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Sample records for aggressive vascular tumor

  1. 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

  2. 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.

  3. Vascular tumors of the choroid and retina.

    PubMed

    Shanmugam, P Mahesh; Ramanjulu, Rajesh

    2015-02-01

    Vascular tumors of the retina and choroid can be seen occasionally. In the following article, the key clinical and diagnostic features of the major retinal and choroidal vascular tumors, their systemic associations, and the literature pertaining to the most currently available treatment strategies are reviewed.

  4. Vascular tumors of the choroid and retina

    PubMed Central

    Shanmugam, P Mahesh; Ramanjulu, Rajesh

    2015-01-01

    Vascular tumors of the retina and choroid can be seen occasionally. In the following article, the key clinical and diagnostic features of the major retinal and choroidal vascular tumors, their systemic associations, and the literature pertaining to the most currently available treatment strategies are reviewed. PMID:25827544

  5. 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

  6. Vascular basophilia in ocular and orbital tumors.

    PubMed

    Stowe, G C; Zakov, Z N; Albert, D M; Smith, T R; Sang, D N; Craft, J L

    1979-10-01

    The occurrence of vascular basophilia in ocular tumors has been a selective histologic feature of retinoblastomas. We recently observed a metastatic oat-cell carcinoma to the choroid which also demonstrated such a vascular hematoxyphilia. Histologic review of a variety of ocular and orbital metastatic carcinomas failed to yield a similar basophilic pattern. Examination of 100 consecutive retinoblastomas for vascular basophilia revealed an incidence of 6.0%. Similar material was not seen in any of 125 melanomas, including 10 with areas of necrosis. Histochemical studies showed the basophilic material to be DNA, and electron microscopy revealed the nuclear debris of pyknotic tumor cells to be continuous with identical material surrounding the adjacent blood vessels. The pathogenesis of vascular deposition of DNA in these two ocular tumors remains unclear. This finding most likely represents a form of tumor activity requiring comparatively healthy blood vessels to adequately precipitate liberated nucleic acids being filtered from the necrotic and degenerating tumor tissue.

  7. [DIAGNOSIS OF VASCULAR INVASION BY PANCREATIC TUMORS].

    PubMed

    Dronov, O I; Zemskov, S V; Bakunets, P P

    2016-02-01

    Basing on analysis of own material (84 patients) and data of literature there was established, that vascular invasion by pancreatic tumors constitutes the main obstacle for conduction of the patients' radical treatment. Early diagnosis permits radical resectability of the patients, what constitutes the only one effective method of treatment. In vascular invasion by tumor a surgeon experience and professional preparation determines possibility of the extended operation performance with intervention on affected main vessel, enhancing the treatment radicalism.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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.

  13. 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

  14. Tumor Vascular Changes Mediated by Inhibition of Oncogenic Signaling

    PubMed Central

    Qayum, Naseer; Muschel, Ruth J.; Im, Jae Hong; Balathasan, Lukxmi; Koch, Cameron J.; Patel, Sonal; McKenna, W. Gillies; Bernhard, Eric J.

    2009-01-01

    Many inhibitors of the EGFR-RAS-PI3 kinase-AKT signaling pathway are in clinical use or under development for cancer therapy. Here we show that treatment of mice bearing human tumor xenografts with inhibitors that block EGFR, RAS, PI3 kinase or AKT resulted in prolonged and durable enhancement of tumor vascular flow, perfusion and decreased tumor hypoxia. The vessels in the treated tumors had decreased tortuosity and increased internodal length accounting for the functional alterations. Inhibition of tumor growth cannot account for these results as the drugs were given at doses that did not alter tumor growth. The tumor cell itself was an essential target as HT1080 tumors that lack EGFR did not respond to an EGFR inhibitor, but did respond with vascular alterations to RAS or PI3 Kinase inhibition. We extended these observations to spontaneously arising tumors in MMTV-neu mice. These tumors also responded to PI3 kinase inhibition with decreased tumor hypoxia, increased vascular flow and morphological alterations of their vessels including increased vascular maturity and acquisition of pericyte markers. These changes are similar to the vascular normalization that has been described after anti-angiogenic treatment of xenografts. One difficulty in the use of vascular normalization as a therapeutic strategy has been its limited duration. In contrast, blocking tumor cell RAS-PI3K-AKT signaling led to persistent vascular changes that might be incorporated into clinical strategies based on improvement of vascular flow or decreased hypoxia. These results indicate that vascular alterations must be considered as a consequence of signaling inhibition in cancer therapy. PMID:19622766

  15. Pseudo-vascular tumor in a renal flow study

    SciTech Connect

    Elgazzar, A.H.; Fernandez-Ulloa, M.; Powers, G.T.

    1985-03-01

    A case in which, for the first time, the superior mesenteric artery caused an appearance mimicking vascular tumor on a kidney radionuclide angiogram (RNA) obtained posteriorly, is reported. A subsequent contrast arteriogram showed that the superior mesenteric artery caused that appearance and confusion with possible vascular tumor on RNA. No similar cases with mesenteric blush simulating vascular tumor have been found in the literature. Mesenteric blushes on RNAs obtained posteriorly have been described only in cases of kidney agenesis and post-nephrectomy. This pattern should be kept in mind when interpreting RNAs to avoid subjecting patients to invasive diagnostic procedures.

  16. 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.

  17. 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.

  18. Vascular involvement in periampullary tumors: MDCT, EUS, and CDU.

    PubMed

    Gusmini, S; Nicoletti, R; Martinenghi, C; Del Maschio, A

    2009-07-01

    In patients affected by periampullary tumors, surgical resection represents the only treatment with curative intent. Preoperative evaluation of vascular involvement is necessary to avoid surgical treatments unable of curative intent resection. The aim of our update article is to assess the performance of multidetector computed tomography (MDCT), endoscopic ultrasonography (EUS), and color Doppler ultrasonography (CDU) in the evaluation of vascular involvement of major peripancreatic vessels, in periampullary tumors, analyzing the current and past literature.

  19. Functional imaging of tumor vascular network in small animal models

    NASA Astrophysics Data System (ADS)

    Kalchenko, Vyacheslav; Madar-Balakirski, Noa; Kuznetsov, Yuri; Meglinski, Igor; Harmelin, Alon

    2011-07-01

    In current report we present synchronized in vivo imaging of tumor vascular network and tumor microenvironment obtained by combined use of Dynamic Light Scattering Imaging, Spectrally Enhanced Microscopy, and Fluorescence Intravital Microscopy. Dynamic Light Scattering Imaging is used for functional imaging of the vascular network and blood microcirculation. Spectrally Enhanced Microscopy provides information regarding blood vessel topography. Fluorescence Intravital Microscopy is used for imaging of tumor microvasculature and tumor microenvironment. These well known modalities have been comprehensively validated in the past and are widely used in various bio-medical applications. As shown here, their combined application has great potential for studies of vascular biology. This multi-modal non-invasive diagnostic technique expands our current capacity to investigate blood microcirculation and tumor angiogenesis in vivo, thereby contributing to the development of cancer research and treatment.

  20. 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.

  1. Enhancing Nanoparticle Accumulation and Retention in Desmoplastic Tumors via Vascular Disruption for Internal Radiation Therapy

    PubMed Central

    Satterlee, Andrew B.; Rojas, Juan D.; Dayton, Paul A.; Huang, Leaf

    2017-01-01

    Aggressive, desmoplastic tumors are notoriously difficult to treat because of their extensive stroma, high interstitial pressure, and resistant tumor microenvironment. We have developed a combination therapy that can significantly slow the growth of large, stroma-rich tumors by causing massive apoptosis in the tumor center while simultaneously increasing nanoparticle uptake through a treatment-induced increase in the accumulation and retention of nanoparticles in the tumor. The vascular disrupting agent Combretastatin A-4 Phosphate (CA4P) is able to increase the accumulation of radiation-containing nanoparticles for internal radiation therapy, and the retention of these delivered radioisotopes is maintained over several days. We use ultrasound to measure the effect of CA4P in live tumor-bearing mice, and we encapsulate the radio-theranostic isotope 177Lutetium as a therapeutic agent as well as a means to measure nanoparticle accumulation and retention in the tumor. This combination therapy induces prolonged apoptosis in the tumor, decreasing both the fibroblast and total cell density and allowing further tumor growth inhibition using a cisplatin-containing nanoparticle. PMID:28042332

  2. Phase transitions in tumor growth: III vascular and metastasis behavior

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, J. A.; Cocho, G.; Mansilla, R.; Nieto-Villar, José Manuel

    2016-11-01

    We propose a mechanism for avascular, vascular and metastasis tumor growth based on a chemical network model. Vascular growth and metastasis, appear as a hard phase transition type, as "first order", through a supercritical Andronov-Hopf bifurcation, emergence of limit cycle and then through a cascade of bifurcations type saddle-foci Shilnikov's bifurcation. Finally, the thermodynamics framework developed shows that the entropy production rate, as a Lyapunov function, indicates the directional character and stability of the dynamical behavior of tumor growth according to this model.

  3. [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.

  4. 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

  5. Primary vascular tumors and tumor-like lesions of the kidney: a clinicopathologic analysis of 25 cases.

    PubMed

    Brown, Jeffrey G; Folpe, Andrew L; Rao, Priya; Lazar, Alexander J; Paner, Gladell P; Gupta, Ruta; Parakh, Rugvedita; Cheville, John C; Amin, Mahul B

    2010-07-01

    Vascular tumors of the kidney are distinctly rare, and to date no large series have been reported. We analyzed a series of primary vascular tumors of the kidney to further delineate their clinicopathologic features and identify organ-specific morphologic features, if present. Twenty-five renal cases previously coded as "arteriovenous malformation," "hemangioma," and "angiosarcoma" were retrieved from the archives of 4 collaborating institutions and were reevaluated histologically. Tumors were classified according to the 2002 World Health Organization classification of tumors of soft tissue and bone. There were 18 males and 7 females (M:F=2.6:1) ranging from 21 to 95 years (mean 56.7 y). Lesions ranged from "microscopic" to 30 cm (mean 6.0 cm) and were tan-brown, cystic, and hemorrhagic. On re-review, cases were classified as arteriovenous malformation (n=3), capillary hemangioma (n=14), and angiosarcoma (n=8). Arteriovenous malformations were identical to their somatic soft tissue counterparts. Renal capillary hemangiomas often lacked a well-formed lobular pattern and 5 cases showed a "sieve-like" arrangement reminiscent of splenic sinusoids, a pattern previously noted by others (anastomosing hemangioma). All hemangiomas were noninfiltrative and lacked cytologic atypia and mitotic activity. GLUT-1, D2-40, and CD8 were performed in 3 anastomosing hemangiomas and were all negative. Angiosarcomas were diffusely infiltrative with extensive parenchymal destruction; all showed at least small areas of conventional vasoformative growth, but were frequently dominated by spindled and epithelioid histology. All cases were positive for some combination of vascular tumor-associated markers (CD31, CD34, and FLI-1). Cytokeratin expression was absent in all angiosarcomas. Follow-up was available for 15 cases: all patients with arteriovenous malformation and hemangioma with follow-up were disease free after complete excision; 4 cases of angiosarcoma died of the disease at 1, 1, 6

  6. 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

  7. In vivo imaging of tumor vascular endothelial cells

    NASA Astrophysics Data System (ADS)

    Zhao, Dawen; Stafford, Jason H.; Zhou, Heling; Thorpe, Philip E.

    2013-02-01

    Phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, becomes exposed on the outer surface of viable (non-apoptotic) endothelial cells in tumor blood vessels, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we optically imaged exposed PS on tumor vasculature in vivo using PGN635, a novel human monoclonal antibody that targets PS. PGN635 F(ab')2 was labeled with the near infrared (NIR) dye, IRDye 800CW. Human glioma U87 cells or breast cancer MDA-MB-231 cells were implanted subcutaneously or orthotopically into nude mice. When the tumors reached ~5 mm in diameter, 800CW- PGN635 was injected via a tail vein and in vivo dynamic NIR imaging was performed. For U87 gliomas, NIR imaging allowed clear detection of tumors as early as 4 h later, which improved over time to give a maximal tumor/normal ratio (TNR = 2.9 +/- 0.5) 24 h later. Similar results were observed for orthotopic MDA-MB-231 breast tumors. Localization of 800CW-PGN635 to tumors was antigen specific since 800CW-Aurexis, a control probe of irrelevant specificity, did not localize to the tumors, and pre-administration of unlabeled PGN635 blocked the uptake of 800CW-PGN635. Fluorescence microscopy confirmed that 800CW-PGN635 was binding to PS-positive tumor vascular endothelium. Our studies suggest that tumor vasculature can be successfully imaged in vivo to provide sensitive tumor detection.

  8. Epithelioid Hemangioendothelioma: An Overview and Update on a Rare Vascular Tumor

    PubMed Central

    Sardaro, Angela; Bardoscia, Lilia; Petruzzelli, Maria Fonte; Portaluri, Maurizio

    2014-01-01

    Epithelioid hemangioendothelioma is a rare vascular tumor, described for the first time in 1975 by Dail and Liebow as an aggressive bronchoalveolar cell carcinoma. The etiology is still a dilemma. Studies about suggestive hypothesis are ongoing. Most of the times it affects lung, liver and bones, although this kind of tumor may involve the head and neck area, breast, lymph nodes, mediastinum, brain and meninges, the spine, skin, abdomen and many other sites. Because of its heterogeneous presentation, as it represents less than 1% of all the vascular tumors, it is often misdiagnosed and not suitably treated, leading to a poor prognosis in some cases. Over 50-76% of the patients are asymptomatic. A small number of them complains respiratory symptoms. Bone metastases might cause pathological fractures or spine compression, if they arise in vertebrae. Imaging is necessary to determine morphological data, the involvement of surrounding tissues, and potentially the cleavage plan. It is important to recognize the expression of vascular markers (Fli-1 and CD31 are endothelial-specific markers), and the microscopic evidence of vascular differentiation to make a correct diagnosis, as many pulmonary diseases show multiple nodular lesions. Because of its rarity, there is no standard for treatment. We focused on radiotherapy as a good therapeutic option: despite the poor prognosis, evidence is in favor of radiotherapy which offers local pain control with good tolerance and better quality of life at least at a one-year follow-up in most of cases. Further studies are needed to establish the standard radiation dose to be used for locoregional control of such a complex and extremely rare disease. PMID:25992243

  9. Effects of vascular targeting photodynamic therapy on lymphatic tumor metastasis

    NASA Astrophysics Data System (ADS)

    Fateye, B.; He, C.; Chen, B.

    2009-06-01

    Vascular targeting photodynamic therapy (vPDT) is currently in clinical trial for prostate cancer (PCa) treatment. In order to study the effect of vPDT on tumor metastasis, GFP-PC3 or PC-3 xenografts were treated with verteporfin (BPD) PDT. Vascular function was assessed by ultrasound imaging; lymph node and lung metastasis were assessed by fluorescence imaging. vPDT significantly reduced tumor blood flow within 30minutes to 2 hours of treatment. Sub-curative treatment resulted in re-perfusion within 2 weeks of treatment and increased lymph node metastasis. With curative doses, no metastasis was observed. In order to identify cellular or matrix factors and cytokines implicated, conditioned medium from BPD PDTtreated endothelial cells was incubated with PC3 cells in vitro. Tumor cell proliferation and migration was assessed. By immunoblotting, we evaluated the change in mediators of intracellular signaling or that may determine changes in tumor phenotype. Low sub-curative dose (200ng/ml BPD) of endothelial cells was associated with ~15% greater migration in PC3 cells when compared with control. This dose was also associated with sustained activation of Akt at Ser 473, an upstream effector in the Akt/ mTOR pathway that has been correlated with Gleason scores in PCa and with survival and metastasis in vitro and in vivo. In conclusion, the study implicates efficacy of PDT of endothelial cells as an important determinant of its consequences on adjacent tumor proliferation and metastasis.

  10. 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.

  11. Integrative models of vascular remodeling during tumor growth

    PubMed Central

    Rieger, Heiko; Welter, Michael

    2015-01-01

    Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551

  12. Mathematical Modeling of Branching Morphogenesis and Vascular Tumor Growth

    NASA Astrophysics Data System (ADS)

    Yan, Huaming

    Feedback regulation of cell lineages is known to play an important role in tissue size control, but the effect in tissue morphogenesis has yet to be explored. We first use a non-spatial model to show that a combination of positive and negative feedback on stem and/or progenitor cell self-renewal leads to bistable or bi-modal growth behaviors and ultrasensitivity to external growth cues. Next, a spatiotemporal model is used to demonstrate spatial patterns such as local budding and branching arise in this setting, and are not consequences of Turing-type instabilities. We next extend the model to a three-dimensional hybrid discrete-continuum model of tumor growth to study the effects of angiogenesis, tumor progression and cancer therapies. We account for the crosstalk between the vasculature and cancer stem cells (CSCs), and CSC transdifferentiation into vascular endothelial cells (gECs), as observed experimentally. The vasculature stabilizes tumor invasiveness but considerably enhances growth. A gEC network structure forms spontaneously within the hypoxic core, consistent with experimental findings. The model is then used to study cancer therapeutics. We demonstrate that traditional anti-angiogenic therapies decelerate tumor growth, but make the tumor highly invasive. Chemotherapies help to reduce tumor sizes, but cannot control the invasion. Anti-CSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness. However, gECs inherit mutations present in CSCs and are resistant to traditional therapies. We show that anti-gEC treatments block the support on CSCs by gECs, and reduce both tumor size and invasiveness. Our study suggests that therapies targeting the vasculature, CSCs and gECs, when combined, are highly synergistic and are capable of controlling both tumor size and shape.

  13. 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.

  14. 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

  15. Developing vascular and hypoxia based theranostics in solid tumors

    NASA Astrophysics Data System (ADS)

    Koonce, Nathan A.

    Tissue hypoxia was recognized for its biological attenuating effects on ionizing radiation over a century ago and is a characteristic feature of many solid tumors. Clinical and experimental evidence indicates tumor hypoxia plays diverse and key roles in tumor progression, angiogenesis, and resistance to chemotherapy/radiotherapy. Hypoxia has known effects on progression and resistance to several standard treatment approaches and the significant history of study might suggest diagnostic imaging and therapeutic interventions would be routine in oncological practice. Curiously, this is not the case and the research results involved in this report will attempt to better understand and contribute to why this gap in knowledge exists and a rationale for harnessing the potential of detecting and targeting hypoxia. Despite the addition of oxygen and reversal of hypoxia being known as the best radiosensitizer, hypoxia remains unexploited in clinical cancer therapy. The studies reported herein detail development of a novel imaging technique to detect a subtype of tumor hypoxia, vascular hypoxia or hypoxemia, with a 17-fold increase (p<0.05) in uptake of pimonidazole targeted microbubbles observed compared to controls. This technique creates the potential to study the role of hypoxemia in progression and therapeutic response. Additionally, description of a nanoparticle-based therapy that targets tumor areas associated with tumor hypoxia and the tumor microenvironment in general is reported. TNF-loaded nanoparticles combined with radiotherapy resulted in a 5.25-fold growth delay that was found to be synergistic (p<0.05) and suggests clinical evaluation is warranted. An additional study to evaluate an approach to use thermal ablation of intratumoral hypoxia by an image-guided technique developed in our group is described along with a sequence dependence of radiation preceding ablation. A final study on the use of galectin-1 antagonist to significantly decrease (p<0.05) hypoxia

  16. 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.

  17. 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.

  18. [Vascular "tumors" and the rules of their surgical management].

