes TNBC cells to Doxo and potentiates doxorubicin-induced elimination of the TNBC cancer stem cell-like phenotype.

  1. Epigenetic silencing of miR-490-3p promotes development of an aggressive colorectal cancer phenotype through activation of the Wnt/β-catenin signaling pathway.

    PubMed

    Zheng, Kehong; Zhou, Xinying; Yu, Jinlong; Li, Qiang; Wang, Hui; Li, Mingyi; Shao, Ziyun; Zhang, Feifei; Luo, Yuhao; Shen, Zetao; Chen, Fei; Shi, Fujun; Cui, Chunhui; Zhao, Dachuan; Lin, Zhiqun; Zheng, Wei; Zou, Zhaowei; Huang, Zonghai; Zhao, Liang

    2016-06-28

    The Wnt/β-catenin pathway is known to contribute to colorectal cancer (CRC) progression, although little is known about the contribution of β-catenin on this process. We investigated the role of miR-490-3p, which was recently reported to suppress tumorigenesis through its effect on Wnt/β-catenin signaling. We found that hypermethylation of the miR-490-3p promoter down-regulates miR-490-3p expression in CRC tissue. Gain- and loss-of-function assays in vitro and in vivo reveal that miR-490-3p suppresses cancer cell proliferation by inducing apoptosis and inhibits cell invasiveness by repressing the initiation of epithelial-to-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. The frequently rearranged in advanced T-cell lymphomas (FRAT1) protein was identified as a direct target of miR-490-3p and contributes to its tumor-suppressing effects. miR-490-3p appears to have an inhibitory effect on β-catenin expression in nuclear fractions of CRC cells, whereas FRAT1 expression is associated with the accumulation of β-catenin in the nucleus of cells, which could be weakened by transfection with miR-490-3p. Our findings suggest that the miR-490-3p/FRAT1/β-catenin axis is important in CRC progression and provides new insight into the molecular mechanisms underlying CRC. They may help to confirm the pathway driving CRC aggressiveness and serve for the development of a novel miRNA-targeting anticancer therapy.

  2. Microarray analysis revealed dysregulation of multiple genes associated with chemoresistance to As(2)O(3) and increased tumor aggressiveness in a newly established arsenic-resistant ovarian cancer cell line, OVCAR-3/AsR.

    PubMed

    Ong, Pei-Shi; Chan, Sui-Yung; Ho, Paul C

    2012-02-14

    The potential of arsenic trioxide (As(2)O(3)) for use as a novel therapy for ovarian cancer treatment has been increasingly recognized. In this study, we developed an arsenic-resistant OVCAR-3 subline (OVCAR-3/AsR) and aimed to identify the molecular mechanisms and signaling pathways contributing to the development of acquired arsenic chemoresistance in ovarian cancer. OVCAR-3/AsR cells were obtained following continual exposure of parental OVCAR-3 cells to low dose As(2)O(3) for 12months. Cytotoxicity of OVCAR-3/AsR cells to As(2)O(3), paclitaxel and cisplatin was investigated. Cell apoptosis and cell cycle distribution following As(2)O(3) treatment of OVCAR-3/AsR cells was also analyzed using flow cytometry. Subsequently, cDNA microarray analysis was performed from the RNA samples of OVCAR-3 and OVCAR-3/AsR cells in duplicate experiments. Microarray data were analyzed using Genespring® and Pathway Studio® Softwares. OVCAR-3/AsR cells showed 9-fold greater resistance to As(2)O(3) and lack of collateral resistance to cisplatin and paclitaxel. Compared with parental OVCAR-3 cells, OVCAR-3/AsR had significantly lower apoptotic rates following As(2)O(3) treatment. These cells were also arrested at both the S phase and G(2)/M phase of the cell cycle after exposure to high concentrations of As(2)O(3). Gene expression profiling revealed significant differences in expression levels of 397 genes between OVCAR-3/AsR and OVCAR-3 cells. The differentially regulated transcripts genes have functional ontologies related to continued cancer cell growth, cell survival, tumor metastasis and tumor aggressiveness. Additionally, numerous gene targets of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor showed elevated expression in OVCAR-3/AsR cells. Subsequent pathway analysis further revealed a gene network involving interleukin 1-alpha (IL1A) in mediating the arsenic-resistant phenotype. These results showed that changes in multiple genes and an

  3. The tumoral A genotype of the MGMT rs34180180 single-nucleotide polymorphism in aggressive gliomas is associated with shorter patients' survival.

    PubMed

    Fogli, Anne; Chautard, Emmanuel; Vaurs-Barrière, Catherine; Pereira, Bruno; Müller-Barthélémy, Mélanie; Court, Franck; Biau, Julian; Pinto, Afonso Almeida; Kémény, Jean-Louis; Khalil, Toufic; Karayan-Tapon, Lucie; Verrelle, Pierre; Costa, Bruno Marques; Arnaud, Philippe

    2016-02-01

    Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ.

  4. Polyomavirus-Negative Merkel Cell Carcinoma: A More Aggressive Subtype Based on Analysis of 282 Cases Using Multimodal Tumor Virus Detection.

    PubMed

    Moshiri, Ata S; Doumani, Ryan; Yelistratova, Lola; Blom, Astrid; Lachance, Kristina; Shinohara, Michi M; Delaney, Martha; Chang, Oliver; McArdle, Susan; Thomas, Hannah; Asgari, Maryam M; Huang, Meei-Li; Schwartz, Stephen M; Nghiem, Paul

    2017-04-01

    Previous studies have reached conflicting conclusions regarding the proportion of Merkel cell carcinomas (MCCs) that contain the Merkel cell polyomavirus (MCPyV) and the clinical significance of tumor viral status. To address these controversies, we detected MCPyV large T antigen using immunohistochemistry with two distinct antibodies and MCPyV DNA using quantitative PCR. Tumors were called MCPyV-positive if two or more of these three assays indicated presence of this virus. A total of 53 of 282 (19%) MCC tumors in this cohort were virus-negative using this multimodal system. Immunohistochemistry with the CM2B4 antibody had the best overall performance (sensitivity = 0.882, specificity = 0.943) compared with the multimodal classification. Multivariate analysis including age, sex, and immunosuppression showed that, relative to MCC patients with virus-positive tumors, virus-negative MCC patients had significantly increased risk of disease progression (hazard ratio = 1.77, 95% confidence interval = 1.20-2.62) and death from MCC (hazard ratio = 1.85, 95% confidence interval = 1.19-2.89). We confirm that approximately 20% of MCCs are not driven by MCPyV and that such virus-negative MCCs, which can be quite reliably identified by immunohistochemistry using the CM2B4 antibody alone, represent a more aggressive subtype that warrants closer clinical follow-up.

  5. Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

    PubMed Central

    Gahete, Manuel D.; Serrano-Somavilla, Ana; Villa-Osaba, Alicia; Adrados, Magdalena; Ibáñez-Costa, Alejandro; Martín-Pérez, Elena; Culler, Michael D.

    2016-01-01

    Purpose Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs. Experimental Design We evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines. Results sst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies. Conclusions sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs. PMID:26673010

  6. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

    SciTech Connect

    Gu Yongpeng; Li Hongzhen; Miki, Jun; Kim, Kee-Hong; Furusato, Bungo; Sesterhenn, Isabell A.; Chu, Wei-Sing; McLeod, David G.; Srivastava, Shiv; Ewing, Charles M.; Isaacs, William B.; Rhim, Johng S. . E-mail: jrhim@cpdr.org

    2006-04-01

    In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents.

  7. Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte (GELA).

    PubMed

    Gisselbrecht, C; Gaulard, P; Lepage, E; Coiffier, B; Brière, J; Haioun, C; Cazals-Hatem, D; Bosly, A; Xerri, L; Tilly, H; Berger, F; Bouhabdallah, R; Diebold, J

    1998-07-01

    Peripheral T-cell lymphomas (PTCL) have been generally reported to have a worse prognosis than B-cell lymphomas (BCL). Because of their heterogeneity and scarcity, the outcomes of the different histological subtypes have not been compared. From October 1987 to March 1993, 1,883 patients with diffuse aggressive non-Hodgkin's lymphomas (NHL) included in the LNH87 protocol could be assessed for both morphology and immunophenotyping. Among them, 288 (15%) had PTCL and 1,595 (85%) had BCL. According to the Kiel classification, most PTCL were classified as angioimmunoblastic (AIL; 23%), pleomorphic medium and large T-cell (PML; 49%), or anaplastic large cell (ALCL; 20%) lymphomas. Comparing PTCL with BCL patients, the former had more disseminated disease (78% v 58%), B symptoms (57% v 40%), bone marrow involvement (31% v 17%), skin involvement (21% v 4%), and increased beta2-microglobulin (50% v 34%), whereas BCL patients had more bulky disease (41% v 26%). According to the International Prognostic Index (IPI), PTCL and BCL scores were, respectively: 0 factors, 13% and 15%; 1 factor, 17% and 22%; 2 factors, 24% and 25%; >/=3 factors, 45% and 37% (P = .09). For BCL and PTCL, respectively, complete remission rates were 63% and 54% (P = .004); the 5-year overall survival (OS) rates were 53% and 41% (P = .0004) and event-free survival (EFS) rates were 42% and 33% (P < . 0001). Comparison of the different histological subtypes of lymphoma showed that the 5-year OS rate for T-ALCL (64%) was superior to those of other PTCL (35%) as well as diffuse large B-cell (53%) NHL. When multivariate analysis was applied using the IPI score as one factor, nonanaplastic PTCL remained an independent parameter (P = . 0004). Although the poor prognosis of non-ALCL PTCL could be due in part to the presence of adverse prognostic factors at diagnosis, this study shows that the T-cell phenotype is an independent significant factor, which should be incorporated into the definition of prognostic

  8. FGFR3 has tumor suppressor properties in cells with epithelial phenotype

    PubMed Central

    2013-01-01

    Background Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical. Results FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors. Conclusion In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context. PMID:23902722

  9. The positive is inside the negative: HER2-negative tumors can express the HER2 intracellular domain and present a HER2-positive phenotype.

    PubMed

    Panis, Carolina; Pizzatti, Luciana; Corrêa, Stephany; Binato, Renata; Lemos, Gabriela Ferreira; Herrera, Ana Cristina da Silva do Amaral; Seixas, Teresa Fernandes; Cecchini, Rubens; Abdelhay, Eliana

    2015-02-01

    Overexpression of human epithelial growth factor receptor 2 (HER2) is a poor prognostic factor in breast cancer. HER2 is a transmembrane receptor comprising an extracellular domain (ECD), a single transmembrane domain, and an intracellular domain (ICD) with tyrosine-kinase activity. Receptor dimerization triggers pivotal effector pathways in cancer, such as phosphatidylinositol 3-kinase (PI3K) signaling. Currently, screening of HER2 in breast tumors for prognostic and therapeutic purposes involves immunohistochemical (IHC) phenotyping for the ECD, in which tumors with IHC scores below 2+ are reported as HER2-negative. We used a label-free liquid chromatography-mass spectrometry (LC-MS) proteomic approach to compare plasma samples from patients with HER2-positive breast tumors and patients with HER2-negative tumors. Patients with HER2-negative tumors expressed higher circulating levels of calpain-10 than patients with HER2-positive tumors. Calpains cleave HER2, releasing its ECD and transforming phenotypically positive tumors into phenotypically negative tumors. Therefore, we investigated the expression of the ICD in HER2-negative samples that overexpressed calpain-10. We found that 16% of HER2-negative tumors were positive for HER2-ICD, which was associated with circulating HER2-ECD. HER2 gene amplification was also observed in some HER2-negative tumors. Positive staining for the PI3K pathway was observed in the HER2-negative, ICD-positive tumors, similar to the HER2-positive cohort. Microarray analysis revealed that HER2-negative, ICD-positive samples clustered between HER2-positive tumors and triple-negative tumors. Survival analysis revealed that outcome in women with HER2-negative, ICD-positive tumors was better than in women bearing HER2-negative, ICD-negative (triple negative) tumors but was quite similar to HER2-positive tumors and worse than women with luminal A tumors. Moreover, in vitro analyses revealed that MDA-MB 231, a triple negative cell line

  10. Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

    PubMed Central

    De, Pradip; Carlson, Jennifer H.; Wu, Hui; Marcus, Adam; Leyland-Jones, Brian; Dey, Nandini

    2016-01-01

    Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronection-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship

  11. Tumor growth affects the metabonomic phenotypes of multiple mouse non-involved organs in an A549 lung cancer xenograft model

    PubMed Central

    Xu, Shan; Tian, Yuan; Hu, Yili; Zhang, Nijia; Hu, Sheng; Song, Dandan; Wu, Zhengshun; Wang, Yulan; Cui, Yanfang; Tang, Huiru

    2016-01-01

    The effects of tumorigenesis and tumor growth on the non-involved organs remain poorly understood although many research efforts have already been made for understanding the metabolic phenotypes of various tumors. To better the situation, we systematically analyzed the metabolic phenotypes of multiple non-involved mouse organ tissues (heart, liver, spleen, lung and kidney) in an A549 lung cancer xenograft model at two different tumor-growth stages using the NMR-based metabonomics approaches. We found that tumor growth caused significant metabonomic changes in multiple non-involved organ tissues involving numerous metabolic pathways, including glycolysis, TCA cycle and metabolisms of amino acids, fatty acids, choline and nucleic acids. Amongst these, the common effects are enhanced glycolysis and nucleoside/nucleotide metabolisms. These findings provided essential biochemistry information about the effects of tumor growth on the non-involved organs. PMID:27329570

  12. FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.

    PubMed

    Mak, Victor C Y; Wong, Oscar G W; Siu, Michelle K Y; Wong, Esther S Y; Ng, Wai-Yan; Wong, Richard W C; Chan, Ka-Kui; Ngan, Hextan Y S; Cheung, Annie N Y

    2015-07-01

    Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts.

  13. IL-4, a direct target of miR-340/429, is involved in radiation-induced aggressive tumor behavior in human carcinoma cells

    PubMed Central

    Hwang, Su Jin; Han, Young-Hoon; Park, Myung-Jin; Bae, In Hwa

    2016-01-01

    Radiotherapy induces the production of cytokines, thereby increasing aggressive tumor behavior. This radiation effect results in the failure of radiotherapy and increases the mortality rate in patients. We found that interleukin-4 (IL-4) and IL-4Rα (IL-4 receptor) are highly expressed in various human cancer cells subsequent to radiation treatment. In addition, IL-4 is highly overexpressed in metastatic carcinoma tissues compared with infiltrating carcinoma tissues. High expression of IL-4 in patients with cancer is strongly correlated with poor survival. The results of this study suggest that radiation-induced IL-4 contributes to tumor progression and metastasis. Radiation-induced IL-4 was associated with tumorigenicity and metastasis. IL-4 expression was downregulated by miR-340 and miR-429, which were decreased by ionizing radiation (IR). Radiation-regulated miR-340/429-IL4 signaling increased tumorigenesis and metastasis by inducing the production of Sox2, Vimentin, VEGF, Ang2, and MMP-2/9 via activating JAK, JNK, β-catenin, and Stat6 in vitro and in vivo. Our study presents a conceptual advance in our understanding of the modification of tumor microenvironment by radiation and suggests that combining radiotherapy with genetic therapy to inhibit IL-4 may be a promising strategy for preventing post-radiation recurrence and metastasis in patients. PMID:27895317

  14. MMP1, MMP9, and COX2 Expressions in Promonocytes Are Induced by Breast Cancer Cells and Correlate with Collagen Degradation, Transformation-Like Morphological Changes in MCF-10A Acini, and Tumor Aggressiveness

    PubMed Central

    Chimal-Ramírez, G. K.; Espinoza-Sánchez, N. A.; Utrera-Barillas, D.; Benítez-Bribiesca, L.; Velázquez, J. R.; Arriaga-Pizano, L. A.; Monroy-García, A.; Reyes-Maldonado, E.; Domínguez-López, M. L.; Piña-Sánchez, Patricia; Fuentes-Pananá, E. M.

    2013-01-01

    Tumor-associated immune cells often lack immune effector activities, and instead they present protumoral functions. To understand how tumors promote this immunological switch, invasive and noninvasive breast cancer cell (BRC) lines were cocultured with a promonocytic cell line in a Matrigel-based 3D system. We hypothesized that if communication exists between tumor and immune cells, coculturing would result in augmented expression of genes associated with tumor malignancy. Upregulation of proteases MMP1 and MMP9 and inflammatory COX2 genes was found likely in response to soluble factors. Interestingly, changes were more apparent in promonocytes and correlated with the aggressiveness of the BRC line. Increased gene expression was confirmed by collagen degradation assays and immunocytochemistry of prostaglandin 2, a product of COX2 activity. Untransformed MCF-10A cells were then used as a sensor of soluble factors with transformation-like capabilities, finding that acini formed in the presence of supernatants of the highly aggressive BRC/promonocyte cocultures often exhibited total loss of the normal architecture. These data support that tumor cells can modify immune cell gene expression and tumor aggressiveness may importantly reside in this capacity. Modeling interactions in the tumor stroma will allow the identification of genes useful as cancer prognostic markers and therapy targets. PMID:23762835

  15. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome.

    PubMed

    Nieuwenhuis, Marry H; Kets, C Marleen; Murphy-Ryan, Maureen; Yntema, Helger G; Evans, D Gareth; Colas, Chrystelle; Møller, Pal; Hes, Frederik J; Hodgson, Shirley V; Olderode-Berends, Maran J W; Aretz, Stefan; Heinimann, Karl; Gómez García, Encarna B; Douglas, Fiona; Spigelman, Allan; Timshel, Susanne; Lindor, Noralane M; Vasen, Hans F A

    2014-03-01

    Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.

  16. Resistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activation.

    PubMed

    Deshmukh, Sachin K; Srivastava, Sanjeev K; Bhardwaj, Arun; Singh, Ajay P; Tyagi, Nikhil; Marimuthu, Saravanakumar; Dyess, Donna L; Dal Zotto, Valeria; Carter, James E; Singh, Seema

    2015-05-10

    African-American (AA) women with breast cancer (BC) are diagnosed with more aggressive disease, have higher risk of recurrence and poorer prognosis as compared to Caucasian American (CA) women. Therefore, it is imperative to define the factors associated with such disparities to reduce the unequal burden of cancer. Emerging data suggest that inherent differences exist in the tumor microenvironment of AA and CA BC patients, however, its molecular bases and functional impact have remained poorly understood. Here, we conducted cytokine profiling in serum samples from AA and CA BC patients and identified resistin and IL-6 to be the most differentially-expressed cytokines with relative greater expression in AA patients. Resistin and IL-6 exhibited positive correlation in serum levels and treatment of BC cells with resistin led to enhanced production of IL-6. Moreover, resistin also enhanced the expression and phosphorylation of STAT3, and treatment of BC cells with IL-6-neutralizing antibody prior to resistin stimulation abolished STAT3 phosphorylation. In addition, resistin promoted growth and aggressiveness of BC cells, and these effects were mediated through STAT3 activation. Together, these findings suggest a crucial role of resistin, IL-6 and STAT3 in BC racial disparity.

  17. Resistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activation

    PubMed Central

    Bhardwaj, Arun; Singh, Ajay P.; Tyagi, Nikhil; Marimuthu, Saravanakumar; Dyess, Donna L.; Zotto, Valeria Dal; Carter, James E.; Singh, Seema

    2015-01-01

    African-American (AA) women with breast cancer (BC) are diagnosed with more aggressive disease, have higher risk of recurrence and poorer prognosis as compared to Caucasian American (CA) women. Therefore, it is imperative to define the factors associated with such disparities to reduce the unequal burden of cancer. Emerging data suggest that inherent differences exist in the tumor microenvironment of AA and CA BC patients, however, its molecular bases and functional impact have remained poorly understood. Here, we conducted cytokine profiling in serum samples from AA and CA BC patients and identified resistin and IL-6 to be the most differentially-expressed cytokines with relative greater expression in AA patients. Resistin and IL-6 exhibited positive correlation in serum levels and treatment of BC cells with resistin led to enhanced production of IL-6. Moreover, resistin also enhanced the expression and phosphorylation of STAT3, and treatment of BC cells with IL-6-neutralizing antibody prior to resistin stimulation abolished STAT3 phosphorylation. In addition, resistin promoted growth and aggressiveness of BC cells, and these effects were mediated through STAT3 activation. Together, these findings suggest a crucial role of resistin, IL-6 and STAT3 in BC racial disparity. PMID:25868978

  18. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

    SciTech Connect

    Coppé, Jean-Philippe; Patil, Christopher; Rodier, Francis; Sun, Yu; Munoz, Denise; Goldstein, Joshua; Nelson, Peter; Desprez, Pierre-Yves; Campisi, Judith

    2008-10-24

    Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.

  19. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

    PubMed Central

    Coppé, Jean-Philippe; Sun, Yu; Muñoz, Denise P; Goldstein, Joshua; Nelson, Peter S; Desprez, Pierre-Yves; Campisi, Judith

    2008-01-01

    Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment. PMID:19053174

  20. miRNA expression profiling of inflammatory breast cancer identifies a 5-miRNA signature predictive of breast tumor aggressiveness.

    PubMed

    Lerebours, Florence; Cizeron-Clairac, Geraldine; Susini, Aurelie; Vacher, Sophie; Mouret-Fourme, Emmanuelle; Belichard, Catherine; Brain, Etienne; Alberini, Jean-Louis; Spyratos, Frédérique; Lidereau, Rosette; Bieche, Ivan

    2013-10-01

    IBC (inflammatory breast cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, genetic and epigenetic alterations specific to IBC remain to be identified. MicroRNAs, a class of small noncoding RNAs able to regulate gene expression, are deregulated in breast cancer and may therefore serve as tools for diagnosis and prediction. This study was designed to determine miRNA expression profiling (microRNAome) in IBC. Quantitative RT-PCR was used to determine expression levels of 804 miRNAs in a screening series of 12 IBC compared to 31 non-stage-matched non-IBC and 8 normal breast samples. The differentially expressed miRNAs were then validated in a series of 65 IBC and 95 non-IBC. From a set of 18 miRNAs of interest selected from the screening series, 13 were differentially expressed with statistical significance in the validation series of IBC compared to non-IBC. Among these, a 5-miRNA signature comprising miR-421, miR-486, miR-503, miR-720 and miR-1303 was shown to be predictive for IBC phenotype with an overall accuracy of 89%. Moreover, multivariate analysis showed that this signature was an independent predictor of poor Metastasis-Free Survival in non-IBC patients.

  1. En bloc excision and autogenous fibular reconstruction for aggressive giant cell tumor of distal radius: a report of 12 cases and review of literature

    PubMed Central

    2011-01-01

    Introduction Giant cell tumor (GCT) of distal radius follows a comparatively aggressive behaviour. Wide excision is the management of choice, but this creates a defect at the distal end of radius. The preffered modalities for reconstruction of such a defect include vascularized/non-vascularized bone graft, osteoarticular allografts and custom-made prosthesis. We here present our experience with wide resection and non-vascularised autogenous fibula grafting for GCT of distal radius. Materials and methods Twelve patients with a mean age of 34.7 years (21-43 years) with Campanacci Grade II/III GCT of distal radius were managed with wide excision of tumor and reconstruction with ipsilateral nonvascularised fibula, fixed with small fragment plate to the remnant of the radius. Primary autogenous iliac crest grafting was done at the fibuloradial junction in all the patients. Results Mean follow up period was 5.8 years (8.2-3.7 years). Average time for union at fibuloradial junction was 33 weeks (14-69 weeks). Mean grip strength of involved side was 71% (42-86%). The average range of movements were 52° forearm supination, 37° forearm pronation, 42° of wrist palmerflexion and 31° of wrist dorsiflexion with combined movements of 162°. Overall revised musculoskeletal tumor society (MSTS) score averaged 91.38% (76.67-93.33%) with five excellent, four good and three satisfactory results. There were no cases with graft related complications or deep infections, 3 cases with wrist subluxation, 2 cases with non union (which subsequently united with bone grafting) and 1 case of tumor recurrence. Conclusion Although complication rate is high, autogenous non-vascularised fibular autograft reconstruction of distal radius can be considered as a reasonable option after en bloc excision of Grade II/III GCT. PMID:21385393

  2. Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors

    PubMed Central

    Manuel, Edwin R.; Chen, Jeremy; D'Apuzzo, Massimo; Lampa, Melanie G.; Kaltcheva, Teodora I.; Thompson, Curtis B.; Ludwig, Thomas; Chung, Vincent; Diamond, Don J.

    2015-01-01

    Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for over twenty-five years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not observed using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex-vivo through mechanisms involving FasL and serine proteases. In addition, CD8+ T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC. PMID:26134178

  3. Glucose utilization by intracranial meningiomas as an index of tumor aggressivity and probability of recurrence: a PET study

    SciTech Connect

    Di Chiro, G.; Hatazawa, J.; Katz, D.A.; Rizzoli, H.V.; De Michele, D.J.

    1987-08-01

    Seventeen patients with intracranial meningiomas were studied with positron emission tomography and fluorine-18-2-fluorodeoxyglucose (PET-FDG) to assess the glucose utilization of these tumors. Four meningiomas followed for 3-5 years after PET-FDG and surgery showed no evidence of recurrence. These tumors had significantly lower glucose utilization rates (1.9 mg/dl/min +/- 1.0) than 11 recurrent or regrowing meningiomas (4.5 mg/dl/min +/- 1.96). The glucose metabolic rates of meningiomas correlated with tumor growth, as estimated from changes in tumor size on repeated computed tomographic scans. Histopathologically, a syncytial (atypical) meningioma had the highest glucose utilization rate, followed by a papillary meningioma and an angioblastic meningioma. Individual transitional and syncytial (typical) meningiomas showed marked differences in glucose metabolism despite similar microscopic appearance. Glucose utilization rate appears to be at least as reliable as histologic classification and other proposed criteria for predicting the behavior and recurrence of intracranial meningiomas.

  4. Low VHL mRNA expression is associated with more aggressive tumor features of papillary thyroid carcinoma.

    PubMed

    Stanojevic, Boban; Saenko, Vladimir; Todorovic, Lidija; Petrovic, Nina; Nikolic, Dragan; Zivaljevic, Vladan; Paunovic, Ivan; Nakashima, Masahiro; Yamashita, Shunichi; Dzodic, Radan

    2014-01-01

    Alterations of the von Hippel-Lindau (VHL) tumor suppressor gene can cause different hereditary tumors associated with VHL syndrome, but the potential role of the VHL gene in papillary thyroid carcinoma (PTC) has not been characterized. This study set out to investigate the relationship of VHL expression level with clinicopathological features of PTC in an ethnically and geographically homogenous group of 264 patients from Serbia, for the first time. Multivariate logistic regression analysis showed a strong correlation between low level of VHL expression and advanced clinical stage (OR = 5.78, 95% CI 3.17-10.53, P<0.0001), classical papillary morphology of the tumor (OR = 2.92, 95% CI 1.33-6.44, P = 0.008) and multifocality (OR = 1.96, 95% CI 1.06-3.62, P = 0.031). In disease-free survival analysis, low VHL expression had marginal significance (P = 0.0502 by the log-rank test) but did not appear to be an independent predictor of the risk for chance of faster recurrence in a proportion hazards model. No somatic mutations or evidence of VHL downregulation via promoter hypermethylation in PTC were found. The results indicate that the decrease of VHL expression associates with tumor progression but the mechanism of downregulation remains to be elucidated.

  5. Low VHL mRNA Expression is Associated with More Aggressive Tumor Features of Papillary Thyroid Carcinoma

    PubMed Central

    Stanojevic, Boban; Saenko, Vladimir; Todorovic, Lidija; Petrovic, Nina; Nikolic, Dragan; Zivaljevic, Vladan; Paunovic, Ivan; Nakashima, Masahiro; Yamashita, Shunichi; Dzodic, Radan

    2014-01-01

    Alterations of the von Hippel–Lindau (VHL) tumor suppressor gene can cause different hereditary tumors associated with VHL syndrome, but the potential role of the VHL gene in papillary thyroid carcinoma (PTC) has not been characterized. This study set out to investigate the relationship of VHL expression level with clinicopathological features of PTC in an ethnically and geographically homogenous group of 264 patients from Serbia, for the first time. Multivariate logistic regression analysis showed a strong correlation between low level of VHL expression and advanced clinical stage (OR = 5.78, 95% CI 3.17–10.53, P<0.0001), classical papillary morphology of the tumor (OR = 2.92, 95% CI 1.33–6.44, P = 0.008) and multifocality (OR = 1.96, 95% CI 1.06–3.62, P = 0.031). In disease-free survival analysis, low VHL expression had marginal significance (P = 0.0502 by the log-rank test) but did not appear to be an independent predictor of the risk for chance of faster recurrence in a proportion hazards model. No somatic mutations or evidence of VHL downregulation via promoter hypermethylation in PTC were found. The results indicate that the decrease of VHL expression associates with tumor progression but the mechanism of downregulation remains to be elucidated. PMID:25490036

  6. Tumor cell vascular mimicry: Novel targeting opportunity in melanoma.

    PubMed

    Hendrix, Mary J C; Seftor, Elisabeth A; Seftor, Richard E B; Chao, Jun-Tzu; Chien, Du-Shieng; Chu, Yi-Wen

    2016-03-01

    In 1999, the American Journal of Pathology published an article, entitled "Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry" by Maniotis and colleagues, which ignited a spirited debate for several years and earned the journal's distinction of a "citation classic" (Maniotis et al., 1999). Tumor cell vasculogenic mimicry (VM), also known as vascular mimicry, describes the plasticity of aggressive cancer cells forming de novo vascular networks and is associated with the malignant phenotype and poor clinical outcome. The tumor cells capable of VM share the commonality of a stem cell-like, transendothelial phenotype, which may be induced by hypoxia. Since its introduction as a novel paradigm for melanoma tumor perfusion, many studies have contributed new findings illuminating the underlying molecular pathways supporting VM in a variety of tumors, including carcinomas, sarcomas, glioblastomas, astrocytomas, and melanomas. Of special significance is the lack of effectiveness of angiogenesis inhibitors on tumor cell VM, suggesting a selective resistance by this phenotype to conventional therapy. Facilitating the functional plasticity of tumor cell VM are key proteins associated with vascular, stem cell, extracellular matrix, and hypoxia-related signaling pathways--each deserving serious consideration as potential therapeutic targets and diagnostic indicators of the aggressive, metastatic phenotype. This review highlights seminal findings pertinent to VM, including the effects of a novel, small molecular compound, CVM-1118, currently under clinical development to target VM, and illuminates important molecular pathways involved in the suppression of this plastic, aggressive phenotype, using melanoma as a model.

  7. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

    PubMed Central

    Martinelli, Simone; De Luca, Alessandro; Stellacci, Emilia; Rossi, Cesare; Checquolo, Saula; Lepri, Francesca; Caputo, Viviana; Silvano, Marianna; Buscherini, Francesco; Consoli, Federica; Ferrara, Grazia; Digilio, Maria C.; Cavaliere, Maria L.; van Hagen, Johanna M.; Zampino, Giuseppe; van der Burgt, Ineke; Ferrero, Giovanni B.; Mazzanti, Laura; Screpanti, Isabella; Yntema, Helger G.; Nillesen, Willy M.; Savarirayan, Ravi; Zenker, Martin; Dallapiccola, Bruno; Gelb, Bruce D.; Tartaglia, Marco

    2010-01-01

    RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies. PMID:20619386

  8. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    PubMed

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types.

  9. Nuclear Translocation of β-Catenin during Mesenchymal Stem Cells Differentiation into Hepatocytes Is Associated with a Tumoral Phenotype

    PubMed Central

    Herencia, Carmen; Martínez-Moreno, Julio M.; Herrera, Concepción; Corrales, Fernando; Santiago-Mora, Raquel; Espejo, Isabel; Barco, Monserrat; Almadén, Yolanda; de la Mata, Manuel; Rodríguez-Ariza, Antonio; Muñoz-Castañeda, Juan R.

    2012-01-01

    Wnt/β-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated the role of Wnt/β-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, β-catenin nuclear translocation, up-regulation of genes related to the Wnt/β-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/β-catenin inactivation. Hepatocytes with nuclear translocation of β-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase β-chain were up-regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin β-chain were down-regulated in this protocol. In conclusion, our results suggest that activation of the Wnt/β-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype. PMID:22506042

  10. Multi-Phenotypic subtyping of circulating tumor cells using sequential fluorescent quenching and restaining

    PubMed Central

    Adams, Daniel L; Alpaugh, R. Katherine; Tsai, Susan; Tang, Cha-Mei; Stefansson, Steingrimur

    2016-01-01

    In tissue biopsies formalin fixed paraffin embedded cancer blocks are micro-sectioned producing multiple semi-identical specimens which are analyzed and subtyped proteomically, and genomically, with numerous biomarkers. In blood based biopsies (BBBs), blood is purified for circulating tumor cells (CTCs) and clinical utility is typically limited to cell enumeration, as only 2–3 positive fluorescent markers and 1 negative marker can be used. As such, increasing the number of subtyping biomarkers on each individual CTC could dramatically enhance the clinical utility of BBBs, allowing in depth interrogation of clinically relevant CTCs. We describe a simple and inexpensive method for quenching the specific fluors of fluorescently stained CTCs followed by sequential restaining with additional biomarkers. As proof of principle a CTC panel, immunosuppression panel and stem cell panel were used to sequentially subtype individual fluorescently stained patient CTCs, suggesting a simple and universal technique to analyze multiple clinically applicable immunomarkers from BBBs. PMID:27647345

  11. Multi-Phenotypic subtyping of circulating tumor cells using sequential fluorescent quenching and restaining

    NASA Astrophysics Data System (ADS)

    Adams, Daniel L.; Alpaugh, R. Katherine; Tsai, Susan; Tang, Cha-Mei; Stefansson, Steingrimur

    2016-09-01

    In tissue biopsies formalin fixed paraffin embedded cancer blocks are micro-sectioned producing multiple semi-identical specimens which are analyzed and subtyped proteomically, and genomically, with numerous biomarkers. In blood based biopsies (BBBs), blood is purified for circulating tumor cells (CTCs) and clinical utility is typically limited to cell enumeration, as only 2–3 positive fluorescent markers and 1 negative marker can be used. As such, increasing the number of subtyping biomarkers on each individual CTC could dramatically enhance the clinical utility of BBBs, allowing in depth interrogation of clinically relevant CTCs. We describe a simple and inexpensive method for quenching the specific fluors of fluorescently stained CTCs followed by sequential restaining with additional biomarkers. As proof of principle a CTC panel, immunosuppression panel and stem cell panel were used to sequentially subtype individual fluorescently stained patient CTCs, suggesting a simple and universal technique to analyze multiple clinically applicable immunomarkers from BBBs.

  12. Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas.

    PubMed

    Qian, Zhi Rong; Sano, Toshiaki; Yoshimoto, Katsuhiko; Asa, Sylvia L; Yamada, Shozo; Mizusawa, Noriko; Kudo, Eiji

    2007-12-01

    The gene products of CDH13 and CDH1, H-cadherin and E-cadherin, respectively, play a key role in cell-cell adhesion. Inactivation of the cadherin-mediated cell adhesion system caused by aberrant methylation is a common finding in human cancers, indicating that the CDH13 and CDH1 function as tumor suppressor and invasion suppressor genes. In this study, we analyzed the expression of H-cadherin mRNA and E-cadherin protein in 5 normal pituitary tissues and 69 primary pituitary adenomas including all major types by quantitative real-time RT-PCR (qRT-PCR) and immunohistochemistry, respectively. Reduced expression of H-cadherin was detected in 54% (28/52) of pituitary tumors and was significantly associated with tumor aggressiveness (P<0.05). E-cadherin expression was lost in 30% (21 of 69) and significantly reduced in 32% (22 of 69) of tumors. E-cadherin expression was significantly lower in grade II, III, and IV than in grade I adenomas (P=0.015, P=0.029, and P=0.01, respectively). Using methylation-specific PCR (MSP), promoter hypermethylation of CDH13 and CDH1 was detected in 30 and 36% of 69 adenomas, respectively, but not in 5 normal pituitary tissues. Methylation of CDH13 was observed more frequently in invasive adenomas (42%) than in non-invasive adenomas (19%) (P<0.05) and methylation of CDH1 was more frequent in grade IV adenomas compared with grade I adenomas (P<0.05). Methylation of either CDH13 or CDH1 was identified in 35 cases (51%) and was more frequent in grade IV invasive adenomas than in grade I non-invasive adenomas (P<0.05 and P<0.05, respectively). Downregulation of expression was correlated with promoter hypermethylation in CDH13 and CDH1. In conclusion, the tumor-specific downregulation of expression and methylation of CDH13 and CDH1, alone or in combination, may be involved in the development and invasive growth of pituitary adenomas.

  13. Hypothalamic tumor

    MedlinePlus

    ... occur at any age. They are often more aggressive in adults than in children. In adults, tumors ... The treatment depends on how aggressive the tumor is, and whether it is a glioma or another type of cancer. Treatment may involve combinations of surgery, radiation , ...

  14. Macrophages are recruited to hypoxic tumor areas and acquire a Pro-Angiogenic M2-Polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin

    PubMed Central

    Tripathi, Chakrapani; Tewari, Brij Nath; Kanchan, Ranjana Kumari; Baghel, Khemraj Singh; Nautiyal, Naveen; Shrivastava, Richa; Kaur, Harbeer; Bhatt, Madan Lal Bramha; Bhadauria, Smrati

    2014-01-01

    TAMs, a unique and distinct M2-skewed myeloid population of tumor stroma, exhibiting pro-tumor functions is fast emerging as a potential target for anti-cancer immunotherapy. Macrophage-recruitment and M2-polarization represent key TAMs-related phenomenon that are amenable to therapeutic intervention. However successful translation of these approaches into effective therapeutic regimen requires better characterization of tumor-microenvironment derived signals that regulate macrophage recruitment and their polarization. Owing to hypoxic milieu being a persistent feature of tumor-microenvironment and a major contributor to malignancy and treatment resistance, the current study was planned with an aim to decipher tumor cell responses to hypoxia vis-a-vis macrophage homing and phenotype switching. Here, we show that hypoxia-primed cancer cells chemoattract and polarize macrophages to pro-angiogenic M2-polarized subtype via Eotaxin and Oncostatin M. Concordantly, hypoxic regions of human breast-cancer specimen exhibited elevated Eotaxin and Oncostatin M levels with concurrently elevated M2-macrophage content. Blockade of Eotaxin/Oncostatin M not only prevented hypoxic breast-cancer cells from recruiting and polarizing macrophages towards an M2-polarized phenotype and retarded tumor progression in 4T1/BALB/c-syngenic-mice-model of breast-cancer but also enhanced the efficacy of anti-angiogenic Bevacizumab. The findings established these two cytokines as novel targets for devising effective anticancer therapy particularly for tumors that are refractory or develop resistance to anti-angiogenic therapeutics. PMID:25051364

  15. Aquaporin 5 expression is frequent in prostate cancer and shows a dichotomous correlation with tumor phenotype and PSA recurrence.

    PubMed

    Pust, Alexandra; Kylies, Dominik; Hube-Magg, Claudia; Kluth, Martina; Minner, Sarah; Koop, Christina; Grob, Tobias; Graefen, Markus; Salomon, Georg; Tsourlakis, Maria Christina; Izbicki, Jakob; Wittmer, Corinna; Huland, Hartwig; Simon, Ronald; Wilczak, Waldemar; Sauter, Guido; Steurer, Stefan; Krech, Till; Schlomm, Thorsten; Melling, Nathaniel

    2016-02-01

    Aquaporin 5 (AQP5) is an androgen-regulated member of a family of small hydrophobic integral transmembrane water channel proteins regulating cellular water homeostasis and growth signaling. To evaluate its clinical impact and relationship with key genomic alterations in prostate cancer, AQP5 expression was analyzed by immunohistochemistry on a tissue microarray containing 12427 prostate cancers. The analysis revealed weak to moderate immunostaining in normal prostate epithelium. In prostate cancers AQP5 staining levels were more variable and also included completely negative and highly overexpressing cases. Negative, weak, moderate, and strong AQP5 staining was found in 25.0%, 32.5%, 32.5%, and 10.0% of 10239 interpretable tumors. Comparison of AQP5 expression levels with tumor characteristics showed a dichotomous pattern with both high and low staining levels being linked to unfavorable tumor phenotype. AQP5 was negative in 28%, 23%, 24%, and 35% of tumors with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4, while the rate of strongly positive cases continuously increased from 7.0% over 10.0% and 12.0% to 13.0% in cancers with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4. AQP5 expression was also related to ERG positivity and phosphatase and tensin homolog (PTEN) deletion (P < .0001 each). Strong AQP5 positivity was seen in 15.5% of ERG-positive and 5.8% of ERG-negative cancers (P < .0001) as well as in 14.7% of cancers with PTEN deletion and 9.4% of cancers without PTEN deletion. Remarkably, both negativity and strong positivity of AQP5 were linked to unfavorable disease outcome. This was however only seen in subgroups defined by TMPRSS2-ERG fusion and/or PTEN deletion. In summary, AQP5 can be both overexpressed and lost in subgroups of prostate cancers. Both alterations are linked to unfavorable outcome in molecularly defined cancer subgroups. It is hypothesized that this dichotomous role of AQP5 is due to two highly different mechanisms as to how the

  16. Phenotypic and functional analysis of tumor-infiltrating lymphocytes compared with tumor-associated lymphocytes from ascitic fluid and peripheral blood lymphocytes in patients with advanced ovarian cancer.

    PubMed

    Santin, A D; Hermonat, P L; Ravaggi, A; Bellone, S; Roman, J J; Smith, C V; Pecorelli, S; Radominska-Pandya, A; Cannon, M J; Parham, G P

    2001-01-01

    To investigate and compare the phenotype and function of lymphocytes collected from patients harboring advanced ovarian cancer, leukocytes from peripheral blood (n = 18), ascitic fluid (n = 13) and tumor tissues (n = 13) were evaluated for the relative proportions of lymphocyte subsets, including CD3+, CD4+, CD8+, CD19+, CD56 and the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells. The ability to synthesize type 1 cytokines (IFN-gamma and IL-2) and a type 2 cytokine (IL-4) was assessed by flow cytometry. In all patients, T cells (CD3+) were the major leukocyte population detected in each tissue, with CD4+ T cells being dominant in peripheral blood lymphocytes (PBL) and tumor-associated lymphocytes (TAL) but not in tumor-infiltrating lymphocytes (TIL) (CD4:CD8 ratios: 3.0 vs. 2.0 vs. 1.0, respectively). CD19+ lymphocytes (B cells) and CD56+ lymphocytes (NK cells) were significantly higher in PBL compared to TAL and TIL (p < 0.05). TAL and TIL had a higher proportion of T cells expressing the late activation marker HLA-DR compared to PBL. In contrast, no significant differences were detected in PBL, TAL and TIL in the expression of the early activation marker CD25. Type 1 cytokines were the dominant type produced by in vitro stimulated T cells for each population, with a greater proportion of IFN-gamma+ T cells in TAL and TIL compared to PBL (p < 0.01), and a higher proportion of IL-2+ T cells in PBL compared with TAL and TIL (p < 0.05). Low percentages of IL-4+ T cells (i.e. Th2) were detected in each tissue. Taken together, these data demonstrate the recruitment and accumulation of high concentrations of antigen-experienced T lymphocytes in TAL and TIL compared to PBL. However, low surface expression of IL-2 receptor (i.e. CD25), as well as depressed intracellular IL-2 production in chronically stimulated TAL and TIL suggests that the impaired antitumor function commonly detected in these lymphocyte populations may be secondary to an acquired

  17. Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype*

    PubMed Central

    Coppé, Jean-Philippe; Rodier, Francis; Patil, Christopher K.; Freund, Adam; Desprez, Pierre-Yves; Campisi, Judith

    2011-01-01

    Cellular senescence suppresses cancer by preventing the proliferation of cells that experience potentially oncogenic stimuli. Senescent cells often express p16INK4a, a cyclin-dependent kinase inhibitor, tumor suppressor, and biomarker of aging, which renders the senescence growth arrest irreversible. Senescent cells also acquire a complex phenotype that includes the secretion of many cytokines, growth factors, and proteases, termed a senescence-associated secretory phenotype (SASP). The SASP is proposed to underlie age-related pathologies, including, ironically, late life cancer. Here, we show that ectopic expression of p16INK4a and another cyclin-dependent kinase inhibitor, p21CIP1/WAF1, induces senescence without a SASP, even though they induced other features of senescence, including a stable growth arrest. Additionally, human fibroblasts induced to senesce by ionizing radiation or oncogenic RAS developed a SASP regardless of whether they expressed p16INK4a. Cells induced to senesce by ectopic p16INK4a expression lacked paracrine activity on epithelial cells, consistent with the absence of a functional SASP. Nonetheless, expression of p16INK4a by cells undergoing replicative senescence limited the accumulation of DNA damage and premature cytokine secretion, suggesting an indirect role for p16INK4a in suppressing the SASP. These findings suggest that p16INK4a-positive cells may not always harbor a SASP in vivo and, furthermore, that the SASP is not a consequence of p16INK4a activation or senescence per se, but rather is a damage response that is separable from the growth arrest. PMID:21880712

  18. Dicer1 dysfunction promotes stemness and aggression in endometrial carcinoma.

    PubMed

    Wang, Xiao-Jun; Jiang, Fei-Zhou; Tong, Huan; Ke, Jie-Qi; Li, Yi-Ran; Zhang, Hui-Lin; Yan, Xiao-Fang; Wang, Fang-Yuan; Wan, Xiao-Ping

    2017-04-01

    Endometrial carcinoma is one of the most common gynecological malignancies, but the molecular events involved in the development and progression of endometrial carcinoma remain unclear. Dicer1 and cancer stem cells play important roles in cell motility and survival. This study investigated the role of the let-7 family and Dicer1 in the stemness of endometrial carcinoma cells. We profiled Dicer1 expression in clinical samples and explored its relationship with stem cell-associated markers and clinical parameters. We showed that Dicer1 dysfunction leads to the enrichment of tumor stemness features and tumor aggression both in vitro and in vivo. We also identified the mechanism related to this potential tumor-predisposing phenotype: loss of Dicer1 induced abnormal expression of the let-7 family, which comprises well-known tumor suppressors, thus regulating stemness in endometrial carcinoma cells.

  19. The joint contribution of tumor phenotype and education to breast cancer survival disparity between Hispanic and non-Hispanic white women.

    PubMed

    Boone, S D; Baumgartner, K B; Joste, N E; Pinkston, C M; Yang, D; Baumgartner, R N

    2014-03-01

    Some studies suggest that Hispanic women are more likely to have ER- and triple-negative (ER-/PR-/HER2-) tumors and subsequently poorer prognosis than non-Hispanic white (NHW) women. In addition, only a handful of studies have examined period-specific effects of tumor phenotype and ethnicity on breast cancer survival, leaving the time-varying effects of hormonal status and ethnicity on breast cancer survival poorly defined. This study describes short and long-term breast cancer survival by ethnicity at 0-5 years and 5+ years post-diagnosis using data from the New Mexico Health, Eating, Activity, and Lifestyle cohort of Hispanic and NHW women ages 29-88 years newly diagnosed with stages I-IIIA breast cancer. The survival rate for Hispanics at 0-5 years was 82.2 % versus 94.3 % for NHW. Hispanics were more likely to have larger tumors, more advanced stage, and ER- phenotypes compared to NHW women. There was a significantly higher risk of breast cancer mortality in Hispanics over 5 years of follow-up compared to NHW (HR = 2.78, 95 % CI 1.39-5.56), adjusting for age, tumor phenotype, stage, and tumor size. This ethnic difference in survival, however, was attenuated and no longer statistically significant when additional adjustment was made for education, although a >1.5-fold increase in mortality was observed. In contrast, there was no difference between ethnic groups for survival after 5 years (HR = 1.08, 95 % CI 0.36-3.24). Our results indicate that the difference in survival between Hispanic and NHW women with breast cancer occurs in the first few years following diagnosis and is jointly associated with tumor phenotype and socio-demographic factors related to education.

  20. The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells.

    PubMed

    Gravina, Giovanni Luca; Marampon, Francesco; Petini, Foteini; Biordi, Leda; Sherris, David; Jannini, Emmanuele A; Tombolini, Vincenzo; Festuccia, Claudio

    2011-08-01

    One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemo-resistant tumors. The aim of this study is to evaluate the role of Palomid 529 (P529), a novel TORC1/TORC2 inhibitor, in association with docetaxel (DTX) and cisplatin (CP). This work utilizes a wide panel of prostatic cancer cell lines with or without basal activation of Akt as well as two in vivo models of aggressive HRPC. The blockade of Akt/mTOR activity was associated to reduced cell proliferation and induction of apoptosis. Comparison of IC50 values calculated for PTEN-positive and PTEN-negative cell lines as well as the PTEN transfection in PC3 cells or PTEN silencing in DU145 cells revealed that absence of PTEN was indicative for a better activity of the drug. In addition, P529 synergized with DTX and CP. The strongest synergism was achieved when prostate cancer (PCa) cells were sequentially exposed to CP or DTX followed by treatment with P529. Treatment with P529 before the exposure to chemotherapeutic drugs resulted in a moderate synergism, whereas intermediated values of combination index were found when drugs were administered simultaneously. In vivo treatment of a combination of P529 with DTX or CP increased the percentage of complete responses and reduced the number of mice with tumor progression. Our results provide a rationale for combinatorial treatment using conventional chemotherapy and a Akt/mTOR inhibitor as promising therapeutic approach for the treatment of HRPC, a disease largely resistant to conventional therapies.

  1. Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer

    PubMed Central

    Gomez-Roman, Natividad; Sahasrabudhe, Neha Mohan; McGregor, Fiona; Chalmers, Anthony J.; Cassidy, Jim; Plumb, Jane

    2016-01-01

    The small GTPase Rab25 has been functionally linked to tumour progression and aggressiveness in ovarian cancer and promotes invasion in three-dimensional environments. This type of migration has been shown to require the expression of the hypoxia-inducible factor 1 alpha (HIF-1α). In this report we demonstrate that Rab25 regulates HIF-1α protein expression in an oxygen independent manner in a panel of cancer cell lines. Regulation of HIF-1α protein expression by Rab25 did not require transcriptional upregulation, but was dependent on de novo protein synthesis through the Erbb2/ERK1/2 and p70S6K/mTOR pathways. Rab25 expression induced HIF-1 transcriptional activity, increased cisplatin resistance, and conferred intraperitoneal growth to the A2780 cell line in immunocompromised mice. Targeting HIF1 activity by silencing HIF-1β re-sensitised cells to cisplatin in vitro and reduced tumour formation of A2780-Rab25 expressing cells in vivo in a mouse ovarian peritoneal carcinomatosis model. Similar effects on cisplatin resistance in vitro and intraperitoneal tumourigenesis in vivo were obtained after HIF1b knockdown in the ovarian cancer cell line SKOV3, which expresses endogenous Rab25 and HIF-1α at atmospheric oxygen concentrations. Our results suggest that Rab25 tumourigenic potential and chemoresistance relies on HIF1 activity in aggressive and metastatic ovarian cancer. Targeting HIF-1 activity may potentially be effective either alone or in combination with standard chemotherapy for aggressive metastatic ovarian cancer. PMID:26967059

  2. Aggressive Behavior

    MedlinePlus

    ... Listen Español Text Size Email Print Share Aggressive Behavior Page Content Article Body My child is sometimes very aggressive. What is the best ... once they are quiet and still reinforces this behavior, so your child learns that time out means “quiet and still.” ...

  3. Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment

    PubMed Central

    Liu, Fang-Lan; Mo, En-Pan; Yang, Liu; Du, Jun; Wang, Hong-Sheng; Zhang, Huan; Kurihara, Hiroshi; Xu, Jun; Cai, Shao-Hui

    2016-01-01

    Transforming growth factor-β1 (TGF-β1) present in tumor microenvironment acts in a coordinated fashion to either suppress or promote tumor development. However, the molecular mechanisms underlying the effects of TGF-β1 on tumor microenvironment are not well understood. Our clinical data showed a positive association between TGF-β1 expression and cancer-associated fibroblasts (CAFs) in tumor microenvironment of breast cancer patients. Thus we employed starved NIH3T3 fibroblasts in vitro and 4T1 cells mixed with NIH3T3 fibroblasts xenograft model in vivo to simulate nutritional deprivation of tumor microenvironment to explore the effects of TGF-β1. We demonstrated that TGF-β1 protected NIH3T3 fibroblasts from Star-induced growth inhibition, mitochondrial damage and cell apoptosis. Interestingly, TGF-β1 induced the formation of CAFs phenotype in starvation (Star)-treated NIH3T3 fibroblasts and xenografted Balb/c mice, which promoted breast cancer tumor growth. In both models, autophagy agonist rapamycin increased TGF-β1-induced protective effects and formation of CAFs phenotypes, while autophagy inhibitor 3-methyladenine, Atg5 knockdown or TGF-β type I receptor kinase inhibitor LY-2157299 blocked TGF-β1 induced these effects. Taken together, our results indicated that TGF-β/Smad autophagy was involved in TGF-β1-induced protective effects and formation of CAFs phenotype in tumor microenvironment, which may be used as therapy targets in breast cancer. PMID:26716641

  4. PLC-β2 is modulated by low oxygen availability in breast tumor cells and plays a phenotype dependent role in their hypoxia-related malignant potential.

    PubMed

    Brugnoli, Federica; Grassilli, Silvia; Al-Qassab, Yasamin; Capitani, Silvano; Bertagnolo, Valeria

    2016-12-01

    Limited oxygen availability plays a critical role in the malignant progression of breast cancer by orchestrating a complex modulation of the gene transcription largely dependent on the tumor phenotype. Invasive breast tumors belonging to different molecular subtypes are characterized by over-expression of PLC-β2, whose amount positively correlates with the malignant evolution of breast neoplasia and supports the invasive potential of breast tumor cells. Here we report that hypoxia modulates the expression of PLC-β2 in breast tumor cells in a phenotype-related manner, since a decrease of the protein was observed in the BT-474 and MCF7 cell lines while an increase was revealed in MDA-MB-231 cells as a consequence of low oxygen availability. Under hypoxia, the down-modulation of PLC-β2 was mainly correlated with the decrease of the EMT marker E-cadherin in the BT-474 cells and with the up-regulation of the stem cell marker CD133 in MCF7 cells. The increase of PLC-β2 induced by low oxygen in MDA-MB-231 cells supports the hypoxia-related reorganization of actin cytoskeleton and sustains invasion capability. In all examined cell lines, but with an opposite role in the ER-positive and ER-negative cells, PLC-β2 was involved in the hypoxia-induced increase of HIF-1α, known to affect both EMT and CD133 expression. Our data include PLC-β2 in the complex and interconnected signaling pathways induced by low oxygen availability in breast tumor cells and suggest that the forced modulation of PLC-β2 programmed on the basis of tumor phenotype may prevent the malignant progression of breast neoplasia as a consequence of intra-tumoral hypoxia. © 2016 Wiley Periodicals, Inc.

  5. Association between body mass index and mortality for colorectal cancer survivors: overall and by tumor molecular phenotype

    PubMed Central

    Campbell, Peter T.; Newton, Christina C.; Newcomb, Polly A.; Phipps, Amanda I.; Ahnen, Dennis J.; Baron, John A.; Buchanan, Daniel D.; Casey, Graham; Cleary, Sean P.; Cotterchio, Michelle; Farris, Alton B.; Figueiredo, Jane C.; Gallinger, Steven; Green, Roger C.; Haile, Robert W.; Hopper, John L.; Jenkins, Mark A.; Le Marchand, Loïc; Makar, Karen W.; McLaughlin, John R.; Potter, John D.; Renehan, Andrew G.; Sinicrope, Frank A.; Thibodeau, Stephen N.; Ulrich, Cornelia M.; Win, Aung Ko; Lindor, Noralane M.; Limburg, Paul J.

    2015-01-01

    Background Microsatellite instability (MSI) and BRAF-mutation status are associated with colorectal cancer survival whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF-mutation, sex, and other factors. Methods This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Pre-diagnosis BMI was derived from self-reported weight approximately 1-year before diagnosis and height. Tumor MSI and BRAF-mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CIs) were estimated from delayed-entry Cox proportional hazards models. Results In multivariable models, high pre-diagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m2, HR = 1.10; 95% CI = 1.06 to 1.15), with similar associations stratified by sex (p-interaction: 0.41), colon vs rectum (p-interaction: 0.86), MSI status (p-interaction: 0.84), and BRAF-mutation status (p-interaction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR: 1.32; p-value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR: 0.86; p-value: 0.29), and approximately the same for MSI-high and obese BMI (HR: 1.00; p-value: 0.98). Conclusions High pre-diagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. Impact High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. PMID:26038390

  6. Chromosome X loci and spontaneous granulosa cell tumor development in SWR mice: epigenetics and epistasis at work for an ovarian phenotype.

    PubMed

    Dorward, Ann M; Yaskowiak, Edward S; Smith, Kerri N; Stanford, Kaitlyn R; Shultz, Kathryn L; Beamer, Wesley G

    2013-02-01

    Females of the SWR/Bm (SWR) inbred mouse strain possess a unique susceptibility to juvenile-onset tumors originating from the granulosa cells (GC) of the ovarian follicles. Tumor susceptibility is an inherited, polygenic trait in SWR females, minimally involving an oncogenic Granulosa cell tumor susceptibility (Gct) locus on chromosome (Chr) 4 (Gct1), and two GC tumor susceptibility modifier genes mapped to distinct regions of Chr X (Gct4 and Gct6). Shifts in the frequency of GC tumor initiation in the SWR female population from low penetrance to moderate penetrance, or phenotype switching between GC tumor-susceptible and GC tumor-resistant, is strongly influenced by the allelic contributions at Gct4 and Gct6. In addition to the allele-specific effects, GC tumor susceptibility is controlled by the mode of X-linked transmission with a dominant, paternal parent-of-origin effect. We took advantage of the robust paternal effect with a recombinant male progeny testing strategy to resolve the Gct4 locus interval to 1.345 million base (Mb) pairs. Based on the mapping resolution and the phenotype sensitivity to endogenous and exogenous androgen exposure, a promising candidate for Gct4 identity is the androgen receptor (Ar) gene. We explored the mechanism of allelic variation for Ar between SWR (low penetrance allele) and SJL/Bm (SJL) (moderate penetrance allele) using an SWR.SJL-X congenic strain resource and a quantitative gene expression method. We report the low GC tumor penetrance allele of the SWR strain correlates with significantly reduced Ar transcript levels in the female ovary at the pubertal transition.

  7. Ameloblastin induces tumor suppressive phenotype and enhances chemosensitivity to doxorubicin via Src-Stat3 inactivation in osteosarcoma

    PubMed Central

    Ando, Toshinori; Kudo, Yasusei; Iizuka, Shinji; Tsunematsu, Takaaki; Umehara, Hanako; Shrestha, Madhu; Matsuo, Toshihiro; Kubo, Tadahiko; Shimose, Shouji; Arihiro, Koji; Ogawa, Ikuko; Ochi, Mitsuo; Takata, Takashi

    2017-01-01

    Ameloblastin (AMBN), the most abundant non-amelogenin enamel matrix protein, plays a role in ameloblast differentiation. Previously, we found that AMBN promoted osteogenic differentiation via the interaction between CD63 and integrin β1, leading to the inactivation of Src; however, how AMBN affects the malignant behavior of osteosarcoma is still unclear. Osteosarcoma affects the bone and is associated with poor prognosis because of the high rate of pulmonary metastases and drug resistance. Here we demonstrated that stable overexpression of AMBN induced apoptosis and suppressed colony formation and cell migration via the inactivation of Src-Stat3 pathway in human osteosarcoma cells. Moreover, AMBN induced chemosensitivity to doxorubicin. Thus, AMBN induced a tumor suppressive phenotype and chemosensitivity to doxorubicin via the AMBN-Src-Stat3 axis in osteosarcoma. Indeed, immunohistochemical expression of AMBN was significantly correlated with better outcome of osteosarcoma patients. Our findings suggest that AMBN can be a new prognostic marker and therapeutic target for osteosarcoma combined with conventional doxorubicin treatment. PMID:28054649

  8. Breed-related differences in altered BRCA1 expression, phenotype and subtype in malignant canine mammary tumors.

    PubMed

    Im, Keum-Soon; Kim, Il-Hwan; Kim, Na-Hyun; Lim, Ha-Young; Kim, Jong-Hyuk; Sur, Jung-Hyang

    2013-03-01

    BRCA1 is a high-penetrance breast cancer susceptibility gene and BRCA1-associated breast cancer has a high familial prevalence that is more common among certain populations of humans. A similar high prevalence also exists for canine mammary tumors (CMTs) and the objective of this study was to determine the breed-related differences in malignant CMTs. Comparative analyses of the expression of various prognostic factors for CMTs, including BRCA1, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) were conducted on 139 malignant CMT cases from five breeds with the highest prevalence of CMTs in Korea. Significant breed-related differences were observed in the expression of BRCA1 (P=0.003), histological grade (P=0.038), and extensive lymphatic invasion (P=0.042). The Shih Tzu breed had the highest proportion of dogs with malignant CMT and strong overexpression of BRCA1. Cytoplasmic and membranous expression of BRCA1 was associated with the ER negative (P=0.004), PR negative (P=0.046), and triple negative (ER, PR, and HER-2 negative; P=0.016) phenotype and the basal-like molecular subtype (P=0.019) in Shih Tzu dogs. Since these features are similar to BRCA1-related human breast cancer, dogs with BRCA1-associated CMT, particularly Shih Tzu dogs, may serve as a suitable spontaneous model, although additional molecular studies are needed.

  9. Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing's sarcoma cells in vitro.

    PubMed

    Chansky, Howard A; Barahmand-Pour, Fariba; Mei, Qi; Kahn-Farooqi, Waqqar; Zielinska-Kwiatkowska, Anna; Blackburn, Michael; Chansky, Kari; Conrad, Ernest U; Bruckner, James D; Greenlee, Theodore K; Yang, Liu

    2004-07-01

    The defining cytogenetic abnormality of Ewing's sarcoma is the presence of a balanced t(11;22) translocation expressing the EWS/FLI-1 chimeric fusion protein. The effect of EWS/FLI-1 appears to be dominant negative since over-expression of EWS does not overcome the sarcoma phenotype. Previous studies have shown that EWS/FLI-1 as well as related sarcoma fusion proteins are necessary and sufficient to induce transformation both in vitro and in vivo. In this study we report that synthetic small interfering RNA (siRNA) specifically suppresses EWS/FLI-1 fusion gene expression in SK-ES Ewing's sarcoma cells. Knockdown of the EWS/FLI-1 fusion protein is correlated with decreased cell proliferation and increased apoptosis. We demonstrate that Ewing's sarcoma tumors as well as Ewing's sarcoma cell lines predominantly express the CXCR4 chemokine receptor. Using an in vitro invasion assay, the SDF-1 ligand of CXCR4 was shown to be a potent stimulus of invasion by SK-ES cells. Knockdown of EWS/FLI-1 by RNA interference abrogates the invasiveness of SK-ES cells. These experiments suggest that targeted silencing of the EWS/FLI-1 fusion gene by siRNA represents a promising strategy to study the loss of EWS/FLI-1 protein in Ewing's sarcoma cells of otherwise identical genetic background.

  10. Retraction: "Activated K-Ras and INK4a/Arf Deficiency Promote Aggressiveness of Pancreatic Cancer by Induction of EMT Consistent With Cancer Stem Cell Phenotype" by Wang et al.

    PubMed

    2016-10-01

    The above article, published online on November 23, 2012 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figure 4B and C to be inappropriately manipulated and re-labeled. Literature Cited Wang Z, Ali S, Banerjee S, Bao B, Li Y, Azmi AS, Korc M, Sarkar FH. 2013. Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype. J Cell Physiol 228:556-562; doi: 10.1002/jcp.24162.

  11. Signaling aggression.

    PubMed

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds.

  12. Molecular Pathways Associated with Aggressiveness of Papillary Thyroid Cancer

    PubMed Central

    Benvenga, Salvatore; Koch, Christian A

    2014-01-01

    The most common thyroid malignancy is papillary thyroid cancer (PTC). Mortality rates from PTC mainly depend on its aggressiveness. Geno- and phenotyping of aggressive PTC has advanced our understanding of treatment failures and of potential future therapies. Unraveling molecular signaling pathways of PTC including its aggressive forms will hopefully pave the road to reduce mortality but also morbidity from this cancer. The mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling pathway as well as the family of RAS oncogenes and BRAF as a member of the RAF protein family and the aberrant expression of microRNAs miR-221, miR-222, and miR-146b all play major roles in tumor initiation and progression of aggressive PTC. Small molecule tyrosine kinase inhibitors targeting BRAF-mediated events, vascular endothelial growth factor receptors, RET/PTC rearrangements, and other molecular targets, show promising results to improve treatment of radioiodine resistant, recurrent, and aggressive PTC. PMID:24955023

  13. Exploring the quantitative relationship between metabolism and enzymatic phenotype by physiological modeling of glucose metabolism and lactate oxidation in solid tumors

    NASA Astrophysics Data System (ADS)

    Wang, Qian; Vaupel, Peter; Ziegler, Sibylle I.; Shi, Kuangyu

    2015-03-01

    Molecular imaging using PET or hyperpolarized MRI can characterize tumor phenotypes by assessing the related metabolism of certain substrates. However, the interpretation of the substrate turnover in terms of a pathophysiological understanding is not straightforward and only semiquantitative. The metabolism of imaging probes is influenced by a number of factors, such as the microvascular structure or the expression of key enzymes. This study aims to use computational simulation to investigate the relationship between the metabolism behind molecular imaging and the underlying tumor phenotype. The study focused on the pathways of glucose metabolism and lactate oxidation in order to establish the quantitative relationship between the expression of several transporters (GLUT, MCT1 and MCT4), expression of the enzyme hexokinase (HK), microvasculature and the metabolism of glucose or lactate and the extracellular pH distribution. A computational model for a 2D tumor tissue phantom was constructed and the spatio-temporal evolution of related species (e.g. oxygen, glucose, lactate, protons, bicarbonate ions) was estimated by solving reaction-diffusion equations. The proposed model was tested by the verification of the simulation results using in vivo and in vitro literature data. The influences of different expression levels of GLUT, MCT1, MCT4, HK and microvessel distribution on substrate concentrations were analyzed. The major results are consistent with experimental data (e.g. GLUT is more influential to glycolytic flux than HK; extracellular pH is not correlated with MCT expressions) and provide theoretical interpretation of the co-influence of multiple factors of the tumor microenvironment. This computational simulation may assist the generation of hypotheses to bridge the discrepancy between tumor metabolism and the functions of transporters and enzymes. It has the potential to accelerate the development of multi-modal imaging strategies for assessment of tumor

  14. Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia

    PubMed Central

    Shi, Changrong; Zhang, Xiangzhong; Chen, Xiaoyuan

    2017-01-01

    Hypoxia promotes not only the invasiveness of tumor cells, but also chemoresistance in cancer. Tumor associated macrophages (TAMs) residing at the site of hypoxic region of tumors have been known to cooperate with tumor cells, and promote proliferation and chemoresistance. Therefore, there is an urgent need for new strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we have taken advantage of high accumulation of TAMs in hypoxic regions of tumor and high reactivity of manganese dioxide nanoparticles (MnO2 NPs) toward hydrogen peroxide (H2O2) for the simultaneous production of O2 and regulation of pH to effectively alleviate tumor hypoxia by targeted delivery of MnO2 NPs to the hypoxic area. Furthermore, we also utilized the ability of hyaluronic acid (HA) modification in reprogramming anti-inflammatory, pro-tumoral M2 TAMs to pro-inflammatory, antitumor M1 macrophages to further enhance the ability of MnO2 NPs to lessen tumor hypoxia and modulate chemoresistance. The HA-coated, mannanconjugated MnO2 particle (Man-HA-MnO2) treatment significantly increased tumor oxygenation and down-regulated hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor (VEGF) in the tumor. Combination treatment of the tumors with Man-HA-MnO2 NPs and doxorubicin significantly increased apparent diffusion coefficient (ADC) values of breast tumor, inhibited tumor growth and tumor cell proliferation as compared with chemotherapy alone. In addition, the reaction of Man-HA-MnO2 NPs toward endogenous H2O2 highly enhanced T1- and T2-MRI performance for tumor imaging and detection. PMID:26650065

  15. Disabling of the erbB Pathway Followed by IFN-γ Modifies Phenotype and Enhances Genotoxic Eradication of Breast Tumors

    PubMed Central

    Nagai, Yasuhiro; Tsuchiya, Hiromichi; Runkle, E. Aaron; Young, Peter D.; Ji, Mei Q.; Norton, Larry; Drebin, Jeffrey A.; Zhang, Hongtao; Greene, Mark I.

    2015-01-01

    Summary Reversion of the malignant phenotype of erbB2-transformed cells can be driven by anti-erbB2/neu monoclonal antibodies (mAb), which disrupt the receptor's kinase activity. We examined the biologic effects of IFN-γ alone or after anti-erbB2/neu mAb treatment of erbB2-positive cells. IFN-γ had no effect on its own. Treatment of the tumors with anti-erbB2/neu mAb followed by IFN-γ led to dramatic inhibition of tumor growth in vitro and in vivo with minimal mAb dosing. Sequential therapy enhanced the effects of chemotherapy. Moreover, IFN-γ with mAb treatment of mice with IFNγR knock down tumors did not demonstrate marked synergistic eradication effects, indicating an unexpected role of IFN-γ on the tumor itself. Additionally, mAb and IFN-γ treatment also in duced immune host responses that enhanced tumor eradication. Biochemical analyses identified loss of Snail expression in tumor cells, reflecting diminution of tumor stem cell-like properties as a consequence of altered activity of GSK3-β and KLF molecules. PMID:26365188

  16. Tumor necrosis factor-α G-308A (rs1800629) polymorphism and aggressive periodontitis susceptibility: a meta-analysis of 16 case-control studies.

    PubMed

    Wei, Xue-Mei; Chen, Yong-Ji; Wu, Lan; Cui, Li-Jun; Hu, Ding-Wei; Zeng, Xian-Tao

    2016-01-11

    Association between tumor necrosis factor-α (TNF-α) G-308A (rs1800629) polymorphism and susceptibility to aggressive periodontitis (AgP) were inconsistent, hence we performed this meta-analysis to clarify the association between them using Comprehensive Meta-Analysis v2.2 software. 16 case-control studies were searched from the PubMed, Embase and CNKI databases up to February 2, 2015. The meta-analysis showed a significantly increased risk in A vs. G (OR = 1.23, 95%CI = 1.04-1.44), AA vs. GG (OR = 2.07, 95%CI = 1.11-3.87), and AA vs. AG+GG genetic models (OR = 2.09, 95%CI = 1.13-3.86); however, the non-significantly increased risk was shown in AG vs. GG (OR = 1.06, 95%CI = 0.85-1.32) and AA+AG vs. GG genetic models (OR = 1.06, 95%CI = 0.85-1.31). Cumulative analysis showed that the association changed from non-significant to significant with new studies accumulated and the CIs became more and more narrow, sensitivity analysis indicated results were statistically robust. Stratified analyses of confirmed of HWE, Asians, Caucasians, and population-based controls obtained results similar to that of overall analysis. There was no evidence of publication bias. In summary, current evidence demonstrates that TNF-a G-308A polymorphism might be associated with AgP susceptibility, especially in Asians and Caucasians.

  17. Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition.

    PubMed

    Li, Shun; Zhang, Jing; Yang, Hong; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

    2015-07-15

    Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors, and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-α accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein, Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-α-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer.

  18. Copper depletion inhibits CoCl2-induced aggressive phenotype of MCF-7 cells via downregulation of HIF-1 and inhibition of Snail/Twist-mediated epithelial-mesenchymal transition

    PubMed Central

    Li, Shun; Zhang, Jing; Yang, Hong; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

    2015-01-01

    Copper, a strictly regulated trace element, is essential for many physiological processes including angiogenesis. Dysregulated angiogenesis has been associated with increased copper in tumors, and thus copper chelators have been used to inhibit tumor angiogenesis. However, it remains unclear whether copper has any effect on epithelial-mesenchymal transition (EMT). Using CoCl2-induced EMT of human breast carcinoma MCF-7 cells, we found that TEPA, a copper chelator, inhibited EMT-like cell morphology and cytoskeleton arrangement triggered by CoCl2; decreased the expression of vimentin and fibronectin, markers typical of EMT; inhibited HIF-1 activation and HIF1-α accumulation in nuclear; and down-regulated the expression of hypoxia-associated transcription factors, Snail and Twist1. Moreover, knockdown copper transport protein, Ctr1, also inhibited CoCl2-induced EMT and reversed the mesenchymal phenotype. In EMT6 xenograft mouse models, TEPA administration inhibited the tumor growth and increased mice survival. Immunohistochemical analysis of the xenograft further demonstrated that TEPA administration significantly inhibited tumor angiogenesis, down-regulated hypoxia-induced transcription factors, Snail and Twist1, leading to decreased transactivation of EMT-associated marker genes, vimentin and fibronectin. These results indicate that TEPA inhibits CoCl2-induced EMT most likely via HIF1-α-Snail/Twist signaling pathway, and copper depletion may be exploited as a therapeutic for breast cancer. PMID:26174737

  19. Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.

    PubMed

    Singh, Manjulata; Mukundan, Shilpaa; Jaramillo, Maria; Oesterreich, Steffi; Sant, Shilpa

    2016-07-01

    Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor-positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor-positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732-43. ©2016 AACR.

  20. The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

    PubMed Central

    Fredericks, William J.; Sepulveda, Jorge; Lal, Priti; Tomaszewski, John E.; Lin, Ming-Fong; McGarvey, Terry; Rauscher, Frank J; Malkowicz, S. Bruce

    2013-01-01

    Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that

  1. Expression of CD133 and CD44 in glioblastoma stem cells correlates with cell proliferation, phenotype stability and intra-tumor heterogeneity

    PubMed Central

    Brown, Daniel V.; Filiz, Gulay; Daniel, Paul M.; Hollande, Frédéric; Dworkin, Sebastian; Amiridis, Stephanie; Kountouri, Nicole; Ng, Wayne; Morokoff, Andrew P.