    PubMed

    Enjolras, O; Deffrennes, D; Borsik, M; Diner, P; Laurian, C

    1998-08-01

    After defining vascular tumors and malformations, formerly called angiomas, the authors adopt the classification of the International Society for the Study of vascular Anomalies. The various groups of malformations, after definition of the subject and the problems raised, are illustrated by a number of clinical cases and the rules of surgical management are discussed. Capillary malformations, formerly called portwine stains, can be treated by dye laser, but sometimes tissue and orthognathic reconstructive surgery in the presence of a skeletal malformation. Lymphatic malformations (lymphangiomas), optimally assessed by CT or MRI, can be treated by a variety of approaches: sclerotherapy, surgery. Venous malformations raise very different problems in the cervicocephalic region and on the limbs and trunk, but always require a multidisciplinary approach with, according to the site, size and repercussions, Ethibloc percutaneous sclerotherapy, embolization, surgery. Arteriovenous malformations require complete surgical treatment, usually preceded by embolization; reconstruction consists of local flaps or skin expansion in simple cases, and revascularized free flaps in difficult cases. If the malformation is cosmetically and functionally acceptable, the authors propose conservative management. The first-line treatment of haemangiomas is pharmacological (corticosteroids, interferon), but surgery may be indicated in two situations: early and late. There is a renewed interest in early surgery, subtended by several factors including cosmetic concerns and the development of new technologies, including the Cavitron. Late surgery retains its classical cosmetic and functional indications. Two key-words dominate the rules of therapeutic management of all types of vascular malformations: a multidisciplinary approach and modesty.

  19. Tumor Angiogenesis and Vascular Patterning: A Mathematical Model

    PubMed Central

    Travasso, Rui D. M.; Corvera Poiré, Eugenia; Castro, Mario; Rodrguez-Manzaneque, Juan Carlos; Hernández-Machado, A.

    2011-01-01

    Understanding tumor induced angiogenesis is a challenging problem with important consequences for diagnosis and treatment of cancer. Recently, strong evidences suggest the dual role of endothelial cells on the migrating tips and on the proliferating body of blood vessels, in consonance with further events behind lumen formation and vascular patterning. In this paper we present a multi-scale phase-field model that combines the benefits of continuum physics description and the capability of tracking individual cells. The model allows us to discuss the role of the endothelial cells' chemotactic response and proliferation rate as key factors that tailor the neovascular network. Importantly, we also test the predictions of our theoretical model against relevant experimental approaches in mice that displayed distinctive vascular patterns. The model reproduces the in vivo patterns of newly formed vascular networks, providing quantitative and qualitative results for branch density and vessel diameter on the order of the ones measured experimentally in mouse retinas. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of different parameters in this process, hence underlining the necessary collaboration between mathematical modeling, in vivo imaging and molecular biology techniques to improve current diagnostic and therapeutic tools. PMID:21637756

  20. MR Vascular Fingerprinting in Stroke and Brain Tumors Models

    NASA Astrophysics Data System (ADS)

    Lemasson, B.; Pannetier, N.; Coquery, N.; Boisserand, Ligia S. B.; Collomb, Nora; Schuff, N.; Moseley, M.; Zaharchuk, G.; Barbier, E. L.; Christen, T.

    2016-11-01

    In this study, we evaluated an MRI fingerprinting approach (MRvF) designed to provide high-resolution parametric maps of the microvascular architecture (i.e., blood volume fraction, vessel diameter) and function (blood oxygenation) simultaneously. The method was tested in rats (n = 115), divided in 3 models: brain tumors (9 L, C6, F98), permanent stroke, and a control group of healthy animals. We showed that fingerprinting can robustly distinguish between healthy and pathological brain tissues with different behaviors in tumor and stroke models. In particular, fingerprinting revealed that C6 and F98 glioma models have similar signatures while 9 L present a distinct evolution. We also showed that it is possible to improve the results of MRvF and obtain supplemental information by changing the numerical representation of the vascular network. Finally, good agreement was found between MRvF and conventional MR approaches in healthy tissues and in the C6, F98, and permanent stroke models. For the 9 L glioma model, fingerprinting showed blood oxygenation measurements that contradict results obtained with a quantitative BOLD approach. In conclusion, MR vascular fingerprinting seems to be an efficient technique to study microvascular properties in vivo. Multiple technical improvements are feasible and might improve diagnosis and management of brain diseases.

  1. MR Vascular Fingerprinting in Stroke and Brain Tumors Models

    PubMed Central

    Lemasson, B.; Pannetier, N.; Coquery, N.; Boisserand, Ligia S. B.; Collomb, Nora; Schuff, N.; Moseley, M.; Zaharchuk, G.; Barbier, E. L.; Christen, T.

    2016-01-01

    In this study, we evaluated an MRI fingerprinting approach (MRvF) designed to provide high-resolution parametric maps of the microvascular architecture (i.e., blood volume fraction, vessel diameter) and function (blood oxygenation) simultaneously. The method was tested in rats (n = 115), divided in 3 models: brain tumors (9 L, C6, F98), permanent stroke, and a control group of healthy animals. We showed that fingerprinting can robustly distinguish between healthy and pathological brain tissues with different behaviors in tumor and stroke models. In particular, fingerprinting revealed that C6 and F98 glioma models have similar signatures while 9 L present a distinct evolution. We also showed that it is possible to improve the results of MRvF and obtain supplemental information by changing the numerical representation of the vascular network. Finally, good agreement was found between MRvF and conventional MR approaches in healthy tissues and in the C6, F98, and permanent stroke models. For the 9 L glioma model, fingerprinting showed blood oxygenation measurements that contradict results obtained with a quantitative BOLD approach. In conclusion, MR vascular fingerprinting seems to be an efficient technique to study microvascular properties in vivo. Multiple technical improvements are feasible and might improve diagnosis and management of brain diseases. PMID:27883015

  2. MR Vascular Fingerprinting in Stroke and Brain Tumors Models.

    PubMed

    Lemasson, B; Pannetier, N; Coquery, N; Boisserand, Ligia S B; Collomb, Nora; Schuff, N; Moseley, M; Zaharchuk, G; Barbier, E L; Christen, T

    2016-11-24

    In this study, we evaluated an MRI fingerprinting approach (MRvF) designed to provide high-resolution parametric maps of the microvascular architecture (i.e., blood volume fraction, vessel diameter) and function (blood oxygenation) simultaneously. The method was tested in rats (n = 115), divided in 3 models: brain tumors (9 L, C6, F98), permanent stroke, and a control group of healthy animals. We showed that fingerprinting can robustly distinguish between healthy and pathological brain tissues with different behaviors in tumor and stroke models. In particular, fingerprinting revealed that C6 and F98 glioma models have similar signatures while 9 L present a distinct evolution. We also showed that it is possible to improve the results of MRvF and obtain supplemental information by changing the numerical representation of the vascular network. Finally, good agreement was found between MRvF and conventional MR approaches in healthy tissues and in the C6, F98, and permanent stroke models. For the 9 L glioma model, fingerprinting showed blood oxygenation measurements that contradict results obtained with a quantitative BOLD approach. In conclusion, MR vascular fingerprinting seems to be an efficient technique to study microvascular properties in vivo. Multiple technical improvements are feasible and might improve diagnosis and management of brain diseases.

  3. 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.

  4. The irradiated tumor microenvironment: role of tumor-associated macrophages in vascular recovery

    PubMed Central

    Russell, Jeffery S.; Brown, J. Martin

    2013-01-01

    Radiotherapy is an important modality used in the treatment of more than 50% of cancer patients in the US. However, despite sophisticated techniques for radiation delivery as well as the combination of radiation with chemotherapy, tumors can recur. Thus, any method of improving the local control of the primary tumor by radiotherapy would produce a major improvement in the curability of cancer patients. One of the challenges in the field is to understand how the tumor vasculature can regrow after radiation in order to support tumor recurrence, as it is unlikely that any of the endothelial cells within the tumor could survive the doses given in a typical radiotherapy regimen. There is now considerable evidence from both preclinical and clinical studies that the tumor vasculature can be restored following radiotherapy from an influx of circulating cells consisting primarily of bone marrow derived monocytes and macrophages. The radiation-induced influx of bone marrow derived cells (BMDCs) into tumors can be prevented through the blockade of various cytokine pathways and such strategies can inhibit tumor recurrence. However, the post-radiation interactions between surviving tumor cells, recruited immune cells, and the remaining stroma remain poorly defined. While prior studies have described the monocyte/macrophage inflammatory response within normal tissues and in the tumor microenvironment, less is known about this response with respect to a tumor after radiation therapy. The goal of this review is to summarize existing research studies to provide an understanding of how the myelomonocytic lineage may influence vascular recovery within the irradiated tumor microenvironment. PMID:23882218

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models.

    PubMed

    Muldoon, Leslie L; Gahramanov, Seymur; Li, Xin; Marshall, Deborah J; Kraemer, Dale F; Neuwelt, Edward A

    2011-01-01

    We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting α(V)-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4-6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting α(V)-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.

  11. 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

  12. 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.

  13. 3D numerical study of tumor microenvironmental flow in response to vascular-disrupting treatments.

    PubMed

    Wu, Jie; Cai, Yan; Xu, Shixiong; Longs, Quan; Ding, Zurong; Dong, Cheng

    2012-06-01

    The effects of vascular-disrupting treatments on normalization of tumor microvasculature and its microenvironmental flow were investigated, by mathematical modeling and numerical simulation of tumor vascular-disrupting and tumor haemodynamics. Four disrupting approaches were designed according to the abnormal characteristics of tumor microvasculature compared with the normal one. The results predict that the vascular-disrupting therapies could improve tumor microenvironment, eliminate drug barrier and inhibit metastasis of tumor cells to some extent. Disrupting certain types of vessels may get better effects. In this study, the flow condition on the networks with "vascular-disrupting according to flowrate" is the best comparing with the other three groups, and disrupting vessels of lower maturity could effectively enhance fluid transport across vasculature into interstitial space.

  14. '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.

  15. '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

  16. 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

  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. Computational Model for Tumor Oxygenation Applied to Clinical Data on Breast Tumor Hemoglobin Concentrations Suggests Vascular Dilatation and Compression

    PubMed Central

    Welter, Michael; Fredrich, Thierry; Rinneberg, Herbert; Rieger, Heiko

    2016-01-01

    We present a computational model for trans-vascular oxygen transport in synthetic tumor and host tissue blood vessel networks, aiming at qualitatively explaining published data of optical mammography, which were obtained from 87 breast cancer patients. The data generally show average hemoglobin concentration to be higher in tumors versus host tissue whereas average oxy-to total hemoglobin concentration (vascular segment RBC-volume-weighted blood oxygenation) can be above or below normal. Starting from a synthetic arterio-venous initial network the tumor vasculature was generated by processes involving cooption, angiogenesis, and vessel regression. Calculations of spatially resolved blood flow, hematocrit, oxy- and total hemoglobin concentrations, blood and tissue oxygenation were carried out for ninety tumor and associated normal vessel networks starting from various assumed geometries of feeding arteries and draining veins. Spatial heterogeneity in the extra-vascular partial oxygen pressure distribution can be related to various tumor compartments characterized by varying capillary densities and blood flow characteristics. The reported higher average hemoglobin concentration of tumors is explained by growth and dilatation of tumor blood vessels. Even assuming sixfold metabolic rate of oxygen consumption in tumorous versus host tissue, the predicted oxygen hemoglobin concentrations are above normal. Such tumors are likely associated with high tumor blood flow caused by high-caliber blood vessels crossing the tumor volume and hence oxygen supply exceeding oxygen demand. Tumor oxy- to total hemoglobin concentration below normal could only be achieved by reducing tumor vessel radii during growth by a randomly selected factor, simulating compression caused by intra-tumoral solid stress due to proliferation of cells and extracellular matrix. Since compression of blood vessels will impede chemotherapy we conclude that tumors with oxy- to total hemoglobin concentration

  19. Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice

    PubMed Central

    Agrawal, Vijayendra; Maharjan, Sony; Kim, Kyeojin; Kim, Nam-Jung; Son, Jimin; Lee, Keunho; Choi, Hyun-Jung; Rho, Seung-Sik; Ahn, Sunjoo; Won, Moo-Ho; Ha, Sang-Jun; Koh, Gou Young; Kim, Young-Myeong; Suh, Young-Ger; Kwon, Young-Guen

    2014-01-01

    Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis. PMID:24811731

  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. Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model.

    PubMed

    McCullough, Danielle J; Nguyen, Linda M-D; Siemann, Dietmar W; Behnke, Bradley J

    2013-12-01

    Regular physical exercise is considered to be an integral component of cancer care strategies. However, the effect of exercise training on tumor microvascular oxygenation, hypoxia, and vascular function, all of which can affect the tumor microenvironment, remains unknown. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that, after exercise training, in the tumor, there would be an enhanced microvascular Po2, increased number of patent vessels, and reduced hypoxia. We also investigated tumor resistance artery contractile properties. Dunning R-3327 AT-1 tumor cells (10(4)) were injected into the ventral prostate of 4-5-mo-old male Copenhagen or Nude rats, which were randomly assigned to tumor-bearing exercise trained (TB-Ex trained; n = 15; treadmill exercise for 5-7 wk) or sedentary groups (TB-Sedentary; n = 12). Phosphorescence quenching was used to measure tumor microvascular Po2, and Hoechst-33342 and EF-5 were used to measure patent vessels and tumor hypoxia, respectively. Tumor resistance artery function was assessed in vitro using the isolated microvessel technique. Compared with sedentary counterparts, tumor microvascular Po2 increased ∼100% after exercise training (TB-Sedentary, 6.0 ± 0.3 vs. TB-Ex Trained, 12.2 ± 1.0 mmHg, P < 0.05). Exercise training did not affect the number of patent vessels but did significantly reduce tumor hypoxia in the conscious, resting condition from 39 ± 12% of the tumor area in TB-Sedentary to 4 ± 1% in TB-Ex Trained. Exercise training did not affect vessel contractile function. These results demonstrate that after exercise training, there is a large increase in the driving force of O2 from the tumor microcirculation, which likely contributes to the considerable reduction in tumor hypoxia. These results suggest that exercise training can modulate the microenvironment of the tumor, such that a sustained reduction in tumor hypoxia occurs, which may lead to a less aggressive phenotype and

  2. Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

    NASA Astrophysics Data System (ADS)

    Roy Chaudhuri, Tista

    An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

  3. Photodynamic therapy for palpebral and conjunctival proliferative vascular tumors: clinical case report.

    PubMed

    Sanchez, Carlos Gustavo; Caballero Chávez, Yolanda V; Plazola, Sara

    2009-01-01

    Photodynamic therapy (PDT) has been widely used in ophthalmology for the treatment of diverse pathologies, but no experience has been reported in the handling of patients with palpebral vascular and conjunctive malformations with PDT, we describe the case of one patient with a palpebral proliferative vascular tumor, treated successfully using the PDT as a new treatment alternative.

  4. 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.

  5. Functional and molecular mapping of uncoupling between vascular permeability and loss of vascular maturation in ovarian carcinoma xenografts: the role of stroma cells in tumor angiogenesis.

    PubMed

    Gilad, Assaf A; Israely, Tomer; Dafni, Hagit; Meir, Gila; Cohen, Batya; Neeman, Michal

    2005-11-01

    Maintaining homogeneous perfusion in tissues undergoing remodeling and vascular expansion requires tight orchestration of the signals leading to endothelial sprouting and subsequent recruitment of perivascular contractile cells and vascular maturation. This regulation, however, is frequently disrupted in tumors. We previously demonstrated the role of tumor-associated myofibroblasts in vascularization and exit from dormancy of human ovarian carcinoma xenografts in nude mice. The aim of this work was to determine the contribution of stroma- and tumor cell-derived angiogenic growth factors to the heterogeneity of vascular permeability and maturation in MLS human ovarian carcinoma tumors. We show by RT-PCR and by in situ hybridization that VEGF was expressed by the tumor cells, while angiopoietin-1 and -2 were expressed only by the infiltrating host stroma cells. Vascular maturation was detected in vivo by vasoreactivity to hypercapnia, measured by BOLD contrast MRI and validated by immunostaining of histologic sections to alpha-smooth muscle actin. Vascular permeability was measured in vivo by dynamic contrast-enhanced MRI using albumin-based contrast material and validated in histologic sections by fluorescent staining of the biotinylated contrast material. MRI as well as histologic correlation maps between vascular maturation and vascular permeability revealed a wide range of vascular phenotypes, in which the distribution of vascular maturation and vasoreactivity did not overlap spatially with reduced permeability. The large heterogeneity in the degree of vascular maturation and permeability is consistent with the differential expression pattern of VEGF and angiopoietins during tumor angiogenesis.

  6. Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound spectroscopy

    SciTech Connect

    El Kaffas, Ahmed; Sadeghi-Naini, Ali; Falou, Omar; Tran, William Tyler; Czarnota, Gregory J.; Zhou, Stephanie; Fernandes, Jason; Giles, Anoja; Hashim, Amr

    2015-08-15

    Purpose: It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments. Methods: Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively. Results: Results indicate a significant midband fit QUS parameter increases of 3.2 ± 0.3 dBr and 5.4 ± 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 ± 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R{sup 2} of 0.9 was observed when quantified cell death was correlated with changes in midband fit. Conclusions: Results from QUS

  7. Tumor associated osteoclast-like giant cells promote tumor growth and lymphangiogenesis by secreting vascular endothelial growth factor-C

    SciTech Connect

    Hatano, Yu; Nakahama, Ken-ichi; Isobe, Mitsuaki; Morita, Ikuo

    2014-03-28

    Highlights: • M-CSF and RANKL expressing HeLa cells induced osteoclastogenesis in vitro. • We established OGC-containing tumor model in vivo. • OGC-containing tumor became larger independent of M-CSF or RANKL effect. • VEGF-C secreted from OGCs was a one of candidates for OGC-containing tumor growth. - Abstract: Tumors with osteoclast-like giant cells (OGCs) have been reported in a variety of organs and exert an invasive and prometastatic phenotype, but the functional role of OGCs in the tumor environment has not been fully clarified. We established tumors containing OGCs to clarify the role of OGCs in tumor phenotype. A mixture of HeLa cells expressing macrophage colony-stimulating factor (M-CSF, HeLa-M) and receptor activator of nuclear factor-κB ligand (RANKL, HeLa-R) effectively supported the differentiation of osteoclast-like cells from bone marrow macrophages in vitro. Moreover, a xenograft study showed OGC formation in a tumor composed of HeLa-M and HeLa-R. Surprisingly, the tumors containing OGCs were significantly larger than the tumors without OGCs, although the growth rates were not different in vitro. Histological analysis showed that lymphangiogenesis and macrophage infiltration in the tumor containing OGCs, but not in other tumors were accelerated. According to quantitative PCR analysis, vascular endothelial growth factor (VEGF)-C mRNA expression increased with differentiation of osteoclast-like cells. To investigate whether VEGF-C expression is responsible for tumor growth and macrophage infiltration, HeLa cells overexpressing VEGF-C (HeLa-VC) were established and transplanted into mice. Tumors composed of HeLa-VC mimicked the phenotype of the tumors containing OGCs. Furthermore, the vascular permeability of tumor microvessels also increased in tumors containing OGCs and to some extent in VEGF-C-expressing tumors. These results suggest that macrophage infiltration and vascular permeability are possible mediators in these tumors. These

  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. 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.

  10. Differential vascular response and relationship to tumor response with photodynamic therapy using WST-09 (TOOKAD)

    NASA Astrophysics Data System (ADS)

    Garbo, Greta M.; Kik, Peter K.; Harrison, Linda T.; Brun, Pierre H.; Blanc, Dominique; Paulin, Pamela S.; Wieman, Thomas J.; Fingar, Victor H.