    2017-01-01

    Glioblastoma (GBM) is a heterogeneous tumor of the brain with a poor prognosis due to recurrence and drug resistance following therapy. Genome-wide profiling has revealed the existence of distinct GBM molecular subtypes that respond differently to aggressive therapies. Despite this, molecular subtype does not predict recurrence or drug resistance and overall survival is similar across subtypes. One of the key features contributing to tumor recurrence and resistance to therapy is proposed to be an underlying subpopulation of resistant glioma stem cells (GSC). CD133 expression has been used as a marker of GSCs, however recent evidence suggests the relationship between CD133 expression, GSCs and molecular subtype is more complex than initially proposed. The expression of CD133, Olig2 and CD44 was investigated using patient derived glioma stem-like cells (PDGCs) in vitro and in vivo. Different PDGCs exhibited a characteristic equilibrium of distinct CD133+ and CD44+ subpopulations and the influence of environmental factors on the intra-tumor equilibrium of CD133+ and CD44+ cells in PDGCs was also investigated, with hypoxia inducing a CD44+ to CD133+ shift and chemo-radiotherapy inducing a CD133+ to CD44+ shift. These data suggest that surveillance and modulation of intra-tumor heterogeneity using molecular markers at initial surgery and surgery for recurrent GBM may be important for more effective management of GBM. PMID:28241049

  2. Loss of Secreted Frizzled-Related Protein 4 Correlates with an Aggressive Phenotype and Predicts Poor Outcome in Ovarian Cancer Patients

    PubMed Central

    Nixdorf, Sheri; Ford, Caroline E.; Olivier, Jake; Caduff, Rosmarie; Scurry, James P.; Guertler, Rea; Hornung, Daniela; Mueller, Renato; Fink, Daniel A.; Hacker, Neville F.; Heinzelmann-Schwarz, Viola A.

    2012-01-01

    Background Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. Methodology/Principal Findings We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. Conclusions/Significance Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets. PMID:22363760

  3. HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes.

    PubMed

    Cui, J; Xia, T; Xie, D; Gao, Y; Jia, Z; Wei, D; Wang, L; Huang, S; Quan, M; Xie, K

    2016-09-08

    Hepatocyte growth factor (HGF)/Met signaling has critical roles in pancreatic ductal adenocarcinoma (PDA) development and progression and is considered a potential therapeutic target for this disease. However, the mechanism of aberrant activation of HGF/Met signaling and resistance to Met inhibition in PDA remains unclear. The mechanistic role of cross talk between Forkhead box M1 (FOXM1) and HGF/Met signaling in promotion of PDA growth and resistance to Met inhibition was examined using cell culture, molecular biology and mouse models; and the relevance of our experimental and mechanistic findings were validated using human PDA tissues. Met was markedly overexpressed in both PDA cell lines and pancreatic tumor specimens, and the expression of Met correlated directly with that of FOXM1 in human tumor specimens. Mechanistically, FOXM1 bound to the promoter region of the Met gene and transcriptionally increased the expression of Met. Increased expression of FOXM1 enhanced the activation of HGF/Met signaling and its downstream pathways, including retrovirus-associated DNA sequences/extracellular signal-regulated kinase 1/2, phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3. Furthermore, activation of HGF/Met signaling increased the expression and transcriptional activity of FOXM1, and the cross talk between FOXM1 and HGF/Met signaling promoted PDA growth and resistance to Met inhibition. Collectively, our findings identified a positive feedback loop formed by FOXM1 and HGF/Met and revealed that this loop is a potentially effective therapeutic target for PDA.

  4. Interleukin-6 Induced “Acute” Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics

    PubMed Central

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L.; Yan, Wei; Xu, Lisa X.

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an “acute” phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated “acute” phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86+MHCII+ dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such “acute” environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest “acute” response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated “acute” microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of “acute” and

  5. Transcriptional analysis of aggressiveness and heterogeneity across grades of astrocytomas.

    PubMed

    Wang, Chunjing; Funk, Cory C; Eddy, James A; Price, Nathan D

    2013-01-01

    Astrocytoma is the most common glioma, accounting for half of all primary brain and spinal cord tumors. Late detection and the aggressive nature of high-grade astrocytomas contribute to high mortality rates. Though many studies identify candidate biomarkers using high-throughput transcriptomic profiling to stratify grades and subtypes, few have resulted in clinically actionable results. This shortcoming can be attributed, in part, to pronounced lab effects that reduce signature robustness and varied individual gene expression among patients with the same tumor. We addressed these issues by uniformly preprocessing publicly available transcriptomic data, comprising 306 tumor samples from three astrocytoma grades (Grade 2, 3, and 4) and 30 non-tumor samples (normal brain as control tissues). Utilizing Differential Rank Conservation (DIRAC), a network-based classification approach, we examined the global and individual patterns of network regulation across tumor grades. Additionally, we applied gene-based approaches to identify genes whose expression changed consistently with increasing tumor grade and evaluated their robustness across multiple studies using statistical sampling. Applying DIRAC, we observed a global trend of greater network dysregulation with increasing tumor aggressiveness. Individual networks displaying greater differences in regulation between adjacent grades play well-known roles in calcium/PKC, EGF, and transcription signaling. Interestingly, many of the 90 individual genes found to monotonically increase or decrease with astrocytoma grade are implicated in cancer-affected processes such as calcium signaling, mitochondrial metabolism, and apoptosis. The fact that specific genes monotonically increase or decrease with increasing astrocytoma grade may reflect shared oncogenic mechanisms among phenotypically similar tumors. This work presents statistically significant results that enable better characterization of different human astrocytoma grades

  6. Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters.

    PubMed

    Carr, Brian I; Pancoska, Petr; Giannini, Edoardo G; Farinati, Fabio; Ciccarese, Francesca; Ludovico Rapaccini, Gian; Di Marco, Maria; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Chiaramonte, Maria; Trevisani, Franco

    2014-06-01

    subsequently validated (using actual scan data) that patients in L phenotype group had 1.5× larger mean tumor masses relative to S, P = 6 × 10(-16). Importantly, with the new data, liver test pattern-identified S-phenotype patients had typically 1.7× longer survival compared to L-phenotype patients. NPS integrated the liver, tumor, and basic demographic factors. Cirrhosis-associated thrombocytopenia was typical for smaller S tumors. In L tumor phenotype, typical platelet levels increased with the tumor mass. Hepatic inflammation and tumor factors contributed to more aggressive L tumors, with parenchymal destruction and shorter survival. NPS provides integrative interpretation for HCC behavior, identifying two tumor and survival phenotypes by clinical parameter patterns. The NPS classifier is provided as an Excel tool. The NPS system shows the importance of considering each tumor marker and parameter in the total context of all the other parameters of an individual patient.

  7. A Pyloric Gland-Phenotype Ovarian Mucinous Tumor Resembling Lobular Endocervical Glandular Hyperplasia in a Patient with Peutz-Jeghers Syndrome.

    PubMed

    Kim, Eun Na; Kim, Gu-Hwan; Kim, Jiyoon; Park, In Ah; Shin, Jin Ho; Chai, Yun; Kim, Kyu-Rae

    2017-03-01

    We describe an ovarian mucinous neoplasm that histologically resembles lobular endocervical glandular hyperplasia (LEGH) containing pyloric gland type mucin in a patient with Peutz-Jeghers syndrome (PJS). Although ovarian mucinous tumors rarely occur in PJS patients, their pyloric gland phenotype has not been clearly determined. The histopathologic features of the ovarian mucinous tumor were reminiscent of LEGH. The cytoplasmic mucin was stained with periodic acid-Schiff reaction after diastase treatment but was negative for Alcian blue pH 2.5, suggesting the presence of neutral mucin. Immunohistochemically, the epithelium expressed various gastric markers, including MUC6, HIK1083, and carbonic anhydrase-IX. Multiple ligation-dependent probe amplification detected a germline heterozygous deletion mutation at exons 1-7 of the STK11 gene (c.1-?_920+?del) in peripheral blood leukocytes and mosaic loss of heterozygosity in ovarian tumor tissue. Considering that LEGH and/or gastric-type cervical adenocarcinoma can be found in patients with PJS carrying germline and/or somatic STK11 mutations, our case indicates that STK11 mutations have an important role in the proliferation of pyloric-phenotype mucinous epithelium at various anatomical locations.

  8. A Pyloric Gland-Phenotype Ovarian Mucinous Tumor Resembling Lobular Endocervical Glandular Hyperplasia in a Patient with Peutz-Jeghers Syndrome

    PubMed Central

    Kim, Eun Na; Kim, Gu-Hwan; Kim, Jiyoon; Park, In Ah; Shin, Jin Ho; Chai, Yun; Kim, Kyu-Rae

    2017-01-01

    We describe an ovarian mucinous neoplasm that histologically resembles lobular endocervical glandular hyperplasia (LEGH) containing pyloric gland type mucin in a patient with Peutz-Jeghers syndrome (PJS). Although ovarian mucinous tumors rarely occur in PJS patients, their pyloric gland phenotype has not been clearly determined. The histopathologic features of the ovarian mucinous tumor were reminiscent of LEGH. The cytoplasmic mucin was stained with periodic acid-Schiff reaction after diastase treatment but was negative for Alcian blue pH 2.5, suggesting the presence of neutral mucin. Immunohistochemically, the epithelium expressed various gastric markers, including MUC6, HIK1083, and carbonic anhydrase-IX. Multiple ligation-dependent probe amplification detected a germline heterozygous deletion mutation at exons 1–7 of the STK11 gene (c.1-?_920+?del) in peripheral blood leukocytes and mosaic loss of heterozygosity in ovarian tumor tissue. Considering that LEGH and/or gastric-type cervical adenocarcinoma can be found in patients with PJS carrying germline and/or somatic STK11 mutations, our case indicates that STK11 mutations have an important role in the proliferation of pyloric-phenotype mucinous epithelium at various anatomical locations. PMID:27550049

  9. Development of a three-dimensional multiscale agent-based tumor model: simulating gene-protein interaction profiles, cell phenotypes and multicellular patterns in brain cancer.

    PubMed

    Zhang, Le; Athale, Chaitanya A; Deisboeck, Thomas S

    2007-01-07

    Experimental evidence suggests that epidermal growth factor receptor (EGFR)-mediated activation of the signaling protein phospholipase Cgamma plays a critical role in a cancer cell's phenotypic decision to either proliferate or to migrate at a given point in time. Here, we present a novel three-dimensional multiscale agent-based model to simulate this cellular decision process in the context of a virtual brain tumor. Each tumor cell is equipped with an EGFR gene-protein interaction network module that also connects to a simplified cell cycle description. The simulation results show that over time proliferative and migratory cell populations not only oscillate but also directly impact the spatio-temporal expansion patterns of the entire cancer system. The percentage change in the concentration of the sub-cellular interaction network's molecular components fluctuates, and, for the 'proliferation-to-migration' switch we find that the phenotype triggering molecular profile to some degree varies as the tumor system grows and the microenvironment changes. We discuss potential implications of these findings for experimental and clinical cancer research.

  10. Adjuvant Cationic Liposomes Presenting MPL and IL-12 Induce Cell Death, Suppress Tumor Growth, and Alter the Cellular Phenotype of Tumors in a Murine Model of Breast Cancer

    PubMed Central

    2015-01-01

    Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80+ macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response. PMID:25179345

  11. MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple negative MDA-MB-231 human breast cancer cells

    PubMed Central

    Browne, Gillian; Dragon, Julie A.; Hong, Deli; Messier, Terri L.; Gordon, Jonathan A. R.; Farina, Nicholas H.; Boyd, Joseph R.; VanOudenhove, Jennifer J.; Perez, Andrew W.; Zaidi, Sayyed K.; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.

    2016-01-01

    The Runx1 transcription factor, known for its essential role normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx 1 increases concomitant with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant down-regulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mouse, and in human breast cancer cell lines MCF7 and triple negative MDA-MB-231 that represent early and late stage disease, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3′UTR and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion; while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer. PMID:26749280

  12. Estimation of the tumor size at cure threshold among aggressive non-small cell lung cancers (NSCLCs): evidence from the surveillance, epidemiology, and end results (SEER) program and the national lung screening trial (NLST).

    PubMed

    Goldwasser, Deborah L

    2017-03-15

    The National Lung Screening Trial (NLST) demonstrated that non-small cell lung cancer (NSCLC) mortality can be reduced by a program of annual CT screening in high-risk individuals. However, CT screening regimens and adherence vary, potentially impacting the lung cancer mortality benefit. We defined the NSCLC cure threshold as the maximum tumor size at which a given NSCLC would be curable due to early detection. We obtained data from 518,234 NSCLCs documented in the U.S. SEER cancer registry between 1988 and 2012 and 1769 NSCLCs detected in the NLST. We demonstrated mathematically that the distribution function governing the cure threshold for the most aggressive NSCLCs, G(x|Φ = 1), was embedded in the probability function governing detection of SEER-documented NSCLCs. We determined the resulting probability functions governing detection over a range of G(x|Φ = 1) scenarios and compared them with their expected functional forms. We constructed a simulation framework to determine the cure threshold models most consistent with tumor sizes and outcomes documented in SEER and the NLST. Whereas the median tumor size for lethal NSCLCs documented in SEER is 43 mm (males) and 40 mm (females), a simulation model in which the median cure threshold for the most aggressive NSCLCs is 10 mm (males) and 15 mm (females) best fit the SEER and NLST data. The majority of NSCLCs in the NLST were treated at sizes greater than our median cure threshold estimates. New technology is needed to better distinguish and treat the most aggressive NSCLCs when they are small (i.e., 5-15 mm).

  13. A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals

    SciTech Connect

    Bourn, D.; Carter, S.A.; Goodship, J.; Strachan, T. ); Evans, G.R.; Coakham, H.

    1994-07-01

    The authors have sought mutations in the recently identified neurofibromatosis type 2 (NF2) tumor-suppressor gene in a large panel of NF2 patients, using PCR-based SSCP and heteroduplex analysis, followed by cloning and sequencing of appropriate PCR products. Two unrelated NF2 patients were found to have identical nonsense mutations caused by a C-to-T transition in a CpG dinucleotide that is a potential mutational hot spot in the NF2 tumor-suppressor gene. Unexpectedly, the two individuals had widely different clinical phenotypes, representing the severe Wishart and mild Gardner clinical subtypes. Analysis of DNA samples from different tissues of the mildly affected patient suggests that he is a somatic mosaic for the mutation. 26 refs., 3 figs.

  14. Matrix Rigidity Regulates the Transition of Tumor Cells to a Bone-Destructive Phenotype through Integrin β3 and TGF-β Receptor Type II

    PubMed Central

    Ruppender, Nazanin S.; Guo, Ruijing; Dadwal, Ushashi C.; Cannonier, Shellese; Basu, Sandip; Guelcher, Scott A.; Sterling, Julie A.

    2015-01-01

    Cancer patients frequently develop skeletal metastases that significantly impact quality of life. Since bone metastases remain incurable, a clearer understanding of molecular mechanisms regulating skeletal metastases is required to develop new therapeutics that block establishment of tumors in bone. While many studies have suggested that the microenvironment contributes to bone metastases, the factors mediating tumors to progress from a quiescent to a bone-destructive state remain unclear. In this study, we hypothesized that the “soil” of the bone microenvironment, specifically the rigid mineralized extracellular matrix, stimulates the transition of the tumor cells to a bone-destructive phenotype. To test this hypothesis, we synthesized 2D polyurethane (PUR) films with elastic moduli ranging from the basement membrane (70 MPa) to cortical bone (3800 MPa) and measured expression of genes associated with mechanotransduction and bone metastases. We found that expression of Integrin β3 (Iβ3), as well as tumor-produced factors associated with bone destruction (Gli2 and parathyroid hormone related protein (PTHrP)), significantly increased with matrix rigidity, and that blocking Iβ3 reduced Gli2 and PTHrP expression. To identify the mechanism by which Iβ3 regulates Gli2 and PTHrP (both are also known to be regulated by TGF-β), we performed Förster resonance energy transfer (FRET) and immunoprecipitation, which indicated that Iβ3 co-localized with TGF-β Receptor Type II (TGF-β RII) on rigid but not compliant films. Finally, transplantation of tumor cells expressing Iβ3 shRNA into the tibiae of athymic nude mice significantly reduced PTHrP and Gli2 expression, as well as bone destruction, suggesting a crucial role for tumor-produced Iβ3 in disease progression. This study demonstrates that the rigid mineralized bone matrix can alter gene expression and bone destruction in an Iβ3/TGF-β-dependent manner, and suggests that Iβ3 inhibitors are a potential

  15. TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells: A potential novel approach to the treatment of metastatic colorectal cancer

    PubMed Central

    Christensen, Ib J.; Nordgaard, Cathrine; Noer, Julie; Guren, Tormod K.; Glimelius, Bengt; Sorbye, Halfdan; Ikdahl, Tone; Kure, Elin H.; Tveit, Kjell M.; Nielsen, Hans J.

    2016-01-01

    It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5-fluorouracil and oxaliplatin) +/− cetuximab (NORDIC VII study). Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels, KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level (> 3rd quartile) showing a significantly longer overall survival if treated with cetuximab (HR, 0.48; 95% CI, 0.25 to 0.93). To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines. We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated cells. The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP- 1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy. PMID:27509063

  16. Human SPF45, a Splicing Factor, Has Limited Expression in Normal Tissues, Is Overexpressed in Many Tumors, and Can Confer a Multidrug-Resistant Phenotype to Cells

    PubMed Central

    Sampath, Janardhan; Long, Pandy R.; Shepard, Robert L.; Xia, Xiaoling; Devanarayan, Viswanath; Sandusky, George E.; Perry, William L.; Dantzig, Anne H.; Williamson, Mark; Rolfe, Mark; Moore, Robert E.

    2003-01-01

    Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance. PMID:14578179

  17. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by or linked with viruses are: Cervical cancer (human papillomavirus) Most anal cancers (human papillomavirus) Some throat ...

  18. Tumor cell vascular mimicry: Novel targeting opportunity in melanoma

    PubMed Central

    Hendrix, Mary J.C.; Seftor, Elisabeth A.; Seftor, Richard E.B.; Chao, Jun-Tzu; Chien, Du-Shieng; Chu, Yi-Wen

    2016-01-01

    In 1999, the American Journal of Pathology published an article, entitled “Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry” by Maniotis and colleagues, which ignited a spirited debate for several years and earned the journal's distinction of a “citation classic” (Maniotis et al., 1999). Tumor cell vasculogenic mimicry (VM), also known as vascular mimicry, describes the plasticity of aggressive cancer cells forming de novo vascular networks and is associated with the malignant phenotype and poor clinical outcome. The tumor cells capable of VM share the commonality of a stem cell-like, transendothelial phenotype, which may be induced by hypoxia. Since its introduction as a novel paradigm for melanoma tumor perfusion, many studies have contributed new findings illuminating the underlying molecular pathways supporting VM in a variety of tumors, including carcinomas, sarcomas, glioblastomas, astrocytomas, and melanomas. Of special significance is the lack of effectiveness of angiogenesis inhibitors on tumor cell VM, suggesting a selective resistance by this phenotype to conventional therapy. Facilitating the functional plasticity of tumor cell VM are key proteins associated with vascular, stem cell, extracellular matrix, and hypoxia-related signaling pathways -- each deserving serious consideration as potential therapeutic targets and diagnostic indicators of the aggressive, metastatic phenotype. This review highlights seminal findings pertinent to VM, including the effects of a novel, small molecular compound, CVM-1118, currently under clinical development to target VM, and illuminates important molecular pathways involved in the suppression of this plastic, aggressive phenotype, using melanoma as a model. PMID:26808163

  19. Assessment of different 3D culture systems to study tumor phenotype and chemosensitivity in pancreatic ductal adenocarcinoma.

    PubMed

    Zeeberg, Katrine; Cardone, Rosa Angela; Greco, Maria Raffaella; Saccomano, Mara; Nøhr-Nielsen, Asbjørn; Alves, Frauke; Pedersen, Stine Falsig; Reshkin, Stephan Joel

    2016-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis, due to the influence of the tumor stroma, which promotes tumor growth, early invasion and chemoradiation resistance. Efforts to develop models for identifying novel anticancer therapeutic compounds have been hampered by the limited ability of in vitro models to mimic these in vivo tumor-stroma interactions. This has led to the development of various three-dimensional (3D) culture platforms recapitulating the in vivo tumor-stroma crosstalk and designed to better understand basic cancer processes and screen drug action. However, a consensus for different experimental 3D platforms is still missing in PDAC. We compared four PDAC cell lines of different malignancy grown in 2D monolayers to three of the more commonly used 3D techniques (ultralow adhesion concave microwells, Matrigel inclusion and organotypic systems) and to tumors derived from their orthotopic implantation in mice. In these 3D platforms, we observed that cells grow with very different tumor morphologies and the organotypic setting most closely resembles the tumor cytoarchitecture obtained by orthotopically implanting the four cell lines in mice. We then analyzed the molecular and cellular responses of one of these cell lines to epidermal growth factor receptor (EGFR) stimulation with EGF and inhibition with erlotinib and found that only in the 3D platforms, and especially the organotypic, cells: i) responded to EGF by changing the expression of signalling components underlying cell-stroma crosstalk and tissue architecture, growth, invasion and drug resistance (E-cadherin, EGFR, ezrin, β1 integrin, NHERF1 and HIF-1α) similar to those reported in vivo; ii) had stimulated growth and increased erlotinib sensitivity in response to EGF, more faithfully mimicking their known in vivo behaviour. Altogether, these results, indicate the organotypic as the most relevant physiological 3D system to study the

  20. Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis.

    PubMed

    Merker, Vanessa L; Bredella, Miriam A; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J; Muzikansky, Alona; Nguyen, Rosa; Mautner, Victor F; Plotkin, Scott R

    2014-06-01

    Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis share a predisposition to develop multiple nerve sheath tumors. Previous studies have demonstrated that patients with NF1 and NF2 have reduced quality of life (QOL), but no studies have examined the relationship between whole-body tumor burden and QOL in these patients. We administered a QOL questionnaire (the SF-36) and a visual analog pain scale (VAS) to a previously described cohort of adult neurofibromatosis patients undergoing whole-body MRI. One-sample t-tests were used to compare norm-based SF-36 scores to weighted population means. Spearman correlation coefficients and multiple linear regression analyses controlling for demographic and disease-specific clinical variable were used to relate whole-body tumor volume to QOL scales. Two hundred forty-five patients (142 NF1, 53 NF2, 50 schwannomatosis) completed the study. Subjects showed deficits in selected subscales of the SF-36 compared to adjusted general population means. In bivariate analysis, increased tumor volume was significantly associated with pain in schwannomatosis patients, as measured by the SF-36 bodily pain subscale (rho = -0.287, P = 0.04) and VAS (rho = 0.34, P = 0.02). Regression models for NF2 patients showed a positive relationship between tumor burden and increased pain, as measured by the SF-36 (P = 0.008). Patients with NF1, NF2, and schwannomatosis suffer from reduced QOL, although only pain shows a clear relationship to patient's overall tumor burden. These findings suggest that internal tumor volume is not a primary contributor to QOL and emphasize the need for comprehensive treatment approaches that go beyond tumor-focused therapies such as surgery by including psychosocial interventions.

  1. Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts.

    PubMed

    Nwani, Nkechiyere G; Deguiz, Maria L; Jimenez, Benilde; Vinokour, Elena; Dubrovskyi, Oleksii; Ugolkov, Andrey; Mazar, Andrew P; Volpert, Olga V

    2016-04-15

    Loss of pigment epithelium-derived factor (PEDF, SERPINF1) in cancer cells is associated with poor prognosis and metastasis, but the contribution of stromal PEDF to cancer evolution is poorly understood. Therefore, we investigated the role of fibroblast-derived PEDF in melanoma progression. We demonstrate that normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. Accordingly, mice with global PEDF knockout were more susceptible to melanoma metastasis. We also demonstrate that normal fibroblasts in close contact with PEDF-null melanoma cells lost PEDF expression and tumor-suppressive properties. Further mechanistic investigations underlying the crosstalk between tumor and stromal cells revealed that melanoma cells produced PDGF-BB and TGFβ, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGFβ-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of IL8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. Collectively, our results demonstrate that PEDF maintains tumor-suppressive functions in fibroblasts to prevent CAF conversion and illustrate the mechanisms by which melanoma cells silence stromal PEDF to promote malignancy. Cancer Res; 76(8); 2265-76. ©2016 AACR.

  2. Stability of the hybrid epithelial/mesenchymal phenotype

    PubMed Central

    Jolly, Mohit Kumar; Mooney, Steven M.; Celiktas, Muge; Hanash, Samir M.; Mani, Sendurai A.; Pienta, Kenneth J.; Ben-Jacob, Eshel; Levine, Herbert

    2016-01-01

    Epithelial-to-Mesenchymal Transition (EMT) and its reverse – Mesenchymal to Epithelial Transition (MET) – are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and ‘metastable’. Here, we identify certain ‘phenotypic stability factors’ (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be ‘metastable’, and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression. PMID:27008704

  3. Decreased expression of CYP27B1 correlates with the increased aggressiveness of ovarian carcinomas

    PubMed Central

    BROŻYNA, ANNA A.; JÓŹWICKI, WOJCIECH; JOCHYMSKI, CEZARY; SLOMINSKI, ANDRZEJ T.

    2015-01-01

    CYP27B1 hydroxylates 25-hydroxyvitamin D3 in position C1α into biologically active 1,25-dihydroxyvitamin D3, calcitriol. CYP27B1 is expressed in normal tissues and tumors. Since calcitriol indicates anticancer activities and CYP27B1 expression can be deregulated during malignant progression, we analyzed its expression in ovarian cancers in relation to pathomorphological features of tumors and overall survival (OS). Expression of CYP27B1 was evaluated in 61 ovarian tumors, 18 metastases and 10 normal ovaries. Normal ovarian epithelium showed the highest levels CYP27B1 with a significant decrease in its expression in ovarian cancers. Both poorly differentiated primary tumors and metastases showed the lowest level of CYP27B1 expression, while non-metastasizing tumors showed a higher CYP27B1 level than tumors that developed metastases. The expression of CYP27B1 was positively correlated with a lower proliferation rate, lower dynamism of tumor growth and tumor infiltrating lymphocyte response. Furthermore, CYP27B1 expression was negatively correlated with tumor cell modeling of their microenvironment. CYP27B1 expression was also associated with longer OS time. In summary, our results suggest that local expression of CYP27B1 in ovarian tumor cells can modify their behavior and promote a less aggressive phenotype by affecting local concentrations of active of vitamin D levels within the tumor microenvironment. PMID:25501638

  4. The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome

    PubMed Central

    Pyfferoen, Lotte; Brabants, Elisabeth; De Cabooter, Nancy; Heyns, Kelly; Deswarte, Kim; Vanheerswynghels, Manon; De Prijck, Sofie; Waegemans, Glenn; Hammad, Hamida; De Wever, Olivier; Mestdagh, Pieter; Lambrecht, Bart N.; Vermaelen, Karim Y.

    2017-01-01

    ABSTRACT Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs are emerging as clinically relevant parameters in lung cancer. In this study, we used an orthotopic preclinical model of lung cancer to dissect how the lung tumor micro-environment affects tissue-resident DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b+ cells that, compare with peritumoral lung DC counterparts, strongly overexpress the T-cell inhibitory molecule PD-L1 and acquire classical surface markers of tumor-associated macrophages (TAMs). Transcriptome analysis of these CD11b+ tumor-infiltrating DCs (TIDCs) indicates impaired antitumoral immunogenicity, confirms the skewing toward TAM-related features, and indicates exposure to a hypoxic environment. In parallel, TIDCs display a specific microRNA (miRNA) signature dominated by the prototypical lung cancer oncomir miR-31. In vitro, hypoxia drives intrinsic miR-31 expression in CD11b+ DCs. Conditioned medium of miR-31 overexpressing CD11b+ DCs induces pro-invasive lung cancer cell shape changes and is enriched with pro-metastatic soluble factors. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which the lung cancer micro-environment exploits the plasticity of the DC system to support tumoral progression. PMID:28197369

  5. An Aggressive Retroperitoneal Fibromatosis

    PubMed Central

    Campara, Zoran; Spasic, Aleksandar; Aleksic, Predrag; Milev, Bosko

    2016-01-01

    Introduction: Aggressive fibromatosis (AF) is a heterogeneous group of mesenchymal tumors that have locally infiltrative growth and a tendency to relapse. The clinical picture is often conditioned by the obstruction of the ureter or small intestine. Diagnosis is based on clinical, radiological and histological parameters. A case report: We report a case of male patient, aged 35 years, with the retroperitoneal fibromatosis. He reported to the physician because of frequent urination with the feeling of pressure and pain. Computed tomography revealed the tumor mass on the front wall of the bladder with diameter of 70mm with signs of infiltration of the musculature of the anterior abdominal wall. Endoscopic transurethral biopsy showed proliferative lesion binders by type of fibromatosis. The tumor was surgically removed in a classical way. The patient feels well and has no recurrence thirty-six months after the operative procedure. Conclusion: The complete tumor resection is the therapeutic choice for the primary tumor as well as for a relapse. PMID:27147794

  6. Mimicking the tumor microenvironment to regulate macrophage phenotype and assessing chemotherapeutic efficacy in embedded cancer cell/macrophage spheroid models.

    PubMed

    Tevis, Kristie M; Cecchi, Ryan J; Colson, Yolonda L; Grinstaff, Mark W

    2017-03-01

    Tumor associated macrophages (TAMs) are critical stromal components intimately involved with the progression, invasion, and metastasis of cancer cells. To address the need for an in vitro system that mimics the clinical observations of TAM localizations and subsequent functional performance, a cancer cell/macrophage spheroid model is described. The central component of the model is a triple negative breast cancer spheroid embedded in a three-dimensional collagen gel. Macrophages are incorporated in two different ways. The first is a heterospheroid, a spheroid containing both tumor cells and macrophages. The heterospheroid mimics the population of TAMs infiltrated into the tumor mass, thus being exposed to hypoxia and metabolic gradients. In the second model, macrophages are diffusely seeded in the collagen surrounding the spheroid, thus modeling TAMs in the cancer stroma. The inclusion of macrophages as a heterospheroid changes the metabolic profile, indicative of synergistic growth. In contrast, macrophages diffusely seeded in the collagen bear the same profile regardless of the presence of a tumor cell spheroid. The macrophages in the heterospheroid secrete EGF, a cytokine critical to tumor/macrophage co-migration, and an EGF inhibitor decreases the metabolic activity of the heterospheroid, which is not observed in the other systems. The increased secretion of IL-10 indicates that the heterospheroid macrophages follow an M2/TAM differentiation pathway. Lastly, the heterospheroid exhibits resistance to paclitaxel. In summary, the collagen embedded heterospheroid model promotes TAM-like characteristics, and will be of utility in cancer biology and drug discovery.

  7. An optimized disaggregation method for human lung tumors that preserves the phenotype and function of the immune cells.

    PubMed

    Quatromoni, Jon G; Singhal, Sunil; Bhojnagarwala, Pratik; Hancock, Wayne W; Albelda, Steven M; Eruslanov, Evgeniy

    2015-01-01

    Careful preparation of human tissues is the cornerstone of obtaining accurate data in immunologic studies. Despite the essential importance of tissue processing in tumor immunology and clinical medicine, current methods of tissue disaggregation have not been rigorously tested for data fidelity. Thus, we critically evaluated the current techniques available in the literature that are used to prepare human lung tumors for immunologic studies. We discovered that these approaches are successful at digesting cellular attachments and ECMs; however, these methods frequently alter the immune cell composition and/or expression of surface molecules. We thus developed a novel approach to prepare human lung tumors for immunologic studies by combining gentle mechanical manipulation with an optimized cocktail of enzymes used at low doses. This enzymatic digestion cocktail optimized cell yield and cell viability, retrieved all major tumor-associated cell populations, and maintained the expression of cell-surface markers for lineage definition and in vivo effector functions. To our knowledge, we present the first rigorously tested disaggregation method designed for human lung tumors.

  8. Suppression of Heregulin-β1/HER2-Modulated Invasive and Aggressive Phenotype of Breast Carcinoma by Pterostilbene via Inhibition of Matrix Metalloproteinase-9, p38 Kinase Cascade and Akt Activation

    PubMed Central

    Pan, Min-Hsiung; Lin, Ying-Ting; Lin, Chih-Li; Wei, Chi-Shiang; Ho, Chi-Tang; Chen, Wei-Jen

    2011-01-01

    Invasive breast cancer is the major cause of death among females and its incidence is closely linked to HER2 (human epidermal growth factor receptor 2) overexpression. Pterostilbene, a natural analog of resveratrol, exerts its cancer chemopreventive activity similar to resveratrol by inhibiting cancer cell proliferation and inducing apoptosis. However, the anti-invasive effect of pterostilbene on HER2-bearing breast cancer has not been evaluated. Here, we used heregulin-β1 (HRG-β1), a ligand for HER3, to transactivate HER2 signaling. We found that pterostilbene was able to suppress HRG-β1-mediated cell invasion, motility and cell transformation of MCF-7 human breast carcinoma through down-regulation of matrix metalloproteinase-9 (MMP-9) activity and growth inhibition. In parallel, pterostilbene also inhibited protein and mRNA expression of MMP-9 driven by HRG-β1, suggesting that pterostilbene decreased HRG-β1-mediated MMP-9 induction via transcriptional regulation. Examining the signaling pathways responsible for HRG-β1-associated MMP-9 induction and growth inhibition, we observed that pterostilbene, as well as SB203580 (p38 kinase inhibitor), can abolish the phosphorylation of p38 mitogen-activated protein kinase (p38 kinase), a downstream HRG-β1-responsive kinase responsible for MMP-9 induction. In addition, HRG-β1-driven Akt phosphorylation required for cell proliferation was also suppressed by pterostilbene. Taken together, our present results suggest that pterostilbene may serve as a chemopreventive agent to inhibit HRG-β1/HER2-mediated aggressive and invasive phenotype of breast carcinoma through down-regulation of MMP-9, p38 kinase and Akt activation. PMID:19617202

  9. Microenvironment influence on human colon adenocarcinoma phenotypes and matrix metalloproteinase-2, p53 and β-catenin tumor expressions from identical monoclonal cell tumor in the orthotopic model in athymic nude rats.

    PubMed

    Priolli, Denise Gonçalves; Abrantes, Ana Margarida; Neves, Silvia; Gonçalves, Ana Cristina; Lopes, Camila Oliveira; Martinez, Natalia Peres; Cardinalli, Izilda Aparecida; Ribeiro, Ana Bela Sarmento; Botelho, Maria Filomena

    2014-03-01

    The present study aims to identify differences between left and right colon adenocarcinoma arising from identical clonal cell and to find out if microenvironment has any influence on matrix metalloproteinase-2 (MMP2), p53 and β-catenin tumor expressions. MATERIAL AND METHODS. Rats (RNU) were submitted to cecostomy to obtain the orthotopic model of right colon tumor (n = 10), while for the left colon model (n = 10), a colon diversion and distal mucous fistula in the descending colon was used. Cultivated human colon adenocarcinoma cells (WiDr) were inoculated in stomas submucosa. Histopathological analysis, real-time reverse transcription-PCR for β-catenin, p53 and MMP2, as well as immunohistochemical analysis for p53 and β-catenin expression were conducted. Central tendency, variance analysis and the Livak delta-delta-CT method were used for statistical analysis, adopting a 5% significance level. RESULTS. All tumors from the left colon exhibited infiltrative ulceration, while in the right colon tumor growth was predominantly exophytic (67%). In the left colon, tumor growth was undifferentiated (100%), while it was moderately differentiated in the right colon (83%). In right colon tumors, MMP2, p53, and β-catenin gene expressions were higher than compared to left colon (p = 4.59354E-05, p = 0.0035179, p = 0.00093798, respectively, for MMP2, p53 and β-catenin). β-catenin and p53 results obtained by real-time polymerase chain reaction were confirmed by immunohistochemistry assay (p = 0.01 and p = 0.001, respectively, for β-catenin and p53). CONCLUSION. Left and right human colon adenocarcinomas developed in animal models have distinct phenotypes even when they have the same clonal origin. Microenvironment has influenced p53, β-catenin, and MMP2 expression in animal models of colon cancer.

  10. Fc block treatment, dead cells exclusion, and cell aggregates discrimination concur to prevent phenotypical artifacts in the analysis of subpopulations of tumor-infiltrating CD11b(+) myelomonocytic cells.

    PubMed

    Kuonen, Francois; Touvrey, Cedric; Laurent, Julien; Ruegg, Curzio

    2010-11-01

    It is well established that cancer cells can recruit CD11b(+) myeloid cells to promote tumor angiogenesis and tumor growth. Increasing interest has emerged on the identification of subpopulations of tumor-infiltrating CD11b(+) myeloid cells using flow cytometry techniques. In the literature, however, discrepancies exist on the phenotype of these cells (Coffelt et al., Am J Pathol 2010;176:1564-1576). Since flow cytometry analysis requires particular precautions for accurate sample preparation and trustable data acquisition, analysis, and interpretation, some discrepancies might be due to technical reasons rather than biological grounds. We used the syngenic orthotopic 4T1 mammary tumor model in immunocompetent BALB/c mice to analyze and compare the phenotype of CD11b(+) myeloid cells isolated from peripheral blood and from tumors, using six-color flow cytometry. We report here that the nonspecific antibody binding through Fc receptors, the presence of dead cells and cell doublets in tumor-derived samples concur to generate artifacts in the phenotype of tumor-infiltrating CD11b(+) subpopulations. We show that the heterogeneity of tumor-infiltrating CD11b(+) subpopulations analyzed without particular precautions was greatly reduced upon Fc block treatment, dead cells, and cell doublets exclusion. Phenotyping of tumor-infiltrating CD11b(+) cells was particularly sensitive to these parameters compared to circulating CD11b(+) cells. Taken together, our results identify Fc block treatment, dead cells, and cell doublets exclusion as simple but crucial steps for the proper analysis of tumor-infiltrating CD11b(+) cell populations.

  11. Growth hormone-releasing hormone-producing pancreatic neuroendocrine tumor in a multiple endocrine neoplasia type 1 family with an uncommon phenotype.

    PubMed

    Sala, Elisa; Ferrante, Emanuele; Verrua, Elisa; Malchiodi, Elena; Mantovani, Giovanna; Filopanti, Marcello; Ferrero, Stefano; Pietrabissa, Andrea; Vanoli, Alessandro; La Rosa, Stefano; Zatelli, Maria C; Beck-Peccoz, Paolo; Verga, Uberta

    2013-07-01

    The objective of this study was to describe a multiple endocrine neoplasia type 1 (MEN1) family characterized by primary hyperparathyroidism, in association with acromegaly because of ectopic growth hormone-releasing hormone (GHRH) secretion by a pancreatic neuroendocrine tumor in a young man and with a bronchial carcinoid in his mother. We investigate the clinical, radiological imaging, histopathologic findings, and therapy. An 18-year-old man successfully underwent subtotal parathyroidectomy for primary hyperparathyroidism. A subsequent genetic analysis showed a MEN1 gene mutation. Three years later, acromegaly because of ectopic GHRH secretion was diagnosed (pituitary MRI negative and elevated GHRH levels). A search for an ectopic tumor was unsuccessful and somatostatin analog therapy was started. Successively, scintigraphy with somatostatin analogs (68-Ga-DOTATOC-PET) showed three focal areas in the pancreatic tail. Distal pancreatectomy showed multiple pancreatic neuroendocrine tumors and hormonal status was normalized. Afterwards, the evaluation of the patient's mother, carrying the same mutation, indicated a primary hyperparathyroidism and a 4 cm lung mass. The patient underwent subtotal pneumonectomy and the histological analysis was consistent with the diagnosis of a typical bronchial carcinoid. In conclusion, an atypical phenotype may be recorded in MEN1 families, thus emphasizing the importance of the new imaging and surgical techniques in the diagnosis and treatment of such a rare disease.

  12. Three-dimensional chemotaxis-driven aggregation of tumor cells

    PubMed Central

    Puliafito, Alberto; De Simone, Alessandro; Seano, Giorgio; Gagliardi, Paolo Armando; Di Blasio, Laura; Chianale, Federica; Gamba, Andrea; Primo, Luca; Celani, Antonio

    2015-01-01

    One of the most important steps in tumor progression involves the transformation from a differentiated epithelial phenotype to an aggressive, highly motile phenotype, where tumor cells invade neighboring tissues. Invasion can occur either by isolated mesenchymal cells or by aggregates that migrate collectively and do not lose completely the epithelial phenotype. Here, we show that, in a three-dimensional cancer cell culture, collective migration of cells eventually leads to aggregation in large clusters. We present quantitative measurements of cluster velocity, coalescence rates, and proliferation rates. These results cannot be explained in terms of random aggregation. Instead, a model of chemotaxis-driven aggregation – mediated by a diffusible attractant – is able to capture several quantitative aspects of our results. Experimental assays of chemotaxis towards culture conditioned media confirm this hypothesis. Theoretical and numerical results further suggest an important role for chemotactic-driven aggregation in spreading and survival of tumor cells. PMID:26471876

  13. Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype

    PubMed Central

    Maggi, E C; Trillo-Tinoco, J; Struckhoff, A P; Vijayaraghavan, J; Del Valle, L; Crabtree, J S

    2016-01-01

    Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines βlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs. PMID:27548814

  14. Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype.

    PubMed

    Maggi, E C; Trillo-Tinoco, J; Struckhoff, A P; Vijayaraghavan, J; Del Valle, L; Crabtree, J S

    2016-08-22

    Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines βlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs.

  15. Attenuated expression of menin and p27 (Kip1) in an aggressive case of multiple endocrine neoplasia type 1 (MEN1) associated with an atypical prolactinoma and a malignant pancreatic endocrine tumor.

    PubMed

    Ishida, Emi; Yamada, Masanobu; Horiguchi, Kazuhiko; Taguchi, Ryo; Ozawa, Atsushi; Shibusawa, Nobuyuki; Hashimoto, Koshi; Satoh, Tetsuro; Yoshida, Sachiko; Tanaka, Yoshiki; Yokota, Machiko; Tosaka, Masahiko; Hirato, Junko; Yamada, Shozo; Yoshimoto, Yuhei; Mori, Masatomo

    2011-01-01

    Tumors in multiple endocrine neoplasia type 1 (MEN1) are generally benign. Since information on the pathogenesis of MEN1 in malignant cases is limited, we conducted genetic analysis and compared the expression of menin, p27(Kip1)(p27)/CDKN1B and p18(Ink4C)(p18)/CDKN2C with levels in benign cases. We describe the case of a 56 year-old male with an atypical prolactinoma and malignant pancreatic neuroenocrine tumor. At age 50, he had undergone transsphenoidal surgery to remove a prolactinoma. However, the tumor relapsed twice. Histological analysis of the recurrent prolactinoma revealed the presence of prolactin, a high MIB-1 index (32.1 %), p53-positive cells (0.2%), and an unusual association with FSH-positive cells. A few years later, he was also found to have a non-functioning pancreatic tumor with probable metastasis to the extradullar region. The metastatic region tested positive for chromogranin and CD56, and negative for prolactin, with 1.2 % of cells p53-positive. Although genetic analyses of the MEN1, p27, and p18 genes demonstrated no mutation, numbers of menin, p27 and p18 immuno-positive cells were significantly down-regulated in the recurrent prolactinoma, but that of p18 was intact in the metastatic region. Furthermore, MEN1 and p27 mRNA levels of the recurrent prolactinoma were down-regulated, particularly the MEN1 mRNA level, compared to levels in 10 cases of benign prolactinoma, while the p18 mRNA level was similar to that of normal pituitary. The tumor in this case may be a subtype of MEN1 showing more aggressive and malignant features probably induced by low levels of menin and p27.

  16. Genetics Home Reference: desmoid tumor

    MedlinePlus

    ... in my area? Other Names for This Condition aggressive fibromatosis deep fibromatosis desmoid fibromatosis familial infiltrative fibromatosis ... catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol. 1997 Aug; ...

  17. Galectin-7 Expression Potentiates HER-2-Positive Phenotype in Breast Cancer

    PubMed Central

    Grosset, Andrée-Anne; Poirier, Françoise; Gaboury, Louis; St-Pierre, Yves

    2016-01-01

    HER-2 positive tumors are among the most aggressive subtypes of breast cancer and are frequently associated with metastasis and poor outcome. As with other aggressive subtypes of breast cancer, these tumors are associated with abnormally high expression of galectin-7 (gal-7), which confers metastatic breast tumor cells with increased invasive behavior. Although previous studies in the rat model of breast tumorigenesis have shown that gal-7 is also increased in primary breast tumor, its contribution to the development of the primary breast tumors remains unclear. In the present work, we have used genetically-engineered gal-7-deficient mice to examine the role of gal-7 in the development of the mammary gland and of breast cancer. Using histological and immunohistological analysis of whole mammary glands at different stages of development, we detected no significant changes between normal and gal-7-deficient mice. To test the involvement of gal-7 in breast cancer, we next examined the effects of loss of gal-7 on mammary tumor development by crossing gal-7-deficient mice with the mammary tumor transgenic mouse strain FVB-Tg(MMTV-Erbb2)NK1Mul/J. Finally, assessment of mice survival and tumor volume showed a delay of mammary tumor growth in the absence of systemic gal-7. These data suggest that gal-7 could potentiate the phenotype of HER-2 positive primary breast cancer. PMID:27902734

  18. Imaging Tumor Hypoxia to Advance Radiation Oncology

    PubMed Central

    Lee, Chen-Ting; Boss, Mary-Keara

    2014-01-01

    Abstract Significance: Most solid tumors contain regions of low oxygenation or hypoxia. Tumor hypoxia has been associated with a poor clinical outcome and plays a critical role in tumor radioresistance. Recent Advances: Two main types of hypoxia exist in the tumor microenvironment: chronic and cycling hypoxia. Chronic hypoxia results from the limited diffusion distance of oxygen, and cycling hypoxia primarily results from the variation in microvessel red blood cell flux and temporary disturbances in perfusion. Chronic hypoxia may cause either tumor progression or regressive effects depending on the tumor model. However, there is a general trend toward the development of a more aggressive phenotype after cycling hypoxia. With advanced hypoxia imaging techniques, spatiotemporal characteristics of tumor hypoxia and the changes to the tumor microenvironment can be analyzed. Critical Issues: In this review, we focus on the biological and clinical consequences of chronic and cycling hypoxia on radiation treatment. We also discuss the advanced non-invasive imaging techniques that have been developed to detect and monitor tumor hypoxia in preclinical and clinical studies. Future Directions: A better understanding of the mechanisms of tumor hypoxia with non-invasive imaging will provide a basis for improved radiation therapeutic practices. Antioxid. Redox Signal. 21, 313–337. PMID:24329000

  19. Polarisation of Tumor-Associated Macrophages toward M2 Phenotype Correlates with Poor Response to Chemoradiation and Reduced Survival in Patients with Locally Advanced Cervical Cancer

    PubMed Central

    Martinelli, Enrica; Pedone Anchora, Luigi; Ferrandina, Gabriella; Tropeano, Giovanna; Fagotti, Anna; Scambia, Giovanni

    2015-01-01

    Objective we investigate the prognostic role of pre-treatment ratio between Type 1 (M1) and Type 2 (M2) tumor-associated macrophages (TAMs) in locally advanced cervical cancer (LACC) patients treated with chemoradiation (CT/RT). Methods 84 consecutive LACC patients treated with cisplatin-based CT/RT for a total dose of 50.0 Gy, followed by radical surgery were analysed. Double-staining immunohistochemistry of CD163/p-STAT, CD68/pSTAT1, CD163/c-MAF, and CD68/c-MAF was performed on tumor samples taken at the time of diagnosis. TAMs with CD163+pSTAT1+, or CD68+pSTAT1+ were defined M1; CD163+c-MAF+ or CD68+c-MAF+ defined the M2 phenotype. The number of M1 and M2 cells was counted at low magnification by evaluating for each case the same tumour area. The ratio between M1 and M2 (M1/M2) was finally calculated. Results At diagnosis, we observed a direct correlation between the number of circulating monocytes and of TAMs (p-value = 0.001). Patients with high M1/M2 experienced more frequently complete pathologic response (no residual tumor) to CT/RT, compared to cases with low M1/M2 (55.0% Vs 29.5%; p-value = 0.029). At multivariate analysis M1/M2 (OR = 2.067; p-value = 0.037) emerged as independent predictor of pathologic response to CT/RT. Women with high M1/M2 showed a longer 5-yrs Disease-free (67.2% Vs. 44.3%; p-value = 0.019), and 5-yrs Overall (69.3% Vs. 46.9%; p-value = 0.037) survival, compared to cases with low M1/M2. The presence of a high M1/M2 ratio was independently associated with an unfavourable survival outcome in multivariate analysis. Conclusions polarisation of TAMs toward a M2 phenotype, as reflected by a lower M1/M2 ratio, is an independent predictor of poor response to CT/RT, and shorter survival in LACC. PMID:26335330

  20. Stressful presentations: mild cold stress in laboratory mice influences phenotype of dendritic cells in naïve and tumor-bearing mice.

    PubMed

    Kokolus, Kathleen M; Spangler, Haley M; Povinelli, Benjamin J; Farren, Matthew R; Lee, Kelvin P; Repasky, Elizabeth A

    2014-01-01

    The ability of dendritic cells (DCs) to stimulate and regulate T cells is critical to effective anti-tumor immunity. Therefore, it is important to fully recognize any inherent factors which may influence DC function under experimental conditions, especially in laboratory mice since they are used so heavily to model immune responses. The goals of this report are to 1) briefly summarize previous work revealing how DCs respond to various forms of physiological stress and 2) to present new data highlighting the potential for chronic mild cold stress inherent to mice housed at the required standard ambient temperatures to influence baseline DCs properties in naïve and tumor-bearing mice. As recent data from our group shows that CD8(+) T cell function is significantly altered by chronic mild cold stress and since DC function is crucial for CD8(+) T cell activation, we wondered whether housing temperature may also be influencing DC function. Here we report that there are several significant phenotypical and functional differences among DC subsets in naïve and tumor-bearing mice housed at either standard housing temperature or at a thermoneutral ambient temperature, which significantly reduces the extent of cold stress. The new data presented here strongly suggests that, by itself, the housing temperature of mice can affect fundamental properties and functions of DCs. Therefore differences in basal levels of stress due to housing should be taken into consideration when interpreting experiments designed to evaluate the impact of additional variables, including other stressors on DC function.

  1. Molecular genetic studies of sporadic pituitary tumors

    SciTech Connect

    Boggild, M.D.; Jenkinson, S.; McTernan, P.; Perrett, C.W.; Clayton, R.N.; Thakker, R.V.; Pistorello, M.; Boscaro, M.; Scanarini, M.

    1994-02-01

    Tumor formation may result from the activation of dominant oncogenes or by inactivation of recessive, tumor suppressor genes. The role of such mutations in the development of pituitary tumors has been studied. Tumors from 88 patients, representing the 4 major classes of adenoma, were investigated. In DNA extracted from matched leukocyte and tumor samples, allelic deletions were sought with 15 probes identifying restriction, fragment length polymorphisms on chromosomes 1, 5, 10, 11, 13, 17, 20, and 22. Evidence of amplification or rearrangement of 10 recognized cellular oncogenes (N-ras, mycL1, mycN, myc, H-ras, bcl1, H-stf1, sea, kraS2, and fos) was sought in tumor DNA. Activating dominant mutations of G{sub s{alpha}} were detected using the polymerase chain reaction to amplify exons 7-10 and hybridizing the product to normal and mutant allele-specific oligonucleotides. Allelic deletions on chromosome 11 were identified in 16 tumors (18%) representing all 4 major subtypes. Deletions on other autosomes were observed in less than 6% of tumors. Three adenomas had deletions on multiple autosomes, 2 of these were aggressive and recurrent. Mutations of G{sub s{alpha}} were confirmed to be specific to somatotrophinomas, being identified in 36% of such tumors in this series. No evidence of amplification or rearrangement of other recognized cellular oncogenes was found. Inactivation of a recessive oncogene on chromosome 11 is an important and possibly early event in the development of the four major types of pituitary adenoma, whereas activating mutations of G{sub s{alpha}} are confirmed to be specific to somatotropinomas. Two aggressive tumors were found to have multiple autosomal losses, suggesting a multistep progression in the development of tumors of this phenotype. 30 refs., 3 figs., 1 tab.

  2. MicroRNA 218 acts as a tumor suppressor by targeting multiple cancer phenotype-associated genes in medulloblastoma.

    PubMed

    Venkataraman, Sujatha; Birks, Diane K; Balakrishnan, Ilango; Alimova, Irina; Harris, Peter S; Patel, Purvi R; Handler, Michael H; Dubuc, Adrian; Taylor, Michael D; Foreman, Nicholas K; Vibhakar, Rajeev

    2013-01-18

    Aberrant expression of microRNAs has been implicated in many cancers. We recently demonstrated differential expression of several microRNAs in medulloblastoma. In this study, the regulation and function of microRNA 218 (miR-218), which is significantly underexpressed in medulloblastoma, was evaluated. Re-expression of miR-218 resulted in a significant decrease in medulloblastoma cell growth, cell colony formation, cell migration, invasion, and tumor sphere size. We used C17.2 neural stem cells as a model to show that increased miR-218 expression results in increased cell differentiation and also decreased malignant transformation when transfected with the oncogene REST. These results suggest that miR-218 acts as a tumor suppressor in medulloblastoma. MicroRNAs function by down-regulating translation of target mRNAs. Targets are determined by imperfect base pairing of the microRNA to the 3'-UTR of the mRNA. To comprehensively identify actual miR-218 targets, medulloblastoma cells overexpressing miR-218 and control cells were subjected to high throughput sequencing of RNA isolated by cross-linking immunoprecipitation, a technique that identifies the mRNAs bound to the RNA-induced silencing complex component protein Argonaute 2. High throughput sequencing of mRNAs identified 618 genes as targets of miR-218 and included both previously validated targets and many targets not predicted computationally. Additional work further confirmed CDK6, RICTOR, and CTSB (cathepsin B) as targets of miR-218 and examined the functional role of one of these targets, CDK6, in medulloblastoma.

  3. Cancer-associated adipocytes promotes breast tumor radioresistance

    SciTech Connect

    Bochet, Ludivine; Meulle, Aline; Imbert, Sandrine; Salles, Bernard; Valet, Philippe; Muller, Catherine

    2011-07-22

    Highlights: {yields} Tumor-surrounding adipocytes contribute to breast cancer progression. {yields} Breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance. {yields} Increased in Chk1 phosphorylation is observed in irradiated co-cultivated tumor cells. {yields} IL-6 is over-expressed in tumor cells co-cultivated with adipocytes. {yields} IL-6 exposure confers increased Chk1 phosphorylation and radioresistance in tumor cells. -- Abstract: Mature adipocytes are excellent candidates to influence tumor behavior through heterotypic signaling processes since these cells produce hormones, growth factors, cytokines and other molecules, a heterogeneous group of molecules named adipokines. Using a 2D coculture system, we demonstrate that breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance and an earlier and higher increase in the effector kinase Chk1, a phenotype that was associated with decreased cell death as compared to tumor cells grown alone. Interestingly, the adipocytes-induced tumor changes taking place during the coculture time preceding the exposure to IR were sufficient to confer the radioresistant effect. Notorious among the changes brought by adipocytes was the significant increase of IL-6 expression in tumor cells, whose activity may well account for the observed tumor cell protection from IR toxicity. Indeed, our data confirmed the protective role of this cytokine as tumor cells incubated after irradiation with recombinant IL-6 exhibit an increased in Chk1 phosphorylation and a radioresistant phenotype, thus far recapitulating the effects observed in the presence of adipocytes. Our current study sheds light on a new role of tumor-surrounding adipocytes in fostering a radioresistant phenotype in breast tumors, a finding that might have important clinical implications in obese patients that frequently exhibit aggressive diseases.

  4. Implications of Oxygen Homeostasis for Tumor Biology and Treatment.

    PubMed

    Garvalov, Boyan K; Acker, Till

    2016-01-01

    Tumors serve as a prototype system to study the role of the hypoxic microenvironment and gain insight in the regulation oxygen homeostasis. A series of biochemical and cell biological studies have significantly extended our knowledge of how tumor cells activate key regulatory mechanisms of oxygen homeostasis not only to adapt to the hostile tumor microenvironment but also to acquire a more aggressive tumor phenotype. Reduced oxygen levels and tumor-specific genetic alterations synergistically drive tumor progression by activating a key transcriptional system, the hypoxia inducible factors (HIFs). HIFs trigger a set of adaptive responses commonly associated with tumor malignancy including tumor angiogenesis, a shift in metabolism, proliferation, invasion, and metastasis. We and others could demonstrate that cancer stem cells are controlled by HIFs within a hypoxic niche, establishing an intriguing link between the well known function of hypoxia in tumor growth and stem cell biology. Additionally, HIF activation potentially conveys resistance to current tumor therapies including the evasive resistance phenotype observed after anti-angiogenic treatment. Together, these findings provide strong evidence that activation of the HIF system is a decisive step in cancer progression that critically shapes therapy response and clinical outcome. Recent insight into the precise mechanisms of oxygen sensing and signalling has offered new promising and potentially selective strategies to counteract this crucial pathway.

  5. Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium.

    PubMed

    Pacheco-Pinedo, Eugenia C; Durham, Amy C; Stewart, Kathleen M; Goss, Ashley M; Lu, Min Min; Demayo, Francesco J; Morrisey, Edward E

    2011-05-01

    Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult mouse lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in lung epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression.

  6. Phenotypic alterations in human saphenous vein culture induced by tumor necrosis factor-alpha and lipoproteins: a preliminary development of an initial atherosclerotic plaque model

    PubMed Central

    2013-01-01

    Background Atherosclerosis is a chronic progressive inflammatory disease of blood vessels particularly the arteries. The development of atherosclerotic plaques or atherogenesis is a complex process that is influenced by cardiovascular risk factors such as vascular inflammation and dyslipidemia. This study demonstrates the ability of tumor necrosis factor-alpha (TNF-α) and low density lipoproteins (LDL) to induce atherosclerotic plaque in human saphenous vein (HSV) organ culture. Methods Normal HSV segments, from male patients who had coronary bypass graft, were cultured in DMEM containing 5% heat inactivated fetal bovine serum. TNF-α (5 ng/ml) was applied in combination with native LDL (nLDL) or oxidized LDL (oxLDL) at the dose of 50 μg/ml for 14 days. The phenotypic changes of the organ cultures characteristic of initial atherosclerotic plaques were evaluated. The effect of anti-atherogenic agent, 17-β estradiol (E2), was also determined. Results Histologic, histomorphometric, and immunohistochemical examinations revealed that HSV rings stimulated with TNF-α + nLDL or TNF-α + oxLDL can exhibit the essential morphological features of atherogenesis, including fibrous cap formation, cholesterol clefts, evident thickening of the intimal layer, increased proliferation of smooth muscle cells (SMC) and migration to the subendothelial layer, significant SMC foam cell formation, and increased expression of adhesion molecules in the vascular wall. Addition of E2 (50 nM) to the culture significantly modulated the critical changes. Consistently, mRNA profiling of the HSV model revealed that 50 of 84 genes of atherosclerosis were up-regulated. Conclusions Phenotypic changes characteristic of the initial development of atherosclerotic plaques can be induced in HSV organ culture. PMID:24010774

  7. Hypothyroidism Enhances Tumor Invasiveness and Metastasis Development

    PubMed Central

    Martínez-Iglesias, Olaia; García-Silva, Susana; Regadera, Javier; Aranda, Ana

    2009-01-01

    Background Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients Methodology/Principal Findings In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRβ1–expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRβ–expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs. Conclusions/Significance These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer. PMID:19641612

  8. Genetics of aggressive behavior: An overview.

    PubMed

    Veroude, Kim; Zhang-James, Yanli; Fernàndez-Castillo, Noèlia; Bakker, Mireille J; Cormand, Bru; Faraone, Stephen V

    2016-01-01

    The Research Domain Criteria (RDoC) address three types of aggression: frustrative non-reward, defensive aggression and offensive/proactive aggression. This review sought to present the evidence for genetic underpinnings of aggression and to determine to what degree prior studies have examined phenotypes that fit into the RDoC framework. Although the constructs of defensive and offensive aggression have been widely used in the animal genetics literature, the human literature is mostly agnostic with regard to all the RDoC constructs. We know from twin studies that about half the variance in behavior may be explained by genetic risk factors. This is true for both dimensional, trait-like, measures of aggression and categorical definitions of psychopathology. The non-shared environment seems to have a moderate influence with the effects of shared environment being unclear. Human molecular genetic studies of aggression are in an early stage. The most promising candidates are in the dopaminergic and serotonergic systems along with hormonal regulators. Genome-wide association studies have not yet achieved genome-wide significance, but current samples are too small to detect variants having the small effects one would expect for a complex disorder. The strongest molecular evidence for a genetic basis for aggression comes from animal models comparing aggressive and non-aggressive strains or documenting the effects of gene knockouts. Although we have learned much from these prior studies, future studies should improve the measurement of aggression by using a systematic method of measurement such as that proposed by the RDoC initiative.

  9. MicroRNA Expression Profile Identifies High Grade, Non-Muscle-Invasive Bladder Tumors at Elevated Risk to Progress to an Invasive Phenotype

    PubMed Central

    Lenherr, Sara M.; Tsai, Sheaumei; Silva Neto, Brasil; Sullivan, Travis B.; Cimmino, Cara B.; Logvinenko, Tanya; Gee, Jason; Huang, Wei; Libertino, John A.; Summerhayes, Ian C.; Rieger-Christ, Kimberly M.

    2017-01-01

    The objective of this study was to identify a panel of microRNAs (miRNAs) differentially expressed in high-grade non-muscle invasive (NMI; TaG3–T1G3) urothelial carcinoma that progress to muscle-invasive disease compared to those that remain non-muscle invasive, whether recurrence happens or not. Eighty-nine high-grade NMI urothelial carcinoma lesions were identified and total RNA was extracted from paraffin-embedded tissue. Patients were categorized as either having a non-muscle invasive lesion with no evidence of progression over a 3-year period or as having a similar lesion showing progression to muscle invasion over the same period. In addition, comparison of miRNA expression levels between patients with and without prior intravesical therapy was performed. Total RNA was pooled for microarray analysis in each group (non-progressors and progressors), and qRT-PCR of individual samples validated differential expression between non-progressive and progressive lesions. MiR-32-5p, -224-5p, and -412-3p were associated with cancer-specific survival. Downregulation of miR-203a-3p and miR-205-5p were significantly linked to progression in non-muscle invasive bladder tumors. These miRNAs include those implicated in epithelial mesenchymal transition, previously identified as members of a panel characterizing transition from the non-invasive to invasive phenotype in bladder tumors. Furthermore, we were able to identify specific miRNAs that are linked to postoperative outcome in patients with high grade NMI urothelial carcinoma of the bladder (UCB) that progressed to muscle-invasive (MI) disease. PMID:28218662

  10. Loss of the tumor suppressor spinophilin (PPP1R9B) increases the cancer stem cell population in breast tumors.

    PubMed

    Ferrer, I; Verdugo-Sivianes, E M; Castilla, M A; Melendez, R; Marin, J J; Muñoz-Galvan, S; Lopez-Guerra, J L; Vieites, B; Ortiz-Gordillo, M J; De León, J M; Praena-Fernandez, J M; Perez, M; Palacios, J; Carnero, A

    2016-05-01

    The spinophilin (Spn, PPP1R9B) gene is located at 17q21.33, a region frequently associated with microsatellite instability and loss of heterozygosity, especially in breast tumors. Spn is a regulatory subunit of phosphatase1a (PP1), which targets the catalytic subunit to distinct subcellular locations. Spn downregulation reduces PPP1CA activity against the retinoblastoma protein, pRb, thereby maintaining higher levels of phosphorylated pRb. This effect contributes to an increase in the tumorigenic properties of cells in certain contexts. Here, we explored the mechanism of how Spn downregulation contributes to the malignant phenotype and poor prognosis in breast tumors and found an increase in the stemness phenotype. Analysis of human breast tumors showed that Spn mRNA and protein are reduced or lost in 15% of carcinomas, correlating with a worse prognosis, a more aggressive tumor phenotype and triple-negative tumors, whereas luminal tumors showed high Spn levels. Downregulation of Spn by shRNA increased the stemness properties along with the expression of stem-related genes (Sox2, KLF4, Nanog and OCT4), whereas ectopic overexpression of Spn cDNA reduced these properties. Breast tumor stem cells appeared to have low levels of Spn mRNA, and Spn loss correlated with increased stem-like cell appearance in breast tumors as indicated by an increase in CD44+/CD24- cells. A reduction of the levels of PPP1CA mimicked the cancer stem-like cell phenotype of Spn downregulation, suggesting that the mechanism of Spn involves PP1a. These increased cancer stem cell-like properties with reduced Spn might account for the malignant phenotype observed in Spn-loss tumors and may contribute to a worse patient prognosis.

  11. Dedifferentiated adamantinoma with revertant mesenchymal phenotype.

    PubMed

    Hazelbag, Hans Marten; Laforga, Juan B; Roels, Hendrik J L; Hogendoorn, Pancras C W

    2003-12-01

    In adamantinoma of long bones, an osteofibrous dysplasia-like form with scattered epithelial elements and a classic form with abundant epithelium are distinguished. Osteofibrous dysplasia-like adamantinomas occur in children and adolescents and behave relatively benign, whereas classic adamantinomas predominate in adults and have a more aggressive clinical course. Because some osteofibrous dysplasia-like tumors have progressed to classic adamantinomas, it is hypothesized that the former is a potential precursor of the latter, showing mesenchymal-to-epithelial transformation. We report a new morphologic variant of adamantinoma in three patients with sarcomatoid transformation of the epithelial component: one in a primary tumor and two in local recurrences. One patient died of metastatic disease. Histologically, the tumors showed loss of the original characteristic epithelial differentiation with transition to fields of highly pleomorphic cells without epithelial features, high mitotic count, and deposition of osteoid and chondroid matrix. These dedifferentiated areas showed pankeratin positivity as well, although there were some changes in keratin subclass profile compared with other classic adamantinomas. This peculiar variant of long bone adamantinoma shows that in addition to mesenchymal-to-epithelial transformation in the early stage of development, progression to an aggressive subtype may be associated with epithelial-to-mesenchymal transition ("sarcomatoid dedifferentiation"), in which the epithelial immunophenotype is conserved. Thereby it may serve as an example of the plasticity of the mesenchymal phenotype. When confronted with a biopsy of a cortical tumor of the tibia showing sarcomatoid morphology and keratin positivity, adamantinoma should be included in the differential diagnosis, as its distinction has important implications for treatment and prognosis.

  12. Context dependent reversion of tumor phenotype by connexin-43 expression in MDA-MB231 cells and MCF-7 cells: Role of β-catenin/connexin43 association

    SciTech Connect

    Talhouk, Rabih S.; Fares, Mohamed-Bilal; Rahme, Gilbert J.; Hariri, Hanaa H.; Rayess, Tina; Dbouk, Hashem A.; Bazzoun, Dana; Al-Labban, Dania; El-Sabban, Marwan E.

    2013-12-10

    Connexins (Cx), gap junction (GJ) proteins, are regarded as tumor suppressors, and Cx43 expression is often down regulated in breast tumors. We assessed the effect of Cx43 over-expression in 2D and 3D cultures of two breast adenocarcinoma cell lines: MCF-7 and MDA-MB-231. While Cx43 over-expression decreased proliferation of 2D and 3D cultures of MCF-7 by 56% and 80% respectively, MDA-MB-231 growth was not altered in 2D cultures, but exhibited 35% reduction in 3D cultures. C-terminus truncated Cx43 did not alter proliferation. Untransfected MCF-7 cells formed spherical aggregates in 3D cultures, and MDA-MB-231 cells formed stellar aggregates. However, MCF-7 cells over-expressing Cx43 formed smaller sized clusters and Cx43 expressing MDA-MB-231 cells lost their stellar morphology. Extravasation ability of both MCF-7 and MDA-MB-231 cells was reduced by 60% and 30% respectively. On the other hand, silencing Cx43 in MCF10A cells, nonneoplastic human mammary cell line, increased proliferation in both 2D and 3D cultures, and disrupted acinar morphology. Although Cx43 over-expression did not affect total levels of β-catenin, α-catenin and ZO-2, it decreased nuclear levels of β-catenin in 2D and 3D cultures of MCF-7 cells, and in 3D cultures of MDA-MB-231 cells. Cx43 associated at the membrane with α-catenin, β-catenin and ZO-2 in 2D and 3D cultures of MCF-7 cells, and only in 3D conditions in MDA-MB-231 cells. This study suggests that Cx43 exerts tumor suppressive effects in a context-dependent manner where GJ assembly with α-catenin, β-catenin and ZO-2 may be implicated in reducing growth rate, invasiveness, and, malignant phenotype of 2D and 3D cultures of MCF-7 cells, and 3D cultures of MDA-MB-231 cells, by sequestering β-catenin away from nucleus. - Highlights: • Cx43 over-expressing MCF-7 and MDA-MB-231 were grown in 2D and 3D cultures. • Proliferation and growth morphology were affected in a context dependent manner. • Extravasation ability of both MCF

  13. Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhance aggressiveness in triple negative breast cancers

    PubMed Central

    Ananthula, Suryatheja; Sinha, Abhilasha; Gassim, Mohamed El; Batth, Simran; Marshall, Gailen D.; Gardner, Lauren H.; Shimizu, Yoshiko; ElShamy, Wael M.

    2016-01-01

    Resident mesenchymal stem cells (MSCs) promote cancer progression. However, pathways and mechanisms involved in recruiting MSCs into breast tumors remain largely undefined. Here we show that geminin-dependent acetylation releases HMGB1 from the chromatin to the cytoplasm and extracellular space. Extracellular acetylated HMGB1 (Ac-HMGB1) promotes geminin overexpressing (GemOE) cells survival by binding to RAGE and activating NF-κB signaling. Extracellular Ac-HMGB1 also triggers expression and activation of RAGE in the non-expressing MSCs. RAGE activation induces expression of CXCR4 in MSCs and directional migration towards SDF1 (aka CXCL12)-expressing GemOE cells in vitro and in vivo. These effects augmented by the necrotic and hypoxic environment in GemOE tumors, especially within their cores. Reciprocal interactions between newly recruited MSCs and GemOE tumor cells elevate tumor-initiating (TIC), basal and epithelial-to-mesenchymal transition (EMT) traits and enhance aggressiveness in vitro and in vivo in GemOE tumor cells. Indeed, faster, larger and more aggressive tumors develop when GemOE cells are co-injected with MSCs in orthotopic breast tumor model. Concurrently, inhibiting c-Abl (and thus geminin function), RAGE or CXCR4 prevented MSCs recruitment to GemOE cells in vitro and in vivo, and decreased the TIC, basal and EMT phenotypes in these tumor cells. Accordingly, we propose that GemOE tumor cells present within tumor cores represent metastatic precursors, and suppressing the GemOE→HMGB1/RAGE→SDF1/CXCR4 signaling circuit could be a valid target for therapies to inhibit GemOE tumors and their metastases. PMID:26989079

  14. KRAS and PIK3CA mutations in colorectal adenocarcinomas correlate with aggressive histological features and behavior.

    PubMed

    Jang, Sejin; Hong, Mineui; Shin, Mi Kyung; Kim, Byung Chun; Shin, Hyung-Sik; Yu, Eunsil; Hong, Seung-Mo; Kim, Jihun; Chun, Sung Min; Kim, Tae-Im; Choi, Kyung-Chan; Ko, Young Woong; Kim, Jeong Won

    2017-02-08

    Tumor budding (TB) in colorectal carcinoma (CRC) is related to epithelial-mesenchymal transition (EMT) and has been recently characterized as an indicator of poor prognosis along with lymphovascular tumor emboli (LVE), perineural invasion (PNI), and an infiltrative growth pattern. Mutations in the genes of the Ras-MAPK and PI3K pathways are associated with EMT and an aggressive CRC phenotype and have been used in patient stratification for anti-EGF receptor therapies; however, the impact of these mutations on CRC morphology and behavior remains unclear. In this study, using a multi-gene panel, we detected KRAS, NRAS, BRAF, PIK3CA, TP53, and POLE mutations in 90 CRCs and investigated their associations with clinicopathological parameters, including TB. Our results showed that 21 of 34 tumors with high-grade TB had KRAS mutations (P=.001) and KRAS G12D and PIK3CA exon 9 variants were significantly associated with high-grade TB (P=.002 and .006, respectively); furthermore, tumors with KRAS mutations in exons 3 and 4 tended to have LVE and PNI (P=.044 and .049, respectively). PIK3CA exon 9 mutations indicated a tendency for shorter disease-free survival (P=.030), whereas BRAF mutations were associated with extracellular mucin deposition (P=.016). Our study revealed a correlation of KRAS mutations with high-grade TB, an association of certain KRAS and PIK3CA variants with aggressive clinicopathological features, as well as a possible relationship between BRAF mutations and mucin production in CRC.

  15. The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma.

    PubMed

    Keane, Colm; Gould, Clare; Jones, Kimberley; Hamm, David; Talaulikar, Dipti; Ellis, Jonathan; Vari, Frank; Birch, Simone; Han, Erica; Wood, Peter; Le-Cao, Kim-Anh; Green, Michael R; Crooks, Pauline; Jain, Sanjiv; Tobin, Josh; Steptoe, Raymond J; Gandhi, Maher K

    2017-04-01

    Purpose: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.Experimental Design: We performed high-throughput unbiased TCRβ sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline "R-CHOP" therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS).Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P < 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%-79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%-88.5%; P = 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%-76.6%) versus 72.6% (95% CI, 58.8%-82.4%, P = 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV(+) DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevated PD-1, PD-L1, and PD-L2 immune checkpoint molecules.Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy. Clin Cancer Res; 23(7); 1820-8. ©2016 AACR.