    2004-06-01

    Bacteriopheophorbide molecules are second-generation photosensitizers with promise for PHotodynamic Therapy applications due largely to their absorption peaks in the near-Infrared region. Palladium bcteriopheophorbide, also called TOOKAD, has been successfully evaluated in several pre-clinical animal models. In this study the effect on tumor and normal vasculature was evaluated using an intravital vascular model on mouse cremaster muscle implanted with the RIF tumor. For tumor response studies, the same RIF tumor was implanted intradermally on the right flank and regression was evaluated for 42 days or until the tumor reached a 12 mm diameter. A light dose 300 J/cm2 were delivered at 763 nm with power density of 100 mW/cm2. Photosensitizer dose was 4 mg/kg body weight. Mice were treated immediately, 10 minutes, 30 minutes, or 24 hours after injection. Only the higher light dose (300 J/cm2) delivered 10 minutes after injection produced a reproducible and complete vascular and tumor response after PDT in these animals. In the cremaster-tumor model, arterioles and venules partially shutdown as early as 40 minutes after the beginning of treatment, while tumor neovasculature was irreversibly closed within 20 minutes of treatment. Tumor response studies demonstrated that the magnitude of vascular stasis correlates with tumor regression studies. Further studies using this photosensitizer are warranted, given its short clearance time and its near-Infrared activation wavelength.

  11. 210Po microsphere radiological design for tumor vascular disruption

    PubMed Central

    2015-01-01

    The feasibility of disrupting a tumor’s vascular structure using 210Po microspheres is investigated using standard ion and photon absorbed dose methodologies. Calculated absorbed dose profiles for 210Po alpha particles are sufficient to disrupt a tumor’s arteriole structure while minimizing the dose outside the blood vessel wall. 210Po photons contribute minimal dose to healthy tissue. The requisite activity of 210Po to facilitate vascular disruption is calculated. PMID:26290796

  12. Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

    DTIC Science & Technology

    2007-12-01

    fluorescence . All images shown include the tumor periphery. Bars = 100um. Figure 5 . In vivo tumor EGFP fluorescence images showing tumor...using a vascular-targeting photosensitizer Photofrin in combination with PDT using a cellular-targeting photosensitizer 5 - aminolevulinic acid ( 5 -ALA...Today (IMPACT) meeting, Sep 5 -8, 2007, Atlanta, Georgia. Chen B, He C, Crane C, Agharkar P, Pogue BW. Fluorescence imaging of verteporfin-mediated

  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. 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.

  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. Glomus tumors of the fingers: Expression of vascular endothelial growth factor

    PubMed Central

    Honsawek, Sittisak; Kitidumrongsook, Pravit; Luangjarmekorn, Pobe; Pataradool, Kawee; Thanakit, Voranuch; Patradul, Adisorn

    2016-01-01

    Glomus tumors are uncommon, benign, small neurovascular neoplasms derived from glomus bodies in the reticular dermis. Glomus bodies are found throughout the body to regulate body temperature and skin circulation; however, they are concentrated in the fingers and the sole of the foot. The typical presentation is a solitary nodule in the subungual or periungual area of the distal phalanx. The primary treatment of choice is surgical removal. We investigated expression of vascular endothelial growth factor (VEGF) using immunohistochemistry in glomus tumors of the fingers. All five glomus tumor samples were positive for VEGF expression. VEGF immunoreactivity was largely localized to the cytoplasm of tumor cells, suggesting a contribution of VEGF to the vascularization of glomus tumors. PMID:28032039

  18. Microfabrication of polydimethylsiloxane phantoms to simulate tumor hypoxia and vascular anomaly.

    PubMed

    Wu, Qiang; Ren, Wenqi; Yu, Zelin; Dong, Erbao; Zhang, Shiwu; Xu, Ronald X

    2015-01-01

    We introduce a microfluidic approach to simulate tumor hypoxia and vascular anomaly. Polydimethylsiloxane (PDMS) phantoms with embedded microchannel networks were fabricated by a soft lithography process. A dialysis membrane was sandwiched between two PDMS slabs to simulate the controlled mass transport and oxygen metabolism. A tortuous microchannel network was fabricated to simulate tumor microvasculature. A dual-modal multispectral and laser speckle imaging system was used for oxygen and blood flow imaging in the tumor-simulating phantom. The imaging results were compared with those of the normal vasculature. Our experiments demonstrated the technical feasibility of simulating tumor hypoxia and vascular anomalies using the proposed PDMS phantom. Such a phantom fabrication technique may be potentially used to calibrate optical imaging devices, to study the mechanisms for tumor hypoxia and angiogenesis, and to optimize the drug delivery strategies.

  19. Microfabrication of polydimethylsiloxane phantoms to simulate tumor hypoxia and vascular anomaly

    NASA Astrophysics Data System (ADS)

    Wu, Qiang; Ren, Wenqi; Yu, Zelin; Dong, Erbao; Zhang, Shiwu; Xu, Ronald X.

    2015-12-01

    We introduce a microfluidic approach to simulate tumor hypoxia and vascular anomaly. Polydimethylsiloxane (PDMS) phantoms with embedded microchannel networks were fabricated by a soft lithography process. A dialysis membrane was sandwiched between two PDMS slabs to simulate the controlled mass transport and oxygen metabolism. A tortuous microchannel network was fabricated to simulate tumor microvasculature. A dual-modal multispectral and laser speckle imaging system was used for oxygen and blood flow imaging in the tumor-simulating phantom. The imaging results were compared with those of the normal vasculature. Our experiments demonstrated the technical feasibility of simulating tumor hypoxia and vascular anomalies using the proposed PDMS phantom. Such a phantom fabrication technique may be potentially used to calibrate optical imaging devices, to study the mechanisms for tumor hypoxia and angiogenesis, and to optimize the drug delivery strategies.

  20. Vascular Tumor on the Forehead of an HIV Patient

    PubMed Central

    Ibarguren, Ander Mayor; Ramos, Jéssica González; Merino, María Beato; Pedrero, Rocío Maseda; Fernández, Cristina Gómez; Pinto, Pedro Herranz

    2015-01-01

    Cirsoid aneurysm is a small vascular proliferation characterized by small to medium-sized channels with features of arteries and veins, that present as small, blue or red asymptomatic papule. We report a case of a crisoid aneurysm on the forhead of an HIV patient that suggested a Kaposi sarcoma as a differential diagnosis. PMID:26288449

  1. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    PubMed Central

    Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization. PMID:27596933

  2. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    NASA Astrophysics Data System (ADS)

    Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-09-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization.

  3. Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis

    PubMed Central

    Lim, Sharon; Hosaka, Kayoko; Nakamura, Masaki; Cao, Yihai

    2016-01-01

    Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth. PMID:27203675

  4. Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

    DTIC Science & Technology

    2009-12-01

    abilization, an early event commonly observed after photody- namic vascular-targeting therapy. Fig. 2. A, intravital microscopic imaging showing the...By permitting high resolution imaging of vessel structure and function in live animals, intravital microscopy offers a powerful tool to study vascular...Tumor blood vessels were continuously imaged by intravital fluorescence microscopy showing the formation of thrombi (indicated by arrows) that caused

  5. 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.

  6. Visualization of tumor vascular reactivity in response to respiratory challenges by optical coherence tomography (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Kim, Hoon Sup; Lee, Songhyun; Lee, Kiri; Eom, Tae Joong; Kim, Jae G.

    2016-02-01

    We previously reported the potential of using vascular reactivity during respiratory challenges as a marker to predict the response of breast tumor to chemotherapy in a rat model by using a continuous wave near-infrared spectroscopy. However, it cannot visualize how the vascular reactivity from tumor vessel can predict the tumor response to its treatment. In this study, we utilized a spectral domain optical coherence tomography (SD-OCT) system to visualize vascular reactivity of both tumor and normal vasculature during respiratory challenges in a mouse model. We adapted intensity based Doppler variance algorithm to draw angiogram from the ear of mouse (8-week-old Balb/c nu/nu). Animals were anesthetized using 1.5% isoflurane, and the body temperature was maintained by a heating pad. Inhalational gas was switched from air (10min) to 100% oxygen (10min), and a pulse oximeter was used to monitor arterial oxygen saturation and heart rate. OCT angiograms were acquired 5 min after the onset of each gas. The vasoconstriction effect of hyperoxic gas on vasculature was shown by subtracting an en-face image acquired during 100% oxygen from the image acquired during air inhalation. The quantitative change in the vessel diameter was measured from the en-face OCT images of the individual blood vessels. The percentage of blood vessel diameter reduction varied from 1% to 12% depending on arterial, capillary, or venous blood vessel. The vascular reactivity change during breast tumor progression and post chemotherapy will be monitored by OCT angiography.

  7. Interstitial hydraulic conductivity and interstitial fluid pressure for avascular or poorly vascularized tumors.

    PubMed

    Liu, L J; Schlesinger, M

    2015-09-07

    A correct description of the hydraulic conductivity is essential for determining the actual tumor interstitial fluid pressure (TIFP) distribution. Traditionally, it has been assumed that the hydraulic conductivities both in a tumor and normal tissue are constant, and that a tumor has a much larger interstitial hydraulic conductivity than normal tissue. The abrupt transition of the hydraulic conductivity at the tumor surface leads to non-physical results (the hydraulic conductivity and the slope of the TIFP are not continuous at tumor surface). For the sake of simplicity and the need to represent reality, we focus our analysis on avascular or poorly vascularized tumors, which have a necrosis that is mostly in the center and vascularization that is mostly on the periphery. We suggest that there is an intermediary region between the tumor surface and normal tissue. Through this region, the interstitium (including the structure and composition of solid components and interstitial fluid) transitions from tumor to normal tissue. This process also causes the hydraulic conductivity to do the same. We introduce a continuous variation of the hydraulic conductivity, and show that the interstitial hydraulic conductivity in the intermediary region should be monotonically increasing up to the value of hydraulic conductivity in the normal tissue in order for the model to correspond to the actual TIFP distribution. The value of the hydraulic conductivity at the tumor surface should be the lowest in value.

  8. Enhancing Tumor Drug Delivery by Laser-Activated Vascular Barrier Disruption

    DTIC Science & Technology

    2008-12-01

    fluorescence was monitored noninvasively with a whole-body fluorescence imaging system. Ex vivo fluorescence mi- croscopy was performed on frozen...time is needed for the degradation of EGFP synthesized FIGURE 5 – In vivo tumor EGFP fluorescence images showing tumor response to vascular-targeting...targeting photosensitizer Photofrin in combination with PDT using a cellular-targeting photosensitizer 5 - aminolevulinic acid ( 5 -ALA) [45], PDT regimen

  9. 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

  10. 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

  11. A Perspective on Vascular Disrupting Agents that Interact with Tubulin: Preclinical Tumor Imaging and Biological Assessment#

    PubMed Central

    Mason, Ralph P.; Zhao, Dawen; Liu, Li; Trawick, Mary Lynn; Pinney, Kevin G.

    2011-01-01

    The tumor microenvironment provides a rich source of potential targets for selective therapeutic intervention with properly designed anticancer agents. Significant physiological differences exist between the microvessels that nourish tumors and those that supply healthy tissue. Selective drug-mediated damage of these tortuous and chaotic microvessels starves a tumor of necessary nutrients and oxygen and eventually leads to massive tumor necrosis. Vascular targeting strategies in oncology are divided into two separate groups: angiogenesis inhibiting agents (AIAs) and vascular disrupting agents (VDAs). The mechanisms of action between these two classes of compounds are profoundly distinct. The AIAs inhibit the actual formation of new vessels, while the VDAs damage and/or destroy existing tumor vasculature. One subset of small-molecule VDAs functions by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature, triggered by a cascade of cell signaling events. Ultimately this results in catastrophic damage to the vessels feeding the tumor. The rapid emergence and subsequent development of the VDA field over the past decade has led to the establishment of a synergistic combination of preclinical state-of-the-art tumor imaging and biological evaluation strategies that are often indicative of future clinical efficacy for a given VDA. This review focuses on an integration of the appropriate biochemical and biological tools necessary to assess (preclinically) new small-molecule, tubulin active VDAs for their potential to be clinically effective anticancer agents. PMID:21321746

  12. 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

  13. 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.

  14. Interstitial Fluid Flow and Drug Delivery in Vascularized Tumors: A Computational Model

    PubMed Central

    Welter, Michael; Rieger, Heiko

    2013-01-01

    Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider–with the help of a theoretical model–the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various

  15. A Vascular Malformation Presenting as a Peripheral Nerve Sheath Tumor

    PubMed Central

    Parmar, Vikas; Haldeman, Clayton; Amaefuna, Steve; Hanna, Amgad S.

    2016-01-01

    We present the case of a venous malformation (VM) masquerading as a schwannoma. VMs are thin-walled vascular dilations of various sizes that typically present as soft, compressible, blue masses that are associated with pain or dysesthesia. VMs are commonly found in the head and neck as well as the distal extremities. Notably, slow-flow VMs are hypointense on T1-weighted imaging, hyperintense on T2-weighted imaging, and enhance markedly with contrast. However, VMs tend to be poorly circumscribed and fraught with venous lakes and phleboliths. Conservative therapy and sclerotherapy are the primary treatment options. In this case report, we present a VM presenting near the neurovascular bundle of the upper extremity axilla. Our case is unique in that the patient presented with symptoms and imaging qualities characteristic for a peripheral nerve schwannoma. PMID:28077959

  16. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy.

    PubMed

    Siemann, Dietmar W; Mercer, Emma; Lepler, Sharon; Rojiani, Amyn M

    2002-05-01

    The utility of combining the vascular targeting agents 5,6-dimethyl-xanthenone-4 acetic acid (DMXAA) and combretastatin A-4 disodium phosphate (CA4DP) with the anticancer drugs cisplatin and cyclophosphamide (CP) was evaluated in experimental rodent (KHT sarcoma), human breast (SKBR3) and ovarian (OW-1) tumor models. Doses of the vascular targeting agents that led to rapid vascular shutdown and subsequent extensive central tumor necrosis were identified. Histologic evaluation showed morphologic damage of tumor cells within a few hours after treatment, followed by extensive hemorrhagic necrosis and dose-dependent neoplastic cell death as a result of prolonged ischemia. Whereas these effects were induced by a range of CA4DP doses (10-150 mg/kg), the dose response to DMXAA was extremely steep; doses < or = 15 mg/kg were ineffective and doses > or = 20 mg/kg were toxic. DMXAA also enhanced the tumor cell killing of cisplatin, but doses > 15 mg/kg were required. In contrast, CA4DP increased cisplatin-induced tumor cell killing at all doses studied. This enhancement of cisplatin efficacy was dependent on the sequence and interval between the agents. The greatest effects were achieved when the vascular targeting agents were administered 1-3 hr after cisplatin. When CA4DP (100 mg/kg) or DMXAA (17.5 mg/kg) were administered 1 hr after a range of doses of cisplatin or CP, the tumor cell kill was 10-500-fold greater than that seen with chemotherapy alone. In addition, the inclusion of the antivascular agents did not increase bone marrow stem cell toxicity associated with these anticancer drugs, thus giving rise to a therapeutic gain.

  17. Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis.

    PubMed

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-03-09

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage.

  18. Vascular Normalization Induced by Sinomenine Hydrochloride Results in Suppressed Mammary Tumor Growth and Metastasis

    PubMed Central

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-01-01

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage. PMID:25749075

  19. 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

  20. 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

  1. Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice.

    PubMed

    Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Minyoung; Lee, Chang Geun; Jo, Wol Soon; Kim, Sung Dae; Yang, Kwangmo

    2015-07-01

    Although granulocyte-colony stimulating factor (G-CSF) is commonly used to support recovery from radiation-induced side-effects, the precise effects of G-CSF on colon cancer under radiotherapy remain poorly understood. In the present study, to investigate the effects of tumor growth following radiotherapy and G-CSF administration in a murine xenograft model of colon cancer, female BALB/c mice were injected with cells of a colon carcinoma cell line (CT26) with irradiation and G-CSF, alone or in combination. Mice received 2 Gy of focal radiation daily for 5 days and intraperitoneal injection of G-CSF (100 µg/kg/day) after irradiation for 7 days. Changes in the levels of myeloperoxidase (MPO), vascular endothelial growth factor (VEGF), matrix metalloproteinase type 9 (MMP-9) and CD31 were assessed in the mouse cancer induced by injection of colon cancer cells. We observed that G-CSF increased the number of circulating neutrophils, but facilitated tumor growth. However, G-CSF treatment did not affect radiation-induced cytotoxicity and cell viability in CT26 cells in vitro. Increased levels of myeloperoxidase, a neutrophil marker and those of vascular endothelial growth factor were observed in tumors with G-CSF supplementation. In addition, we found that increased levels of CD31 and matrix metalloproteinase-9 were correlated with the enhanced tumor growth after G-CSF treatment. Therefore, these data suggest that G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions.

  2. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.

    PubMed

    Benjamin, L E; Golijanin, D; Itin, A; Pode, D; Keshet, E

    1999-01-01

    Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.

  3. 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

  4. 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

  5. Photoacoustic imaging of breast tumor vascularization: a comparison with MRI and histopathology

    NASA Astrophysics Data System (ADS)

    Heijblom, Michelle; Piras, Daniele; van den Engh, Frank M.; Klaase, Joost M.; Brinkhuis, Mariël.; Steenbergen, Wiendelt; Manohar, Srirang

    2013-06-01

    Breast cancer is the most common form of cancer and the leading cause of cancer death among females. Early diagnosis improves the survival chances for the disease and that is why there is an ongoing search for improved methods for visualizing breast cancer. One of the hallmarks of breast cancer is the increase in tumor vascularization that is associated with angiogenesis: a crucial factor for survival of malignancies. Photoacoustic imaging can visualize the malignancyassociated increased hemoglobin concentration with optical contrast and ultrasound resolution, without the use of ionizing radiation or contrast agents and is therefore theoretically an ideal method for breast imaging. Previous clinical studies using the Twente Photoacoustic Mammoscope (PAM), which works in forward mode using a single wavelength (1064 nm), showed that malignancies can indeed be identified in the photoacoustic imaging volume as high contrast areas. However, the specific appearance of the malignancies led to questions about the contrast mechanism in relation to tumor vascularization. In this study, the photoacoustic lesion appearance obtained with an updated version of PAM is compared with the lesion appearance on Magnetic Resonance Imaging (MRI), both in general (19 patients) and on an individual basis (7 patients). Further, in 3 patients an extended histopathology protocol is being performed in which malignancies are stained for vascularity using an endothelial antibody: CD31. The correspondence between PAM and MRI and between PAM and histopathology makes it likely that the high photoacoustic contrast at 1064 nm is indeed largely the consequence of the increased tumor vascularization.

  6. Assessment and Monitoring Tumor Vascularity With Contrast-Enhanced Ultrasound Maximum Intensity Persistence Imaging

    PubMed Central

    Pysz, Marybeth A.; Foygel, Kira; Panje, Cedric M.; Needles, Andrew; Tian, Lu; Willmann, Jürgen K.