  16. PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis.

    PubMed

    Su, Z Z; Goldstein, N I; Jiang, H; Wang, M N; Duigou, G J; Young, C S; Fisher, P B

    1999-12-21

    Cancer is a progressive disease culminating in acquisition of metastatic potential by a subset of evolving tumor cells. Generation of an adequate blood supply in tumors by production of new blood vessels, angiogenesis, is a defining element in this process. Although extensively investigated, the precise molecular events underlying tumor development, cancer progression, and angiogenesis remain unclear. Subtraction hybridization identified a genetic element, progression elevated gene-3 (PEG-3), whose expression directly correlates with cancer progression and acquisition of oncogenic potential by transformed rodent cells. We presently demonstrate that forced expression of PEG-3 in tumorigenic rodent cells, and in human cancer cells, increases their oncogenic potential in nude mice as reflected by a shorter tumor latency time and the production of larger tumors with increased vascularization. Moreover, inhibiting endogenous PEG-3 expression in progressed rodent cancer cells by stable expression of an antisense expression vector extinguishes the progressed cancer phenotype. Cancer aggressiveness of PEG-3 expressing rodent cells correlates directly with increased RNA transcription, elevated mRNA levels, and augmented secretion of vascular endothelial growth factor (VEGF). Furthermore, transient ectopic expression of PEG-3 transcriptionally activates VEGF in transformed rodent and human cancer cells. Taken together these data demonstrate that PEG-3 is a positive regulator of cancer aggressiveness, a process regulated by augmented VEGF production. These studies also support an association between expression of a single nontransforming cancer progression-inducing gene, PEG-3, and the processes of cancer aggressiveness and angiogenesis. In these contexts, PEG-3 may represent an important target molecule for developing cancer therapeutics and inhibitors of angiogenesis.

  17. Hypoxia in Microscopic Tumors

    PubMed Central

    Li, Xiao-Feng; O’Donoghue, Joseph A

    2008-01-01

    Tumor hypoxia has been commonly observed in a broad spectrum of primary solid malignancies. Hypoxia is associated with tumor progression, increased aggressiveness, enhanced metastatic potential and poor prognosis. Hypoxic tumor cells are resistant to radiotherapy and some forms of chemotherapy. Using an animal model, we recently showed that microscopic tumors less than 1 mm diameter were severely hypoxic. In this review, models and techniques for the study of hypoxia in microscopic tumors are discussed. PMID:18384940

  18. The neurobiology of aggression and violence.

    PubMed

    Rosell, Daniel R; Siever, Larry J

    2015-06-01

    Aggression and violence represent a significant public health concern and a clinical challenge for the mental healthcare provider. A great deal has been revealed regarding the neurobiology of violence and aggression, and an integration of this body of knowledge will ultimately serve to advance clinical diagnostics and therapeutic interventions. We will review here the latest findings regarding the neurobiology of aggression and violence. First, we will introduce the construct of aggression, with a focus on issues related to its heterogeneity, as well as the importance of refining the aggression phenotype in order to reduce pathophysiologic variability. Next we will examine the neuroanatomy of aggression and violence, focusing on regional volumes, functional studies, and interregional connectivity. Significant emphasis will be on the amygdala, as well as amygdala-frontal circuitry. Then we will turn our attention to the neurochemistry and molecular genetics of aggression and violence, examining the extensive findings on the serotonergic system, as well as the growing literature on the dopaminergic and vasopressinergic systems. We will also address the contribution of steroid hormones, namely, cortisol and testosterone. Finally, we will summarize these findings with a focus on reconciling inconsistencies and potential clinical implications; and, then we will suggest areas of focus for future directions in the field.

  19. Vision 20/20: Molecular-guided surgical oncology based upon tumor metabolism or immunologic phenotype: Technological pathways for point of care imaging and intervention

    PubMed Central

    Paulsen, Keith D.; Samkoe, Kimberley S.; Elliott, Jonathan T.; Hasan, Tayyaba; Strong, Theresa V.; Draney, Daniel R.; Feldwisch, Joachim

    2016-01-01

    Surgical guidance with fluorescence has been demonstrated in individual clinical trials for decades, but the scientific and commercial conditions exist today for a dramatic increase in clinical value. In the past decade, increased use of indocyanine green based visualization of vascular flow, biliary function, and tissue perfusion has spawned a robust growth in commercial systems that have near-infrared emission imaging and video display capabilities. This recent history combined with major preclinical innovations in fluorescent-labeled molecular probes, has the potential for a shift in surgical practice toward resection guidance based upon molecular information in addition to conventional visual and palpable cues. Most surgical subspecialties already have treatment management decisions partially based upon the immunohistochemical phenotype of the cancer, as assessed from molecular pathology of the biopsy tissue. This phenotyping can inform the surgical resection process by spatial mapping of these features. Further integration of the diagnostic and therapeutic value of tumor metabolism sensing molecules or immune binding agents directly into the surgical process can help this field mature. Maximal value to the patient would come from identifying the spatial patterns of molecular expression in vivo that are well known to exist. However, as each molecular agent is advanced into trials, the performance of the imaging system can have a critical impact on the success. For example, use of pre-existing commercial imaging systems are not well suited to image receptor targeted fluorophores because of the lower concentrations expected, requiring orders of magnitude more sensitivity. Additionally the imaging system needs the appropriate dynamic range and image processing features to view molecular probes or therapeutics that may have nonspecific uptake or pharmacokinetic issues which lead to limitations in contrast. Imaging systems need to be chosen based upon objective

  20. Alcohol and Aggression.

    ERIC Educational Resources Information Center

    Gustafson, Roland

    1994-01-01

    Reviews the acute effects of alcohol on aggressive responding. From experimental studies that use human subjects, it is concluded that a moderate dose of alcohol does not increase aggression if subjects are unprovoked. Under provocative situations, aggression is increased as a function of alcohol intoxication, provided that subjects are restricted…

  1. Modeling Aggressive Medulloblastoma Using Human-Induced Pluripotent Stem Cells

    DTIC Science & Technology

    2015-07-01

    AWARD NUMBER: W81XWH-14-1-0176 TITLE: Modeling Aggressive Medulloblastoma Using Human-Induced Pluripotent Stem Cells PRINCIPAL INVESTIGATOR...Prescribed by ANSI Std. Z39.18 July 2015 Annual 01-July 2014 -- 30 Jun 2015 Modeling Aggressive Medulloblastoma Using Human-Induced Pluripotent Stem...induced pluripotent stem cells by Atoh1 induction can be efficiently transformed by MYC oncogene to form aggressive brain tumors that recapitulate human

  2. High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures

    PubMed Central

    Penfornis, Patrice; Cai, David Z; Harris, Michael R; Walker, Ryan; Licini, David; Fernandes, Joseph D A; Orr, Griffin; Koganti, Tejaswi; Hicks, Chindo; Induru, Spandana; Meyer, Mark S; Khokha, Rama; Barr, Jennifer; Pochampally, Radhika R

    2014-01-01

    Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have isolated and characterized cell cultures derived from four central high-grade human OS samples. Furthermore, we used the cell cultures to study the role of CD49f in OS progression. Recent studies have implicated CD49f in stemness and multipotency of both cancer stem cells and mesenchymal stem cells. Therefore, we investigated the role of CD49f in osteosarcomagenesis. First, single cell suspensions of tumor biopsies were subcultured and characterized for cell surface marker expression. Next, we characterized the growth and differentiation properties, sensitivity to chemotherapy drugs, and anchorage-independent growth. Xenograft assays showed that cell populations expressing CD49fhi/CD90lo cell phenotype produced an aggressive tumor. Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability. Furthermore, the CD49fhi/CD90lo cell population is generating more aggressive OS tumor growth and indicating this cell surface marker could be a potential candidate for the isolation of an aggressive cell type in OSs. PMID:24802970

  3. Highly and moderately aggressive mouse ovarian cancer cell lines exhibit differential gene expression

    PubMed Central

    Zhang, Wensheng; Kale, Shubha P.; McFerrin, Harris; Davenport, Ian; Wang, Guangdi; Skripnikova, Elena; Li, Xiao-Lin; Bowen, Nathan J.; McDaniels, Leticia B; Meng, Yuan-Xiang; Polk, Paula; Liu, Yong-Yu; Zhang, Qian-Jin

    2017-01-01

    Patients with advanced epithelial ovarian cancer often experience disease recurrence after standard therapies, a critical factor in determining their five-year survival rate. Recent reports indicated that long-term or short-term survival is associated with varied gene expression of cancer cells. Thus, identification of novel prognostic biomarkers should be considered. Since the mouse genome is similar to the human genome, we explored potential prognostic biomarkers using two groups of mouse ovarian cancer cell lines (group 1: IG-10, IG-10pw, and IG-10pw/agar; group 2: IG-10 clones 2, 3, and 11) which display highly and moderately aggressive phenotypes in vivo. Mice injected with these cell lines have different survival time and rates, capacities of tumor, and ascites formations, reflecting different prognostic potentials. Using an Affymetrix Mouse Genome 430 2.0 Array, a total of 181 genes were differentially expressed (P<0.01) by at least twofold between two groups of the cell lines. Of the 181 genes, 109 and 72 genes were overexpressed in highly and moderately aggressive cell lines, respectively. Analysis of the 109 and 72 genes using Ingenuity Pathway Analysis (IPA) tool revealed two cancer-related gene networks. One was associated with the highly aggressive cell lines and affiliated with MYC gene, and another was associated with the moderately aggressive cell lines and affiliated with the androgen receptor (AR). Finally, the gene enrichment analysis indicated that the overexpressed 89 genes (out of 109 genes) in highly aggressive cell lines had a function annotation in the David database. The cancer-relevant significant gene ontology (GO) terms included Cell cycle, DNA metabolic process, and Programmed cell death. None of the genes from a set of the 72 genes overexpressed in the moderately aggressive cell lines had a function annotation in the David database. Our results suggested that the overexpressed MYC and 109 gene set represented highly aggressive ovarian

  4. Hearing regulates Drosophila aggression.

    PubMed

    Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C; Heinrich, Ralf; Callaerts, Patrick

    2017-02-21

    Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly's auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level.

  5. Imaging Prostatic Lipids to Distinguish Aggressive Prostate Cancer

    DTIC Science & Technology

    2014-09-01

    FAS activity in prostatectomy samples, intraprostatic lipid as measured by MRSI and prostate tumor aggressiveness. 3) To quantify key metabolic ...intermediates involved in lipid metabolism , mitochondrial function, inflammation, and apoptosis in the prostatectomy samples. 15. SUBJECT TERMS : none...vivo intraprostatic fat as measured by 1H MRSI, metabolic signatures of lipid oxidation and metabolism , and prostate cancer aggressiveness, our

  6. Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival.

    PubMed

    Fink, Stephen P; Myeroff, Lois L; Kariv, Revital; Platzer, Petra; Xin, Baozhong; Mikkola, Debra; Lawrence, Earl; Morris, Nathan; Nosrati, Arman; Willson, James K V; Willis, Joseph; Veigl, Martina; Barnholtz-Sloan, Jill S; Wang, Zhenghe; Markowitz, Sanford D

    2015-10-13

    Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target.

  7. IGF-1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors

    PubMed Central

    Rota, Lauren M.; Albanito, Lidia; Shin, Marcus E.; Goyeneche, Corey L.; Shushanov, Sain; Gallagher, Emily J.; LeRoith, Derek; Lazzarino, Deborah A.; Wood, Teresa L.

    2014-01-01

    Triple-negative breast cancers (TNBC) are an aggressive disease subtype which unlike other subtypes lack an effective targeted therapy. Inhibitors of the insullin-like growth factor receptor (IGF-1R) have been considered for use in treating TNBC. Here we provide genetic evidence that IGF-1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt-1 and mutant IGF-1R, a reduction in IGF-1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamal cell phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29hi/CD24+) and luminal (CD24+/CD61+/CD29lo) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacological inhibition of the IGF-1R in vitro was sufficient to increase the tumorsphere-forming efficiency of MMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor vs the IR-B isoform, which in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors an attenuation of IGF-1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes, with potential implications for understanding TNBC pathobiology and treatment. PMID:25092896

  8. [Enophthalmos in an orbital tumor].

    PubMed

    Szabo, Bianca; Szabo, I; Nicula, Cristina; Popescu, Livia Adriana

    2013-01-01

    Enophtalmus is an unusual sign of the orbital tumors often represented by proptosis. One patient with enophtalmus and intraorbital tumor and aplasy is presented. The treatment of choice of orbital tumor is complete surgical excision and careful follow-up. Considering the more aggressive course followed by recurrent tumor, correct diagnosis and management is essential.

  9. A feasibility study for enrichment of highly-aggressive cancer subpopulations by their biophysical properties via dielectrophoresis enhanced with synergistic fluid flow.

    PubMed

    Douglas, Temple Anne; Cemazar, Jaka; Balani, Nikita; Sweeney, Daniel C; Schmelz, Eva M; Davalos, Rafael V

    2017-03-25

    A common problem with cancer treatment is the development of treatment resistance and tumor recurrence that result from treatments that kill most tumor cells yet leave behind aggressive cells to repopulate. Presented here is a microfluidic device that can be used to isolate tumor subpopulations to optimize treatment selection. Dielectrophoresis (DEP) is a phenomenon where particles are polarized by an electric field and move along the electric field gradient. Different cell subpopulations have different DEP responses depending on their bioelectrical phenotype, which, we hypothesize, correlate with aggressiveness. We have designed a microfluidic device in which a region containing posts locally distorts channel of the electric field created by an AC voltage across a microfluidic channel and which forces cells toward the posts through DEP. This force is balanced with a simultaneous drag force from fluid motion that pulls cells away from the posts. We have shown that by adjusting the drag force, cells with aggressive phenotypes are influenced more by the DEP force and trap on posts while others flow through the chip unaffected. Utilizing single-cell trapping on cell-sized posts by a drag-DEP force balance, we show that separation of very similar cell subpopulations may be achieved, a result that was previously impossible with DEP alone. Separated subpopulations maintain high viability downstream, and remain in a native state, without fluorescent labeling. These cells can then be cultured to help select a therapy that kills aggressive subpopulations equally or better than the bulk of the tumor, mitigating resistance and recurrence. This article is protected by copyright. All rights reserved.

  10. Melanoma cells revive an embryonic transcriptional network to dictate phenotypic heterogeneity.

    PubMed

    Vandamme, Niels; Berx, Geert

    2014-01-01

    Compared to the overwhelming amount of literature describing how epithelial-to-mesenchymal transition (EMT)-inducing transcription factors orchestrate cellular plasticity in embryogenesis and epithelial cells, the functions of these factors in non-epithelial contexts, such as melanoma, are less clear. Melanoma is an aggressive tumor arising from melanocytes, endowed with unique features of cellular plasticity. The reversible phenotype-switching between differentiated and invasive phenotypes is increasingly appreciated as a mechanism accounting for heterogeneity in melanoma and is driven by oncogenic signaling and environmental cues. This phenotypic switch is coupled with an intriguing and somewhat counterintuitive signaling switch of EMT-inducing transcription factors. In contrast to carcinomas, different EMT-inducing transcription factors have antagonizing effects in melanoma. Balancing between these different EMT transcription factors is likely the key to successful metastatic spread of melanoma.

  11. DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors.

    PubMed

    Sin-Chan, Patrick; Huang, Annie

    2014-10-01

    Malignant brain tumors, which are the leading cause of cancer-related morbidity and mortality in children, span a wide spectrum of diseases with distinct clinical phenotypes but may share remarkably similar morphologic features. Until recently, few molecular markers of childhood brain tumors have been identified, which has limited therapeutic advances. Recent global genomic studies have enabled robust molecular classification of childhood brain tumors and the identification and consolidation of rare, seemingly disparate clinical entities. It is now increasingly evident that deregulation of epigenetic processes contributes substantially to heterogeneity in tumor phenotypes and comprise significant drivers of cancer initiation and progression. Specifically, DNA hypermethylation and silencing of critical tumor suppressor genes by DNA methyltransferases (DNMT) has emerged as an important and fundamental mechanism in brain tumor pathogenesis. These observations have been underscored by the recent discovery of TTYH1-C19MC gene fusions in an aggressive pediatric embryonal brain tumor, which results in deregulation and increased expression of a neural-specific DNMT3B isoform in C19MC-associated brain tumors. Our observations that pharmacological inhibitors of DNMTs and histone deacetylases significantly inhibit growth of cells derived from C19MC-associated tumors indicate targeting of epigenomic modifiers as a novel therapeutic approach for these highly treatment-resistant tumors.

  12. Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells.

    PubMed

    Fielitz, Kathrin; Althoff, Kristina; De Preter, Katleen; Nonnekens, Julie; Ohli, Jasmin; Elges, Sandra; Hartmann, Wolfgang; Klöppel, Günter; Knösel, Thomas; Schulte, Marc; Klein-Hitpass, Ludger; Beisser, Daniela; Reis, Henning; Eyking, Annette; Cario, Elke; Schulte, Johannes H; Schramm, Alexander; Schüller, Ulrich

    2016-11-15

    Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies.

  13. Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells

    PubMed Central

    Fielitz, Kathrin; Althoff, Kristina; De Preter, Katleen; Nonnekens, Julie; Ohli, Jasmin; Elges, Sandra; Hartmann, Wolfgang; Klöppel, Günter; Knösel, Thomas; Schulte, Marc; Klein-Hitpass, Ludger; Beisser, Daniela; Reis, Henning; Eyking, Annette; Cario, Elke; Schulte, Johannes H.

    2016-01-01

    Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies. PMID:27769070

  14. Differentiated thyroid tumors: surgical indications.

    PubMed

    Lucchini, R; Monacelli, M; Santoprete, S; Triola, R; Conti, C; Pecoriello, R; Favoriti, P; Di Patrizi, M S; Barillaro, I; Boccolini, A; Avenia, S; D'Ajello, M; Sanguinetti, A; Avenia, N

    2013-01-01

    Thyroid gland tumors represent 1% of malignant tumors. In Italy their incidence is in constant growth. The aggressiveness depends on the histological type. The relative non-aggressive grade of different forms of tumors is the basis for discussing the treatment of choice: total thyroidectomy vs lobectomy with or without lymphadenectomy of the sixth level in the absence of metastasis. Authors report about their experience, and they advocate, given the high percentage of multicentric forms, total thyroidectomy as treatment of choice.

  15. Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model

    PubMed Central

    Brenneman, Mark; Field, Amanda; Yang, Jiandong; Williams, Gretchen; Doros, Leslie; Rossi, Christopher; Schultz, Kris Ann; Rosenberg, Avi; Ivanovich, Jennifer; Turner, Joyce; Gordish-Dressman, Heather; Stewart, Douglas; Yu, Weiying; Harris, Anne; Schoettler, Peter; Goodfellow, Paul; Dehner, Louis; Messinger, Yoav; Hill, D. Ashley

    2015-01-01

    Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition,  DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of  DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of  DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing  DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or  de novo germline LOF mutations, most of which truncate the  DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing  DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of  DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in  DICER1-associated  tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development. PMID:26925222

  16. Opposing roles of glutaminase isoforms in determining glioblastoma cell phenotype.

    PubMed

    Szeliga, Monika; Albrecht, Jan

    2015-09-01

    Glutamine (Gln) and glutamate (Glu) play pivotal roles in the malignant phenotype of brain tumors via multiple mechanisms. Glutaminase (GA, EC 3.5.1.2) metabolizes Gln to Glu and ammonia. Human GA isoforms are encoded by two genes: GLS gene codes for kidney-type isoforms, KGA and GAC, whereas GLS2 codes for liver-type isoforms, GAB and LGA. The expression pattern of both genes in different neoplastic cell lines and tissues implicated that the kidney-type isoforms are associated with cell proliferation, while the liver-type isoforms dominate in, and contribute to the phenotype of quiescent cells. GLS gene has been demonstrated to be regulated by oncogene c-Myc, whereas GLS2 gene was identified as a target gene of p53 tumor suppressor. In glioblastomas (GBM, WHO grade IV), the most aggressive brain tumors, high levels of GLS and only traces or lack of GLS2 transcripts were found. Ectopic overexpression of GLS2 in human glioblastoma T98G cells decreased their proliferation and migration and sensitized them to the alkylating agents often used in the chemotherapy of gliomas. GLS silencing reduced proliferation of glioblastoma T98G cells and strengthen the antiproliferative effect evoked by previous GLS2 overexpression.

  17. Extra-Abdominal Desmoid Tumors (Aggressive Fibromatoses)

    MedlinePlus

    ... not intended to serve as medical advice. Anyone seeking specific orthopaedic advice or assistance should consult his ... topic.cfm?topic=A00188) Editorial Board & Staff Contributors Online Agreements Linking Policy Advertising & Sponsorship Privacy Policy AAOS ...

  18. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    DTIC Science & Technology

    2009-07-01

    does. To test the efficacy of these two approaches, we carried an experiment using Intralipid -10% suspension in water as a model medium, and two...absorptive targets. The concentration of Intralipid -10% was adjusted to provide a transport mean free path lt ~ 1.43 mm and an absorption coefficient...efficacy is d emonstrated b y imaging t wo targ ets embedded in Intralipid -10% suspension in water. @2009 Optical Society of America OCIS codes

  19. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    DTIC Science & Technology

    2010-07-01

    given source– detector pair is sensitive to a change in the optical properties [10,11]. Compared to Monte Carlo method, reconstruction based on FEM...suspension in water . @2009 Optical Society of America OCIS codes: (110.0113) Imaging through turbid media; (170.3880) Medical and biological imaging...However, the overlapping lipid and adjacent water signals obscure lactate in the conventional MRSI. Over the last few years, the double frequency

  20. Photonic Breast Tomography and Tumor Aggressiveness Assessment

    DTIC Science & Technology

    2011-07-01

    Optical Imaging III, edited by Andreas H. Hielscher , Paola Taroni, Proc. of SPIE-OSA Biomedical Optics, SPIE Vol. 8088, 80880Y · © 2011 SPIE-OSA · CCC...acoustic mirrors,” in IEEE Ultrasonics Symposium Proceedings (Montreal, Que., Canada, 1989), vol. 2, pp. 681–686. 27. M. Fink, “Time reversal of... ultrasonic fields. I. Basic principles,” IEEE Trans. Ultrason . Ferroelectr. Freq. Control 39(5), 555–566 (1992). 28. M. Fink, “Time reversal mirrors,” J

  1. Mesenchymal Stem Cell Transition to Tumor-Associated Fibroblasts Contributes to Fibrovascular Network Expansion and Tumor Progression

    PubMed Central

    Sasser, A. Kate; Watson, Keri; Klopp, Ann; Hall, Brett; Andreeff, Michael; Marini, Frank

    2009-01-01

    Background Tumor associated fibroblasts (TAF), are essential for tumor progression providing both a functional and structural supportive environment. TAF, known as activated fibroblasts, have an established biological impact on tumorigenesis as matrix synthesizing or matrix degrading cells, contractile cells, and even blood vessel associated cells. The production of growth factors, cytokines, chemokines, matrix-degrading enzymes, and immunomodulatory mechanisms by these cells augment tumor progression by providing a suitable environment. There are several suggested origins of the TAF including tissue-resident, circulating, and epithelial-to-mesenchymal-transitioned cells. Methodology/Principal Findings We provide evidence that TAF are derived from mesenchymal stem cells (MSC) that acquire a TAF phenotype following exposure to or systemic recruitment into adenocarcinoma xenograft models including breast, pancreatic, and ovarian. We define the MSC derived TAF in a xenograft ovarian carcinoma model by the immunohistochemical presence of 1) fibroblast specific protein and fibroblast activated protein; 2) markers phenotypically associated with aggressiveness, including tenascin-c, thrombospondin-1, and stromelysin-1; 3) production of pro-tumorigenic growth factors including hepatocyte growth factor, epidermal growth factor, and interleukin-6; and 4) factors indicative of vascularization, including alpha-smooth muscle actin, desmin, and vascular endothelial growth factor. We demonstrate that under long-term tumor conditioning in vitro, MSC express TAF–like proteins. Additionally, human MSC but not murine MSC stimulated tumor growth primarily through the paracrine production of secreted IL6. Conclusions/Significance Our results suggest the dependence of in vitro Skov-3 tumor cell proliferation is due to the presence of tumor-stimulated MSC secreted IL6. The subsequent TAF phenotype arises from the MSC which ultimately promotes tumor growth through the contribution of

  2. Testosterone and Aggression.

    ERIC Educational Resources Information Center

    Archer, John

    1994-01-01

    Studies comparing aggressive and nonaggressive prisoners show higher testosterone levels among the former. While there is limited evidence for a strong association between aggressiveness and testosterone during adolescence, other studies indicate that testosterone levels are responsive to influences from the social environment, particularly those…

  3. Social Aggression among Girls.

    ERIC Educational Resources Information Center

    Underwood, Marion K.

    Noting recent interest in girls' social or "relational" aggression, this volume offers a balanced, scholarly analysis of scientific knowledge in this area. The book integrates current research on emotion regulation, gender, and peer relations, to examine how girls are socialized to experience and express anger and aggression from infancy…

  4. Neuropsychiatry of Aggression

    PubMed Central

    Lane, Scott D.; Kjome, Kimberly L.; Moeller, F. Gerard

    2010-01-01

    Synopsis Aggression is a serious medical problem that can place both the patient and the health care provider at risk. Aggression can result from medical, neurologic and or psychiatric disorders. A comprehensive patient evaluation is needed. Treatment options include pharmacotherapy as well as non-pharmacologic interventions, both need to be individualized to the patient. PMID:21172570

  5. Humor, Aggression, and Aging.

    ERIC Educational Resources Information Center

    Barrick, Ann Louise; And Others

    Although humor is an important phenomenon in human interactions, it has rarely been studied in the elderly. An understanding of responses to humor in aggressive cartoons as a function of advancing age would provide information regarding both the development of humor and the negative (aggressive) emotional experiences of the elderly. This study was…

  6. Serotonin and Aggression.

    ERIC Educational Resources Information Center

    Brown, Serena-Lynn; And Others

    1994-01-01

    Decreased serotonin function has consistently been shown to be highly correlated with impulsive aggression across a number of different experimental paradigms. Such lowered serotonergic indices appear to correlate with the dimension of aggression dyscontrol and/or impulsivity rather than with psychiatric diagnostic categories per se. Implications…

  7. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes.

    PubMed

    Thompson, Camilla A; Purushothaman, Anurag; Ramani, Vishnu C; Vlodavsky, Israel; Sanderson, Ralph D

    2013-04-05

    Emerging evidence indicates that exosomes play a key role in tumor-host cross-talk and that exosome secretion, composition, and functional capacity are altered as tumors progress to an aggressive phenotype. However, little is known regarding the mechanisms that regulate these changes. Heparanase is an enzyme whose expression is up-regulated as tumors become more aggressive and is associated with enhanced tumor growth, angiogenesis, and metastasis. We have discovered that in human cancer cells (myeloma, lymphoblastoid, and breast cancer), when expression of heparanase is enhanced or when tumor cells are exposed to exogenous heparanase, exosome secretion is dramatically increased. Heparanase enzyme activity is required for robust enhancement of exosome secretion because enzymatically inactive forms of heparanase, even when present in high amounts, do not dramatically increase exosome secretion. Heparanase also impacts exosome protein cargo as reflected by higher levels of syndecan-1, VEGF, and hepatocyte growth factor in exosomes secreted by heparanase-high expressing cells as compared with heparanase-low expressing cells. In functional assays, exosomes from heparanase-high cells stimulated spreading of tumor cells on fibronectin and invasion of endothelial cells through extracellular matrix better than did exosomes secreted by heparanase-low cells. These studies reveal that heparanase helps drive exosome secretion, alters exosome composition, and facilitates production of exosomes that impact both tumor and host cell behavior, thereby promoting tumor progression.

  8. Broadening the spectrum of SMARCB1-associated malignant tumors: a case of uterine leiomyosarcoma in a patient with schwannomatosis.

    PubMed

    Paganini, Irene; Sestini, Roberta; Cacciatore, Matilde; Capone, Gabriele L; Candita, Luisa; Paolello, Concetta; Sbaraglia, Marta; Dei Tos, Angelo P; Rossi, Sabrina; Papi, Laura

    2015-08-01

    Schwannomatosis is a tumor predisposition syndrome characterized by development of multiple intracranial, spinal, and peripheral schwannomas. Constitutional alterations in either SMARCB1 or LZTR1 on 22q are responsible of the phenotype. We describe a 34-year-old woman who developed multiple benign peripheral sheath tumors and a uterine leiomyosarcoma. The patient carried a de novo constitutional alteration in exon 8 of SMARCB1, c.1118G > A, which destroyed the splice donor site of intron 8. Two schwannomas and the leiomyosarcoma of the patient retained the SMARCB1 mutation; in addition, the tumors showed loss of the normal chromosome 22. In conclusion, our findings enlarged the spectrum of SMARCB1-predisposing tumors and demonstrated, for the first time, the association of a malignant smooth muscle tumor to schwannomatosis. Therefore, clinicians should definitely be aware that a constitutional SMARCB1 mutation, which mainly predisposes to benign nerve sheath tumors, may also predispose to aggressive neoplasms throughout life, within an unexpected spectrum.

  9. WE-EF-BRA-11: Precision Partial-Tumor Irradiation of Dorsal Rodent Mammary Tumors

    SciTech Connect

    Malcolm, J; Boss, K; Dewhirst, M; Oldham, M

    2015-06-15

    Purpose: To introduce a pre-clinical treatment technique on a micro-irradiator to treat specific volumes of dorsal mammary tumors in BALB/c mice while sparing lungs and spine. This technique facilitates pre-clinical investigation of tumor response to sub-optimal radiation treatments in which a portion of the tumor is unirradiated, known as a “marginal miss”. In-vitro data suggests that partial tumor radiations trigger a more aggressive phenotype in non-irradiated, regional tumor cells via bystander effects. As the lung tissue is spared, the impact of marginal miss on the development of pulmonary metastasis may be assessed. Methods: End to end test was performed on three BALB/c mice as proof of concept for larger studies. 1Gy was delivered on the micro-irradiator employing previously unexplored lateral parallel-opposed diamond and/or triangle-shaped beams. The margins of the treatment beam were defined using a combination of tumor palpation, barium fiducial markers, and real-time fluoroscopic images. The dose distribution was independently verified with kilovoltage beam Monte Carlo dose calculations with 7% statistical uncertainty and double exposure images. As a final step, the technique was used in a larger pre-clinical study (15Gy, 36 BALB/c mice) and lung metastasis in response to tumor irradiation of 100%, 50% and 0% was quantified. Results: For the Monte-Carlo dose calculations, the dose volume histograms established a maximum dose within the un-irradiated and radiated portions of the mammary tumor of 0.3Gy and 1.5Gy respectively, with a sharp gradient at the boundary. 100% of the lung volume received less than 0.5Gy. This technique proved suitable for a pre-clinical marginal miss study with 50% more lung metastases in partially-radiated mouse models compared to completely. Conclusion: We have developed a novel treatment technique for partial or full irradiation of dorsal mammary tumors incorporating lung sparing.The technique will be useful for exploring

  10. Aggressive Chordomas: Clinical Outcome of 13 Patients.

    PubMed

    Mavrogenis, Andreas F; Angelini, Andrea; Panagopoulos, Georgios N; Pala, Elisa; Calabrò, Teresa; Igoumenou, Vasilios G; Katzouraki, Galatia; Megaloikonomos, Panayiotis D; Pneumaticos, Spyros G; Papagelopoulos, Panayiotis J; Ruggieri, Pietro

    2017-03-01

    The authors reviewed the files of all patients with chordomas who were admitted and treated at their institutions from 1975 to 2012. Patients were categorized by early local recurrence and metastasis. Aggressive clinical behavior was defined as local recurrence and metastasis within 24 months of diagnosis and adequate treatment (wide en bloc resection with microscopically negative tumor margins). According to these criteria, 13 patients (14.3%) had aggressive chordomas, including 7 men and 6 women, with mean age of 54 years (range, 37-65 years) at diagnosis and treatment. All patients had preoperative tumor biopsy, followed by resection with partial (7 patients) or total sacrectomy (6 patients). In all cases, biopsy and histologic analysis of resected tumor specimens showed conventional chordomas. Resection margins were wide (grossly negative) in 6 patients and wide contaminated in 7 patients. Mean maximum tumor diameter was 11.8 cm (range, 5-21 cm). Mean follow-up was 43 months (range, 8-131 months). Rates of local recurrence, metastasis, and death were evaluated. At the last follow-up, all patients had local recurrence at a mean of 13 months (range, 5-22 months). Histologic examination of recurrent tumors showed a dedifferentiated chordoma with a fibrosarcoma component in 2 patients and no histologic change in the remaining patients. In addition, 8 patients had metastases at a mean of 13 months (range, 4-24 months) and died of their disease. All histologic findings of metastatic lesions were similar to those of primary tumors. Early diagnosis of aggressive tumors requires close follow-up of patients with chordomas. Metastasis is common, with resultant poor survival. [Orthopedics. 2017; 40(2):e248-e254.].

  11. Quantitative Genomics of Aggressive Behavior in Drosophila melanogaster

    PubMed Central

    Edwards, Alexis C; Rollmann, Stephanie M; Morgan, Theodore J; Mackay, Trudy F. C

    2006-01-01

    Aggressive behavior is important for animal survival and reproduction, and excessive aggression is an enormous social and economic burden for human society. Although the role of biogenic amines in modulating aggressive behavior is well characterized, other genetic mechanisms affecting this complex behavior remain elusive. Here, we developed an assay to rapidly quantify aggressive behavior in Drosophila melanogaster, and generated replicate selection lines with divergent levels of aggression. The realized heritability of aggressive behavior was approximately 0.10, and the phenotypic response to selection specifically affected aggression. We used whole-genome expression analysis to identify 1,539 probe sets with different expression levels between the selection lines when pooled across replicates, at a false discovery rate of 0.001. We quantified the aggressive behavior of 19 mutations in candidate genes that were generated in a common co-isogenic background, and identified 15 novel genes affecting aggressive behavior. Expression profiling of genetically divergent lines is an effective strategy for identifying genes affecting complex traits. PMID:17044737

  12. Multivariate Behavior Genetic Analyses of Aggressive Behavior Subtypes

    PubMed Central

    Yeh, Michelle T.; Coccaro, Emil F.; Jacobson, Kristen C.

    2012-01-01

    This study examined the genetic and environmental architecture underlying aggressive behavior measured by the Life History of Aggression Questionnaire (LHA; Coccaro et al. 1997a). Following preliminary phenotypic factor analysis procedures, multivariate behavioral genetics models were fit to responses from 2,925 adult twins from the PennTwins cohort on five LHA items assessing lifetime frequency of temper tantrums, indirect aggression, verbal aggression, fighting, and physical assault. The best-fitting model was a 2-factor common pathway model, indicating that these five aggressive behaviors are underpinned by two distinct etiological factors with different genetic and nonshared environmental influences. Although there was evidence of significant sex differences, the structure of the two factors appeared to be quite similar in males and females, where General Aggression and Physical Aggression factors emerged. Heritability of these factors ranged from .37 to .57, and nonshared environmental effects ranged from .43 to .63. The results of this study highlight the heterogeneous nature of the aggression construct and the need to consider differences in genetic and environmental influences on individual aggressive behaviors in a multivariate context. PMID:20432061

  13. Aggression and sport.

    PubMed

    Burton, Robert W

    2005-10-01

    Viewing aggression in its healthy form, in contrast to its extreme and inappropriate versions, and sport as a health-promoting exercise in psychological development and maturation may allow participants and spectators alike to retain an interest in aggression and sport and derive further enjoyment from them. In addition, it will benefit all involved with sport to have a broader understanding of human aggression. Physicians, mental health professionals, and other health care providers can be influential in this process, and should be willing to get involved and speak out when issues and problems arise.

  14. miR-181a Induces Macrophage Polarized to M2 Phenotype and Promotes M2 Macrophage-mediated Tumor Cell Metastasis by Targeting KLF6 and C/EBPα

    PubMed Central

    Bi, Jia; Zeng, Xianxin; Zhao, Lin; Wei, Qian; Yu, Lifeng; Wang, Xinnan; Yu, Zhaojin; Cao, Yaming; Shan, Fengping; Wei, Minjie

    2016-01-01

    Macrophages can acquire a variety of polarization status and functions: classically activated macrophages (M1 macrophages); alternatively activated macrophages (M2 macrophages). However, the molecular basis of the process is still unclear. Here, this study addresses that microRNA-181a (miR-181a) is a key molecule controlling macrophage polarization. We found that miR-181a is overexpressed in M2 macrophages than in M1 macrophages. miR-181a expression was decreased when M2 phenotype converted to M1, whereas it increased when M1 phenotype converted to M2. Overexpression of miR-181a in M1 macrophages diminished M1 phenotype expression while promoting polarization to the M2 phenotype. In contrast, knockdown of miR-181a in M2 macrophages promoted M1 polarization and diminished M2 phenotype expression. Mechanistically, Bioinformatic analysis revealed that Kruppel-like factor 6 (KLF6) and CCAAT/enhancer binding protein-α (C/EBPα) is a potential target of miR-181a and luciferase assay confirmed that KLF6 and C/EBPα translation is suppressed by miR-181a through interaction with the 3′UTR of KLF6 and C/EBPα mRNA. Further analysis showed that induction of miR-181a suppressed KLF6 and C/EBPα protein expression. Importantly, miR-181a also diminishes M2 macrophages-mediated migration and invasion capacity of tumor cells. Collectively, our results suggest that miR-181a plays a significant role in regulating macrophage polarization through directly target KLF6 and C/EBPα. PMID:27673564

  15. Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7-driven metastatic spread of luminal-A breast tumors.