    2015-01-01

    Objectives Contrast-enhanced ultrasound imaging is increasingly being used in the clinic for assessment of tissue vascularity. The purpose of our study was to evaluate the effect of different contrast administration parameters on the in vivo ultrasound imaging signal in tumor-bearing mice using a maximum intensity persistence (MIP) algorithm and to evaluate the reliability of in vivo MIP imaging in assessing tumor vascularity. The potential of in vivo MIP imaging for monitoring tumor vascularity during antiangiogenic cancer treatment was further evaluated. Materials and Methods In intraindividual experiments, varying contrast microbubble concentrations (5 × 105, 5 × 106, 5 × 107, 5 × 108 microbubbles in 100 µL saline) and contrast injection rates (0.6, 1.2, and 2.4 mL/min) in subcutaneous tumor-bearing mice were applied and their effects on in vivo contrast-enhanced ultrasound MIP imaging plateau values were obtained using a dedicated small animal ultrasound imaging system (40 MHz). Reliability of MIP ultrasound imaging was tested following 2 injections of the same micro-bubble concentration (5 × 107 microbubbles at 1.2 mL/min) in the same tumors. In mice with subcutaneous human colon cancer xenografts, longitudinal contrast-enhanced ultrasound MIP imaging plateau values (baseline and at 48 hours) were compared between mice with and without antiangiogenic treatment (anti-vascular endothelial growth factor antibody). Ex vivo CD31 immunostaining of tumor tissue was used to correlate in vivo MIP imaging plateau values with microvessel density analysis. Results In vivo MIP imaging plateau values correlated significantly (P = 0.001) with contrast microbubble doses. At 3 different injection rates of 0.6, 1.2, and 2.4 mL/min, MIP imaging plateau values did not change significantly (P = 0.61). Following 2 injections with the same microbubble dose and injection rate, MIP imaging plateau values were obtained with high reliability with an intraclass correlation

  7. Optical tomographic monitoring of vascular responses to anti-angiogenic drugs in preclinical tumor models

    NASA Astrophysics Data System (ADS)

    Flexman, Molly L.; Kim, Hyun K.; Hernandez, Sonia L.; Huang, Jianzhong; Johung, Tessa J.; Lee, Jonghwan; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

    2011-02-01

    It is well acknowledged that treatment efficacy could be increased and unnecessary toxicities reduced if a rapid assessment strategy were available to allow individual tailoring of cancer therapy. In this work we focus on using optical tomographic imaging to detect tumor response to anti-angiogenic treatment within the first 5 days of therapy. For this study we used two models with well-characterized and divergent responses to inhibition of vascular endothelial growth factor (VEGF). SK-NEP and NGP cells were implanted intrarenally into NCR nude mice and the resulting tumors were monitored until a threshold of 1-2 g was reached. Optical tomographic imaging with a dual-wavelength (λ = 765nm and 830nm) continuous wave system, was performed prior to the first treatment with the anti-VEGF bevacizumab (BV), as well as 1, 3, and 5 days later. We found that the SK-NEP tumor model, known to be responsive to BV treatment, shows a decrease in hemoglobin levels over the 5 days. Mice implanted with the NGP tumor model, known to be less responsive to treatment, do not show such decreases. These results were further validated with histopathological findings that showed a decrease in tumor vascularization in treated SK-NEP mice. These results suggest that optical tomography is a promising tool for monitoring early tumor response to drug therapy.

  8. Emerging role of TRP channels in cell migration: from tumor vascularization to metastasis

    PubMed Central

    Fiorio Pla, Alessandra; Gkika, Dimitra

    2013-01-01

    Transient Receptor Potential (TRP) channels modulate intracellular Ca2+ concentrations, controlling critical cytosolic and nuclear events that are involved in the initiation and progression of cancer. It is not, therefore, surprising that the expression of some TRP channels is altered during tumor growth and metastasis. Cell migration of both epithelial and endothelial cells is an essential step of the so-called metastatic cascade that leads to the spread of the disease within the body. It is in fact required for both tumor vascularization as well as for tumor cell invasion into adjacent tissues and intravasation into blood/lymphatic vessels. Studies from the last 15 years have unequivocally shown that the ion channles and the transport proteins also play important roles in cell migration. On the other hand, recent literature underlies a critical role for TRP channels in the migration process both in cancer cells as well as in tumor vascularization. This will be the main focus of our review. We will provide an overview of recent advances in this field describing TRP channels contribution to the vascular and cancer cell migration process, and we will systematically discuss relevant molecular mechanism involved. PMID:24204345

  9. [Therapeutic indications for percutaneous laser in patients with vascular malformations and tumors].

    PubMed

    Labau, D; Cadic, P; Ouroussoff, G; Ligeron, C; Laroche, J-P; Guillot, B; Dereure, O; Quéré, I; Galanaud, J-P

    2014-12-01

    Lasers are increasingly used to treat vascular abnormalities. Indeed, this technique is non-invasive and allows a specific treatment. The aim of this review is to present some biophysical principles of the lasers, to describe the different sorts of lasers available for treatment in vascular medicine indications. Three principal lasers exist in vascular medicine: the pulsed-dye laser, for the treatment of superficial pink lesions, the NdYAG-KTP laser for purple and bigger lesions, and the NdYAG long pulse laser for even deeper and bigger vascular lesions. In vascular malformations, port wine stains can also be treated by pulsed-dye laser, KTP or NdYAG when they are old and thick. Telangiectasias are good indications for the three sorts of lasers, depending on their depth, color and size. Microcystic lymphatic malformations can be improved by laser treatment. Arterio-venous malformations constitute a contraindication of laser treatment. In vascular tumors, involuted infantile hemangiomas constitute an excellent indication of pulsed-dye laser treatment. Controlled studies are necessary to evaluate and to compare the efficacy of each laser, in order to determine their optimal indications and optimal parameters for each machine.

  10. Immunohistochemical expression of vascular endothelial growth factor in keratocystic odontogenic tumor, dentigerous cyst, and radicular cyst: A comparative study

    PubMed Central

    Khajuria, Nidhi; Metgud, Rashmi; Naik, Smitha; Lerra, Sahul; Tiwari, Priya; Mamta; Katakwar, Payal; Tak, Anirudh

    2016-01-01

    Background: Cyst and tumors arise from tissue remains of odontogenesis, these interactions have been considered to play an important role in the tumorigenesis of odontogenic lesions. The connective tissue stroma has an essential role in the preservation of epithelial tissues and minor alterations in the epithelium are followed by corresponding changes in the stroma, such as angiogenesis. Vascular endothelial growth factor (VEGF) is considered the first factor which maintains its position as the most critical driver of vascular formation and is required to initiate the formation of immature vessels, with this aim, present study was executed to evaluate VEGF expression in kertocystic odontogenic tumor, dentigerous cyst and radicular cyst (RC). Materials and Methods: A retrospective study was carried out comprising a total of 31 cases; 13 cases of keratocystic odontogenic tumor (KCOT), nine cases of dentigerous cyst (DC) and nine cases of RC. The sections were stained immunohistochemically with VEGF antibody and were evaluated for the presence and intensity of the immuno reactive cells. Statistical analysis was carried out using Chi-square test to inter-compare the VEGF expression between KCOT, DC, and RC. Results: VEGF expression in the epithelium and connective tissue was significantly higher in KCOT compared to dentigerous and RC. One case of KCOT with carcinomatous change also revealed positive results for the VEGF expression in the dysplastic epithelium, tumor islands, and connective tissue. The significant difference was observed on inter-comparison of the VEGF expression in the connective tissue of KCOT and DC, whereas no significant difference was observed in the VEGF expression in the connective tissue of KCOT and DC. Conclusion: The present study data supports the literature finding that angiogenesis can be important in the progression and enlargement of odontogenic cysts similarly to what occurs in neoplastic conditions and further it can be concluded that

  11. NG2 proteoglycan-dependent recruitment of tumor macrophages promotes pericyte-endothelial cell interactions required for brain tumor vascularization

    PubMed Central

    Yotsumoto, Fusanori; You, Weon-Kyoo; Cejudo-Martin, Pilar; Kucharova, Karolina; Sakimura, Kenji; Stallcup, William B

    2015-01-01

    Early stage growth of intracranial B16F10 tumors is reduced by 87% in myeloid-specific NG2 null (Mac-NG2ko) mice and by 77% in pericyte-specific NG2 null (PC-NG2ko) mice, demonstrating the importance of the NG2 proteoglycan in each of these stromal compartments. In both genotypes, loss of pericyte-endothelial cell interaction results in numerous structural defects in tumor blood vessels, including decreased formation of endothelial cell junctions and decreased assembly of the vascular basal lamina. All vascular deficits are larger in Mac-NG2ko mice than in PC-NG2ko mice, correlating with the greater decrease in pericyte-endothelial cell interaction in Mac-NG2ko animals. Accordingly, tumor vessels in Mac-NG2ko mice have a smaller diameter, lower degree of patency, and higher degree of leakiness than tumor vessels in PC-NG2ko mice, leading to less efficient tumor blood flow and to increased intratumoral hypoxia. While reduced pericyte interaction with endothelial cells in PC-NG2ko mice is caused by loss of NG2-dependent pericyte activation of β1 integrin signaling in endothelial cells, reduced pericyte-endothelial cell interaction in Mac-NG2ko mice is due to a 90% reduction in NG2-dependent macrophage recruitment to tumors. The absence of a macrophage-derived signal(s) in Mac-NG2ko mice results in the loss of pericyte ability to associate with endothelial cells, possibly due to reduced expression of N-cadherin by both pericytes and endothelial cells. PMID:26137396

  12. Development, differentiation, and vascular components of subcutaneous and intrahepatic Hepa129 tumors in a mouse model of hepatocellular carcinoma.

    PubMed

    Robertson, Richard T; Gutierrez, Paula M; Baratta, Janie L; Thordarson, Kristoffer; Braslow, Joshua; Haynes, Sherry M; Longmuir, Kenneth J

    2016-04-01

    Tumor models in mice offer opportunities for understanding tumor formation and development of therapeutic treatments for hepatocellular carcinoma. In this study, subcutaneous or intra-hepatic Hepa129 tumors were established in C3H mice. Tumor growth was determined by daily measurements of subcutaneous tumors and post-mortem studies of subcutaneous and intrahepatic tumors. Administration of Edu was used to determine cell generation dates of tumor cells. Immunohistochemistry with antibodies directed at CD31 or CD34, and intravenous injection of labeled tomato lectin revealed tumor vasculature. Tissue sections also were processed for immunohistochemistry using a panel of antibodies to proteoglycans. Comparison of Edu labeled cells with immunoreactivity allowed determination of development and differentiation of tumor cells after cell generation. Subcutaneous and intrahepatic tumors displayed similar growth over 3 weeks. Immunohistochemistry showed strong labeling for glypican-3, 9BA12, and chondroitin sulfate of tumors in both loci, while normal liver was negative. Tumor regions containing Edu labeled cells did not show significant immunohistochemical labeling for the tumor markers until 2-3 days after Edu treatment; overlap of Edu labeled cells and immunohistochemically labeled tumor regions appeared to reach a maximum at 5 days after Edu treatment. Ectopic subcutaneous tumors displayed vascular ingrowth as the tumor cells expressed immunocytochemical markers; subcutaneous tumors displayed significantly more vascular elements than did intrahepatic tumors.

  13. 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

  14. 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.

  15. alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis.

    PubMed

    Dimberg, Anna; Rylova, Svetlana; Dieterich, Lothar C; Olsson, Anna-Karin; Schiller, Petter; Wikner, Charlotte; Bohman, Svante; Botling, Johan; Lukinius, Agneta; Wawrousek, Eric F; Claesson-Welsh, Lena

    2008-02-15

    Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.

  16. 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.

  17. Selective Alpha-Particle Mediated Depletion of Tumor Vasculature with Vascular Normalization

    PubMed Central

    Seshan, Surya V.; Kappel, Barry J.; Chattopadhyay, Debjit; May, Chad; McDevitt, Michael R.; Nolan, Daniel; Mittal, Vivek; Benezra, Robert; Scheinberg, David A.

    2007-01-01

    Background Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature. Methodology and Principal Findings Actinium-225 (225Ac)-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, 225Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in 225Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following 225Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following 225Ac-E4G10 therapy. Conclusions The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy. PMID:17342201

  18. Development of 124I-Immuno-PET Targeting Tumor Vascular TEM1/Endosialin

    PubMed Central

    Nayak, Madhura; Mikitsh, John L.; Hu, Jia; Hou, Catherine; Grasso, Luigi; Nicolaides, Nicholas C.; Muzykantov, Vladimir R.; Divgi, Chaitanya R.; Coukos, George

    2014-01-01

    Tumor endothelial marker 1 (TEM1/endosialin) is a tumor vascular marker highly overexpressed in multiple human cancers with minimal expression in normal adult tissue. In this study, we report the preparation and evaluation of 124I-MORAb-004, a 124I-labeled humanized monoclonal antibody targeting an extracellular epitope of human TEM1 (hTEM1), for its ability to specifically and sensitively detect vascular cells expressing hTEM1 in vivo. Methods MAb MORAb-004 was directly iodinated with 125I and 124I, and in vitro binding and internalization parameters were characterized. The in vivo behavior of radioiodinated-MORAb-004 was characterized in mice bearing subcutaneous ID8 tumors enriched with mouse endothelial cells expressing hTEM1, or control tumors, by biodistribution studies and small animal immuno-PET studies. Results MORAb-004 was radiolabeled with high efficiency and isolated in high purity. In vitro studies demonstrated specific and sensitive binding of MORAb-004 to MS1 mouse endothelial cells expressing hTEM1, with no binding to control MS1 cells. 125I-MORAb-004 and 124I MORAb-004 both had an immunoreactivity of approximately 90%. In vivo biodistribution experiments revealed rapid, highly specific and sensitive uptake of MORAb-004 in MS1-TEM1 tumors at 4 h (153.2 ± 22.2 percent of injected dose per gram [%ID/g]), 24 h (127.1 ± 42.9 %ID/g), 48 h (130.3 ± 32.4 %ID/g), 72 h (160.9 ± 32.1 %ID/g), and 6 d (10.7 ± 1.8 %ID/g). Excellent image contrast was observed with 124I-immuno-PET. MORAb-004 uptake was statistically higher in TEM1-positive tumors versus control tumors, as measured by biodistribution and immuno-PET studies. Binding specificity was confirmed by blocking studies using excess nonlabeled MORAb-004. Conclusion In our preclinical model, with hTEM1 exclusively expressed on engineered murine endothelial cells that integrate into the tumor vasculature, 124I-MORAb-004 displays high tumor–to–background tissue contrast fordetection of hTEM1 in

  19. 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

  20. Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors

    SciTech Connect

    Siemann, Dietmar W. . E-mail: siemadw@ufl.edu; Shi Wenyin

    2004-11-15

    Purpose: To evaluate the antitumor efficacy of a vascular targeting strategy that combines an agent that disrupts established tumor blood vessels (ZD6126) with one that interferes with new vessel formation (ZD6474) in models of human renal cell carcinoma (Caki-1) and Kaposi's sarcoma (KSY-1). Methods and materials: Caki-1 and KSY-1 xenograft-bearing nude mice were treated with ZD6126 and ZD6474 either as single agents or in combination when the tumors reached a size of {approx}200 mm{sup 3}. ZD6126 therapy consisted of three doses of 100 mg/kg administered 1, 3, and 5 days after the tumor reached the starting size. ZD6474 was administered daily (25 mg/kg) on Days 1-5. In the combination studies, ZD6474 treatment began immediately after the first dose of ZD6126. The tumor response to treatment was evaluated using a regrowth delay endpoint. Results: Significant tumor growth delays were observed in both tumor models with either agent with the treatment regimen used. In the Caki-1 and KSY-1 models, respectively, ZD6126 treatment resulted in a tumor growth delay of 23 and 26 days and ZD6474 produced a tumor growth delay of 24.5 and 14.5 days. When ZD6126 and ZD6474 were combined, the tumor growth delays increased to 55 (Caki-1) and 86 (KSY-1) days. In the KSY-1 model, the combination therapy also resulted in 3 of 8 long-term tumor-free survivors. Conclusion: These results indicate that statistically significant antitumor efficacy can be achieved using a treatment strategy that combines a therapy that targets the established tumor blood vessels with one that interferes with the process of angiogenesis.

  1. Gray scale and contrast-enhanced ultrasound imaging of malignant liver tumors of vascular origin

    PubMed Central

    Schweitzer, Nora; Soudah, Bisharah; Gebel, Michael; Manns, Michael Peter

    2015-01-01

    Objectives Malignant vascular tumors of the liver are rare. The aim of this study was to investigate the applicability of gray scale and contrast-enhanced ultrasonography in patients with epithelioid hemangioendothelioma (EHE) of the liver and hepatic angiosarcoma (HA) and to describe the clinical presentation. Methods We retrospectively analyzed all patients with epithelioid hemangioendothelioma or hemangiosarcoma of the liver from 1998 to 2011, who underwent ultrasound investigation. We describe the findings in gray scale and contrast-enhanced ultrasound and the clinical course of the disease of seven patients with EHE and five patients with HA. Results Ultrasound investigation in EHE showed mostly multiple hypoechoic irregular lesions close to the liver capsule and with a halo in some cases. Contrast enhancement revealed inhomogeneously and through all contrast phases vascularized tumors with a rim enhancement in 50%, with or without early wash out. All tumors had avascular parts. HA presented as multiple and irregular hypo-, iso- or hyperechoic lesions. After contrast enhancement, hypervascularization with individual patterns was evident in all patients. Of five, three had liquid parts. Patients with HA were significantly older (58 vs. 37 years, p = 0.014) and presented with lower thrombocyte counts (84 vs. 264, p = 0.0025) and with higher CEA levels (4.6 vs. 1.5, p = 0.03). Conclusion EHE and HA are inhomogeneous tumors, explaining the high inter-individual variability and heterogeneity in ultrasound examination. The presence of multifocal lesions, heterogeneity and undefined margins may differentiate EHE or HA from hemangioma. A biopsy is essential in the diagnosis of vascular tumors. PMID:25653860

  2. Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma.

    PubMed

    Togashi, Yosuke; Masago, Katsuhiro; Kubo, Takeshi; Fujimoto, Daichi; Sakamori, Yuichi; Nagai, Hiroki; Kim, Young Hak; Togashi, Kaori; Mishima, Michiaki

    2012-12-01

    Mutation of the epidermal growth factor receptor gene (EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4 %). EGFR mutation was found to be significantly related to women (P = 0.0070), never-smokers (P < 0.0001), and tumors without vascular-poor area (P < 0.0001). Based on a multivariate analysis, presence of EGFR mutations was independently associated with never-smokers (P = 0.0046), lack of vascular-poor area (P = 0.0001), and tumor size >30 mm (P = 0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular-poor area (80.4 %), 19 of 36 never-smokers with vascular-poor area (52.8 %), 19 of 37 current or former-smokers without vascular-poor area (51.4 %), and 16 of 54 current or former-smokers with vascular-poor area (29.6 %). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency.

  3. 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

  4. 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

  5. Fractal analysis of two-dimensional vascularity in primary prostate cancer and surrounding non-tumoral parenchyma.

    PubMed

    Taverna, Gianluigi; Colombo, Piergiuseppe; Grizzi, Fabio; Franceschini, Barbara; Ceva-Grimaldi, Giorgia; Seveso, Mauro; Giusti, Guido; Piccinelli, Alessandro; Graziotti, Pierpaolo

    2009-01-01

    Prostate cancer is the fifth most frequent cancer in the world. However, none of the actual prognostic factors provide a valid index for predicting patient outcome. Here, we evaluate the two-dimensional vascularity in primary prostate tumors and surrounding non-tumoral parenchyma by means of fractal geometry, and assess any correlations between the results and some clinical and pathological parameters of prostate carcinoma. Prostate sections from 27 carcinoma patients were treated with CD34 antibodies. Two >10mm(2) areas of tumoral and surrounding non-tumoral parenchyma were digitized using an image analysis system that automatically quantified the fractal dimension of the vascular surface. Data were correlated with patient's age, PSA level, clinical and pathological stage, Gleason score, tumor volume, vascular invasion, surgical margins, and biochemical relapse. Two groups of patients were distinguished on the basis of whether the fractal dimension of their tumoral vascular surface was higher (group 1) or lower (group 2) than that of the surrounding non-tumoral parenchyma. Statistically significant between-group differences were found in terms of serum PSA levels (p=0.0061), tumor volume (p=0.0017), and biochemical relapse (p=0.031). The patients in group 2 had a poorer outcome. Our findings suggest a group of prostate cancer patients with a poor outcome, and the vascular surface fractal dimension as a helpful geometrical index in clinical practice.