    PubMed

    Weitzenfeld, Polina; Kossover, Olga; Körner, Cindy; Meshel, Tsipi; Wiemann, Stefan; Seliktar, Dror; Legler, Daniel F; Ben-Baruch, Adit

    2016-06-01

    Chemokine axes have been shown to mediate site-specific metastasis in breast cancer, but their relevance to different subtypes has been hardly addressed. Here, with the focus on the CCR7-CCL21 axis, patient datasets demonstrated that luminal-A tumors express relatively low CCR7 levels compared with more aggressive disease subtypes. Furthermore, lymph node metastasis was not associated with high CCR7 levels in luminal-A patients. The metastatic pattern of luminal-A breast tumors may be influenced by the way luminal-A tumor cells interpret signals provided by factors of the primary tumor microenvironment. Thus, CCR7-expressing human luminal-A cells were stimulated simultaneously by factors representing 3 tumor microenvironment arms typical of luminal-A tumors, hormonal, inflammatory, and growth stimulating: estrogen + TNF-α + epidermal growth factor. Such tumor microenvironment stimulation down-regulated the migration of CCR7-expressing tumor cells toward CCL21 and inhibited the formation of directional protrusions toward CCL21 in a novel 3-dimensional hydrogel system. CCL21-induced migration of CCR7-expressing tumor cells depended on PI3K and MAPK activation; however, when CCR7-expressing cancer cells were prestimulated by tumor microenvironment factors, CCL21 could not effectively activate these signaling pathways. In vivo, pre-exposure of the tumor cells to tumor microenvironment factors has put restraints on CCL21-mediated lymph node-homing cues and shifted the metastatic pattern of CCR7-expressing cells to the aggressive phenotype of dissemination to bones. Several of the aspects were also studied in the CXCR4-CXCL12 system, demonstrating similar patient and in vitro findings. Thus, we provide novel evidence to subtype-specific regulation of the CCR7-CCL21 axis, with more general implications to chemokine-dependent patterns of metastatic spread, revealing differential regulation in the luminal-A subtype.

  16. Amplified centrosomes may underlie aggressive disease course in pancreatic ductal adenocarcinoma

    PubMed Central

    Mittal, Karuna; Ogden, Angela; Reid, Michelle D; Rida, Padmashree CG; Varambally, Sooryanarayana; Aneja, Ritu

    2015-01-01

    Centrosome amplification (CA), the presence of centrosomes that are abnormally numerous or enlarged, is a well-established driver of tumor initiation and progression associated with poor prognosis across a diversity of malignancies. Pancreatic ductal adenocarcinoma (PDAC) carries one of the most dismal prognoses of all cancer types. A majority of these tumors are characterized by numerical and structural centrosomal aberrations, but it is unknown how CA contributes to the disease and patient outcomes. In this study, we sought to determine whether CA was associated with worse clinical outcomes, poor prognostic indicators, markers of epithelial-mesenchymal transition (EMT), and ethnicity in PDAC. We also evaluated whether CA could precipitate more aggressive phenotypes in a panel of cultured PDAC cell lines. Using publicly available microarray data, we found that increased expression of genes whose dysregulation promotes CA was associated with worse overall survival and increased EMT marker expression in PDAC. Quantitative analysis of centrosomal profiles in PDAC cell lines and tissue sections uncovered varying levels of CA, and the expression of CA markers was associated with the expression of EMT markers. We induced CA in PDAC cells and found that CA empowered them with enhanced invasive and migratory capabilities. In addition, we discovered that PDACs from African American (AA) patients exhibited a greater extent of both numerical and structural CA than PDACs from European American (EA) patients. Taken together, these findings suggest that CA may fuel a more aggressive disease course in PDAC patients. PMID:26151406

  17. Use of haloperidol and risperidone in highly aggressive Swiss Webster mice by applying the model of spontaneous aggression (MSA).

    PubMed

    Fragoso, Viviane Muniz da Silva; Hoppe, Luanda Yanaan; de Araújo-Jorge, Tânia Cremonini; de Azevedo, Marcos José; Campos, Jerônimo Diego de Souza; Cortez, Célia Martins; de Oliveira, Gabriel Melo

    2016-03-15

    Aggression is defined as the act in which an individual intentionally harms or injures another of their own species. Antipsychotics are a form of treatment used in psychiatric routine. They have been used for decades in treatment of patients with aggressive behavior. Haloperidol and risperidone promote the control of psychiatric symptoms, through their respective mechanisms of action. Experimental models are obtained by behavioral, genetic, and pharmacological manipulations, and use a reduced number of animals. In this context, we applied the model of spontaneous aggression (MSA), originating the presence of highly aggressive mice (AgR) when reassembled in adulthood. We administered haloperidol and risperidone in escalating doses, for ten consecutive days. Using positive and negative control groups, we evaluated the effectiveness of these drugs and the reversal of the aggressive behavior, performing the tail suspension test (TST) and open field test (OFT) on 10th day of treatment and 10 days after its discontinuation. The results showed that both antipsychotic drugs were effective in AgR and reversed the aggressive phenotype, reducing the number of attacks by AgR and the extent of lesions in the subordinate mice (AgD) exposed to the pattern of aggressive behavior (PAB) of the aggressors. This conclusion is based on the reduction in the animals' motor and exploratory activity, and on the reversal of patterns of aggressive behavior. The association between the MSA and experiments with other therapeutic protocols and different antipsychotics can be an important methodology in the study of aggressive behavior in psychiatric patients.

  18. In vitro expansion of human glioblastoma cells at non-physiological oxygen tension irreversibly alters subsequent in vivo aggressiveness and AC133 expression

    PubMed Central

    BOURSEAU-GUILMAIN, ERIKA; LEMAIRE, LAURENT; GRIVEAU, AUDREY; HERVOUET, ERIC; VALLETTE, FRANÇOIS; BERGER, FRANÇOIS; MENEI, PHILIPPE; BENOIT, JEAN-PIERRE; WION, DIDIER; GARCION, EMMANUEL

    2012-01-01

    Among markers of glioblastoma initiating cells, AC133 has been shown to be associated with glioblastoma resistance and malignancy. Recently, it was demonstrated that increasing oxygen tension (pO2) down-regulated AC133 expression in glioblastoma cells in vitro. In order to better understand extrinsic factor regulation of AC133, this work aimed to investigate the relationship between cell culture pO2, AC133 expression, and tumor development and phenotype. Using treatments with CoCl2 and HIF-1α shRNA knockdowns on non-sorted human primary glioblastoma cells cultured at low (3%) versus high (21%) oxygen tension, we established a responsibility for low pO2 in the maintenance of high levels of AC133 expression, with a major but non-exclusive role for HIF-1α. We also demonstrated that human glioblastoma cells previously cultured under high oxygen tension can lose part of their aggressiveness when orthotopically engrafted in SCID mice or lead to tumors with distinct phenotypes and no re-expression of AC133. These observations showed that the specific pO2 microenvironment irreversibly impacts glioblastoma cell phenotypes, highlighting the pertinence of culture conditions when extrapolating data from xenogenic models to human cells in their source environment. They also raised AC133 as a marker of non-exposure to oxygenated areas rather than a marker of aggressiveness or low pO2 niches. PMID:22134773

  19. Hypoxia induces macrophage polarization and re-education toward an M2 phenotype in U87 and U251 glioblastoma models

    PubMed Central

    Leblond, Marine M; Gérault, Aurélie N; Corroyer-Dulmont, Aurélien; MacKenzie, Eric T; Petit, Edwige; Bernaudin, Myriam; Valable, Samuel

    2016-01-01

    Hypoxia is a common feature of solid tumors, particularly in glioblastoma (GBM), and known to be a poor prognosis factor in GBM patients. The growth of GBM is also associated with a marked inflammation partially characterized by an accumulation of macrophage (MΦ) of the M2 phenotype. However, the transition between M1 MΦ (antitumoral) and M2 MΦ (protumoral) phenotypes is a dynamic process. We made the assumption that oxygen (O2) availability could be a major regulator of this transition and that the intratumoral O2 gradient is of importance. We evaluated, in vivo, the impact of hypoxia on MΦ tropism and polarization in two models of human GBM, well differentiated by their degree of hypoxia. MΦ migration in the tumor was more pronounced in the more hypoxic tumor of the two GBM models. In the more hypoxic of the models, we have shown that MΦ migrated at the tumor site only when hypoxia takes place. We also demonstrated that the acquisition of the M2 phenotype was clearly an evolving phenomenon with hypoxia as the major trigger for this transition. In support of these in vivo finding, M0 but also M1 MΦ cultured in moderate or severe hypoxia displayed a phenotype close to that of M2 MΦ whose phenotype was further reinforced by severe hypoxia. These results highlight the role of hypoxia in the aggressiveness of GBM, in part, by transforming MΦ such that a protumoral activity is expressed. PMID:26942063

  20. Aggression in Pretend Play and Aggressive Behavior in the Classroom

    ERIC Educational Resources Information Center

    Fehr, Karla K.; Russ, Sandra W.

    2013-01-01

    Research Findings: Pretend play is an essential part of child development and adjustment. However, parents, teachers, and researchers debate the function of aggression in pretend play. Different models of aggression predict that the expression of aggression in play could either increase or decrease actual aggressive behavior. The current study…

  1. Glucose promotes breast cancer aggression and reduces metformin efficacy

    PubMed Central

    Wahdan-Alaswad, Reema; Fan, Zeying; Edgerton, Susan M; Liu, Bolin; Deng, Xin-Sheng; Arnadottir, Sigrid Salling; Richer, Jennifer K; Anderson, Steven M; Thor, Ann D

    2013-01-01

    Metformin treatment has been associated with a decrease in breast cancer risk and improved survival. Metformin induces complex cellular changes, resulting in decreased tumor cell proliferation, reduction of stem cells, and apoptosis. Using a carcinogen-induced rodent model of mammary tumorigenesis, we recently demonstrated that overfeeding in obese animals is associated with a 50% increase in tumor glucose uptake, increased proliferation, and tumor cell reprogramming to an “aggressive” metabolic state. Metformin significantly inhibited these pro-tumorigenic effects. We hypothesized that a dynamic relationship exists between chronic energy excess (glucose by dose) and metformin efficacy/action. Media glucose concentrations above 5 mmol/L was associated with significant increase in breast cancer cell proliferation, clonogenicity, motility, upregulation/activation of pro-oncogenic signaling, and reduction in apoptosis. These effects were most significant in triple-negative breast cancer (TNBC) cell lines. High-glucose conditions (10 mmol/L or above) significantly abrogated the effects of metformin. Mechanisms of metformin action at normal vs. high glucose overlapped but were not identical; for example, metformin reduced IGF-1R expression in both the HER2+ SK-BR-3 and TNBC MDA-MB-468 cell lines more significantly at 5, as compared with 10 mmol/L glucose. Significant changes in gene profiles related to apoptosis, cellular processes, metabolic processes, and cell proliferation occurred with metformin treatment in cells grown at 5 mmol/L glucose, whereas under high-glucose conditions, metformin did not significantly increase apoptotic/cellular death genes. These data indicate that failure to maintain glucose homeostasis may promote a more aggressive breast cancer phenotype and alter metformin efficacy and mechanisms of action. PMID:24107633

  2. Association of dopamine- and serotonin-related genes with canine aggression.

    PubMed

    Våge, J; Wade, C; Biagi, T; Fatjó, J; Amat, M; Lindblad-Toh, K; Lingaas, F

    2010-06-01

    Human-directed canine aggression was studied using 50 aggressive and 81 non-aggressive dogs. We examined 62 single nucleotide polymorphisms (SNPs) occurring in or in the close vicinity of 16 neurotransmitter-related genes. Allelic associations with aggression were identified for DRD1, HTR1D, HTR2C and SLC6A1. Risk or protective haplotypes for aggressive behaviour based on 2-5 SNPs were identified. The frequency of aggressive dogs varied significantly between the haplotypes within loci and the odds ratios of aggression in dogs with risk haplotypes compared with protective haplotypes varied from 4.4 (HTR2C) to 9.0 (SLC6A1). A risk haplotype across the neurotransmitter receptor gene HTR1D harboured a non-synonymous SNP with a potential effect on protein function. We identified no haplotypes in complete association with the recorded phenotypes, supporting a complex inheritance of aggression.

  3. Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

    PubMed Central

    Dobroff, Andrey S.; D’Angelo, Sara; Eckhardt, Bedrich L.; Ferrara, Fortunato; Staquicini, Daniela I.; Cardó-Vila, Marina; Staquicini, Fernanda I.; Nunes, Diana N.; Kim, Kisu; Driessen, Wouter H. P.; Hajitou, Amin; Lomo, Lesley C.; Barry, Marc; Krishnamurthy, Savitri; Sahin, Aysegul; Woodward, Wendy A.; Prossnitz, Eric R.; Dias-Neto, Emmanuel; Brown-Glaberman, Ursa A.; Royce, Melanie E.; Ueno, Naoto T.; Cristofanilli, Massimo; Hortobagyi, Gabriel N.; Marchiò, Serena; Gelovani, Juri G.; Sidman, Richard L.; Arap, Wadih; Pasqualini, Renata

    2016-01-01

    Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors. PMID:27791177

  4. Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities?

    DTIC Science & Technology

    2014-10-01

    award is to characterize differential splicing of oncongenes and tumor suppressor genes in prostate cancer disparities between African American ( AA ...splicing where the AA -specific variants are engendered with a more aggressive oncogenic phenotype in vitro and in vivo. Full-length cloning of the AA ...and CA variants of both PIK3CD and FGFR3 have been accomplished. PCa cell lines genetically manipulated to predominantly express the AA -variant of

  5. Tumor-associated macrophages and stromal TNF-α regulate collagen structure in a breast tumor model as visualized by second harmonic generation.

    PubMed

    Burke, Ryan M; Madden, Kelley S; Perry, Seth W; Zettel, Martha L; Brown, Edward B

    2013-08-01

    Collagen fibers can be imaged with second harmonic generation (SHG) and are associated with efficient tumor cell locomotion. Preferential locomotion along these fibers correlates with a more aggressively metastatic phenotype, and changes in SHG emission properties accompany changes in metastatic outcome. We therefore attempted to elucidate the cellular and molecular machinery that influences SHG in order to understand how the microstructure of tumor collagen fibers is regulated. By quantifying SHG and immunofluorescence (IF) from tumors grown in mice with and without stromal tumor necrosis factor (TNF)-α and in the presence or absence of tumor-associated macrophages (TAMs), we determined that depletion of TAMs alters tumor collagen fibrillar microstructure as quantified by SHG and IF. Furthermore, we determined that abrogation of TNF-α expression by tumor stromal cells also alters fibrillar microstructure and that subsequent depletion of TAMs has no further effect. In each case, metastatic burden correlated with optical readouts of collagen microstructure. Our results implicate TAMs and stromal TNF-α as regulators of breast tumor collagen microstructure and suggest that this regulation plays a role in tumor metastasis. Furthermore, these results indicate that quantification of SHG represents a useful strategy for evaluating the cells and molecular pathways responsible for manipulating fibrillar collagen in breast tumor models.

  6. Tumor-associated macrophages and stromal TNF-α regulate collagen structure in a breast tumor model as visualized by second harmonic generation

    NASA Astrophysics Data System (ADS)

    Burke, Ryan M.; Madden, Kelley S.; Perry, Seth W.; Zettel, Martha L.; Brown, Edward B.

    2013-08-01

    Collagen fibers can be imaged with second harmonic generation (SHG) and are associated with efficient tumor cell locomotion. Preferential locomotion along these fibers correlates with a more aggressively metastatic phenotype, and changes in SHG emission properties accompany changes in metastatic outcome. We therefore attempted to elucidate the cellular and molecular machinery that influences SHG in order to understand how the microstructure of tumor collagen fibers is regulated. By quantifying SHG and immunofluorescence (IF) from tumors grown in mice with and without stromal tumor necrosis factor (TNF)-α and in the presence or absence of tumor-associated macrophages (TAMs), we determined that depletion of TAMs alters tumor collagen fibrillar microstructure as quantified by SHG and IF. Furthermore, we determined that abrogation of TNF-α expression by tumor stromal cells also alters fibrillar microstructure and that subsequent depletion of TAMs has no further effect. In each case, metastatic burden correlated with optical readouts of collagen microstructure. Our results implicate TAMs and stromal TNF-α as regulators of breast tumor collagen microstructure and suggest that this regulation plays a role in tumor metastasis. Furthermore, these results indicate that quantification of SHG represents a useful strategy for evaluating the cells and molecular pathways responsible for manipulating fibrillar collagen in breast tumor models.

  7. Viral proliferation and expression of tumor-related gene in different chicken embryo fibroblasts infected with different tumorigenic phenotypes of avian leukosis virus subgroup J.

    PubMed

    Qu, Yajin; Liu, Litao; Niu, Yujuan; Qu, Yue; Li, Ning; Sun, Wei; Lv, Chuanwei; Wang, Pengfei; Zhang, Guihua; Liu, Sidang

    2016-10-01

    Subgroup J avian leukosis virus (ALV-J) causes a neoplastic disease in infected chickens. The ALV-J strain NX0101, which was isolated from broiler breeders in 2001, mainly induced formation of myeloid cell tumors. However, strain HN10PY01, which was recently isolated from laying hens, mainly induces formation of myeloid cell tumors and hemangioma. To identify the molecular pathological mechanism underlying changes in host susceptibility and tumor classification induced by these two types of ALV-J strains, chicken embryo fibroblasts derived from chickens with different genetic backgrounds (broiler breeders and laying hens) and an immortalized chicken embryo fibroblasts (DF-1) were prepared and infected with strain NX0101 or HN10PY01, respectively. The 50% tissue culture infective dose (TCID50) and levels of ALV group-specific antigen p27 and heat shock protein 70 in the supernatant collected from the ALV-J infected cells were detected. Moreover, mRNA expression levels of tumor-related genes p53, c-myc, and Bcl-2 in ALV-J-infected cells were quantified. The results indicated that the infection of ALV-J could significantly increase mRNA expression levels of p53, c-myc, and Bcl-2 Strain HN10PY01 exhibited a greater influence on the three tumor-related genes in each of the three types of cells when compared with strain NX0101, and the TCID50 and p27 levels in the supernatant collected from HN10PY01-infected cells were higher than those collected from NX0101-infected cells. These results indicate that the infection of the two ALV-J strains influenced the gene expression levels in the infected cells, while the newly isolated strain HN10PY01 showed higher replication ability in cells and induced higher expression levels of tumor-related genes in infected cells. Furthermore, virus titers and expression levels of tumor-related genes and cellular stress responses of cells with different genetic backgrounds when infected with each of the two ALV-J strain were different

  8. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.

    PubMed

    McAllister, Sean D; Christian, Rigel T; Horowitz, Maxx P; Garcia, Amaia; Desprez, Pierre-Yves

    2007-11-01

    Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progression, and is the least understood genetically. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Clearly, effective and nontoxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. Using a mouse model, we previously determined that metastatic breast cancer cells became significantly less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated by stable transduction with antisense Id-1. It is not possible at this point, however, to use antisense technology to reduce Id-1 expression in patients with metastatic breast cancer. Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. These effects seemed to occur as the result of an inhibition of the Id-1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness.

  9. The dopaminergic system and aggression in laying hens.

    PubMed

    Dennis, R L; Cheng, H W

    2011-11-01

    The dopaminergic system is involved in the regulation of aggression in many species, especially via dopamine (DA) D1 and D2 receptor pathways. To investigate heritable differences in this regulation, 2 high aggressive strains [Dekalb XL (DXL) and low group egg productivity and survivability (LGPS)] and one low aggressive strain (low group egg productivity and survivability; HGPS) of laying hens were used in the study. The HGPS and LGPS lines were diversely selected using group selection for high and low group production and survivability. The DXL line is a commercial line selected through individual selection based on egg production. Heritable differences in aggressive propensity between the strains have been previously assessed. The birds were pair housed within the same strain and labeled as dominant or subordinate based on behavioral observation. For both experiments 1 and 2, behavioral analysis was performed on all 3 strains whereas neurotransmitter analysis was performed only on the most aggressive (DXL) and least aggressive (HGPS) strains. In experiment 1, the subordinate birds were treated with D1 agonist, D2 agonist, or saline controls (n = 12). In experiment 2, the dominant birds from a separate flock were treated with D1 antagonist, D2 antagonist, or saline controls (n = 12). Treatment-associated changes in aggressive behaviors and central neurotransmitters were measured. Aggression was increased in all strains in response to D1 agonism but increased only in the less aggressive HGPS birds with D2 agonism. Aggression was decreased and hypothalamic serotonin and epinephrine were increased in birds from all strains treated with D2 receptor antagonist. The D1 receptor antagonism elicited different behavioral and neurotransmitter responses based on the aggressive phenotype of the genetic strains. Aggressive strains DXL and LGPS but not the HGPS strain decreased aggressiveness following antagonism of the D1 receptor. The data show evidence for distinct

  10. Aberrant Retinoblastoma (RB)-E2F Transcriptional Regulation Defines Molecular Phenotypes of Osteosarcoma.

    PubMed

    Scott, Milcah C; Sarver, Aaron L; Tomiyasu, Hirotaka; Cornax, Ingrid; Van Etten, Jamie; Varshney, Jyotika; O'Sullivan, M Gerard; Subramanian, Subbaya; Modiano, Jaime F

    2015-11-20

    We previously identified two distinct molecular subtypes of osteosarcoma through gene expression profiling. These subtypes are associated with distinct tumor behavior and clinical outcomes. Here, we describe mechanisms that give rise to these molecular subtypes. Using bioinformatic analyses, we identified a significant association between deregulation of the retinoblastoma (RB)-E2F pathway and the molecular subtype with worse clinical outcomes. Xenotransplantation models recapitulated the corresponding behavior for each osteosarcoma subtype; thus, we used cell lines to validate the role of the RB-E2F pathway in regulating the prognostic gene signature. Ectopic RB resets the patterns of E2F regulated gene expression in cells derived from tumors with worse clinical outcomes (molecular phenotype 2) to those comparable with those observed in cells derived from tumors with less aggressive outcomes (molecular phenotype 1), providing a functional association between RB-E2F dysfunction and altered gene expression in osteosarcoma. DNA methyltransferase and histone deacetylase inhibitors similarly reset the transcriptional state of the molecular phenotype 2 cells from a state associated with RB deficiency to one seen with RB sufficiency. Our data indicate that deregulation of RB-E2F pathway alters the epigenetic landscape and biological behavior of osteosarcoma.

  11. Unravelling the neurophysiological basis of aggression in a fish model

    PubMed Central

    2010-01-01

    Background Aggression is a near-universal behaviour with substantial influence on and implications for human and animal social systems. The neurophysiological basis of aggression is, however, poorly understood in all species and approaches adopted to study this complex behaviour have often been oversimplified. We applied targeted expression profiling on 40 genes, spanning eight neurological pathways and in four distinct regions of the brain, in combination with behavioural observations and pharmacological manipulations, to screen for regulatory pathways of aggression in the zebrafish (Danio rerio), an animal model in which social rank and aggressiveness tightly correlate. Results Substantial differences occurred in gene expression profiles between dominant and subordinate males associated with phenotypic differences in aggressiveness and, for the chosen gene set, they occurred mainly in the hypothalamus and telencephalon. The patterns of differentially-expressed genes implied multifactorial control of aggression in zebrafish, including the hypothalamo-neurohypophysial-system, serotonin, somatostatin, dopamine, hypothalamo-pituitary-interrenal, hypothalamo-pituitary-gonadal and histamine pathways, and the latter is a novel finding outside mammals. Pharmacological manipulations of various nodes within the hypothalamo-neurohypophysial-system and serotonin pathways supported their functional involvement. We also observed differences in expression profiles in the brains of dominant versus subordinate females that suggested sex-conserved control of aggression. For example, in the HNS pathway, the gene encoding arginine vasotocin (AVT), previously believed specific to male behaviours, was amongst those genes most associated with aggression, and AVT inhibited dominant female aggression, as in males. However, sex-specific differences in the expression profiles also occurred, including differences in aggression-associated tryptophan hydroxylases and estrogen receptors

  12. Surgical treatment of aggressive vertebral hemangiomas.

    PubMed

    Vasudeva, Viren S; Chi, John H; Groff, Michael W

    2016-08-01

    OBJECTIVE Vertebral hemangiomas are common tumors that are benign and generally asymptomatic. Occasionally these lesions can exhibit aggressive features such as bony expansion and erosion into the epidural space resulting in neurological symptoms. Surgery is often recommended in these cases, especially if symptoms are severe or rapidly progressive. Some surgeons perform decompression alone, others perform gross-total resection, while others perform en bloc resection. Radiation, embolization, vertebroplasty, and ethanol injection have also been used in combination with surgery. Despite the variety of available treatment options, the optimal management strategy is unclear because aggressive vertebral hemangiomas are uncommon lesions, making it difficult to perform large trials. For this reason, the authors chose instead to report their institutional experience along with a comprehensive review of the literature. METHODS A departmental database was searched for patients with a pathological diagnosis of "hemangioma" between 2008 and 2015. Medical records were reviewed to identify patients with aggressive vertebral hemangiomas, and these cases were reviewed in detail. RESULTS Five patients were identified who underwent surgery for treatment of aggressive vertebral hemangiomas during the specified time period. There were 2 lumbar and 3 thoracic lesions. One patient underwent en bloc spondylectomy, 2 patients had piecemeal gross-total resection, and the remaining 2 had subtotal tumor resection. Intraoperative vertebroplasty was used in 3 cases to augment the anterior column or to obliterate residual tumor. Adjuvant radiation was used in 1 case where there was residual tumor as well. The patient who underwent en bloc spondylectomy experienced several postoperative complications requiring additional medical care and reoperation. At an average follow-up of 31 months (range 3-65 months), no patient had any recurrence of disease and all were clinically asymptomatic, except the

  13. Isolation of stem-like cells from spontaneous feline mammary carcinomas: Phenotypic characterization and tumorigenic potential

    SciTech Connect

    Barbieri, Federica; Wurth, Roberto; Ratto, Alessandra; Campanella, Chiara; Vito, Guendalina; Thellung, Stefano; Daga, Antonio; Cilli, Michele; Ferrari, Angelo; Florio, Tullio

    2012-04-15

    Current carcinogenesis theory states that only a small subset of tumor cells, the cancer stem cells or tumor initiating cells (TICs), are responsible for tumor formation and progression. Human breast cancer-initiating cells have been identified as CD44-expressing cells, which retain tumorigenic activity and display stem cell-like properties. Spontaneous feline mammary carcinoma (FMC) is an aggressive cancer, which shows biological similarities to the human tumor counterpart. We report the isolation and phenotypic characterization of FMC-derived stem/progenitor cells, showing in vitro self-renewal, long-lasting proliferation and in vivo tumorigenicity. Twenty-one FMC samples were collected, histologically classified and characterized for the expression of Ki67, EGFR, ER-{alpha} and CD44, by immunohistochemistry. By culture in stem cell permissive conditions, we isolated, from 13 FMCs, a CD44-positive subpopulation able to survive and proliferate in vitro as mammospheres of different sizes and morphologies. When injected in NOD/SCID mice, FMC stem-like cells initiate tumors, generating cell heterogeneity and recapitulating the original histotype. In serum-containing medium, spheroid cells showed differentiation properties as shown by morphological changes, the loss of CD44 expression and tumorigenic potential. These data show that stem-defined culture of FMC enriches for TICs and validate the use of these cells as a suitable model for comparative oncology studies of mammary biology and testing therapeutic strategies aimed at eradicating TICs. -- Highlights: Black-Right-Pointing-Pointer Feline mammary carcinoma contain a sub-population of stem-like cells expressing CD44 Black-Right-Pointing-Pointer These grow as spheres in serum-free medium and self-renew Black-Right-Pointing-Pointer Isolated stem-like cancer cells initiate tumor in immunodeficient mice Black-Right-Pointing-Pointer Xenografted tumors are phenotypically similar to the original tumor Black

  14. Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function.

    PubMed

    Del Mare, Sara; Aqeilan, Rami I

    2015-08-10

    Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases' seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.

  15. Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function

    PubMed Central

    Del Mare, Sara; Aqeilan, Rami I.

    2015-01-01

    Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases’ seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease. PMID:26256646

  16. LncRNA GAS5 is a critical regulator of metastasis phenotype of melanoma cells and inhibits tumor growth in vivo

    PubMed Central

    Chen, Long; Yang, Huixin; Xiao, Yanbin; Tang, Xiaoxia; Li, Yuqian; Han, Qiaoqiao; Fu, Junping; Yang, Yuye; Zhu, Yuechun

    2016-01-01

    The present study intended to demonstrate the effects of long noncoding RNA growth arrest-specific transcript 5 (GAS5) on the migration and invasion of melanoma cells. We first detected the expression of GAS5 among four kinds of melanoma cell lines, followed by constructing GAS5-knocked down and overexpressed stable cells. Next, we evaluated the effects of GAS5 on cell migration and invasion using wound healing and gelatin zymography assays. Finally, melanoma cells with different GAS5 expression were injected into nude mice, and the tumor volumes were recorded and tumor tissues were analyzed after sacrificing the mice. This study systematically examined the function of GAS5 in mediating melanoma metastasis and revealed that GAS5 plays an anticancer role in melanoma via regulating gelatinase A and B, both in vitro and in vivo. PMID:27445498

  17. PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment.

    PubMed

    Li, Jing; Jie, Hyun-Bae; Lei, Yu; Gildener-Leapman, Neil; Trivedi, Sumita; Green, Tony; Kane, Lawrence P; Ferris, Robert L

    2015-02-01

    Immune rejection of tumors is mediated by IFNγ production and T-cell cytolytic activity. These processes are impeded by PD-1, a coinhibitory molecule expressed on T cells that is elevated in tumor-infiltrating lymphocytes (TIL). PD-1 elevation may reflect T-cell exhaustion marked by decreased proliferation, production of type I cytokines, and poor cytolytic activity. Although anti-PD-1 antibodies enhance IFNγ secretion after stimulation of the T-cell receptor (TCR), the mechanistic link between PD-1 and its effects on T-cell help (Tc1/Th1 skewing) remains unclear. In prospectively collected cancer tissues, we found that TIL exhibited dampened Tc1/Th1 skewing and activation compared with peripheral blood lymphocytes (PBL). When PD-1 bound its ligand PD-L1, we observed a marked suppression of critical TCR target genes and Th1 cytokines. Conversely, PD-1 blockade reversed these suppressive effects of PD-1:PD-L1 ligation. We also found that the TCR-regulated phosphatase SHP-2 was expressed higher in TIL than in PBL, tightly correlating with PD-1 expression and negative regulation of TCR target genes. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.

  18. The transcriptional network for mesenchymal transformation of brain tumors

    PubMed Central

    Carro, Maria Stella; Lim, Wei Keat; Alvarez, Mariano Javier; Bollo, Robert J.; Zhao, Xudong; Snyder, Evan Y.; Sulman, Erik P.; Anne, Sandrine L.; Doetsch, Fiona; Colman, Howard; Lasorella, Anna; Aldape, Ken; Califano, Andrea; Iavarone, Antonio

    2013-01-01

    Inference of transcriptional networks that regulate transitions into physiologic or pathologic cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumor aggressiveness in human malignant glioma but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here, we show that reverse-engineering and unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPβ and Stat3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and Stat3 reprograms neural stem cells along the aberrant mesenchymal lineage whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumor aggressiveness. In human glioma, expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results reveal that activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells. PMID:20032975

  19. Renal primitive neuroectodermal tumors.

    PubMed

    Bartholow, Tanner; Parwani, Anil

    2012-06-01

    Primitive neuroectodermal tumors exist as a part of the Ewing sarcoma/primitive neuroectodermal tumor family. These tumors most commonly arise in the chest wall and paraspinal regions; cases with a renal origin are rare entities, but have become increasingly reported in recent years. Although such cases occur across a wide age distribution, the average age for a patient with a renal primitive neuroectodermal tumor is the mid- to late 20s, with both males and females susceptible. Histologically, these tumors are characterized by pseudorosettes. Immunohistochemically, CD99 is an important diagnostic marker. Clinically, these are aggressive tumors, with an average 5-year disease-free survival rate of only 45% to 55%. Given that renal primitive neuroectodermal tumor bears many similarities to other renal tumors, it is important to review the histologic features, immunostaining profile, and genetic abnormalities that can be used for its correct diagnosis.

  20. Spectrum of tumors with follicular differentiation in a patient with the clinical phenotype of multiple familial trichoepitheliomas: a clinicopathological and molecular biological study, including analysis of the CYLD and PTCH genes.

    PubMed

    Kazakov, Dmitry V; Vanecek, Tomas; Nemcova, Jana; Kacerovska, Denisa; Spagnolo, Dominic V; Mukensnabl, Petr; Michal, Michal

    2009-12-01

    We report a patient with multiple trichoepitheliomas whose biopsy material also demonstrated a range of other neoplasms with follicular differentiation, including small nodular trichoblastoma, small nodular basal cell carcinoma (BCC), and areas resembling infundibulocystic BCC/basaloid follicular hamartoma. These were all intimately associated with otherwise typical trichoepitheliomas that dominated the microscopic appearances. Peripheral blood and tumor tissues of the patient and his 2 daughters, who apparently had a milder phenotype, were studied for alterations in the CYLD and PTCH genes, but mutations or loss of heterozygosity was not found in either gene. The occurrence of multiple follicular neoplasms within a single lesion adds evidence that, although in most cases BCC and trichoblastoma are distinct lesions, the 2 neoplasms do encompass a morphological spectrum of follicular differentiation, which is probably more overtly expressed in syndromic patients.

  1. Experimental Functional Analysis of Aggression in Children with Angelman Syndrome

    ERIC Educational Resources Information Center

    Strachan, Rachel; Shaw, Rebecca; Burrow, Caroline; Horsler, Kate; Allen, Debbie; Oliver, Chris

    2009-01-01

    Background: Kinship theory suggests that genomic imprinting could account for phenotypic behaviors that increase (in the case of Angelman syndrome) or decrease (for Prader-Willi syndrome) the drive to access social resources (adult contact) depending on the imprinting parent-of-origin. Difficult to manage behaviors, such as aggression that is…

  2. Targeting Aggressive Cancer Stem Cells in Glioblastoma

    PubMed Central

    Seymour, Tracy; Nowak, Anna; Kakulas, Foteini

    2015-01-01

    Glioblastoma (GBM) is the most common and fatal type of primary brain tumor. Gliosarcoma (GSM) is a rarer and more aggressive variant of GBM that has recently been considered a potentially different disease. Current clinical treatment for both GBM and GSM includes maximal surgical resection followed by post-operative radiotherapy and concomitant and adjuvant chemotherapy. Despite recent advances in treating other solid tumors, treatment for GBM and GSM still remains palliative, with a very poor prognosis and a median survival rate of 12–15 months. Treatment failure is a result of a number of causes, including resistance to radiotherapy and chemotherapy. Recent research has applied the cancer stem cells theory of carcinogenesis to these tumors, suggesting the existence of a small subpopulation of glioma stem-like cells (GSCs) within these tumors. GSCs are thought to contribute to tumor progression, treatment resistance, and tumor recapitulation post-treatment and have become the focus of novel therapy strategies. Their isolation and investigation suggest that GSCs share critical signaling pathways with normal embryonic and somatic stem cells, but with distinct alterations. Research must focus on identifying these variations as they may present novel therapeutic targets. Targeting pluripotency transcription factors, SOX2, OCT4, and Nanog homeobox, demonstrates promising therapeutic potential that if applied in isolation or together with current treatments may improve overall survival, reduce tumor relapse, and achieve a cure for these patients. PMID:26258069

  3. Functional Sphere Profiling Reveals the Complexity of Neuroblastoma Tumor-Initiating Cell Model12

    PubMed Central

    Coulon, Aurélie; Flahaut, Marjorie; Mühlethaler-Mottet, Annick; Meier, Roland; Liberman, Julie; Balmas-Bourloud, Katia; Nardou, Katya; Yan, Pu; Tercier, Stéphane; Joseph, Jean-Marc; Sommer, Lukas; Gross, Nicole

    2011-01-01

    Neuroblastoma (NB) is a neural crest-derived childhood tumor characterized by a remarkable phenotypic diversity, ranging from spontaneous regression to fatal metastatic disease. Although the cancer stem cell (CSC) model provides a trail to characterize the cells responsible for tumor onset, the NB tumor-initiating cell (TIC) has not been identified. In this study, the relevance of the CSC model in NB was investigated by taking advantage of typical functional stem cell characteristics. A predictive association was established between self-renewal, as assessed by serial sphere formation, and clinical aggressiveness in primary tumors. Moreover, cell subsets gradually selected during serial sphere culture harbored increased in vivo tumorigenicity, only highlighted in an orthotopic microenvironment. A microarray time course analysis of serial spheres passages from metastatic cells allowed us to specifically “profile” the NB stem cell-like phenotype and to identify CD133, ABC transporter, and WNT and NOTCH genes as spheres markers. On the basis of combined sphere markers expression, at least two distinct tumorigenic cell subpopulations were identified, also shown to preexist in primary NB. However, sphere markers-mediated cell sorting of parental tumor failed to recapitulate the TIC phenotype in the orthotopic model, highlighting the complexity of the CSC model. Our data support the NB stem-like cells as a dynamic and heterogeneous cell population strongly dependent on microenvironmental signals and add novel candidate genes as potential therapeutic targets in the control of high-risk NB. PMID:22028624

  4. Stability of Aggressive Behavior.

    ERIC Educational Resources Information Center

    Eron, Leonard D.; Huesmann, L. Rowell

    As indicated by multiple measures (including overt criminal behavior), stability of aggressive behavior was investigated across 22 years for males and females in a variety of situations. Originally, subjects included the entire population enrolled in the third grade in a semi-rural county in New York State. The sample included approximately 870…

  5. Aggressiveness and Disobedience

    ERIC Educational Resources Information Center

    Vaaland, Grete Sorensen; Idsoe, Thormod; Roland, Erling

    2011-01-01

    This study aims to conceptualize disobedient pupil behavior within the more general framework of antisocial behavior and to reveal how two forms of aggressiveness are related to disobedience. Disobedience, in the context of this article, covers disruptive pupil behavior or discipline problems when the pupil is aware of breaking a standard set by…

  6. Intellectual Competence and Aggression.

    ERIC Educational Resources Information Center

    Huesmann, L. Rowell; Yarmel, Patty Warnick

    Using data from a broader longitudinal study, this investigation explores within-subject and cross-generational stability of intellectual competence and the relationship of such stability to aggressive behavior. Data were gathered three times (when subjects' modal age was 8, 19, and 30 years). Initially, subjects included the entire population…

  7. Relational Aggression among Students

    ERIC Educational Resources Information Center

    Young, Ellie L.; Nelson, David A.; Hottle, America B.; Warburton, Brittney; Young, Bryan K.