  6. Applying gold nanoparticles as tumor-vascular disrupting agents during brachytherapy: estimation of endothelial dose enhancement

    NASA Astrophysics Data System (ADS)

    Ngwa, Wilfred; Makrigiorgos, G. Mike; Berbeco, Ross I.

    2010-11-01

    Tumor vascular disrupting agents (VDAs) represent a promising approach to the treatment of cancer, in view of the tumor vasculature's pivotal role in tumor survival, growth and metastasis. VDAs targeting the tumor's dysmorphic endothelial cells can cause selective and rapid occlusion of the tumor vasculature, leading to tumor cell death from ischemia and extensive hemorrhagic necrosis. In this study, the potential for applying gold nanoparticles (AuNPs) as VDAs, during brachytherapy, is examined. Analytic calculations based on the electron energy loss formula of Cole were carried out to estimate the endothelial dose enhancement caused by radiation-induced photo/Auger electrons originating from AuNPs targeting the tumor endothelium. The endothelial dose enhancement factor (EDEF), representing the ratio of the dose to the endothelium with and without gold nanoparticles was calculated for different AuNP local concentrations, and endothelial cell thicknesses. Four brachytherapy sources were investigated, I-125, Pd-103, Yb-169, as well as 50 kVp x-rays. The results reveal that, even at relatively low intra-vascular AuNP concentrations, ablative dose enhancement to tumor endothelial cells due to photo/Auger electrons from the AuNPs can be achieved. Pd-103 registered the highest EDEF values of 7.4-271.5 for local AuNP concentrations ranging from 7 to 350 mg g-1, respectively. Over the same concentration range, I-125, 50 kVp and Yb-169 yielded values of 6.4-219.9, 6.3-214.5 and 4.0-99.7, respectively. Calculations of the EDEF as a function of endothelial cell thickness showed that lower energy sources like Pd-103 reach the maximum EDEF at smaller thicknesses. The results also reveal that the highest contribution to the EDEF comes from Auger electrons, apparently due to their shorter range. Overall, the data suggest that ablative dose enhancement to tumor endothelial cells can be achieved by applying tumor vasculature-targeted AuNPs as adjuvants to brachytherapy, with lower

  7. Cell-permeable iron inhibits vascular endothelial growth factor receptor-2 signaling and tumor angiogenesis

    PubMed Central

    Kir, Devika; Saluja, Manju; Modi, Shrey; Venkatachalam, Annapoorna; Schnettler, Erica; Roy, Sabita; Ramakrishnan, Sundaram

    2016-01-01

    Angiogenesis is important for tumor growth and metastasis. Hypoxia in tumors drives this angiogenic response by stabilizing Hypoxia Inducible Factors (HIF) and target genes like Vascular Endothelial Growth Factor (VEGF). HIF stability is regulated by Prolylhydroxylases (PHD)-mediated modification. Iron is an important cofactor in regulating the enzymatic activity of PHDs. Reducing intracellular iron, for instance, mimics hypoxia and induces a pro-angiogenic response. It is hypothesized that increasing the intracellular iron levels will have an opposite, anti-angiogenic effect. We tested this hypothesis by perturbing iron homeostasis in endothelial cells using a unique form of iron, Ferric Ammonium Citrate (FAC). FAC is a cell-permeable form of iron, which can passively enter into cells bypassing the transferrin receptor mediated uptake of transferrin-bound iron. Our studies show that FAC does not decrease the levels of HIF-1α and HIF-2α in endothelial cells but inhibits the autocrine stimulation of VEGF-Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) system by blocking receptor tyrosine kinase phosphorylation. FAC inhibits VEGF-induced endothelial cell proliferation, migration, tube formation and sprouting. Finally, systemic administration of FAC inhibits VEGF and tumor cell-induced angiogenesis in vivo. In conclusion, our studies show that cell-permeable iron attenuates VEGFR-2 mediated signaling and inhibits tumor angiogenesis. PMID:27589831

  8. Optimization of vascular-targeting drugs in a computational model of tumor growth

    NASA Astrophysics Data System (ADS)

    Gevertz, Jana

    2012-04-01

    A biophysical tool is introduced that seeks to provide a theoretical basis for helping drug design teams assess the most promising drug targets and design optimal treatment strategies. The tool is grounded in a previously validated computational model of the feedback that occurs between a growing tumor and the evolving vasculature. In this paper, the model is particularly used to explore the therapeutic effectiveness of two drugs that target the tumor vasculature: angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs). Using sensitivity analyses, the impact of VDA dosing parameters is explored, as is the effects of administering a VDA with an AI. Further, a stochastic optimization scheme is utilized to identify an optimal dosing schedule for treatment with an AI and a chemotherapeutic. The treatment regimen identified can successfully halt simulated tumor growth, even after the cessation of therapy.

  9. NG2 PROTEOGLYCAN-DEPENDENT CONTRIBUTIONS OF PERICYTES AND MACROPHAGES TO BRAIN TUMOR VASCULARIZATION AND PROGRESSION

    PubMed Central

    Stallcup, William B.; You, Weon-Kyoo; Kucharova, Karolina; Cejudo-Martin, Pilar; Yotsumoto, Fusanori

    2015-01-01

    The NG2 proteoglycan promotes tumor growth as a component of both tumor and stromal cells. Using intracranial, NG2-negative B16F10 melanomas, we have investigated the importance of pericyte and macrophage NG2 in brain tumor progression. Reduced melanoma growth in myeloid-specific NG2 null (Mac-NG2ko) and pericyte-specific NG2 null (PC-NG2ko) mice demonstrates the importance of NG2 in both stromal compartments. In each genotype, loss of pericyte-endothelial cell interaction diminishes formation of endothelial junctions and assembly of the basal lamina. Tumor vessels in Mac-NG2ko mice have smaller diameters, reduced patency, and increased leakiness compared to PC-NG2ko mice, thus decreasing tumor blood supply and increasing hypoxia. While reduced pericyte interaction with endothelial cells in PC-NG2ko mice results from loss of pericyte activation of β1 integrin signaling in endothelial cells, reduced pericyte-endothelial cell interaction in Mac-NG2ko mice results from 90% reduced macrophage recruitment. The absence of macrophage-derived signals in Mac-NG2ko mice causes loss of pericyte association with endothelial cells. Reduced macrophage recruitment may be due to diminished activation of integrins in the absence of NG2, causing decreased macrophage interaction with endothelial adhesion molecules that are needed for extravasation. These results reflect the complex interplay that occurs between macrophages, pericytes, and endothelial cells during tumor vascularization. PMID:26465118

  10. Evaluation of Vascular Supply with Angio-Computed Tomography During Intra-Arterial Chemotherapy for Brain Tumors

    SciTech Connect

    Hirai, Toshinori Korogi, Yukunori; Ono, Ken; Yamashita, Yasuyuki

    2005-04-15

    We report the utility of a combined angiography and computed tomography (angio-CT) system in assessing drug distribution to the tumor during intra-arterial chemotherapy for metastatic brain tumors in a 65-year-old man. Although digital subtraction angiography did not clearly show tumor perfusion in two cerebellar tumors, angio-CT provided definite tumor perfusion in the complicated vascular territory, and anticancer agents were infused based on its findings. To our knowledge, however, this application for intra-arterial chemotherapy of brain tumors has not been previously described.

  11. H460 non-small cell lung cancer stem-like holoclones yield tumors with increased vascularity

    PubMed Central

    Manley, Eugene; Waxman, David J.

    2014-01-01

    Cancer stem-like cells were isolated from several human tumor cell lines by limiting dilution assays and holoclone morphology, followed by assessment of self-renewal capacity, tumor growth, vascularity, and blood perfusion. H460 holoclone-derived tumors grew slower than parental H460 tumors, but displayed significantly increased microvessel density and tumor blood perfusion. Microarray analysis identified 177 differentially regulated genes in the holoclone-derived tumors, of which 47 were associated with angiogenesis. The dysregulated genes include several small leucine-rich proteoglycans that may modulate angiogenesis and serve as novel therapeutic targets for inhibiting cancer stem cell-driven angiogenesis. PMID:24334139

  12. H460 non-small cell lung cancer stem-like holoclones yield tumors with increased vascularity.

    PubMed

    Manley, Eugene; Waxman, David J

    2014-04-28

    Cancer stem-like cells were isolated from several human tumor cell lines by limiting dilution assays and holoclone morphology, followed by assessment of self-renewal capacity, tumor growth, vascularity, and blood perfusion. H460 holoclone-derived tumors grew slower than parental H460 tumors, but displayed significantly increased microvessel density and tumor blood perfusion. Microarray analysis identified 177 differentially regulated genes in the holoclone-derived tumors, of which 47 were associated with angiogenesis. The dysregulated genes include several small leucine-rich proteoglycans that may modulate angiogenesis and serve as novel therapeutic targets for inhibiting cancer stem cell-driven angiogenesis.

  13. Serial evaluation of retinal vascular changes in infants treated with intravitreal bevacizumab for aggressive posterior retinopathy of prematurity in zone I

    PubMed Central

    Padhi, T R; Das, T; Rath, S; Pradhan, L; Sutar, S; Panda, K G; Modi, R; Jalali, S

    2016-01-01

    Purpose To evaluate the serial changes in retinal vasculature in infants treated with intravitreal bevacizumab (IVB) for aggressive posterior retinopathy of prematurity (APROP) in zone I. Methods Retrospective analysis of serial changes in retinal vasculature after IVB in the seven eyes of four babies with APROP in zone I. Results The initial regression, following IVB, was dramatic with reduction in vessel caliber and marked thinning and invisibility of the bridging shunts. Resurgent vascular development was very slow radially though there was continued abnormal vascular growth circumferentially. Common findings in all eyes were tangled vasculature and fine saw-toothed shunts. The variable findings were (1) new closely packed multilayered bridging shunts, long arching mature looking vessels, and finally a ridge at the periphery (n=3 eyes) at 52 weeks of postmenstrual age (PMA); (2) status quo at the stage of saw-toothed shunt and ridge in both eyes for a long time (n=2 eyes); and (3) multiple retinal hemorrhages within the vascularized retina and thick preretinal hemorrhage overlying the saw-toothed shunts and ridge that persisted for another 3 weeks and regressed 2 weeks after laser (n=1). The eyes that received bevacizumab alone (3) did not show any abnormal vascularization at 56 weeks of PMA or beyond. Conclusions The retinal vascularization following IVB was different than normal in terms of its time, speed, and morphology; few of these changes are first to be reported in the literature (Medline search) and warrants further studies. PMID:26584796

  14. The analysis of feasibility and effectiveness of vascular targeting radiotherapy based on a model of tumor growth and angiogenesis

    NASA Astrophysics Data System (ADS)

    Ding, Yihong

    Targeting cytotoxic agents to tumor angiogenesis, instead of the tumor itself, is an attractive new approach in Radiation Oncology. Unlike tumor cells, endothelial cells are less likely to develop radio-resistance. Investigations have shown that radiation can cause a definite increase in cell permeability. Permeability changes in the tumor capillary endothelium can contribute to circulatory failure and serve as a site for clot formation. Therefore, radiation could initiate platelet aggregation and blood coagulation locally within the tumor vasculature, leading to tumor cell killing through depletion of oxygen and nutrients. In order to analyze the efficacy of a potential 90Y-labeled compound for vascular targeting radiotherapy and to evaluate the factors that may affect targets' absorbed dose, a tumor vasculature model including its angiogenesis process as a function of time and tumor growth are adopted and improved from the Liotta model. Its output is used to estimate targets' absorbed doses by Monte Carlo simulation. The results show that the effectiveness of vascular targeting therapy depends on the existence of available tumor endothelial cells and target expression. The alphavbeta3 antagonist model compound is less effective in the early stage tumors, which have very few vessels. Although a high administered dose, such as injecting of 2.1 mCi/kg to saturate all available binding sites, can destroy tumor endothelium network, the toxicity to bone marrow makes it impossible to inject such a dose. To a vascularized tumor, after giving one maximum allowable administered activity, 0.83 mCi/kg for the 90Y-labeled model compound, an average of 9.8%, 27.3%, 34.7% and 37.8% of endothelial cells would be killed when treatment starts at day 4, 7, 9 and 12 after tumor development, respectively. Therefore, recurrent treatment by vascular targeting therapy to well-vascularized tumor has the potential to slow down tumor growth or may even cause tumor regression at the primary

  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. 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.

  17. The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems

    PubMed Central

    Wu, Min; Frieboes, Hermann B.; Chaplain, Mark A.J.; McDougall, Steven R.; Cristini, Vittorio; Lowengrub, John

    2014-01-01

    Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but leads to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the

  18. NDRG1 overexpressing gliomas are characterized by reduced tumor vascularization and resistance to antiangiogenic treatment.

    PubMed

    Broggini, Thomas; Wüstner, Marie; Harms, Christoph; Stange, Lena; Blaes, Jonas; Thomé, Carina; Harms, Ulrike; Mueller, Susanne; Weiler, Markus; Wick, Wolfgang; Vajkoczy, Peter; Czabanka, Marcus

    2016-10-01

    Hypoxia-regulated molecules play an important role in vascular resistance to antiangiogenic treatment. N-myc downstream-regulated-gene 1 (NDRG1) is significantly upregulated during hypoxia in glioma. It was the aim of the present study to analyze the role of NDRG1 on glioma angiogenesis and on antiangiogenic treatment. Orthotopically implanted NDRG1 glioma showed reduced tumor growth and vessel density compared to controls. RT-PCR gene array analysis revealed a 30-fold TNFSF15 increase in NDRG1 tumors. Consequently, the supernatant from NDRG1 transfected U87MG glioma cells resulted in reduced HUVEC proliferation, migration and angiogenic response in tube formation assays in vitro. This effect was provoked by increased TNFSF15 promoter activity in NDRG1 cells. Mutations in NF-κB and AP-1 promoter response elements suppressed TNFSF15 promoter activity. Moreover, U87MG glioma NDRG1 knockdown supernatant contained multiple proangiogenic proteins and increased HUVEC spheroid sprouting. Sunitinib treatment of orhotopically implanted mice reduced tumor volume and vessel density in controls; in NDRG1 overexpressing cells no reduction of tumor volume or vessel density was observed. NDRG1 overexpression leads to reduced tumor growth and angiogenesis in experimental glioma via upregulation of TNFSF15. In NDRG1 overexpressing glioma antiangiogenic treatment does not yield a therapeutic response.

  19. Cytohesin-3 is upregulated in hepatocellular carcinoma and contributes to tumor growth and vascular invasion

    PubMed Central

    Fu, Ying; Li, Jun; Feng, Ming-Xuan; Yang, Xiao-Mei; Wang, Ya-Hui; Zhang, Yan-Li; Qin, Wenxin; Xia, Qiang; Zhang, Zhi-Gang

    2014-01-01

    Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality, and is characterized by high potential for metastasis and recurrence. The outcome of it is still poor due to lacking of targeted therapeutic strategies. There is an urgent need to find new therapeutic targets for interventions against HCC metastasis and recurrence. In the present study, we found cytohesin-3, a member of the cytohesin family, was upregulated in HCC tissues, and its expression was negatively correlated with the overall survival and relapse-free survival of HCC patients. Further clinicopathological correlation analysis revealed that cytohesin-3 expression was related with tumor size and vascular invasion. And in vitro studies revealed that knock-down of cytohesin-3 suppressed HCC cells proliferation and migration. These results suggest that cytohesin-3 may act as a novel prognostic factor of HCC, and it might also be useful to exploit targeted therapeutic drugs against HCC growth and metastasis. PMID:24966920

  20. 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.

  1. 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

  2. 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

  3. Concurrent anti-vascular therapy and chemotherapy in solid tumors using drug-loaded acoustic nanodroplet vaporization.

    PubMed

    Ho, Yi-Ju; Yeh, Chih-Kuang

    2017-02-01

    Drug-loaded nanodroplets (NDs) can be converted into gas bubbles through ultrasound (US) stimulation, termed acoustic droplet vaporization (ADV), which provides a potential strategy to simultaneously induce vascular disruption and release drugs for combined physical anti-vascular therapy and chemotherapy. Doxorubicin-loaded NDs (DOX-NDs) with a mean size of 214nm containing 2.48mg DOX/mL were used in this study. High-speed images displayed bubble formation and cell debris, demonstrating the reduction in cell viability after ADV. Intravital imaging provided direct visualization of disrupted tumor vessels (vessel size <30μm), the extravasation distance was 12μm in the DOX-NDs group and increased over 100μm in the DOX-NDs+US group. Solid tumor perfusion on US imaging was significantly reduced to 23% after DOX-NDs vaporization, but gradually recovered to 41%, especially at the tumor periphery after 24h. Histological images of the DOX-NDs+US group revealed tissue necrosis, a large amount of drug extravasation, vascular disruption, and immune cell infiltration at the tumor center. Tumor sizes decreased 22%, 36%, and 68% for NDs+US, DOX-NDs, and DOX-NDs+US, respectively, to prolong the survival of tumor-bearing mice. Therefore, this study demonstrates that the combination of physical anti-vascular therapy and chemotherapy with DOX-NDs vaporization promotes uniform treatment to improve therapeutic efficacy.

  4. In vivo spectral and fluorescence imaging microscopy of tumor microvessel blood supply and oxygenation changes following vascular targeting agent treatment

    NASA Astrophysics Data System (ADS)

    Lee, Jennifer; Kozikowski, Raymond; Molnar, Nikolett; Siemann, Dietmar W.; Sorg, Brian S.

    2012-03-01

    The formation of new microvasculature is essential for a tumor mass to grow. Vascular targeting agents (VTAs), including anti-angiogenic drugs and vascular disrupting agents, aim to either inhibit new vasculature growth or destroy existing vasculature, respectively. Because the mechanisms for anti-angiogenic drugs and vascular disrupting agents are complementary, analysis of these drugs used together is under investigation for the enhanced treatment of tumors in comparison to each treatment alone. The preclinical evaluation of the effects of VTAs on tumor growth in small animal models is vital for the development of effective drugs for clinical use. In vivo hyperspectral imaging microscopy of hemoglobin saturation has been used previously to investigate the efficacy of VTAs through analysis of tumor microvessel oxygenation after drug administration. Combining this imaging modality with first-pass fluorescence angiographic imaging can give additional important information about the vessel morphology and blood flow changes that occur after VTA treatment, thus elucidating the relationship between microvessel structure changes and oxygenation. In this study, we report the combined use of hyperspectral and first pass fluorescence angiographic imaging to examine the relationship between vessel morphology and oxygenation of human prostate cancer tumors in mice following treatment with vascular disrupting agents, OXi4503, and anti-VEGF angiogenesis inhibitor, cediranib. Imaging of the tumors is completed before treatment as well as in the days following treatment.