    2011-01-01

    "Relational aggression" refers to harm within relationships caused by covert bullying or manipulative behavior. Examples include isolating a youth from his or her group of friends (social exclusion), threatening to stop talking to a friend (the silent treatment), or spreading gossip and rumors by email. This type of bullying tends to be…

  8. Neuroimaging and Aggression.

    ERIC Educational Resources Information Center

    Mills, Shari; Raine, Adrian

    1994-01-01

    Brain imaging research allows direct assessment of structural and functional brain abnormalities, and thereby provides an improved methodology for studying neurobiological factors predisposing to violent and aggressive behavior. This paper reviews 20 brain imaging studies using four different types of neuroimaging techniques that were conducted in…

  9. Human Aggression and Suicide

    ERIC Educational Resources Information Center

    Brown, Gerald L.; Goodwin, Frederick K

    1986-01-01

    The central nervous system transmitter serontonin may be altered in aggressive/impulsive and suicidal behaviors in humans. These reports are largely consistent with animal data, and constitute one of the most highly replicated set of findings in biological psychiatry. Suggests that some suicidal behavior may be a special kind of aggressive…

  10. Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype

    PubMed Central

    Xue, Nina; Zhou, Qin; Ji, Ming; Jin, Jing; Lai, Fangfang; Chen, Ju; Zhang, Mengtian; Jia, Jing; Yang, Huarong; Zhang, Jie; Li, Wenbin; Jiang, Jiandong; Chen, Xiaoguang

    2017-01-01

    Glioblastoma is an aggressive tumor that is associated with distinctive infiltrating microglia/macrophages populations. Previous studies demonstrated that chlorogenic acid (5-caffeoylquinic acid, CHA), a phenolic compound with low molecular weight, has an anti-tumor effect in multiple malignant tumors. In the present study, we focused on the macrophage polarization to investigate the molecular mechanisms behind the anti-glioma response of CHA in vitro and in vivo. We found that CHA treatment increased the expression of M1 markers induced by LPS/IFNγ, including iNOS, MHC II (I-A/I-E subregions) and CD11c, and reduced the expression of M2 markers Arg and CD206 induced by IL-4, resulting in promoting the production of apoptotic-like cancer cells and inhibiting the growth of tumor cells by co-culture experiments. The activations of STAT1 and STAT6, which are two crucial signaling events in M1 and M2-polarization, were significantly promoted and suppressed by CHA in macrophages, respectively. Furthermore, In G422 xenograft mice, CHA increased the proportion of CD11c-positive M1 macrophages and decreased the distribution of CD206-positive M2 macrophages in tumor tissue, consistent with the reduction of tumor weight observed in CHA-treated mice. Overall these findings indicated CHA as a potential therapeutic approach to reduce glioma growth through promoting M1-polarized macrophage and inhibiting M2 phenotypic macrophage. PMID:28045028

  11. The autophagic tumor stroma model of cancer or “battery-operated tumor growth”

    PubMed Central

    Martinez-Outschoorn, Ubaldo E; Whitaker-Menezes, Diana; Pavlides, Stephanos; Chiavarina, Barbara; Bonuccelli, Gloria; Trimmer, Casey; Tsirigos, Aristotelis; Migneco, Gemma; Witkiewicz, Agnieszka K; Balliet, Renee; Mercier, Isabelle; Wang, Chengwang; Flomenberg, Neal; Howell, Anthony; Lin, Zhao; Caro, Jaime; Pestell, Richard G

    2010-01-01

    stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a “lethal” aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia. PMID:21051947

  12. Of fish and mirrors: Fluoxetine disrupts aggression and learning for social rewards.

    PubMed

    Eisenreich, Benjamin R; Greene, Susan; Szalda-Petree, Allen

    2017-05-01

    Aggressive signaling is a key social behavior of male Siamese fighting fish (Betta splendens). Successfully establishing a territory and defending it from intruders has direct fitness effects, making Betta splendens a prime model for studies examining the biological underpinnings of aggressive behavior. Current research has outlined serotonin transporter pathways as one key component for the engagement and coordination of aggressive behavior in Betta splendens. Using the selective serotonin reuptake inhibitor fluoxetine, we examined the impact of 10μmol exposures on associative learning and aggression between mirror and conspecific social reinforcers. Our results provide clear evidence that exposure to fluoxetine reduces aggression and impairs learning independent of social reinforce type. In addition, our results provide support for motor inhibition of aggressive behavior as the main behavioral mechanism of action for fluoxetine. Placed within the broader context of behavioral syndromes, our results, along with others, implicate serotonergic pathways as a key biological correlate of the bold-aggressive phenotype.

  13. Parents' Aggressive Influences and Children's Aggressive Problem Solutions with Peers

    ERIC Educational Resources Information Center

    Duman, Sarah; Margolin, Gayla

    2007-01-01

    This study examined children's aggressive and assertive solutions to hypothetical peer scenarios in relation to parents' responses to similar hypothetical social scenarios and parents' actual marital aggression. The study included 118 children ages 9 to 10 years old and their mothers and fathers. Children's aggressive solutions correlated with…

  14. Relational Aggression and Physical Aggression among Adolescent Cook Islands Students

    ERIC Educational Resources Information Center

    Page, Angela; Smith, Lisa F.

    2016-01-01

    Both physical and relational aggression are characterised by the intent to harm another. Physical aggression includes direct behaviours such as hitting or kicking; relational aggression involves behaviours designed to damage relationships, such as excluding others, spreading rumours, and delivering threats and verbal abuse. This study extended…

  15. Effect of Doxorubicin/Pluronic SP1049C on Tumorigenicity, Aggressiveness, DNA Methylation and Stem Cell Markers in Murine Leukemia

    PubMed Central

    Li, Shu; Kabanov, Alexander V.

    2013-01-01

    Purpose Pluronic block copolymers are potent sensitizers of multidrug resistant cancers. SP1049C, a Pluronic-based micellar formulation of doxorubicin (Dox) has completed Phase II clinical trial and demonstrated safety and efficacy in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction. This study elucidates the ability of SP1049C to deplete cancer stem cells (CSC) and decrease tumorigenicity of cancer cells in vivo. Experimental Design P388 murine leukemia ascitic tumor was grown in BDF1 mice. The animals were treated with: (a) saline, (b) Pluronics alone, (c) Dox or (d) SP1049C. The ascitic cancer cells were isolated at different passages and examined for 1) in vitro colony formation potential, 2) in vivo tumorigenicity and aggressiveness, 3) development of drug resistance and Wnt signaling activation 4) global DNA methylation profiles, and 5) expression of CSC markers. Results SP1049C treatment reduced tumor aggressiveness, in vivo tumor formation frequency and in vitro clonogenic potential of the ascitic cells compared to drug, saline and polymer controls. SP1049C also prevented overexpression of BCRP and activation of Wnt-β-catenin signaling observed with Dox alone. Moreover, SP1049C significantly altered the DNA methylation profiles of the cells. Finally, SP1049C decreased CD133+ P388 cells populations, which displayed CSC-like properties and were more tumorigenic compared to CD133− cells. Conclusions SP1049C therapy effectively suppresses the tumorigenicity and aggressiveness of P388 cells in a mouse model. This may be due to enhanced activity of SP1049C against CSC and/or altered epigenetic regulation restricting appearance of malignant cancer cell phenotype. PMID:23977261

  16. Surprisal analysis of transcripts expression levels in the presence of noise: a reliable determination of the onset of a tumor phenotype.

    PubMed

    Gross, Ayelet; Levine, Raphael D

    2013-01-01

    Towards a reliable identification of the onset in time of a cancer phenotype, changes in transcription levels in cell models were tested. Surprisal analysis, an information-theoretic approach grounded in thermodynamics, was used to characterize the expression level of mRNAs as time changed. Surprisal Analysis provides a very compact representation for the measured expression levels of many thousands of mRNAs in terms of very few - three, four - transcription patterns. The patterns, that are a collection of transcripts that respond together, can be assigned definite biological phenotypic role. We identify a transcription pattern that is a clear marker of eventual malignancy. The weight of each transcription pattern is determined by surprisal analysis. The weight of this pattern changes with time; it is never strictly zero but it is very low at early times and then rises rather suddenly. We suggest that the low weights at early time points are primarily due to experimental noise. We develop the necessary formalism to determine at what point in time the value of that pattern becomes reliable. Beyond the point in time when a pattern is deemed reliable the data shows that the pattern remain reliable. We suggest that this allows a determination of the presence of a cancer forewarning. We apply the same formalism to the weight of the transcription patterns that account for healthy cell pathways, such as apoptosis, that need to be switched off in cancer cells. We show that their weight eventually falls below the threshold. Lastly we discuss patient heterogeneity as an additional source of fluctuation and show how to incorporate it within the developed formalism.

  17. The genetics of aggression: Where are we now?

    PubMed

    Asherson, Philip; Cormand, Bru

    2016-07-01

    Aggression, an overt behaviour with the intention to inflict damage, is a physiological trait with important roles throughout evolution, both in defence and predation. However, when expressed in humans in the wrong context, aggression leads to social maladjustment and crime. This special issue is about the genetic and neurobiological basis for aggression. Most of the 12 works presented here have been prepared by members of five international consortia established under the auspice of the FP7 and H2020 programs of the European Union to investigate different aspects of aggression and related behavioural phenotypes, including delineation of subtypes, aetiological mechanisms, neurobiology, neuroimaging, biomarkers, animal models and development and assessment of new treatments. Research on human aggression has largely focused on the societal causes of violent behaviour with relatively little focus on the underlying neuroscientific basis. However, interesting findings are emerging which suggest that by identifying distinct pathways to aggression, better targeting of social, psychological and medical treatments, can lead to improved outcomes for individuals and society. This issue represents a state of the art review of current neurobiological understanding of human aggression and a starting point for concerted efforts to move the field towards the development of new strategies for prevention and treatment. © 2016 Wiley Periodicals, Inc.

  18. Changing paradigms with molecular imaging of neuroendocrine tumors.

    PubMed

    Hofman, Michael S; Hicks, Rodney J

    2012-07-01

    Molecular imaging is changing diagnostic and treatment paradigms in patients with neuroendocrine tumors through its ability to non-invasively characterize disease, supplementing the traditional role of using imaging for localizing and measuring disease. For patients with metastatic disease, there is an increasing range of therapies but these must be individualized to the specific subtype of tumor expressed, which varies in aggressiveness from well to poorly differentiated phenotypes. Positron emission tomography (PET) is now able to characterize these subtypes through its ability to quantify somatostatin receptor cell surface (SSTR) expression and glycolytic metabolism with SSTR and fluorodeoxyglucose (FDG) PET, respectively. The ability to perform this as a whole body study is highlighting the limitations of relying on histopathology obtained from a single site. Through earlier diagnosis, improved selection of the most appropriate therapy and better assessment of therapeutic response for an individual patient, molecular imaging is improving the outcome for patients with NET.

  19. The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome.

    PubMed

    de Keyzer, Y; Lenne, F; Auzan, C; Jégou, S; René, P; Vaudry, H; Kuhn, J M; Luton, J P; Clauser, E; Bertagna, X

    1996-03-01

    Ectopic ACTH secretion occurs in highly differentiated and rather indolent tumors like bronchial carcinoids or, in contrast, in various types of aggressive and poorly differentiated neuroendocrine tumors. We explored this phenomenon using the recently cloned human pituitary V3 vasopressin receptor as an alternate molecular marker of the corticotroph phenotype. Expression of V3 receptor, corticotrophin releasing hormone (CRH) receptor, and proopiomelanocortin (POMC) genes was examined in tumors of pituitary and nonpituitary origin. A comparative RT-PCR approach revealed signals for both V3 receptor and CHR receptor mRNAs in 17 of 18 ACTH-secreting pituitary adenomas, and 6 of 6 normal pituitaries; in six growth hormone- or prolactin-secreting adenomas, a very faint V3 receptor signal was observed in three cases, and CRH receptor signal was undetected in all. Six of eight bronchial carcinoids responsible for the ectopic ACTH syndrome had both POMC and V3 receptor signals as high as those in ACTH-secreting pituitary adenomas; in contrast, no POMC signal and only a very faint V3 receptor signal were detected in six of eight nonsecreting bronchial carcinoids. Northern blot analysis showed V3 receptor mRNA of identical size in ACTH-secreting bronchial carcinoids and pituitary tumors. Other types of nonpituitary tumors responsible for ectopic ACTH syndrome presented much lower levels of both POMC and V3 receptor gene expression than those found in ACTH-secreting bronchial carcinoids. In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status. These results show that expression of the V3 receptor gene participates in the corticotroph phenotype. Its striking association with ACTH-secreting bronchial carcinoids defines a subset of nonpituitary tumors in which ectopic POMC gene expression is but one aspect of a wider process of corticotroph cell differentiation, and opens new possibilities of

  20. LASP1-S100A11 axis promotes colorectal cancer aggressiveness by modulating TGFβ/Smad signaling

    PubMed Central

    Niu, Ya; Shao, Ziyun; Wang, Hui; Yang, Jiaqi; Zhang, Feifei; Luo, Yuhao; Xu, Lijun; Ding, Yanqing; Zhao, Liang

    2016-01-01

    LIM and SH3 protein 1(LASP1) can promote colorectal cancer (CRC) progression and metastasis, but the mechanism remains unclear. Here, we show that LASP1 interacts with S100 calcium binding protein A11(S100A11) and enhances its expression in CRC. LASP1-S100A11 axis is essential for TGFβ-mediated epithelial-mesenchymal transition (EMT) and cell aggressive phenotype. Clinically, S100A11 is overexpressed in CRC tissues and localized in both the cytoplasm and the nucleus of CRC cells. Overexpression of S100A11 in cytoplasmic and nuclear subcellular compartments is associated with tumor metastasis and poor prognosis of CRC patients. Introduction of cytoplasmic and nuclear S100A11 promotes aggressive phenotypes of CRC cells in vitro as well as growth and metastasis of CRC xenografts, whereas suppressing S100A11 abrogates these effects. Furthermore, we identify flotillin-1 (FLOT1) and histone H1 as downstream factors for cytoplasmic and nuclear pathway of S100A11, which are required for LASP1-S100A11 axis-mediated EMT and CRC progression. These findings indicate S100A11, combined with LASP1, plays a critical role in promoting CRC metastasis via its subcellular effectors, FLOT1 and histone H1. PMID:27181092

  1. Serotonin and Aggressiveness in Chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Serotonin (5-HT) regulates aggressive behavior in animals. This study examined if 5-HT regulation of aggressiveness is gene-dependent. Chickens from two divergently selected lines KGB and MBB (Kind Gentle Birds and Mean Bad Birds displaying low and high aggressiveness, respectively) and DXL (Dekalb ...

  2. Expression of nicotinic receptors in normal and tumoral pulmonary neuroendocrine cells (PNEC).

    PubMed

    Sartelet, Hervé; Maouche, Kamel; Totobenazara, Jean-laurent; Petit, Jessica; Burlet, Henriette; Monteau, Michel; Tournier, Jean Marie; Birembaut, Philippe

    2008-01-01

    Neuroendocrine (NE) tumors of the lung represent a wide spectrum of phenotypically distinct entities, with differences in tumor progression and aggressiveness, which include carcinoid tumor (CT) and small-cell lung carcinoma (SCLC). Approximately 20-40% of patients with both typical and atypical CT are non-smokers, while virtually all patients with SCLC are cigarette smokers. Cigarette smoke contains numerous molecules which have been identified as carcinogens. The real impact of nicotine in the development of tumors is not well known. Recent studies show that nicotine upregulates factors of transcription through the nicotinic receptors. The aim of our work was to study the expression of the nicotinic receptors in normal and neoplastic pulmonary NE cells. An immunohistochemical study was carried out with antibodies against NE markers and subunits alpha7 and beta2 of nicotinic receptors in 7 normal lungs, 10 CT (8 typical and 2 atypical) and 10 SCLC fixed in formalin and embedded in paraffin. This study was completed with reverse transcription-polymerase chain reactions (RT-PCR) detection of alpha7-subunit nicotinic receptor mRNA expression. Our data showed that beta2-subunit of nicotinic receptors is never expressed in normal NE cells of lungs and very rarely in NE tumors. In contrast, alpha7-subunit is constantly found in NE cells in normal lungs. In tumors, its expression is significantly higher in SCLC than in CT (p=0.009). Thus, alpha7 subunit nicotinic receptor in a context of chronic nicotinic intoxication seems to be associated with an aggressive phenotype in the spectrum of the NE tumors.

  3. Combined inhibition of p38 and Akt signaling pathways abrogates cyclosporine A-mediated pathogenesis of aggressive skin SCCs

    SciTech Connect

    Arumugam, Aadithya; Walsh, Stephanie B.; Xu, Jianmin; Afaq, Farrukh; Elmets, Craig A.; Athar, Mohammad

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer p38 and Akt are the crucial molecular targets in the pathogenesis of SCCs in OTRs. Black-Right-Pointing-Pointer Combined inhibition of these targets diminished tumor growth by 90%. Black-Right-Pointing-Pointer Inhibition of these targets act through downregulating mTOR signaling pathway. -- Abstract: Non-melanoma skin cancers (NMSCs) are the most common neoplasm in organ transplant recipients (OTRs). These cancers are more invasive and metastatic as compared to those developed in normal cohorts. Previously, we have shown that immunosuppressive drug, cyclosporine A (CsA) directly alters tumor phenotype of cutaneous squamous cell carcinomas (SCCs) by activating TGF-{beta} and TAK1/TAB1 signaling pathways. Here, we identified novel molecular targets for the therapeutic intervention of these SCCs. We observed that combined blockade of Akt and p38 kinases-dependent signaling pathways in CsA-promoted human epidermoid carcinoma A431 xenograft tumors abrogated their growth by more than 90%. This diminution in tumor growth was accompanied by a significant decrease in proliferation and an increase in apoptosis. The residual tumors following the combined treatment with Akt inhibitor triciribine and p38 inhibitors SB-203580 showed significantly diminished expression of phosphorylated Akt and p38 and these tumors were less invasive and highly differentiated. Diminished tumor invasiveness was associated with the reduced epithelial-mesenchymal transition as ascertained by the enhanced E-cadherin and reduced vimentin and N-cadherin expression. Consistently, these tumors also manifested reduced MMP-2/9. The decreased p-Akt expression was accompanied by a significant reduction in p-mTOR. These data provide first important combinatorial pharmacological approach to block the pathogenesis of CsA-induced highly aggressive cutaneous neoplasm in OTRs.

  4. pERK/pAkt phenotyping in circulating tumor cells as a biomarker for sorafenib efficacy in patients with advanced hepatocellular carcinoma.

    PubMed

    Li, Jun; Shi, Lehua; Zhang, Xiaofeng; Sun, Bin; Yang, Yefa; Ge, Naijian; Liu, Huiying; Yang, Xia; Chen, Lei; Qian, Haihua; Wu, Mengchao; Yin, Zhengfeng

    2016-01-19

    Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, therapeutic response to sorafenib was not equal among HCC patients. Here we present a novel system to provide quantitative information concerning sorafenib-related targets by simultaneous detection of phosphorylated ERK (pERK) and pAkt expressions in circulating tumor cells (CTCs) isolated from HCC patients. Our results showed that 90.0% of patients had a molecular classification of tissues concordant with that of CTCs. CTC counts showed a shaper decline in patients with pERK+/pAkt- CTCs after two weeks of sorafenib treatment (P < 0.01). Disease control rates were significantly different between patients with pERK+/pAkt- CTCs (11/15; 73.3%) and those without (13/44; 29.5%) (P < 0.05). Univariate and multivariate analysis indicated pERK+/pAkt- CTCs as an independent predictive factor of progression-free survival (PFS) (hazard ratio = 9.389; P < 0.01). PFS correlated with the proportion of pERK+/pAkt- CTCs (r = 0.968, P < 0.01), and was higher in patients with ≥ 40% pERK+/pAkt- CTCs compared to those with < 40% (8.4 vs. 1.3 mo; P < 0.05). In a validation set of twenty HCC patients, CTCs from patients with ≥ 40% pERK+/pAkt- CTCs had significantly higher inhibition rates of spheroid formation compared to those with < 40% (61.2 vs. 19.8%; P < 0.01). Our findings demonstrated that CTCs can be used in place of tumor tissue for characterization of pERK/pAkt expression. pERK+/pAkt- CTCs are most sensitive to sorafenib and an independent predictive factor of PFS in HCC patients treated with sorafenib.

  5. Endolymphatic sac tumors.

    PubMed

    Wick, Cameron C; Manzoor, Nauman F; Semaan, Maroun T; Megerian, Cliff A

    2015-04-01

    Endolymphatic sac tumors (ELST) are slow-growing, locally aggressive, low-grade malignancies that originate from the epithelium of the endolymphatic duct and sac. ELST often present with sensorineural hearing loss, tinnitus, and vertigo, which may mimic Meniere disease. Large tumors may present with additional cranial neuropathies. Management is primarily via microsurgical excision. Radiation therapy has a limited role for residual or unresectable disease. Early detection may enable hearing preservation techniques. ELST have an association with von Hippel-Lindau disease.

  6. A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma.

    PubMed

    Misir Krpan, Ana; Dusek, Tina; Rakusic, Zoran; Solak, Mirsala; Kraljevic, Ivana; Bisof, Vesna; Ozretic, David; Kastelan, Darko

    2017-01-01

    Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma.

  7. A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma

    PubMed Central

    2017-01-01

    Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma. PMID:28357143

  8. Dissociation of mitogenesis and late-stage promotion of tumor cell phenotype by phorbol esters: mitogen-resistant variants are sensitive to promotion.

    PubMed Central

    Colburn, N H; Wendel, E J; Abruzzo, G

    1981-01-01

    The JB-6 mouse epidermal cell line has been used as a model system for studying the mechanism of late-stage promoter-dependent preneoplastic progression. The studies reported here are concerned with determining whether there is a requirement for mitogenic stimulation in promotion of anchorage independence and tumorigenicity in JB-6 cells. Such a requirement would predict that variants selected for 12-O-tetradecanoylphorbol 13-acetate (TPA) mitogen resistance would also be promotion resistant. Promotion-responsive cell lines have been selected for resistance to TPA-induced mitogenic stimulation at plateau density by cotreatment with colchicine and removal of mitogen-responsive colchicine-detached cells. The selected TPA-resistant population of cells showed a mitogenic response that was diminished by a factor of four but showed no diminution in the promotion-of-anchorage-independence response to TPA. Mitogen-resistant clonal lines derived from the selected population fell into three phenotypic classes when assayed in soft agar: (i) anchorage-independent transformants; (ii) variants resistant to promotion of anchorage independence by TPA; and (iii) variants sensitive to promotion by TPA. The existence of the latter class (i.e., the mitogen-resistant promotable variants) indicates a lack of obligatory causal relationship between TPa-induced mitogenesis and late-stage promotion and, thereby suggests that the two events can be dissociated. Images PMID:6947266

  9. Aggressive papillary adenocarcinoma on atypical localization

    PubMed Central

    Balci, Mecdi Gurhan; Tayfur, Mahir; Deger, Ayse Nur; Cimen, Orhan; Eken, Huseyin

    2016-01-01

    Abstract Introduction: Aggressive digital papillary adenocarcinoma (ADPA) is a rare sweat gland tumor that is found on the fingers, toes, and the digits. To date, <100 cases have been reported in the literature. Apart from 1 case reported in the thigh, all of them were on digital or nondigital acral skin. Case presentation: A 67-year-old Caucasian woman was admitted to the hospital due to a mass on the scalp. This lesion was present for almost a year. It was a semimobile cyctic mass that elevated the scalp. There was no change in the skin color. Its dimensions were 1.5 × 1 × 0.6 cm. The laboratory, clinic, and radiologic findings (head x-ray) of the patient were normal. It was evaluated as a benign lesion such as lipoma or epidermal cyst by a surgeon due to a small semimobile mass and no erosion of the skull. It was excised by a local surgery excision. The result of the pathologic examination was aggressive papillary adenocarcinoma. This diagnosis is synonymous with ADPA. Conclusion: In our case, localization was scalp. This localization is the first for this tumor in the literature. In addition, another atypical localization of this tumor (ADPA) is thigh in the literature. This case was presented due to both the rare and atypical localizations. That is why, in our opinion, revision of “digital” term in ADPA is necessary due to seem in atypical localizations like thigh and scalp. PMID:27428196

  10. [Classic and aggressive Kaposi sarcoma with bone involvement].

    PubMed

    Sbiyaa, Mouhcine; El Alaoui, Adil; El Bardai, Mohammed; Mezzani, Amine; Lahrach, Kamal; Marzouki, Amine; Boutayeb, Fawzi

    2016-01-01

    Classic Kaposi sarcoma is a multifocal rare tumor originating from vascular endothelial cells with progressive evolution and little malignant predisposition. Although Kaposi sarcoma with extensive visceral involvement is sometimes observed among HIV-positive patients, tumor dissemination to visceral lymph nodes in classic SK remains very rare. We report a rare case of aggressive classic Kaposi sarcoma of the hand with a rapid and destructive development.

  11. Motives in Sexual Aggression: The Chinese Context.

    ERIC Educational Resources Information Center

    Tang, Catherine So-Kum; And Others

    1993-01-01

    Compared sexual and aggressive motives for sexual aggression in Chinese college students. Male undergraduates (N=146) completed self-report measures. Results suggest that sex guilt and aggressive guilt acted as inhibitors for their respective drives and sexual aggression resulted from aggressive, rather than sexual, motives. Sexual aggression may…

  12. A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors.

    PubMed

    Staal, Jerome A; Pei, Yanxin; Rood, Brian R

    2016-10-19

    Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities.

  13. A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors

    PubMed Central

    Staal, Jerome A.; Pei, Yanxin; Rood, Brian R.

    2016-01-01

    Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities. PMID:27775567

  14. Differentiated thyroid tumors: surgical indications

    PubMed Central

    LUCCHINI, R.; MONACELLI, M.; SANTOPRETE, S.; TRIOLA, R.; CONTI, C.; PECORIELLO, R.; FAVORITI, P.; DI PATRIZI, M.S.; BARILLARO, I.; BOCCOLINI, A.; AVENIA, S.; D’AJELLO, M.; SANGUINETTI, A.; AVENIA, N.

    2013-01-01

    Summary: Thyroid gland tumors represent 1% of malignant tumors. In Italy their incidence is in constant growth. The aggressiveness depends on the histological type. The relative non-aggressive grade of different forms of tumors is the basis for discussing the treatment of choice: total thyroidectomy vs lobectomy with or without lymphadenectomy of the sixth level in the absence of metastasis. Authors report about their experience, and they advocate, given the high percentage of multicentric forms, total thyroidectomy as treatment of choice. PMID:23837952

  15. E6 and E7 gene silencing results in decreased methylation of tumor suppressor genes and induces phenotype transformation of human cervical carcinoma cell lines.

    PubMed

    Li, Liming; Xu, Cui; Long, Jia; Shen, Danbei; Zhou, Wuqing; Zhou, Qiyan; Yang, Jia; Jiang, Mingjun

    2015-09-15

    In SiHa and CaSki cells, E6 and E7-targeting shRNA specifically and effectively knocked down human papillomavirus (HPV) 16 E6 and E7 at the transcriptional level, reduced the E6 and E7 mRNA levels by more than 80% compared with control cells that expressed a scrambled-sequence shRNA. E6 and E7 repression resulted in down-regulation of DNA methyltransferase mRNA and protein expression, decreased DNA methylation and increased mRNA expression levels of tumor suppressor genes, induced a certain apoptosis and inhibited proliferation in E6 and E7 shRNA-infected SiHa and CaSki cells compared with the uninfected cells. Repression of E6 and E7 oncogenes resulted in restoration of DNA methyltransferase suppressor pathways and induced apoptosis in HPV16-positive cervical carcinoma cell lines. Our findings suggest that the potential carcinogenic mechanism of HPV16 through influencing DNA methylation pathway to activate the development of cervical cancer exist, and maybe as a candidate therapeutic strategy for cervical and other HPV-associated cancers.

  16. Imaging Prostatic Lipids to Distinguish Aggressive Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    this application, we propose to build upon our current work to determine the association between fatty acid synthase (FAS) overexpression and...Mechanisms linking fatty acid synthase overexpression, lipid accumulation, lipid oxidation, and tumor aggressiveness will be explored using...INTRODUCTION: Mounting evidence suggests that dysregulation of fatty acid synthase (FAS), the rate limiting multienzyme in the de novo formation of free

  17. Expression of CD44 isoforms in renal cell tumors. Positive correlation to tumor differentiation.

    PubMed Central

    Terpe, H. J.; Störkel, S.; Zimmer, U.; Anquez, V.; Fischer, C.; Pantel, K.; Günthert, U.

    1996-01-01

    CD44 isoforms have been implicated in tumor progression and embryogenesis. Primary renal cell tumors (n = 100) of various histopathological differentiation and grading stages were analyzed for expression of CD44 isoforms in comparison with nonmalignant adult and fetal renal tissues. Evaluations were performed by immunohistochemistry using CD44 isoform-specific monoclonal antibodies and by reverse transcriptase polymerase chain reactions (RT-PCR). In the nonmalignant kidney no CD44 variant isoforms were detected. There was a significant increase in expression of CD44 standard (CD44s) and several variant isoforms (CD44v) in the course of tumor differentiation in clear cell carcinomas (n = 68) from stages G1 to G3 (P < 0.0001 for CD44s and isoforms containing CD44-6v, and P < 0.007 for those containing CD44-9v). Also, in chromophilic cell carcinomas (n = 13), CD44 isoform expression correlated with grading; ie, no CD44 expression was detected in G1 tumors, whereas in approximately 50% of the G2 tumors, CD44s, CD44-6v, and CD44-9v isoforms were present. Oncocytomas (n = 8), which are benign renal cell tumors, did not express CD44 isoforms, whereas invasive chromophobe cell carcinomas (n = 11) were positive for CD44s and CD44v isoforms. Transcript analyses by RT-PCR revealed that the upregulated isoforms in the carcinoma cells contained exons 8 to 10 and 3, 8 to 10 in combination from the variant region. In conclusion, expression of variant CD44 isoforms was strongly correlated with grading and appears to mediate a more aggressive phenotype to renal cell tumors. Images Figure 3 Figure 4 Figure 5 Figure 6 PMID:8579108

  18. Genome-wide methylation profiling identifies novel methylated genes in neuroblastoma tumors.

    PubMed

    Olsson, Maja; Beck, Stephan; Kogner, Per; Martinsson, Tommy; Carén, Helena

    2016-01-01

    Neuroblastoma is a very heterogeneous tumor of childhood. The clinical spectra range from very aggressive metastatic disease to spontaneous regression, even without therapy. Aberrant DNA methylation pattern is a common feature of most cancers. For neuroblastoma, it has been demonstrated both for single genes as well as genome-wide, where a so-called methylator phenotype has been described. Here, we present a study using Illumina 450K methylation arrays on 60 neuroblastoma tumors. We show that aggressive tumors, characterized by International Neuroblastoma Risk Group (INRG) as stage M, are hypermethylated compared to low-grade tumors. On the contrary, INRG stage L tumors display more non-CpG methylation. The genes with the highest number of hypermethylated CpG sites in INRG M tumors are TERT, PCDHGA4, DLX5, and DLX6-AS1. Gene ontology analysis showed a representation of neuronal tumor relevant gene functions among the differentially methylated genes. For validation, we used a set of independent tumors previously analyzed with the Illumina 27K methylation arrays, which confirmed the differentially methylated sites. Top candidate genes with aberrant methylation were analyzed for altered gene expression through the R2 platform ( http://r2.amc.nl), and for correlations between methylation and gene expression in a public dataset. Altered expression in nonsurvivors was found for the genes B3GALT4 and KIAA1949, CLIC5, DLX6-AS, TERT, and PIRT, and strongest correlations were found for TRIM36, KIAA0513, and PIRT. Our data indicate that methylation profiling can be used for patient stratification and informs on epigenetically deregulated genes with the potential of increasing our knowledge about the underlying mechanisms of tumor development.

  19. Genome-wide methylation profiling identifies novel methylated genes in neuroblastoma tumors

    PubMed Central

    Olsson, Maja; Beck, Stephan; Kogner, Per; Martinsson, Tommy; Carén, Helena

    2016-01-01

    ABSTRACT Neuroblastoma is a very heterogeneous tumor of childhood. The clinical spectra range from very aggressive metastatic disease to spontaneous regression, even without therapy. Aberrant DNA methylation pattern is a common feature of most cancers. For neuroblastoma, it has been demonstrated both for single genes as well as genome-wide, where a so-called methylator phenotype has been described. Here, we present a study using Illumina 450K methylation arrays on 60 neuroblastoma tumors. We show that aggressive tumors, characterized by International Neuroblastoma Risk Group (INRG) as stage M, are hypermethylated compared to low-grade tumors. On the contrary, INRG stage L tumors display more non-CpG methylation. The genes with the highest number of hypermethylated CpG sites in INRG M tumors are TERT, PCDHGA4, DLX5, and DLX6-AS1. Gene ontology analysis showed a representation of neuronal tumor relevant gene functions among the differentially methylated genes. For validation, we used a set of independent tumors previously analyzed with the Illumina 27K methylation arrays, which confirmed the differentially methylated sites. Top candidate genes with aberrant methylation were analyzed for altered gene expression through the R2 platform (http://r2.amc.nl), and for correlations between methylation and gene expression in a public dataset. Altered expression in nonsurvivors was found for the genes B3GALT4 and KIAA1949, CLIC5, DLX6-AS, TERT, and PIRT, and strongest correlations were found for TRIM36, KIAA0513, and PIRT. Our data indicate that methylation profiling can be used for patient stratification and informs on epigenetically deregulated genes with the potential of increasing our knowledge about the underlying mechanisms of tumor development. PMID:26786290

  20. Tumor Budding, Micropapillary Pattern, and Polyploidy Giant Cancer Cells in Colorectal Cancer: Current Status and Future Prospects

    PubMed Central

    Zhang, Dan; Yang, Zhengduo; Zhang, Xipeng

    2016-01-01

    We previously reported that polyploid giant cancer cells (PGCGs) induced by CoCl2 could form through endoreduplication or cell fusion. A single PGCC formed tumors in immunodeficient mice. PGCCs are also the key contributors to the cellular atypia and associate with the malignant grade of tumors. PGCCs have the properties of cancer stem cells and produce daughter cells via asymmetric cell division. Compared with diploid cancer cells, these daughter cells express less epithelial markers and acquire mesenchymal phenotype with importance in cancer development and progression. Tumor budding is generally recognized to correlate with a high recurrence rate, lymph node metastasis, chemoresistance, and poor prognosis of colorectal cancers (CRCs) and is a good indicator to predict the metastasis and aggressiveness in CRCs. Micropapillary pattern is a special morphologic pattern and also associates with tumor metastasis and poor prognosis. There are similar morphologic features and molecular phenotypes among tumor budding, micropapillary carcinoma pattern, and PGCCs with their budding daughter cells and all of them show strong ability of tumor invasion and migration. In this review, we discuss the cancer stem cell properties of PGCCs, the molecular mechanisms of their regulation, and the relationships with tumor budding and micropapillary pattern in CRCs. PMID:27843459

  1. Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate

    PubMed Central

    Proia, Theresa A.; Keller, Patricia J.; Gupta, Piyush B.; Klebba, Ina; Jones, Ainsley D.; Sedic, Maja; Gilmore, Hannah; Tung, Nadine; Naber, Stephen P.; Schnitt, Stuart; Lander, Eric S.; Kuperwasser, Charlotte

    2011-01-01

    Women with inherited mutations in the BRCA1 gene have increased risk of developing breast cancer, but also exhibit a predisposition for the development of aggressive basal-like breast tumors. We report here that breast epithelial cells derived from patients harboring deleterious mutations in BRCA1 (BRCA1mut/+) give rise to tumors with increased basal differentiation relative to cells from BRCA1+/+ patients. Molecular analysis of disease-free breast tissues from BRCA1mut/+ patients revealed defects in progenitor cell lineage commitment even before cancer incidence. Moreover, we discovered that the transcriptional repressor Slug is an important functional regulator of human breast progenitor cell lineage commitment and differentiation and that it is aberrantly expressed in BRCA1mut/+ tissues. Slug expression is necessary for increased basal-like phenotypes prior to and following neoplastic transformation. These findings demonstrate that the genetic background of patient populations, in addition to affecting incidence rates, significantly impacts progenitor cell fate commitment and, therefore, tumor phenotype. PMID:21295272

  2. Primary renal primitive neuroectodermal tumor.

    PubMed

    Goel, V; Talwar, V; Dodagoudar, C; Singh, S; Sharma, A; Patnaik, N

    2015-01-01

    Primitive Neuroectodermal Tumor of the kidney is a rare entity. Very few cases of primary renal PNET have been reported to date. Most literature about rPNET is isolated case reports. We report a case of rPNET in a 39-year-old male with a pre-operative diagnosis of renal cell carcinoma with renal vein thrombosis. The patient underwent radical nephrectomy with thrombolectomy, and histopathological examination revealed a highly aggressive tumor composed of monotonous sheets of round cells. Tumor cells were positive for CD 99 and FLI-1, hence confirming the diagnosis of Primitive Neuroectodermal Tumor. Post-surgery, patient was given VAC/IE-based adjuvant chemotherapy. In view of highly aggressive nature of this tumor, prompt diagnosis and imparting effective chemotherapy regimen to the patient is required, and it is important to differentiate PNET from other small round-cell tumors because of different therapeutic approach.