  5. Tumor-associated primo vascular system is derived from xenograft, not host.

    PubMed

    Islam, Md Ashraful; Thomas, Shelia D; Sedoris, Kara J; Slone, Stephen P; Alatassi, Houda; Miller, Donald M

    2013-02-01

    The primo vascular system (PVS), which is composed of very small primo-vessels (PV) and primo-nodes (PN), has recently emerged as a third component of circulatory system. Here, we report the presence of a tumor derived PVS in murine xenografts of human histiocytic lymphoma (U937) in close proximity to the tumor. Within this system, PNs are small (~500-600 μM diameter) membranous sac-like structures which contain numerous small cells which can be demonstrated by DAPI staining. Hematoxylin and Eosin (H&E) staining of the peri-tumoral PVS shows the presence of loose structures lined by fibroblasts but filled with dense fibers, cells, lacunae and nerve-like structures. The origin and type of cells within the PVS was characterized by immunostaining with antibodies for CD68, CD45 and lysozyme. The results of these studies reveal that the PVS of the xenograft originates from the human U937 tumor cells. qRT-PCR analysis of mRNA isolated from PVS cells reveals a striking predominance of human, rather than mouse, sequences. Of particular interest, human stem cell specific transcription factors were overexpressed, most notably KLF4, an upstream regulator of NANOG which maintains the pluripotent and undifferentiated state of stem cells. These results suggest that the cells present within the PVS are derived from the human xenograft and suggests that the primo-vessels associated with the xenografted tumor may provide a safe haven for a select population of cancer stem cells. Further understanding of the biological properties of these cells may allow the development of new anti-cancer interventions.

  6. Developmental and tumoral vascularization is regulated by G protein–coupled receptor kinase 2

    PubMed Central

    Rivas, Verónica; Carmona, Rita; Muñoz-Chápuli, Ramón; Mendiola, Marta; Nogués, Laura; Reglero, Clara; Miguel-Martín, María; García-Escudero, Ramón; Dorn, Gerald W.; Hardisson, David; Mayor, Federico; Penela, Petronila

    2013-01-01

    Tumor vessel dysfunction is a pivotal event in cancer progression. Using an in vivo neovascularization model, we identified G protein–coupled receptor kinase 2 (GRK2) as a key angiogenesis regulator. An impaired angiogenic response involving immature vessels was observed in mice hemizygous for Grk2 or in animals with endothelium-specific Grk2 silencing. ECs isolated from these animals displayed intrinsic alterations in migration, TGF-β signaling, and formation of tubular networks. Remarkably, an altered pattern of vessel growth and maturation was detected in postnatal retinas from endothelium-specific Grk2 knockout animals. Mouse embryos with systemic or endothelium-selective Grk2 ablation had marked vascular malformations involving impaired recruitment of mural cells. Moreover, decreased endothelial Grk2 dosage accelerated tumor growth in mice, along with reduced pericyte vessel coverage and enhanced macrophage infiltration, and this transformed environment promoted decreased GRK2 in ECs and human breast cancer vessels. Our study suggests that GRK2 downregulation is a relevant event in the tumoral angiogenic switch. PMID:24135140

  7. Rare presentation of intracranial vascular blowout after tumor resection and radiation therapy

    PubMed Central

    Alaraj, Ali; Behbahani, Mandana; Valyi-Nagy, Tibor; Aardsma, Nathan; Aletich, Victor A

    2014-01-01

    A middle-aged patient presented with a rapidly growing right dural-based extra-axial posterior clinoid mass extending to the right cavernous sinus that was surgically resected. Histological examination showed solid growth of primitive neuroectodermal tumor arising from the third nerve. Following surgical resection, the patient was further managed by radiation and chemotherapy. Two years later the patient developed new intracranial hemorrhage in the area adjacent to the previous surgical cavity. A cerebral angiogram showed contrast extravasation at the junction of the posterior communicating artery (Pcom) and the right posterior cerebral artery (PCA), with an expanding pseudoaneurysm. This was managed with N-butyl cyanoacrylate embolization. Autopsy showed microscopic recurrence of tumor into the PCA/PCom region with invasion of the wall of the Pcom. This case report illustrates the concept of vascular blowout in intracranial cerebral vasculature. It appears that, in the presence of risk factors that contribute to weakening of vessel walls (surgery, radiation, tumor recurrence), a blowout can occur intracranially. PMID:24748141

  8. Combinatorial effects of doxorubicin and retargeted tissue factor by intratumoral entrapment of doxorubicin and proapoptotic increase of tumor vascular infarction

    PubMed Central

    Brand, Caroline; Höltke, Carsten; Schliemann, Christoph; Kessler, Torsten; Schmidt, Lars Henning; Harrach, Saliha; Mantke, Verena; Hintelmann, Heike; Hartmann, Wolfgang; Wardelmann, Eva; Lenz, Georg; Wünsch, Bernhard; Müller-Tidow, Carsten; Mesters, Rolf M.; Schwöppe, Christian; Berdel, Wolfgang E.

    2016-01-01

    Truncated tissue factor (tTF), retargeted to tumor vasculature by GNGRAHA peptide (tTF-NGR), and doxorubicin have therapeutic activity against a variety of tumors. We report on combination experiments of both drugs using different schedules. We have tested fluorescence- and HPLC-based intratumoral pharmacokinetics of doxorubicin, flow cytometry for cellular phosphatidylserine (PS) expression, and tumor xenograft studies for showing in vivo apoptosis, proliferation decrease, and tumor shrinkage upon combination therapy with doxorubicin and induced tumor vascular infarction. tTF-NGR given before doxorubicin inhibits the uptake of the drug into human fibrosarcoma xenografts in vivo. Reverse sequence does not influence the uptake of doxorubicin into tumor, but significantly inhibits the late wash-out phase, thus entrapping doxorubicin in tumor tissue by vascular occlusion. Incubation of endothelial and tumor cells with doxorubicin in vitro increases PS concentrations in the outer layer of the cell membrane as a sign of early apoptosis. Cells expressing increased PS concentrations show comparatively higher procoagulatory efficacy on the basis of equimolar tTF-NGR present in the Factor X assay. Experiments using human M21 melanoma and HT1080 fibrosarcoma xenografts in athymic nude mice indeed show a combinatorial tumor growth inhibition applying doxorubicin and tTF-NGR in sequence over single drug treatment. Combination of cytotoxic drugs such as doxorubicin with tTF-NGR-induced tumor vessel infarction can improve pharmacodynamics of the drugs by new mechanisms, entrapping a cytotoxic molecule inside tumor tissue and reciprocally improving procoagulatory activity of tTF-NGR in the tumor vasculature via apoptosis induction in tumor endothelial and tumor cells. PMID:27738341

  9. 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.

  10. 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.

  11. Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate

    SciTech Connect

    Sun, Qingwen; Jiang, Songmin; Han, Baohui; Sun, Tongwen; Li, Zhengnan; Zhao, Lina; Gao, Qiang; Sun, Jialin

    2012-11-02

    Highlights: Black-Right-Pointing-Pointer We construct and purify a fusion protein VEGF-SEA. Black-Right-Pointing-Pointer VEGF-SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. Black-Right-Pointing-Pointer T cells driven by VEGF-SEA were accumulated around tumor cells bearing VEGFR by mice image model. Black-Right-Pointing-Pointer VEGF-SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. Black-Right-Pointing-Pointer The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15 {mu}g, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4{sup +} and CD8{sup +} T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

  12. 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

  13. Improving Nanoparticle Penetration in Tumors by Vascular Disruption with Acoustic Droplet Vaporization

    PubMed Central

    Ho, Yi-Ju; Chang, Yuan-Chih; Yeh, Chih-Kuang

    2016-01-01

    Drug penetration influences the efficacy of tumor therapy. Although the leaky vessels of tumors can improve the penetration of nanodrugs via the enhanced permeability and retention (EPR) effect, various aspects of the tumor microenvironment still restrict this process. This study investigated whether vascular disruption using the acoustic vaporization of micro- or nanoscale droplets (MDs or NDs) induced by ultrasound sonication can overcome the limitations of the EPR effect to allow drug diffusion into extensive regions. The intravital penetration of DiI-labeled liposomes (as a drug model with red fluorescence) was observed using an acousto-optical integrated system comprising a 2-MHz focused ultrasound transducer (transmitting a three-cycle single pulse and a peak negative pressure of 10 MPa) in a window-chamber mouse model. Histology images of the solid tumor were also used to quantify and demonstrate the locations where DiI-labeled liposomes accumulated. In the intravital image analyses, the cumulative diffusion area and fluorescence intensity at 180 min were 0.08±0.01 mm2 (mean±standard deviation) and 8.5±0.4%, respectively, in the EPR group, 0.33±0.01 mm2 and 13.1±0.4% in the MD group (p<0.01), and 0.63±0.01 mm2 and 18.9±1.1% in the ND group (p<0.01). The intratumoral accumulations of DiI-labeled liposomes were 1.7- and 2.3-fold higher in the MD and ND groups, respectively, than in the EPR group. These results demonstrate that vascular disruption induced by acoustic droplet vaporization can improve drug penetration more than utilizing the EPR effect. The NDs showed longer lifetime in vivo than MDs and provided potential abilities of long periods of treatment, intertissue ND vaporization, and intertissue NDs-converted bubble cavitation to improve the drug penetration and transport distance. PMID:26909113

  14. 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.

  15. [The vascular endothelial growth factor (VEGF): a model of gene regulation and a marker of tumour aggressiveness. An obvious therapeutic target?].

    PubMed

    Grépin, Renaud; Pagès, Gilles

    2009-01-01

    VEGF represents a model of gene expression regulation. RAS/RAF/MEK/ERK and PI3 Kinase pathways, activated in response to growth factors stimulation or by oncogenes, contribute to its expression by activating transcription factors or inactivating proteins implicated in degradation of its mRNA. These factors (Sp1/Sp3, HIF-1 and TTP) constitute molecular markers of tumor aggressiveness. VEGF is overexpressed in solid or hematologic tumors. Thus, numerous compounds regulating angiogenesis by targeting VEGF have been developed. However, their effects are not as spectacular as expected. The existence of anti-angiogenic isoforms of VEGF could be a cause of their less potent activity. These different points are discussed in this review article.

  16. Study of the primo vascular system utilizing a melanoma tumor model in a green fluorescence protein expressing mouse.

    PubMed

    Heo, Chaejeong; Hong, Min Young; Jo, Areum; Lee, Young Hee; Suh, Minah

    2011-09-01

    A melanoma tumor is a representative malignant tumor. Melanoma tumor growth involves vigorous angiogenesis around the tumor and a vasculogenic-like network inside an aggressive tumor. Primo vessels (PVs) are also found on the surface of the tumor and coexist alongside blood vessels (BVs), and sometimes within the BVs. We hypothesized that the primo vessels system plays a significant role in regulating the development of a melanoma tumor, and therefore has a tight coupling with BVs and angiogenesis. To prove this hypothesis, we developed a murine melanoma model by inoculating melanoma cell lines into the abdominal region. We used a green fluorescent protein (GFP) expressing mouse as a host to distinguish the endogenous source of the tumor PVs. We found strong formation of PVs on the tumor that coexisted with BVs and expression of GFP. PVs also had a tight coupling with adipose tissues, especially with white adipose tissue. These data suggest that the PVs of an induced melanoma tumor evolve endogenously from the host body and may be highly related to BVs and adipose tissue. This model of PVs in an overexpressing GFP mouse is a useful system for observing PVs, primo nodes, and primo vessel networks, and has potential to be developed as a model for examining novel treatments for cancer metastasis.

  17. The vascular disrupting agent ZD6126 shows increased antitumor efficacy and enhanced radiation response in large, advanced tumors

    SciTech Connect

    Siemann, Dietmar W. . E-mail: siemadw@ufl.edu; Rojiani, Amyn M.

    2005-07-01

    Purpose: ZD6126 is a vascular-targeting agent that induces selective effects on the morphology of proliferating and immature endothelial cells by disrupting the tubulin cytoskeleton. The efficacy of ZD6126 was investigated in large vs. small tumors in a variety of animal models. Methods and Materials: Three rodent tumor models (KHT, SCCVII, RIF-1) and three human tumor xenografts (Caki-1, KSY-1, SKBR3) were used. Mice bearing leg tumors ranging in size from 0.1-2.0 g were injected intraperitoneally with a single 150 mg/kg dose of ZD6126. The response was assessed by morphologic and morphometric means as well as an in vivo to in vitro clonogenic cell survival assay. To examine the impact of tumor size on the extent of enhancement of radiation efficacy by ZD6126, KHT sarcomas of three different sizes were irradiated locally with a range of radiation doses, and cell survival was determined. Results: All rodent tumors and human tumor xenografts evaluated showed a strong correlation between increasing tumor size and treatment effect as determined by clonogenic cell survival. Detailed evaluation of KHT sarcomas treated with ZD6126 showed a reduction in patent tumor blood vessels that was {approx}20% in small (<0.3 g) vs. >90% in large (>1.0 g) tumors. Histologic assessment revealed that the extent of tumor necrosis after ZD6126 treatment, although minimal in small KHT sarcomas, became more extensive with increasing tumor size. Clonogenic cell survival after ZD6126 exposure showed a decrease in tumor surviving fraction from approximately 3 x 10{sup -1} to 1 x 10{sup -4} with increasing tumor size. When combined with radiotherapy, ZD6126 treatment resulted in little enhancement of the antitumor effect of radiation in small (<0.3 g) tumors but marked increases in cell kill in tumors larger than 1.0 g. Conclusions: Because bulky neoplastic disease is typically the most difficult to manage, the present findings provide further support for the continued development of vascular

  18. [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.

  19. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    PubMed Central

    Li, Xiaoyu; Wu, Meiying; Pan, Limin; Shi, Jianlin

    2016-01-01

    To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. PMID:26766908

  20. Flow shear stress regulates endothelial barrier function and expression of angiogenic factors in a 3D microfluidic tumor vascular model

    PubMed Central

    Buchanan, Cara F; Verbridge, Scott S; Vlachos, Pavlos P; Rylander, Marissa Nichole

    2014-01-01

    Endothelial cells lining blood vessels are exposed to various hemodynamic forces associated with blood flow. These include fluid shear, the tangential force derived from the friction of blood flowing across the luminal cell surface, tensile stress due to deformation of the vessel wall by transvascular flow, and normal stress caused by the hydrodynamic pressure differential across the vessel wall. While it is well known that these fluid forces induce changes in endothelial morphology, cytoskeletal remodeling, and altered gene expression, the effect of flow on endothelial organization within the context of the tumor microenvironment is largely unknown. Using a previously established microfluidic tumor vascular model, the objective of this study was to investigate the effect of normal (4 dyn/cm2), low (1 dyn/cm2), and high (10 dyn/cm2) microvascular wall shear stress (WSS) on tumor-endothelial paracrine signaling associated with angiogenesis. It is hypothesized that high WSS will alter the endothelial phenotype such that vascular permeability and tumor-expressed angiogenic factors are reduced. Results demonstrate that endothelial permeability decreases as a function of increasing WSS, while co-culture with tumor cells increases permeability relative to mono-cultures. This response is likely due to shear stress-mediated endothelial cell alignment and tumor-VEGF-induced permeability. In addition, gene expression analysis revealed that high WSS (10 dyn/cm2) significantly down-regulates tumor-expressed MMP9, HIF1, VEGFA, ANG1, and ANG2, all of which are important factors implicated in tumor angiogenesis. This result was not observed in tumor mono-cultures or static conditioned media experiments, suggesting a flow-mediated paracrine signaling mechanism exists with surrounding tumor cells that elicits a change in expression of angiogenic factors. Findings from this work have significant implications regarding low blood velocities commonly seen in the tumor vasculature

  1. Degradable poly(apigenin) polymer inhibits tumor cell adhesion to vascular endothelial cells.

    PubMed

    Cochran, David B; Gray, Lindsay N; Anderson, Kimberly W; Dziubla, Thomas D

    2016-10-01

    Cancer and the inflammatory system share a complex intertwined relationship. For instance, in response to an injury or stress, vascular endothelial cells will express cell adhesion molecules as a means of recruiting leukocytes. However, circulating tumor cells (CTCs) have been shown to highjack this expression for the adhesion and invasion during the metastatic cascade. As such, the initiation of endothelial cell inflammation, either by surgical procedures (cancer resection) or chemotherapy can inadvertently increase the metastatic potential of CTCs. Yet, systemic delivery of anti-inflammatories, which weaken the entire immune system, may not be preferred in some treatment settings. In this work, we demonstrate that a long-term releasing flavone-based polymer and subsequent nanoparticle delivery system can inhibit tumor cell adhesion, through the suppression of endothelial cell adhesion molecule expression. The degradation of a this anti-inflammatory polymer provides longer term, localized release profile of active therapeutic drug in nanoparticle form as compared with that of the free drug, permitting more targeted anti-metastatic therapies. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1438-1447, 2016.

  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. Immunohistochemical expression of vascular endothelial growth factor and vascular endothelial growth factor receptor associated with tumor cell proliferation in canine cutaneous squamous cell carcinomas and trichoepitheliomas.

    PubMed

    Al-Dissi, A N; Haines, D M; Singh, B; Kidney, B A

    2007-11-01

    The expression of 5 markers associated with angiogenesis was studied in canine squamous cell carcinomas (SCCs) (n = 19) and canine trichoepitheliomas (TCPs) (n = 24). SCCs were assigned histologic grades, and tissue sections from both tumor types were immunohistochemially stained for the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), as well as intratumoral microvessel density (iMVD), tumor proliferation index (PI), and tumor apoptotic index (AI), using antibodies against VEGF, VEGFR-2, von Willebrand's factor, Ki-67 antigen, and the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate end-labeling method (TUNEL), respectively. VEGF and VEGFR-2 were detected in 17/19 (89.4%) and 19/19 (100%) SCCs and in 17/24 (70.8%) and 20/24 (83.3%) TCPs, respectively. In SCCs, there was substantial correlation between histologic grade and PI (r = 0.51); and moderate correlation between VEGF and histologic grade (r = 0.43), VEGFR-2 and histologic grade (r = 0.47), VEGF and PI (r = 0.47), and VEGFR-2 and PI (r = 0.47) (Spearman rank correlation coefficient). In TCPs, there was substantial correlation between VEGF and PI (r = 0.51) and a moderate correlation between VEGFR-2 and iMVD (r = 0.36). The median iMVD of SCCs (15.5) was significantly higher than the median iMVD of TCPs (9.05) (P value < .05). It was concluded that VEGF and VEGFR-2 may promote tumor cell proliferation in TCPs and SCCs. An autocrine pathway for VEGF probably operates in canine SCCs and TCPs, as VEGF and VEGFR-2 expression was found in most tumors and was associated with evidence for tumor cell proliferation.

  4. Associations between Tumor Vascularity, Vascular Endothelial Growth Factor Expression and PET/MRI Radiomic Signatures in Primary Clear-Cell-Renal-Cell-Carcinoma: Proof-of-Concept Study.

    PubMed

    Yin, Qingbo; Hung, Sheng-Che; Wang, Li; Lin, Weili; Fielding, Julia R; Rathmell, W Kimryn; Khandani, Amir H; Woods, Michael E; Milowsky, Matthew I; Brooks, Samira A; Wallen, Eric M; Shen, Dinggang

    2017-03-03

    Studies have shown that tumor angiogenesis is an essential process for tumor growth, proliferation and metastasis. Also, tumor angiogenesis is an important prognostic factor of clear cell renal cell carcinoma (ccRCC), as well as a factor in guiding treatment with antiangiogenic agents. Here, we attempted to find the associations between tumor angiogenesis and radiomic imaging features from PET/MRI. Specifically, sparse canonical correlation analysis was conducted on 3 feature datasets (i.e., radiomic imaging features, tumor microvascular density (MVD), and vascular endothelial growth factor (VEGF) expression) from 9 patients with primary ccRCC. In order to overcome the potential bias of intratumoral heterogeneity of angiogenesis, this study investigated the relationship between regional expressions of angiogenesis and VEGF, and localized radiomic features from different parts within the tumors. Our study highlighted the significant strong correlations between radiomic features and MVD, and also demonstrated that the spatiotemporal features extracted from DCE-MRI provided stronger radiomic correlation to MVD than the textural features extracted from Dixon sequences and FDG PET. Furthermore, PET/MRI, which takes advantage of the combined functional and structural information, had higher radiomics correlation to MVD than solely utilizing PET or MRI alone.