  3. Heterospecific aggression bias towards a rarer colour morph.

    PubMed

    Lehtonen, Topi K; Sowersby, Will; Wong, Bob B M

    2015-09-22

    Colour polymorphisms are a striking example of phenotypic diversity, yet the sources of selection that allow different morphs to persist within populations remain poorly understood. In particular, despite the importance of aggression in mediating social dominance, few studies have considered how heterospecific aggression might contribute to the maintenance or divergence of different colour morphs. To redress this gap, we carried out a field-based study in a Nicaraguan crater lake to investigate patterns of heterospecific aggression directed by the cichlid fish, Hypsophrys nicaraguensis, towards colour polymorphic cichlids in the genus Amphilophus. We found that H. nicaraguensis was the most frequent territorial neighbour of the colour polymorphic A. sagittae. Furthermore, when manipulating territorial intrusions using models, H. nicaraguensis were more aggressive towards the gold than dark colour morph of the sympatric Amphilophus species, including A. sagittae. Such a pattern of heterospecific aggression should be costly to the gold colour morph, potentially accounting for its lower than expected frequency and, more generally, highlighting the importance of considering heterospecific aggression in the context of morph frequencies and coexistence in the wild.

  4. Impaired Nitric Oxide Synthase Signaling Dissociates Social Investigation and Aggression

    PubMed Central

    Trainor, Brian C.; Workman, Joanna L.; Jessen, Ruth; Nelson, Randy J.

    2007-01-01

    A combination of social withdrawal and increased aggression is characteristic of several mental disorders. Most previous studies have investigated the neurochemical bases of social behavior and aggression independently, as opposed to how these behaviors are regulated in concert. Neuronal nitric oxide synthase (nNOS) produces gaseous nitric oxide, which functions as a neurotransmitter and is known to affect several types of behavior including mating and aggression. Compared with wild-type mice, we observed that nNOS knockout mice showed reduced behavioral responses to an intruder behind a wire barrier. Similar results were observed in mice treated with the selective nNOS inhibitor 3-bromo-7-nitroindazole (3BrN). In habituation–dishabituation tests, treatment with 3BrN did not block recognition of male urine but did attenuate investigation time compared with oil-treated animals. Finally, nNOS knockout mice and 3BrN treated mice were significantly more aggressive than wild-type and oil-treated males, respectively. In general, these behavioral effects are less pronounced in pair-housed males compared with singly-housed males. Thus, nNOS inhibition results in a phenotype that displays reduced social investigation and increased aggression. These data suggest that further study of nNOS signaling is warranted in mental disorders characterized by social withdrawal and increased aggression. PMID:17469926

  5. Heterospecific aggression bias towards a rarer colour morph

    PubMed Central

    Lehtonen, Topi K.; Sowersby, Will; Wong, Bob B. M.

    2015-01-01

    Colour polymorphisms are a striking example of phenotypic diversity, yet the sources of selection that allow different morphs to persist within populations remain poorly understood. In particular, despite the importance of aggression in mediating social dominance, few studies have considered how heterospecific aggression might contribute to the maintenance or divergence of different colour morphs. To redress this gap, we carried out a field-based study in a Nicaraguan crater lake to investigate patterns of heterospecific aggression directed by the cichlid fish, Hypsophrys nicaraguensis, towards colour polymorphic cichlids in the genus Amphilophus. We found that H. nicaraguensis was the most frequent territorial neighbour of the colour polymorphic A. sagittae. Furthermore, when manipulating territorial intrusions using models, H. nicaraguensis were more aggressive towards the gold than dark colour morph of the sympatric Amphilophus species, including A. sagittae. Such a pattern of heterospecific aggression should be costly to the gold colour morph, potentially accounting for its lower than expected frequency and, more generally, highlighting the importance of considering heterospecific aggression in the context of morph frequencies and coexistence in the wild. PMID:26378216

  6. Age-related macular degeneration phenotypes are associated with increased tumor necrosis-alpha and subretinal immune cells in aged Cxcr5 knockout mice

    PubMed Central

    Huang, Hu; Liu, Ying; Wang, Lei; Li, Wen

    2017-01-01

    The role of chemokine receptor in age-related macular degeneration (AMD) remains elusive. The objective of this study is to investigate the role of chemokine receptor Cxcr5 in the pathogenesis of AMD. Cxcr5 gene expression levels (mRNA and protein) are higher in the retina and retinal pigment epithelium (RPE) of aged C57BL/6 wild type mice than younger ones. Vascular and glial cells express Cxcr5 and its ligand Cxcl13 in mouse retina. Aged Cxcr5 knockout (-/-) mice develop both early and late AMD-like pathological features. White and yellow spots, which look like drusen in humans, were identified with fundscopic examination. Drusen-like sub-RPE deposits with dome-shaped morphology were characterized on the sections. RPE vacuolization, swelling, and sub-RPE basal deposits were illustrated with light and transmission electron microscope (TEM). TEM further illustrated degenerated and disorganized RPE basal infoldings, phagosomes and melanosomes inside RPE, as well as abnormal photoreceptor outer segments. Lipofuscin granules and lipid droplets in the subretinal space, RPE, and choroid were revealed with fluorescence microscope and oil-red-O staining. Increased IgG in RPE/choroid were determined with Western blots (WB). WB and immunofluorescence staining determined RPE zona occuldens (ZO)-1 protein reduction and abnormal subcellular localization. TUNEL staining, outer nuclear layer (ONL) measurement and electroretinogram (ERG) recording indicated that photoreceptors underwent apoptosis, degeneration, and functional impairment. Additionally, spontaneous neovascularization (NV)-like lesions develop in the subretinal space of aged Cxcr5-/- mice. The underlying mechanisms are associated with increased subretinal F4/80+ immune cells, some of which contain RPE marker RPE65, and up-regulation of the multifunctional cytokine tumor necrosis factor-alpha (TNF-α) in RPE/choroid and retina. These findings suggest that Cxcr5 itself may be involved in the protection of RPE and

  7. Age-related macular degeneration phenotypes are associated with increased tumor necrosis-alpha and subretinal immune cells in aged Cxcr5 knockout mice.

    PubMed

    Huang, Hu; Liu, Ying; Wang, Lei; Li, Wen

    2017-01-01

    The role of chemokine receptor in age-related macular degeneration (AMD) remains elusive. The objective of this study is to investigate the role of chemokine receptor Cxcr5 in the pathogenesis of AMD. Cxcr5 gene expression levels (mRNA and protein) are higher in the retina and retinal pigment epithelium (RPE) of aged C57BL/6 wild type mice than younger ones. Vascular and glial cells express Cxcr5 and its ligand Cxcl13 in mouse retina. Aged Cxcr5 knockout (-/-) mice develop both early and late AMD-like pathological features. White and yellow spots, which look like drusen in humans, were identified with fundscopic examination. Drusen-like sub-RPE deposits with dome-shaped morphology were characterized on the sections. RPE vacuolization, swelling, and sub-RPE basal deposits were illustrated with light and transmission electron microscope (TEM). TEM further illustrated degenerated and disorganized RPE basal infoldings, phagosomes and melanosomes inside RPE, as well as abnormal photoreceptor outer segments. Lipofuscin granules and lipid droplets in the subretinal space, RPE, and choroid were revealed with fluorescence microscope and oil-red-O staining. Increased IgG in RPE/choroid were determined with Western blots (WB). WB and immunofluorescence staining determined RPE zona occuldens (ZO)-1 protein reduction and abnormal subcellular localization. TUNEL staining, outer nuclear layer (ONL) measurement and electroretinogram (ERG) recording indicated that photoreceptors underwent apoptosis, degeneration, and functional impairment. Additionally, spontaneous neovascularization (NV)-like lesions develop in the subretinal space of aged Cxcr5-/- mice. The underlying mechanisms are associated with increased subretinal F4/80+ immune cells, some of which contain RPE marker RPE65, and up-regulation of the multifunctional cytokine tumor necrosis factor-alpha (TNF-α) in RPE/choroid and retina. These findings suggest that Cxcr5 itself may be involved in the protection of RPE and

  8. Transperineal aggressive angiomyxoma.

    PubMed

    Pereira, Pedro; Melo Abreu, Elisa; Cunha, Teresa Margarida; Rolim, Inês

    2017-04-11

    A 45-year-old woman with a history of total hysterectomy with adnexal preservation for uterine leiomyomas presented to our hospital with a right gluteal palpable mass, which she first noticed 6 months before and had progressively enlarged since then.Radiological studies revealed a 14 cm lesion with translevator growth that displaced rather than invaded adjacent structures, with a peculiar whorled pattern on T2-weighted MRI, which enhanced following gadolinium administration. CT-guided biopsy was performed, and in conjunction with imaging features the diagnosis of an aggressive angiomyxoma was assumed and confirmed following surgical excision.

  9. Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung

    PubMed Central

    Lugo, Roberto; Gabasa, Marta; Andriani, Francesca; Puig, Marta; Facchinetti, Federica; Ramírez, Josep; Gómez-Caro, Abel; Pastorino, Ugo; Fuster, Gemma; Almendros, Isaac; Gascón, Pere; Davalos, Albert; Reguart, Noemí; Roz, Luca; Alcaraz, Jordi

    2016-01-01

    Senescence in cancer cells acts as a tumor suppressor, whereas in fibroblasts enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of cancer subtypes. However, the presence of senescent TAFs in lung cancer remains undefined. We examined senescence in TAFs from primary lung cancer and paired control fibroblasts from unaffected tissue in three major histologic subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Three independent senescence markers (senescence-associated beta-galactosidase, permanent growth arrest and spreading) were consistently observed in cultured LCC-TAFs only, revealing a selective premature senescence. Intriguingly, SCC-TAFs exhibited a poor growth response in the absence of senescence markers, indicating a dysfunctional phenotype rather than senescence. Co-culturing normal fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to render fibroblasts senescent through oxidative stress, indicating that senescence in LCC-TAFs is driven by heterotypic signaling. In addition, senescent fibroblasts provided selective growth and invasive advantages to LCC cells in culture compared to normal fibroblasts. Likewise, senescent fibroblasts enhanced tumor growth and lung dissemination of tumor cells when co-injected with LCC cells in nude mice beyond the effects induced by control fibroblasts. These results define the subtype-specific aberrant phenotypes of lung TAFs, thereby challenging the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless of their subtype. Importantly, because LCC often distinguishes itself in the clinic by its aggressive nature, we argue that senescent TAFs may contribute to the selective aggressive behavior of LCC tumors. PMID:27384989

  10. Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung.

    PubMed

    Lugo, Roberto; Gabasa, Marta; Andriani, Francesca; Puig, Marta; Facchinetti, Federica; Ramírez, Josep; Gómez-Caro, Abel; Pastorino, Ugo; Fuster, Gemma; Almendros, Isaac; Gascón, Pere; Davalos, Albert; Reguart, Noemí; Roz, Luca; Alcaraz, Jordi

    2016-12-13

    Senescence in cancer cells acts as a tumor suppressor, whereas in fibroblasts enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of cancer subtypes. However, the presence of senescent TAFs in lung cancer remains undefined. We examined senescence in TAFs from primary lung cancer and paired control fibroblasts from unaffected tissue in three major histologic subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Three independent senescence markers (senescence-associated beta-galactosidase, permanent growth arrest and spreading) were consistently observed in cultured LCC-TAFs only, revealing a selective premature senescence. Intriguingly, SCC-TAFs exhibited a poor growth response in the absence of senescence markers, indicating a dysfunctional phenotype rather than senescence. Co-culturing normal fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to render fibroblasts senescent through oxidative stress, indicating that senescence in LCC-TAFs is driven by heterotypic signaling. In addition, senescent fibroblasts provided selective growth and invasive advantages to LCC cells in culture compared to normal fibroblasts. Likewise, senescent fibroblasts enhanced tumor growth and lung dissemination of tumor cells when co-injected with LCC cells in nude mice beyond the effects induced by control fibroblasts. These results define the subtype-specific aberrant phenotypes of lung TAFs, thereby challenging the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless of their subtype. Importantly, because LCC often distinguishes itself in the clinic by its aggressive nature, we argue that senescent TAFs may contribute to the selective aggressive behavior of LCC tumors.

  11. Plasticity in anterior hypothalamic vasopressin correlates with aggression during anabolic-androgenic steroid withdrawal in hamsters.

    PubMed

    Grimes, Jill M; Ricci, Lesley A; Melloni, Richard H

    2006-02-01

    In hamsters, adolescent anabolic-androgenic steroid (AAS) exposure facilitates offensive aggression, in part by altering the development and activity of anterior hypothalamic arginine vasopressin (AH-AVP). This study assessed whether these effects were lasting by examining aggression and AH-AVP during AAS withdrawal. Adolescent hamsters administered AAS were tested as adults for aggression at 1, 4, 11, 18, or 25 days of withdrawal, sacrificed the following day, and examined for AH-AVP afferent innervation using immunohistochemistry. Through Day 12 of withdrawal, aggression and AVP were significantly higher in AAS-treated hamsters than in controls. These differences were no longer observable by Day 19 of withdrawal, at which point the behavior and neurobiology of AAS-treated hamsters reverted to that observed in controls. These data indicate that adolescent AAS exposure has short-term, reversible effects on both aggression and AH-AVP, correlating AH-AVP with the aggressive/nonaggressive behavioral phenotype during AAS withdrawal.

  12. The Genetic and Environmental Covariation Among Psychopathic Personality Traits, and Reactive and Proactive Aggression in Childhood

    PubMed Central

    Bezdjian, Serena; Raine, Adrian; Tuvblad, Catherine; Baker, Laura A.

    2011-01-01

    The present study investigated the genetic and environmental covariance between psychopathic personality traits with reactive and proactive aggression in 9- to 10-year-old twins (N = 1,219). Psychopathic personality traits were assessed with the Child Psychopathy Scale (D. R. Lynam, 1997), while aggressive behaviors were assessed using the Reactive Proactive Questionnaire (A. Raine et al., 2006). Significant common genetic influences were found to be shared by psychopathic personality traits and aggressive behaviors using both caregiver (mainly mother) and child self-reports. Significant genetic and nonshared environmental influences specific to psychopathic personality traits and reactive and proactive aggression were also found, suggesting etiological independence among these phenotypes. Additionally, the genetic relation between psychopathic personality traits and aggression was significantly stronger for proactive than reactive aggression when using child self-reports. PMID:21557742

  13. The nature of human aggression.

    PubMed

    Archer, John

    2009-01-01

    Human aggression is viewed from four explanatory perspectives, derived from the ethological tradition. The first consists of its adaptive value, which can be seen throughout the animal kingdom, involving resource competition and protection of the self and offspring, which has been viewed from a cost-benefit perspective. The second concerns the phylogenetic origin of aggression, which in humans involves brain mechanisms that are associated with anger and inhibition, the emotional expression of anger, and how aggressive actions are manifest. The third concerns the origin of aggression in development and its subsequent modification through experience. An evolutionary approach to development yields conclusions that are contrary to the influential social learning perspective, notably that physical aggression occurs early in life, and its subsequent development is characterized by learned inhibition. The fourth explanation concerns the motivational mechanisms controlling aggression: approached from an evolutionary background, these mechanisms range from the inflexible reflex-like responses to those incorporating rational decision-making.

  14. Aggression can be contagious: Longitudinal associations between proactive aggression and reactive aggression among young twins.

    PubMed

    Dickson, Daniel J; Richmond, Ashley D; Brendgen, Mara; Vitaro, Frank; Laursen, Brett; Dionne, Ginette; Boivin, Michel

    2015-01-01

    The present study examined sibling influence over reactive and proactive aggression in a sample of 452 same-sex twins (113 male dyads, 113 female dyads). Between and within siblings influence processes were examined as a function of relative levels of parental coercion and hostility to test the hypothesis that aggression contagion between twins occurs only among dyads who experience parental coerciveness. Teacher reports of reactive and proactive aggression were collected for each twin in kindergarten (M = 6.04 years; SD = 0.27) and in first grade (M = 7.08 years; SD = 0.27). Families were divided into relatively low, average, and relatively high parental coercion-hostility groups on the basis of maternal reports collected when the children were 5 years old. In families with relatively high levels of parental coercion-hostility, there was evidence of between-sibling influence, such that one twin's reactive aggression at age 6 predicted increases in the other twin's reactive aggression from ages 6 to 7, and one twin's proactive aggression at age 6 predicted increases in the other twin's proactive aggression from ages 6 to 7. There was also evidence of within-sibling influence such that a child's level of reactive aggression at age 6 predicted increases in the same child's proactive aggression at age 7, regardless of parental coercion-hostility. The findings provide new information about the etiology of reactive and proactive aggression and individual differences in their developmental interplay.

  15. Arsenic Exposure Transforms Human Epithelial Stem/Progenitor Cells into a Cancer Stem-like Phenotype

    PubMed Central

    Tokar, Erik J.; Diwan, Bhalchandra A.; Waalkes, Michael P.

    2010-01-01

    Background Inorganic arsenic is a ubiquitous environmental carcinogen affecting millions of people worldwide. Evolving theory predicts that normal stem cells (NSCs) are transformed into cancer stem cells (CSCs) that then drive oncogenesis. In humans, arsenic is carcinogenic in the urogenital system (UGS), including the bladder and potentially the prostate, whereas in mice arsenic induces multiorgan UGS cancers, indicating that UGS NSCs may represent targets for carcinogenic initiation. However, proof of emergence of CSCs induced by arsenic in a stem cell population is not available. Methods We continuously exposed the human prostate epithelial stem/progenitor cell line WPE-stem to an environmentally relevant level of arsenic (5 μM) in vitro and determined the acquired cancer phenotype. Results WPE-stem cells rapidly acquired a malignant CSC-like phenotype by 18 weeks of exposure, becoming highly invasive, losing contact inhibition, and hypersecreting matrix metalloproteinase-9. When hetero-transplanted, these cells (designated As-CSC) formed highly pleomorphic, aggressive tumors with immature epithelial- and mesenchymal-like cells, suggesting a highly pluripotent cell of origin. Consistent with tumor-derived CSCs, As-CSCs formed abundant free-floating spheres enriched in CSC-like cells, as confirmed by molecular analysis and the fact that only these floating cells formed xenograft tumors. An early loss of NSC self-renewal gene expression (p63, ABCG2, BMI-1, SHH, OCT-4, NOTCH-1) during arsenite exposure was subsequently reversed as the tumor suppressor gene PTEN was progressively suppressed and the CSC-like phenotype acquired. Conclusions Arsenite transforms prostate epithelial stem/progenitor cells into CSC-like cells, indicating that it can produce CSCs from a model NSC population. PMID:20056578

  16. A Brief Report of Immunohistochemical Markers to Identify Aggressive Hepatoblastoma.

    PubMed

    Singh, Vivekanand; Manalang, Michelle; Singh, Meenal; Apte, Udayan

    2017-02-09

    Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although survival of patients has improved significantly over the last 2 decades, a significant number of patients do not respond to standard chemotherapy. We conducted a pilot study to understand if there was immunophenotypic difference between tumors that respond well to chemotherapy versus that do not. We selected 10 cases of HB from children presenting at our hospital. All patients had initial tissue diagnosis, underwent chemotherapy followed by surgical resection. The cases were divided into 2 groups: aggressive group with 5 cases (all of which had a poor response to chemotherapy); and a good clinical outcome group with 5 cases (all of which responded well to chemotherapy). We excluded the small cell variant of HB from the study because its poor clinical outcome is well known. To be placed in the aggressive group we used the following criteria: <70% necrosis following chemotherapy or recurrence/distant metastasis following chemotherapy. From tissue obtained before chemotherapy, 1 representative block of formalin-fixed, paraffin-embedded tissue was selected for immunohistochemistry. Following review of published literature, antibodies were selected to detect Survivin, PLK-1, Cytokeratin19 (CK19), N-Myc, Yap, Notch2, Hes1, Hes5, and C-Myc. Our results show that Survivin, CK19, and Yap have a diffuse (>75%) positive staining of tumor cells in the aggressive tumors compared with good outcome tumors. However, staining for Yap was weak. Interestingly, there was loss of nuclear expression of C-Myc in majority of tumor cells in aggressive tumors, whereas nuclear staining was retained in most tumor cells of good responders. The N-Myc and PLK-1 immunostains did not reveal any significant differences in the 2 groups of HB. The immunostains for Notch2, Hes1, and Hes5 showed weak to moderately strong staining in tumor cells, but there was no obvious difference in the 2 groups. Our pilot study

  17. Television viewing, aggression, and ethnicity.

    PubMed

    Harris, M B

    1992-02-01

    For 416 college students, questioned about their experiences with aggression and television viewing, only very weak correlations between preference for violent shows and aggression were observed. Black males watched significantly more television than other respondents. These findings suggest that the frequently reported correlation between viewing televised violence and aggression may not appear when sex, ethnicity, and education are controlled in a sample of young adults.

  18. Bone Marrow Microenvironment Modulation of Acute Lymphoblastic Leukemia Phenotype

    PubMed Central

    Moses, Blake S; Slone, William L; Thomas, Patrick; Evans, Rebecca; Piktel, Debbie; Angel, Peggi M; Walsh, Callee M; Cantrell, Pamela S; Rellick, Stephanie L; Martin, Karen H; Simpkins, James W; Gibson, Laura F

    2015-01-01

    Acute lymphoblastic leukemia (ALL) treatment regimens have dramatically improved the survival of ALL patients. However, chemoresistant minimal residual disease (MRD) that persists following cessation of therapy contributes to aggressive relapse. The bone marrow microenvironment (BMM) is an established “site of sanctuary” for ALL as well as myeloid lineage hematopoietic disease, with signals in this unique anatomical location contributing to drug resistance. Several models have been developed to recapitulate the interactions between the BMM and ALL cells. However, many in vitro models fail to accurately reflect the level of protection afforded to the most resistant sub-set of leukemic cells during co-culture with BMM elements. Pre-clinical in vivo models have advantages, but can be costly, and are often not fully informed by optimal in vitro studies. In the current report we describe an innovative extension of 2D co-culture wherein ALL cells uniquely interact with bone marrow derived stromal cells. Tumor cells in this model bury beneath primary human bone marrow derived stromal cells or osteoblasts, termed “phase dim” (PD) ALL, and exhibit a unique phenotype characterized by altered metabolism, distinct protein expression profiles, increased quiescence, and pronounced chemotherapy resistance. Investigation focused on the PD subpopulation may more efficiently inform pre-clinical design and investigation of MRD and relapse that arises from BMM supported leukemic tumor cells. PMID:26407636

  19. Myeloablative chemotherapy for recurrent aggressive oligodendroglioma.

    PubMed Central

    Cairncross, G.; Swinnen, L.; Bayer, R.; Rosenfeld, S.; Salzman, D.; Paleologos, N.; Kaminer, L.; Forsyth, P.; Stewart, D.; Peterson, K.; Hu, W.; Macdonald, D.; Ramsay, D.; Smith, A.

    2000-01-01

    The objective of this study was to ascertain the duration of tumor control and the toxicities of dose-intense myeloablative chemotherapy for patients with recurrent oligodendrogliomas. Patients with previously irradiated oligodendrogliomas, either pure or mixed, that were contrast enhancing, measurable, and behaving aggressively at recurrence were eligible for this study. Only complete responders or major partial responders (75 % reduction in tumor size) to induction chemotherapy--either intensive-dose procarbazine, lomustine, and vincristine or cisplatin plus etoposide-could receive high-dose thiotepa (300 mg/m2/day for 3 days) followed by hematopoietic reconstitution using either bone marrow or peripheral blood stem cells. Thirty-eight patients began induction chemotherapy and 20 (10 men, 10 women; median age 46 years; median Karnofsky score 80) received high-dose thiotepa. For the high-dose group, the median event-free, progression-free, and overall survival times from recurrence were 17, 20, and 49 months, respectively. Tumor control in excess of 2 years was observed in 6 patients (30%). Four patients (20%) are alive and tumor free 27 to 77 months (median, 42 months) from the start of induction therapy; however, fatal treatment-related toxicities also occurred in 4 patients (20%). Three patients died as a result of a progressive encephalopathy which, in 2 instances, was accompanied by a wasting syndrome; 1 patient died as a consequence of an intracerebral (intratumoral) hemorrhage. Fatal toxicities occurred in patients with pretreatment Karnofsky scores of 60 or 70. High-dose thiotepa to consolidate response was a disappointing treatment strategy for patients with recurrent aggressive oligodendroglial neoplasms, although several patients had durable responses. Moreover, as prescribed, high-dose thiotepa had significant toxic effects in previously irradiated patients, especially those with poorer performance status. PMID:11303620

  20. Tumor hypoxia enhances non-small cell lung cancer metastasis by selectively promoting macrophage M2 polarization through the activation of ERK signaling

    PubMed Central

    Ma, Shenglin; Dong, Rong; Meng, Wen; Ying, Meidan; Weng, Qinjie; Chen, Zibo; Ma, Jian; Fang, Qingxia; He, Qiaojun; Yang, Bo

    2014-01-01

    Hypoxia is a common phenomenon occurring in the majority of human tumors and has been proved to play an important role in tumor progression. However, it remains unclear that whether the action of hypoxia on macrophages is a main driving force of hypoxia-mediated aggressive tumor behaviors. In the present study, we observe that high density of M2 macrophages is associated with metastasis in adenocarcinoma Non-Small Cell Lung Cancer (NSCLC) patients. By applying the in vivo hypoxia model, the results suggest that intermittent hypoxia significantly promotes the metastasis of Lewis lung carcinoma (LLC), accompanied with more CD209+ macrophages infiltrated in primary tumor tissue. More intriguingly, by skewing macrophages polarization away from the M1- to a tumor-promoting M2-like phenotype, hypoxia and IL-6 cooperate to enhance the LLC metastasis both in vitro and in vivo. In addition, we also demonstrate that skewing of macrophage M2 polarization by hypoxia relies substantially on activation of ERK signaling. Collectively, these observations unveil a novel tumor hypoxia concept involving the macrophage phenotype shift and provide direct evidence for lung cancer intervention through modulating the phenotype of macrophages. PMID:25313135

  1. An Aggressive Primary Cutaneous Follicle Center Lymphoma With c-MYC Translocation and CDKN2A (9p21) Deletion: A Case Report and Review of the Literature.

    PubMed

    Tsang, Hamilton C; Mathew, Susan; Magro, Cynthia M

    2017-03-01

    Diffuse large cell B-cell lymphoma of the skin is most commonly represented by diffuse large cell variants of primary cutaneous follicle center lymphoma and the leg-type lymphoma. In a minority of cases, the infiltrates are an expression of stage 4 disease of established extracutaneous B-cell lymphoma. We describe 1 female patient 85 years of age with an aggressive form of primary cutaneous B-cell lymphoma manifesting in multiple firm erythematous indurated solid nodules 1-2 cm each symmetrically on the face periorbitally and on the upper extremities bilaterally. The tumor was a de novo presentation of this aggressive form of lymphoma. The disease demonstrated an aggressive course with only transient improvement of skin lesions after chemotherapy. Punch biopsy taken from a left arm skin lesion showed a diffuse and nodular large cell lymphocytic infiltrate in the 15-20 μm range exhibiting round to oval nuclei and prominent eosinophilic nucleoli. Phenotypically, the tumor cells were CD10, Bcl-2, Bcl-6, and CD43 positive with a residuum of a follicular dendritic cell network revealed by CD21 staining. There was c-MYC rearrangement and CDKN2A deletion in this sample. The importance in reporting this case is to emphasize that in the context of primary cutaneous B-cell lymphoma, the 9p21 deletion while characteristic of the leg-type lymphoma is not a unique signature of the leg-type lymphoma and is not exclusionary to lymphomas falling under the designation of follicle center lymphoma. As with the leg-type lymphoma, however, this cytogenetic abnormality is a critical determinant to a more aggressive clinical course.

  2. PHOSPHOLIPASE D (PLD) DRIVES CELL INVASION, TUMOR GROWTH AND METASTASIS IN A HUMAN BREAST CANCER XENOGRAPH MODEL

    PubMed Central

    Henkels, Karen M.; Boivin, Gregory P.; Dudley, Emily S.; Berberich, Steven J.; Gomez-Cambronero, Julian

    2014-01-01

    Breast cancer is one of the most common malignancies in human females in the world. One protein that has elevated enzymatic lipase activity in breast cancers in vitro is phospholipase D (PLD), which is also involved in cell migration. We demonstrate that the PLD2 isoform, which was analyzed directly in the tumors, is crucial for cell invasion that contributes critically to the growth and development of breast tumors and lung metastases in vivo. We used three complementary strategies in a SCID mouse model and also addressed the underlying molecular mechanism. First, the PLD2 gene was silenced in highly metastatic, aggressive breast cancer cells (MDA-MB-231) with lentivirus-based shRNA, which were xenotransplanted in SCID mice. The resulting mouse primary mammary tumors were reduced in size (65%, p<0.05) and their onset delayed when compared to control tumors. Second, we stably overexpressed PLD2 in low-invasive breast cancer cells (MCF-7) with a biscistronic MIEG retroviral vector and observed that these cells were converted into a highly aggressive phenotype, as primary tumors that formed following xenotransplantation were larger, grew faster and developed lung metastases more readily. Third, we implanted osmotic pumps into SCID xenotransplanted mice that delivered two different small-molecule inhibitors of PLD activity (FIPI and NOPT). These inhibitors led to significant (>70%, p<0.05) inhibition of primary tumor growth, metastatic axillary tumors and lung metastases. In order to define the underlying mechanism, we determined that the machinery of PLD-induced cell invasion is mediated by phosphatidic acid (PA), WASp, Grb2 and Rac2 signaling events that ultimately affect actin polymerization and cell invasion. In summary, this study shows that PLD has a central role in the development, metastasis and level of aggressiveness of breast cancer, raising the possibility that PLD2 could be used as a new therapeutic target. PMID:23752189

  3. Metabolic genes in cancer: their roles in tumor progression and clinical implications

    PubMed Central

    Furuta, Eiji; Okuda, Hiroshi; Kobayashi, Aya; Watabe, Kounosuke

    2010-01-01

    Re-programming of metabolic pathways is a hallmark of physiological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis are drastically altered at different stages of tumor progression. These alterations are generally considered as an adaptation of tumor cells; however, they also contribute to the progression of tumor cells to become more aggressive phenotypes. This review summarizes the recent information about the mechanistic link of these genes to oncogenesis and their potential utility as diagnostic markers as well as for therapeutic targets. We particularly focus on three groups of genes; GLUT1, G6PD, TKTL1 and PGI/AMF in glycolytic pathway, ACLY, ACC1 and FAS in lipogenesis and RRM1, RRM2 and TYMS for nucleotide synthesis. All these genes are highly up-regulated in a variety of tumor cells in cancer patients, and they play active roles in tumor progression rather than expressing merely as a consequence of phenotypic change of the cancer cells. Molecular dissection of their orchestrated networks and understanding the exact mechanism of their expression will provide a window of opportunity to target these genes for specific cancer therapy. We also reviewed existing database of gene microarray to validate the utility of these genes for cancer diagnosis. PMID:20122995

  4. Gastrointestinal stromal tumors - quantitative detection of the Ki-67, TPX2, TOP2A, and hTERT telomerase subunit mRNA levels to determine proliferation activity and a potential for aggressive biological behavior.

    PubMed

    Kalfusova, A; Hilska, I; Krskova, L; Kalinova, M; Linke, Z; Kodet, R

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) have an unpredictable biological potential ranging from benign to malignant. Molecular markers involved in the mechanisms of proliferation and cellular senescence may provide additional information about biological behavior of the tumor. The aim of the present study was to investigate Ki-67, TPX2, TOP2A and hTERT mRNA expression levels in specimens from patients with GISTs to define relationships between proliferation activity and biological potential and progression of the disease. We measured Ki-67, TPX2, TOP2A and hTERT mRNA levels using quantitative real-time reverse transcription PCR (RQ RT PCR). The highest Ki-67, TPX2, TOP2A and hTERT mRNA expression levels were found in the highly proliferative BLs (18 specimens), in comparison with GISTs (137 specimens) and LMSs (9 specimens). Patients with GISTs and adequate information about mitotic activity, tumor size and anatomical site (84 specimens) were divided into two groups - GISTs with benign (29 patients) and with malignant (55 patients) potential. We observed association between higher Ki-67, TPX2 and hTERT mRNA levels and the GISTs with malignant potential. Univariate analysis (57 patients with available follow-up information) of survival (Kaplan Meier curves method) revealed a correlation between higher levels of TPX2, Ki-67 and hTERT markers and shorter event-free survival (EFS) or poorer overall survival (OS). The results demonstrate the importance of quantitative assessment of the proliferation activity in GISTs. Proliferation markers of Ki-67, TPX2, TOP2A and hTERT are suitable markers for detection the proliferation activity and telomerase activity of these tumors. Furthermore, the assessment of TPX2, Ki-67 and hTERT expression levels is appropriate for determination of malignant potential of GISTs.

  5. Transcriptional activation of hedgehog pathway components in aggressive hemangioma.

    PubMed

    Wendling-Keim, Danielle S; Wanie, Lynn; Grantzow, Rainer; Kappler, Roland

    2017-03-31

    Infantile hemangioma is a vascular neoplasm and is one of the most common tumors diagnosed in young children. Although most hemangiomas are harmless and involute spontaneously, some show severe progression, leading to serious complications, such as high output cardiac failure, ulcerations, compression of the trachea or deprivation amblyopia, depending on their size and localization. However, the pathogenesis and cause of hemangioma are largely unknown to date. The goal of this study was to identify markers that could predict hemangiomas with aggressive growth and severe progression that would benefit from early intervention. By using a PCR-based screening approach, we first confirmed that previously known markers of hemangioma, namely FGF2 and GLUT1, are highly expressed in hemangioma. Nevertheless, these genes did not show any differential expression between severely progressing tumors and mild tumors. However, transcriptional upregulation of several Hedgehog signaling components, comprising the ligand Sonic Hedgehog (SHH),the transcription factor GLI2 and its target gene FOXA2 were detected in extremely aggressive hemangioma specimens during the proliferation phase. Notably, GLI2 was even overexpressed in involuting hemangiomas if they showed an aggressive growth pattern. In conclusion, our data suggest that overexpression of the Hedgehog components SHH, GLI2 and FOXA2 might be used as markers of an aggressive hemangioma that would benefit from too early intervention, while FGF2 and GLUT1 are more general markers of hemangiomas. This article is protected by copyright. All rights reserved.

  6. Brief Report: Aggression and Stereotypic Behavior in Males with Fragile X Syndrome-- Moderating Secondary Genes in a "Single Gene" Disorder

    ERIC Educational Resources Information Center

    Hessl, David; Tassone, Flora; Cordeiro, Lisa; Koldewyn, Kami; McCormick, Carolyn; Green, Cherie; Wegelin, Jacob; Yuhas, Jennifer; Hagerman, Randi J.

    2008-01-01

    Although fragile X syndrome (FXS) is a single gene disorder with a well-described phenotype, it is not known why some individuals develop more significant maladaptive behaviors such as aggression or autistic symptoms. Here, we studied two candidate genes known to affect mood and aggression, the serotonin transporter (5-HTTLPR) and monoamine…

  7. Novel Treatment Shrinks Ovarian Tumors in Mice