  5. Associations between Tumor Vascularity, Vascular Endothelial Growth Factor Expression and PET/MRI Radiomic Signatures in Primary Clear-Cell–Renal-Cell-Carcinoma: Proof-of-Concept Study

    PubMed Central

    Yin, Qingbo; Hung, Sheng-Che; Wang, Li; Lin, Weili; Fielding, Julia R.; Rathmell, W. Kimryn; Khandani, Amir H.; Woods, Michael E.; Milowsky, Matthew I.; Brooks, Samira A.; Wallen, Eric. M.; Shen, Dinggang

    2017-01-01

    Studies have shown that tumor angiogenesis is an essential process for tumor growth, proliferation and metastasis. Also, tumor angiogenesis is an important prognostic factor of clear cell renal cell carcinoma (ccRCC), as well as a factor in guiding treatment with antiangiogenic agents. Here, we attempted to find the associations between tumor angiogenesis and radiomic imaging features from PET/MRI. Specifically, sparse canonical correlation analysis was conducted on 3 feature datasets (i.e., radiomic imaging features, tumor microvascular density (MVD), and vascular endothelial growth factor (VEGF) expression) from 9 patients with primary ccRCC. In order to overcome the potential bias of intratumoral heterogeneity of angiogenesis, this study investigated the relationship between regional expressions of angiogenesis and VEGF, and localized radiomic features from different parts within the tumors. Our study highlighted the significant strong correlations between radiomic features and MVD, and also demonstrated that the spatiotemporal features extracted from DCE-MRI provided stronger radiomic correlation to MVD than the textural features extracted from Dixon sequences and FDG PET. Furthermore, PET/MRI, which takes advantage of the combined functional and structural information, had higher radiomics correlation to MVD than solely utilizing PET or MRI alone. PMID:28256615

  6. Thrombomodulin as a marker for vascular tumors. Comparative study with factor VIII and Ulex europaeus I lectin.

    PubMed

    Yonezawa, S; Maruyama, I; Sakae, K; Igata, A; Majerus, P W; Sato, E

    1987-10-01

    Thrombomodulin (TM) is a newly described endothelial cell-associated protein that functions as a potent natural anticoagulant by converting thrombin from a procoagulant protease to an anticoagulant. Various vascular tumors were characterized with immunoperoxidase staining with the use of a polyclonal anti-TM serum. The staining patterns of TM were compared with those of Factor VIII-related antigen (FVIII-RAG) and Ulex europaeus agglutinin-I (UEA-I), which have been used as markers for endothelial cells. The results showed that TM is a specific and a highly sensitive marker for angiosarcomas in comparison with FVIII-RAG or UEA-I. In contrast, UEA-I is more sensitive for benign vascular tumors than TM or FVIII-RAG. The other mesenchymal tumors of nonvascular origin showed negative staining for three endothelial markers. These results indicate that TM is a new specific and sensitive tool for the diagnosis of angiosarcomas.

  7. Palomid 529, a Novel Small-Molecule Drug, Is a TORC1/TORC2 Inhibitor That Reduces Tumor Growth, Tumor Angiogenesis, and Vascular Permeability

    PubMed Central

    Xue, Qi; Hopkins, Benjamin; Perruzzi, Carole; Udayakumar, Durga; Sherris, David; Benjamin, Laura E.

    2009-01-01

    It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells. [Cancer Res 2008;68(22):9551–7] PMID:19010932

  8. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability.

    PubMed

    Xue, Qi; Hopkins, Benjamin; Perruzzi, Carole; Udayakumar, Durga; Sherris, David; Benjamin, Laura E

    2008-11-15

    It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells.

  9. Vatuximab(Trademark): Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

    DTIC Science & Technology

    2010-01-01

    being developed by Peregrine Pharmaceuticals for clinical trials. Investigations of tumor hypoxia indicated that non-invasive oxygen sensitive 1H MRI ...waiting versus aggressive therapy. 15. SUBJECT TERMS Vascular targeting; MRI ; bioluminescent imaging 16. SECURITY CLASSIFICATION OF: 17. LIMITATION...prostate tumor growth delay. MRI was used to assess the onset and distribution of tumor vascular damage in a series of Dunning prostate rat tumors (R3327

  10. Resection followed by vascularized bone autograft in patients with possible recurrence of malignant bone tumors after conservative treatment

    SciTech Connect

    Metaizeau, J.P.; Olive, D.; Bey, P.; Bordigoni, P.; Plenat, F.; Prevot, J.

    1984-04-01

    In conservative treatment of malignant bone tumors, assessment of the local condition is difficult. The radiological changes seen in the irradiated tumor and the frequent occurrence of pathological fractures at this site may give rise to the fear that the tumor has relapsed. Resection of the whole of the involved bone is the best way to assure adequate local control but the extent of the bone defect and the bad local conditions secondary to irradiation make reconstruction hazardous. In two patients (one with Ewing's sarcoma of the femur and one with osteogenic sarcoma of the humerus) the authors used a free, vascularized fibular graft for the reconstruction having obtained consolidation of the limb after resection of the irradiated tumor, with preservation of its function. The encouraging results obtained have suggested a conservative attitude as primary treatment of specific malignant bone tumors.

  11. Effects of vascularization on cancer nanochemotherapy outcomes

    NASA Astrophysics Data System (ADS)

    Paiva, L. R.; Ferreira, S. C.; Martins, M. L.

    2016-08-01

    Cancer therapy requires anticancer agents capable of efficient and uniform systemic delivery. One promising route to their development is nanotechnology. Here, a previous model for cancer chemotherapy based on a nanosized drug carrier (Paiva et al., 2011) is extended by including tissue vasculature and a three-dimensional growth. We study through computer simulations the therapy against tumors demanding either large or small nutrient supplies growing under different levels of tissue vascularization. Our results indicate that highly vascularized tumors demand more aggressive therapies (larger injected doses administrated at short intervals) than poorly vascularized ones. Furthermore, nanoparticle endocytic rate by tumor cells, not its selectivity, is the major factor that determines the therapeutic success. Finally, our finds indicate that therapies combining cytotoxic agents with antiangiogenic drugs that reduce the abnormal tumor vasculature, instead of angiogenic drugs that normalize it, can lead to successful treatments using feasible endocytic rates and administration intervals.

  12. miR-320 regulates tumor angiogenesis driven by vascular endothelial cells in oral cancer by silencing neuropilin 1.

    PubMed

    Wu, Yi-Ying; Chen, Yuh-Ling; Jao, Yun-Chia; Hsieh, I-Shan; Chang, Kung-Chao; Hong, Tse-Ming

    2014-01-01

    Tumor angiogenesis is a critical process during cancer progression that modulates tumor growth and metastasis. Here, we identified an anti-angiogenic microRNA, miR-320, which is decreased in oral squamous cell carcinoma (OSCC) cell lines and tumor tissues from OSCC patients, down-regulated in blood vessels and inversely correlated with vascularity in OSCC tissues. Neuropilin 1 (NRP1), an important regulator of angiogenesis, was found to be a target of miR-320. The 3'-untranslated region of NRP1 mRNA contains multiple miR-320 binding sites, and its expression was regulated by miR-320. By administering either miR-320 precursor or antagonist, we found that miR-320 suppressed the migration, adhesion and tube formation of vascular endothelial cells. Knockdown of NRP1 abolished antagomiR-320-induced cell migration. Additionally, miR-320 expression was regulated by hypoxia in growth factor-deficient conditions by the hypoxia-inducible factor 1-alpha. Furthermore, lentivirus carrying the miR-320 precursor suppressed the tumorigenicity of OSCC cells and tumor angiogenesis in vivo. Taken together, these data show that miR-320 regulates the function of vascular endothelial cells by targeting NRP1 and has the potential to be developed as an anti-angiogenic or anti-cancer drug.

  13. Low-Dose Metronomic Cyclophosphamide Combined with Vascular Disrupting Therapy Induces Potent Anti-Tumor Activity in Preclinical Human Tumor Xenograft Models

    PubMed Central

    Daenen, Laura G.; Shaked, Yuval; Man, Shan; Xu, Ping; Voest, Emile E.; Hoffman, Robert M.; Chaplin, David; Kerbel, Robert S.

    2009-01-01

    Purpose Vascular disrupting agents (VDAs) preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part via mobilization and tumor colonization of circulating endothelial progenitor cells (CEPs). Co-treatment with an agent that blocks CEPs, such as VEGF-pathway targeting biologic antiangiogenic drugs, results in enhanced anti-tumor efficacy. We asked whether an alternative therapeutic modality – low-dose metronomic (LDM) chemotherapy could achieve the same result, given its CEP targeting effects. Experimental Design We studied the combination of the VDA OXi-4503 with daily administration of CEP-inhibiting, low-dose metronomic (LDM) cyclophosphamide to treat primary orthotopic tumors using the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. Results We found that daily oral LDM cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi-4503; this was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as SCID mice. Similar results were found in MeWo bearing nude mice. The delay in tumor growth was accompanied by significant decreases in micro-vessel density, perfusion and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. Conclusions The combination of OXi-4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy. PMID:19825805

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. DCE-MRI Detects Early Vascular Response in Breast Tumor Xenografts Following Anti-DR5 Therapy

    PubMed Central

    Kim, Hyunki; Folks, Karri D.; Guo, Lingling; Stockard, Cecil R.; Fineberg, Naomi S.; Grizzle, William E.; George, James F.; Buchsbaum, Donald J.; Morgan, Desiree E.; Zinn, Kurt R.

    2014-01-01

    Purpose Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measured the early vascular changes after administration of TRA-8, bevacizumab, or TRA-8 combined with bevacizumab in breast tumor xenografts. Procedures Groups 1–4 of nude mice bearing human breast carcinoma were injected with phosphate-buffered saline, TRA-8, bevacizumab, and TRA-8 + bevacizumab on day0, respectively. DCE-MRI was performed on days0, 1, 2, and 3, and thereafter tumors were collected for terminal deoxynucleotidyl transferase-mediated dUT nick end labeling and CD31 staining. Results DCE-MRI measured a significant Ktrans change within 3 days after TRA-8 therapy that correlated with tumor growth arrest, whichwas not shown with statistical significance by histopathology at these early time points posttreatment. The Ktrans changes followed quadratic polynomial curves. Conclusion DCE-MRI detected significantly lower Ktrans levels in breast tumor xenografts following TRA-8 monotherapy or combined therapy with bevacizumab. PMID:20383593

  20. 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

  1. Tyrosine Phosphatase PTPRJ/DEP-1 Is an Essential Promoter of Vascular Permeability, Angiogenesis, and Tumor Progression.

    PubMed

    Fournier, Patrick; Dussault, Sylvie; Fusco, Alfredo; Rivard, Alain; Royal, Isabelle

    2016-09-01

    The protein tyrosine phosphatase PTPRJ/DEP-1 has been implicated in negative growth regulation in endothelial cells, where its expression varies at transitions between proliferation and contact inhibition. However, in the same cells, DEP-1 has also been implicated in VEGF-dependent Src activation, permeability, and capillary formation, suggesting a positive role in regulating these functions. To resolve this dichotomy in vivo, we investigated postnatal angiogenesis and vascular permeability in a DEP-1-deficient mouse. In this study, we report that DEP-1 is required for Src activation and phosphorylation of its endothelial cell-specific substrate, VE-cadherin, after systemic injection of VEGF. Accordingly, VEGF-induced vascular leakage was abrogated in the DEP-1-deficient mice. Furthermore, capillary formation was impaired in murine aortic tissue rings or Matrigel plugs infused with VEGF. In the absence of DEP-1, angiogenesis triggered by ischemia or during tumor formation was defective, which in the latter case was associated with reduced tumor cell proliferation and increased apoptosis. Macrophage infiltration was also impaired, reflecting reduced vascular permeability in the tumors or a possible cell autonomous effect of DEP-1. Consequently, the formation of spontaneous and experimental lung metastases was strongly decreased in DEP-1-deficient mice. In clinical specimens of cancer, less vascularized tumors exhibited lower microvascular expression of DEP-1. Altogether, our results established DEP-1 as an essential driver of VEGF-dependent permeability, angiogenesis, and metastasis, suggesting a novel therapeutic route to cancer treatment. Cancer Res; 76(17); 5080-91. ©2016 AACR.

  2. Anti-tumor immunity of BAM-SiPc-mediated vascular photodynamic therapy in a BALB/c mouse model

    PubMed Central

    Yeung, Hing-Yuen; Lo, Pui-Chi; Ng, Dennis K.P.; Fong, Wing-Ping

    2017-01-01

    In recent decades, accumulating evidence from both animal and clinical studies has suggested that a sufficiently activated immune system may strongly augment various types of cancer treatment, including photodynamic therapy (PDT). Through the generation of reactive oxygen species, PDT eradicates tumors by triggering localized tumor damage and inducing anti-tumor immunity. As the major component of anti-tumor immunity, the involvement of a cell-mediated immune response in PDT has been well investigated in the past decade, whereas the role of humoral immunity has remained relatively unexplored. In the present investigation, using the photosensitizer BAM-SiPc and the CT26 tumor-bearing BALB/c mouse model, it was demonstrated that both cell-mediated and humoral adaptive immune components could be involved in PDT. With a vascular PDT (VPDT) regimen, BAM-SiPc could eradicate the tumors of ∼70% of tumor-bearing mice and trigger an anti-tumor immune response that could last for more than 1 year. An elevation of Th2 cytokines was detected ex vivo after VPDT, indicating the potential involvement of a humoral response. An analysis of serum from the VPDT-cured mice also revealed elevated levels of tumor-specific antibodies. Moreover, this serum could effectively hinder tumor growth and protect the mice against further re-challenge in a T-cell-dependent manner. Taken together, these results show that the humoral components induced after BAM-SiPc-VPDT could assist the development of anti-tumor immunity. PMID:26388236

  3. Vascular Targeted Radioimmunotherapy for the Treatment of Glioblastoma.

    PubMed

    Behling, Katja; Maguire, William F; López Puebla, José Carlos; Sprinkle, Shanna R; Ruggiero, Alessandro; O'Donoghue, Joseph; Gutin, Philip H; Scheinberg, David A; McDevitt, Michael R

    2016-10-01

    Glioblastoma is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 mo despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium of glioblastoma with cytotoxic short-range, high-energy α-particles would be an effective therapeutic approach.

  4. Correlation between CT Perfusion Parameters and Microvessel Density and Vascular Endothelial Growth Factor in Adrenal Tumors

    PubMed Central

    Wang, Xifu; Bai, Renju; Li, Yajun; Zhao, Jinkun

    2013-01-01

    We evaluated the correlation between computed tomography (CT) perfusion parameters and markers of angiogenesis in adrenal adenomas and non-adenomas to determine if perfusion CT can be used to distinguish between them. Thirty-four patients with pathologically-confirmed adrenal tumors (17 adenomas, 17 non-adenomas) received CT perfusion imaging before surgery. CT perfusion parameters (blood flow [BF], blood volume [BV], mean transit time [MTT], and permeability surface area product [PS]) were calculated. Tumor tissue sections were examined with immunohistochemical methods for vascular endothelial growth factor (VEGF) expression and microvessel density (MVD). The mean age of the 34 patients was 43 years. The median BV was significantly higher in adenomas than in non-adenomas [12.3 ml/100 g, inter-quartile range (IQR): 10.4 to 16.5 ml/100 g vs. 8.8 ml/100 g, IQR: 3.3 to 9.4 ml/100 g, p = 0.001]. Differences in BF, MTT, and PS parameter values between adenomas and non-adenomas were not significant (p>0.05). The mean MVD was significantly higher in adenomas compared to non-adenomas (98.5±28.5 vs. 53.5±27.0, p<0.0001). Adenomas also expressed significantly higher median VEGF than non-adenomas (65%, IQR: 50 to 79% vs. 45%, IQR: 35 to 67%, p = 0.02). A moderately strong correlation between BF and VEGF (r = 0.53, p = 0.03) and between BV and MVD among adenomas (r = 0.57, p = 0.02) exist. Morphology, MVD, and VEGF expression in adenomas differ significantly from non-adenomas. Of the CT perfusion parameters examined, both BF and BV correlate with MVD, but only BF correlates with VEGF, and only in adenomas. The significant difference in BV suggests that BV may be used to differentiate adenomas from non-adenomas. However, the small difference in BV shows that it may only be possible to use BV to identify adenomas vs. non-adenomas at extreme BV values. PMID:24260316

  5. Three-Dimensional Microfluidic Collagen Hydrogels for Investigating Flow-Mediated Tumor-Endothelial Signaling and Vascular Organization

    PubMed Central

    Voigt, Elizabeth E.; Szot, Christopher S.; Freeman, Joseph W.; Vlachos, Pavlos P.; Rylander, Marissa Nichole

    2014-01-01

    Hyperpermeable tumor vessels are responsible for elevated interstitial fluid pressure and altered flow patterns within the tumor microenvironment. These aberrant hydrodynamic stresses may enhance tumor development by stimulating the angiogenic activity of endothelial cells lining the tumor vasculature. However, it is currently not known to what extent shear forces affect endothelial organization or paracrine signaling during tumor angiogenesis. The objective of this study was to develop a three-dimensional (3D), in vitro microfluidic tumor vascular model for coculture of tumor and endothelial cells under varying flow shear stress conditions. A central microchannel embedded within a collagen hydrogel functions as a single neovessel through which tumor-relevant hydrodynamic stresses are introduced and quantified using microparticle image velocimetry (μ-PIV). This is the first use of μ-PIV in a tumor representative, 3D collagen matrix comprised of cylindrical microchannels, rather than planar geometries, to experimentally measure flow velocity and shear stress. Results demonstrate that endothelial cells develop a confluent endothelium on the microchannel lumen that maintains integrity under physiological flow shear stresses. Furthermore, this system provides downstream molecular analysis capability, as demonstrated by quantitative RT-PCR, in which, tumor cells significantly increase expression of proangiogenic genes in response to coculture with endothelial cells under low flow conditions. This work demonstrates that the microfluidic in vitro cell culture model can withstand a range of physiological flow rates and permit quantitative measurement of wall shear stress at the fluid–collagen interface using μ-PIV optical flow diagnostics, ultimately serving as a versatile platform for elucidating the role of fluid forces on tumor–endothelial cross talk. PMID:23730946

  6. Affinity cytochemistry of vascular endothelia in brain tumors by biotinylated Ulex europaeus type I lectin (UEA I).

    PubMed

    Weber, T; Seitz, R J; Liebert, U G; Gallasch, E; Wechsler, W

    1985-01-01

    The vascularization of 50 tumors of the central nervous system (CNS) including 17 meningiomas, 25 neuroectodermal tumors, i.e., astrocytomas, oligodendrogliomas, mixed gliomas, glioblastomas, medulloblastomas, seven metastatic carcinomas, and one malignant hemangioendothelioma were investigated using biotinylated Ulex europaeus type I lectin (UEA I) in an indirect avidinbiotin-peroxidase procedure. The cytochemical staining pattern of UEA I on paraffin sections was compared with that of biotinylated Dolichos biflorus lectin (DBA), and with the immunocytochemical staining of factor VIII related antigen (F VIII/RAG) by polyclonal antisera using the PAP technique. UEA I visualized the endothelia of blood vessels with equal intensity, sensitivity, and reliability in normal brain and in tumor tissue with neovascularization. While large, medium, and small vessels were equally well demonstrated by UEA I and antibodies against FVIII/RAG, capillaries and endothelial sprouts were stained more consistently and intensely by UEA I. No reliable cytochemical staining could be obtained by DBA regardless of tissue or cell type investigated. It is concluded that UEA I is a highly useful cytochemical marker for the identification of vascular endothelia in paraffin sections of human brain tumors.

  7. Vascular endothelial-targeted therapy combined with cytotoxic chemotherapy induces inflammatory intratumoral infiltrates and inhibits tumor relapses after surgery.

    PubMed

    Judy, Brendan F; Aliperti, Louis A; Predina, Jarrod D; Levine, Daniel; Kapoor, Veena; Thorpe, Philip E; Albelda, Steven M; Singhal, Sunil

    2012-04-01

    Surgery is the most effective therapy for cancer in the United States, but disease still recurs in more than 40% of patients within 5 years after resection. Chemotherapy is given postoperatively to prevent relapses; however, this approach has had marginal success. After surgery, recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen. Phosphatidylserine (PS) is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues. Thus, PS is an attractive target for cancer therapy after surgery. Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 (a novel mouse chimeric monoclonal antibody that targets PS), cisplatin (cis), or combination after surgery. Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone (P = .02). Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals. Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells, particularly granulocytes. This strategy was independent of the adaptive immune system. Together, these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery.

  8. Medial hypertrophy of the ovarian vein: a novel type of vascular pathology associated with a primary ovarian carcinoid tumor.

    PubMed

    Dessauvagie, Benjamin F; Lai, Patrick H; Oost, Ebo; Thomas, Anitha; Stewart, Colin J R

    2015-01-01

    Primary carcinoid tumors of the ovary are rare accounting for only 1% of neoplasms that are associated with the carcinoid syndrome. However, the carcinoid syndrome can occur in the absence of hepatic metastases due to the release of vasoactive peptides directly into the systemic circulation via the ovarian vein. We present a 69-yr-old woman presenting with carcinoid valvular disease and congestive cardiac failure who was found to have a primary left ovarian carcinoid tumor. At operation it was noted that the left ovarian vein had an unusually firm and thickened appearance, and histologic examination revealed marked fibromuscular medial hypertrophy with luminal compression. There was no associated vascular elastosis. This ovarian venous alteration appears to represent a novel addition to the spectrum of cardiovascular injuries associated with carcinoid tumors.

  9. Hypoxia in Astrocytic Tumors and Implications for Therapy

    PubMed Central

    Cavazos, David A.; Brenner, Andrew J.

    2015-01-01

    Glioblastoma (GBM, Grade IV astrocytoma) is the most common and most aggressive of the primary malignant brain tumors in adults. Hypoxia is a distinct feature in GBM and plays a significant role in tumor progression, resistance to treatment and poor outcomes. This review considers the effects of hypoxia on astrocytic tumors and the mechanisms that contribute to tumor progression and therapeutic resistance, with a focus on the vascular changes, chemotaxic signaling pathways and metabolic alterations involved. PMID:26094595

  10. Multimodal navigated skull base tumor resection using image-based vascular and cranial nerve segmentation: A prospective pilot study

    PubMed Central

    Dolati, Parviz; Gokoglu, Abdulkerim; Eichberg, Daniel; Zamani, Amir; Golby, Alexandra; Al-Mefty, Ossama

    2015-01-01

    Background: Skull base tumors frequently encase or invade adjacent normal neurovascular structures. For this reason, optimal tumor resection with incomplete knowledge of patient anatomy remains a challenge. Methods: To determine the accuracy and utility of image-based preoperative segmentation in skull base tumor resections, we performed a prospective study. Ten patients with skull base tumors underwent preoperative 3T magnetic resonance imaging, which included thin section three-dimensional (3D) space T2, 3D time of flight, and magnetization-prepared rapid acquisition gradient echo sequences. Imaging sequences were loaded in the neuronavigation system for segmentation and preoperative planning. Five different neurovascular landmarks were identified in each case and measured for accuracy using the neuronavigation system. Each segmented neurovascular element was validated by manual placement of the navigation probe, and errors of localization were measured. Results: Strong correspondence between image-based segmentation and microscopic view was found at the surface of the tumor and tumor-normal brain interfaces in all cases. The accuracy of the measurements was 0.45 ± 0.21 mm (mean ± standard deviation). This information reassured the surgeon and prevented vascular injury intraoperatively. Preoperative segmentation of the related cranial nerves was possible in 80% of cases and helped the surgeon localize involved cranial nerves in all cases. Conclusion: Image-based preoperative vascular and neural element segmentation with 3D reconstruction is highly informative preoperatively and could increase the vigilance of neurosurgeons for preventing neurovascular injury during skull base surgeries. Additionally, the accuracy found in this study is superior to previously reported measurements. This novel preliminary study is encouraging for future validation with larger numbers of patients. PMID:26674155

  11. 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

  12. Gold nanoparticle-aided brachytherapy with vascular dose painting: Estimation of dose enhancement to the tumor endothelial cell nucleus

    SciTech Connect

    Ngwa, Wilfred; Makrigiorgos, G. Mike; Berbeco, Ross I.

    2012-01-15

    Purpose: Theoretical microdosimetry at the subcellular level is employed in this study to estimate the dose enhancement to tumor endothelial cell nuclei, caused by radiation-induced photo/Auger electrons originating from gold nanoparticles (AuNPs) targeting the tumor endothelium, during brachytherapy. Methods: A tumor vascular endothelial cell (EC) is modeled as a slab of 2 {mu}m (thickness) x 10 {mu}m (length) x 10 {mu}m (width). The EC contains a nucleus of 5 {mu}m diameter and thickness of 0.5-1 {mu}m, corresponding to nucleus size 5%-10% of cellular volume, respectively. Analytic calculations based on the electron energy loss formula of Cole were carried out to estimate the dose enhancement to the nucleus caused by photo/Auger electrons from AuNPs attached to the exterior surface of the EC. The nucleus dose enhancement factor (nDEF), representing the ratio of the dose to the nucleus with and without the presence of gold nanoparticles was calculated for different AuNP local concentrations. The investigated concentration range considers the potential for significantly higher local concentration near the EC due to preferential accumulation of AuNP in the tumor vasculature. Four brachytherapy sources: I-125, Pd-103, Yb-169, and 50 kVp x-rays were investigated. Results: For nucleus size of 10% of the cellular volume and AuNP concentrations ranging from 7 to 140 mg/g, brachytherapy sources Pd-103, I-125, 50 kVp, and Yb-169 yielded nDEF values of 5.6-73, 4.8-58.3, 4.7-56.6, and 3.2-25.8, respectively. Meanwhile, for nucleus size 5% of the cellular volume in the same concentration range, Pd-103, I-125, 50 kVp, and Yb-169 yielded nDEF values of 6.9-79.2, 5.1-63.2, 5.0-61.5, and 3.3-28.3, respectively. Conclusions: The results predict that a substantial dose boost to the nucleus of endothelial cells can be achieved by applying tumor vasculature-targeted AuNPs in combination with brachytherapy. Such vascular dose boosts could induce tumor vascular shutdown, prompting

  13. 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.

  14. 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

  15. Vascularization of syngenic intracerebral RG2 and F98 rat transplantation tumors. A histochemical and morphometric study by use of ricinus communis agglutinin I.

    PubMed

    Seitz, R J; Deckert, M; Wechsler, W

    1988-01-01

    The vascularization of intracerebral transplantation tumors of the two rat glioma clones RG2 and F98 was studied in various stages of progressive tumor growth by use of biotinylated Ricinus communis agglutinin I (B-RCA I) in avidin-biotin-peroxidase complex (ABC)-histochemistry. The tumors were induced by stereotactic implantation of 1000 glioma cells into the right caudate nucleus of 26 adult CDF-rats and examined after 10, 14, 18, and 21 days following controlled intracardial perfusion of the host animals. Our histochemical results on paraffin sections demonstrate that B-RCA I selectively stains vascular endothelial cells of arteries, veins, and capillaries not only in the normal rat brain but also in the transplantation tumors. Subsequently morphometric measurements of the B-RCA I-stained sections were performed to define the tumor vascularization in quantitative terms. There was an increase in the mean tumor vessel diameters during tumor growth in both transplantation tumor types leading to values about two times above those of the normal rat striatum. On the contrary, the mean vessel density and the mean vessel surface per tumor area were markedly reduced in the late stages of both tumor types when compared to the normal striatum. The RG2 and F98 transplantation tumors differed with regard to the intercapillary distance, which was two times higher in the F98 transplantation tumors than in the RG2 tumors on day 21. In conclusion, B-RCA I is a very sensitive histochemical marker for rat vascular endothelia on paraffin sections. Moreover, this method appears to provide the possibility for qualitative and quantitative study of the development of vasculature in intracerebral transplantation systems including tumors.

  16. Specific Accumulation of Tumor-Derived Adhesion Factor in Tumor Blood Vessels and in Capillary Tube-Like Structures of Cultured Vascular Endothelial Cells

    NASA Astrophysics Data System (ADS)

    Akaogi, Kotaro; Okabe, Yukie; Sato, Junji; Nagashima, Yoji; Yasumitsu, Hidetaro; Sugahara, Kazuyuki; Miyazaki, Kaoru

    1996-08-01

    Tumor-derived adhesion factor (TAF) was previously identified as a cell adhesion molecule secreted by human bladder carcinoma cell line EJ-1. To elucidate the physiological function of TAF, we examined its distribution in human normal and tumor tissues. Immunochemical staining with an anti-TAF monoclonal antibody showed that TAF was specifically accumulated in small blood vessels and capillaries within and adjacent to tumor nests, but not in those in normal tissues. Tumor blood vessel-specific staining of TAF was observed in various human cancers, such as esophagus, brain, lung, and stomach cancers. Double immunofluorescent staining showed apparent colocalization of TAF and type IV collagen in the vascular basement membrane. In vitro experiments demonstrated that TAF preferentially bound to type IV collagen among various extracellular matrix components tested. In cell culture experiments, TAF promoted adhesion of human umbilical vein endothelial cells to type IV collagen substrate and induced their morphological change. Furthermore, when the endothelial cells were induced to form capillary tube-like structures by type I collagen, TAF and type IV collagen were exclusively detected on the tubular structures. The capillary tube formation in vitro was prevented by heparin, which inhibited the binding of TAF to the endothelial cells. These results strongly suggest that TAF contributes to the organization of new capillary vessels in tumor tissues by modulating the interaction of endothelial cells with type IV collagen.

  17. 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

  18. Impact of vascular invasion of a primary tumor as a strong risk factor for disease recurrence in patients with node-positive breast cancer.

    PubMed

    Fujii, Takaaki; Yajima, Reina; Morita, Hiroki; Hirakata, Tomoko; Miyamoto, Takeshi; Fujisawa, Tomomi; Tsutsumi, Soichi; Ynagita, Yasuhiro; Iijima, Misa; Kuwano, Hiroyuki

    2015-05-01

    The presence of lymph node metastasis is considered to be the most significant indicator of prognosis. However, in some cases with node-positive breast cancer, cancer cell dissemination is localized to the lymphatic systems. It is, therefore, important to develop selection criteria for strong adjuvant therapy in patients with node-positive breast cancer. This study was undertaken to evaluate the presence of vascular invasion that may reflect systemic disease as a predictor of disease recurrence in node-positive breast cancer. We retrospectively evaluated the cases of 134 consecutive female patients with breast cancer with lymph node metastasis who underwent radical breast operations. We examined the relationship between recurrence and clinicopathological factors, particularly vascular invasion. The presence of vascular invasion was found to be significant in a univariate analysis. The presence of vascular invasion was the independent risk factor in a multivariate analysis. Among the 66 patients without vascular invasion, four (6.1%) had disease recurrence. On the other hand, among the 68 patients with vascular invasion, 15 (22.1%) had a recurrence. It is interesting to note that despite the presence of lymph node metastasis, the group without vascular invasion had few patients with distant metastases. Our results suggest that the presence of vascular invasion could be an indicator of high biological aggressiveness and may be a strong prognostic factor for node-positive breast cancer.

  19. Tumor necrosis factor improves vascularization in osteogenic grafts engineered with human adipose-derived stem/stromal cells.

    PubMed

    Hutton, Daphne L; Kondragunta, Renu; Moore, Erika M; Hung, Ben P; Jia, Xiaofeng; Grayson, Warren L

    2014-01-01

    The innate immune response following bone injury plays an important role in promoting cellular recruitment, revascularization, and other repair mechanisms. Tumor necrosis factor-α (TNF) is a prominent pro-inflammatory cytokine in this cascade, and has been previously shown to improve bone formation and angiogenesis in a dose- and timing-dependent manner. This ability to positively impact both osteogenesis and vascular growth may benefit bone tissue engineering, as vasculature is essential to maintaining cell viability in large grafts after implantation. Here, we investigated the effects of exogenous TNF on the induction of adipose-derived stem/stromal cells (ASCs) to engineer pre-vascularized osteogenic tissue in vitro with respect to dose, timing, and co-stimulation with other inflammatory mediators. We found that acute (2-day), low-dose exposure to TNF promoted vascularization, whereas higher doses and continuous exposure inhibited vascular growth. Co-stimulation with platelet-derived growth factor (PDGF), another key factor released following bone injury, increased vascular network formation synergistically with TNF. ASC-seeded grafts were then cultured within polycaprolactone-fibrin composite scaffolds and implanted in nude rats for 2 weeks, resulting in further tissue maturation and increased angiogenic ingrowth in TNF-treated grafts. VEGF-A expression levels were significantly higher in TNF-treated grafts immediately prior to implantation, indicating a long-term pro-angiogenic effect. These findings demonstrate that TNF has the potential to promote vasculogenesis in engineered osteogenic grafts both in vitro and in vivo. Thus, modulation and/or recapitulation of the immune response following bone injury may be a beneficial strategy for bone tissue engineering.

  20. 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.

  1. Chemotherapy enhances tumor vascularization via Notch signaling-mediated formation of tumor-derived endothelium in breast cancer.

    PubMed

    Zhang, Peng; He, Dongxu; Chen, Zhen; Pan, Qiongxi; Du, Fangfang; Zang, Xian; Wang, Yan; Tang, Chunlei; Li, Hong; Lu, He; Yao, Xiaoqiang; Jin, Jian; Ma, Xin

    2016-10-15

    It is believed that tumor cells can give rise to endothelial cells and tumor endothelium has a neoplastic origin. Yet, the stimuli and underlying mechanism remain unclear. Here, we demonstrate that adriamycin or paclitaxel, first-line chemotherapy agent, induced breast cancer cells to generate morphological, phenotypical and functional features of endothelial cells in vitro. In xenografts models, challenges from adriamycin or paclitaxel induced cancer cells to generate the majority of microvessels. Importantly, in breast cancer specimens from patients with neoadjuvant anthracycline-based or taxane-based chemotherapy, tumor-derived endothelial microvessels, lined by EGFR-amplified or/and TP53(+)-CD31(+) endothelial cells, was significantly higher in patients with progressive or stable disease (PD/SD) than in those with a partial or complete response (PR/CR). Further, exposure to the Notch signaling inhibitor and gene silencing studies showed that Notch signaling inhibition or silencing Nothc4/Dll3 decreased endothelial markers and function of tumor-derived endothelial cells under chemotherapy treatment, which may be through VEGFR3. Thus, our findings demonstrate that chemotherapy induces functional tumor-derived endothelial microvessels by mediating Notch signaling and VEGF signaling, and may provide new targets for anti-angiogenesis therapy in breast cancer.

  2. 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

  3. Endocrine Gland-Derived Vascular Endothelial Growth Factor/Prokineticin-1 in Cancer Development and Tumor Angiogenesis

    PubMed Central

    Corlan, Ana Silvia; Jitariu, Adriana-Andreea; Melnic, Eugen; Raica, Marius

    2017-01-01

    A lot of data suggests endocrine gland-derived vascular endothelial growth factor (EG-VEGF) to be restricted to endocrine glands and to some endocrine-dependent organs. Many evidences show that EG-VEGF stimulates angiogenesis and cell proliferation, although it is not a member of the VEGF family. At the time, a lot of data regarding the role of this growth factor in normal development are available. However, controversial results have been published in the case of pathological conditions and particularly in malignant tumors. Thus, our present paper has been focused on the role of EG-VEGF in normal tissues and various malignant tumors and their angiogenic processes. PMID:28386275

  4. Assessing Vascular Oxygen Dynamics for Breast Tumor Prognosis: Comparison Between MR BOLD and Near Infrared Method

    DTIC Science & Technology

    2005-09-01

    channel NIR system against the fiber optic needle measurements . Aim 2: To compare and correlate the measurement results of the breast tumors under...Kodibagkar, Anca Constantinescu, Ralph Mason, “Tumor oxygen dynamics measured simultaneously by near-infrared spectroscopy and MR EPI imaging,” in...tumors measured by NIR spectroscopy and 19 F MRS of PFOB,” OSA Biomedical Topical Meetings, Technical Digest, SuH5, Miami Beach, FL, April 7-10, 2002

  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. Photodynamic tumor eradication with a novel targetable photosensitizer: strong vascular effects and dependence on treatment repetition versus potentiation.

    PubMed

    Savellano, Mark D; Owusu-Brackett, Nicci; Son, Ji; Ganga, Tanay; Leung, Nadia L; Savellano, Dagmar H

    2013-01-01

    A novel pyropheophorbide-a (PPa) derivative, Ac-sPPp, was developed in our lab for targeted photodynamic therapy (PDT) and combination therapies. Its versatile peptide moiety, high water-solubility, amphiphilicity, and micellar aggregation allow efficient coupling to targeting moieties and convenient mixing with other therapeutics. Photosensitizer immunoconjugate (PIC) targeted PDT, using Ac-sPPp conjugated to therapeutic anti-epidermal growth factor receptor (EGFR) antibody cetuximab, and PDT + chemotherapy combination treatment, using Ac-sPPp mixed with stealth liposomal doxorubicin (Doxil), were investigated as promising strategies for potentiating PDT and improving target specificity. Passively targeted PDT with Ac-sPPp only or surfactant-solubilized PPa was also investigated for comparison. The A-431 human vulvar squamous cell carcinoma, xenografted in nude mice, was chosen as a tumor model because of its high EGFR expression and sensitivity to liposomal doxorubicin in vitro. Fluorescence imaging and PDT experiments showed that Ac-sPPp formulations circulated far longer and provided superior tumor contrast and superior tumor control compared to PPa. Strong PDT vascular effects were observed by laser Doppler imaging regardless of whether Ac-sPPp was passively or actively targeted. Passively targeted Ac-sPPp PDT gave equivalent or better tumor control than PIC-targeted PDT or PDT + Doxil combination therapy, and when treatments were repeated, it also yielded the highest cure rate.

  7. Tumor Vascularity in Renal Masses: Correlation of Arterial Spin-Labeled and Dynamic Contrast Enhanced MR Imaging Assessments

    PubMed Central

    Zhang, Yue; Kapur, Payal; Yuan, Qing; Xi, Yin; Carvo, Ingrid; Signoretti, Sabina; Dimitrov, Ivan; Cadeddu, Jeffrey A.; Margulis, Vitaly; Muradyan, Naira; Brugarolas, James; Madhuranthakam, Ananth J.; Pedrosa, Ivan

    2015-01-01

    Objective To investigate potential correlations between perfusion by arterial spin-labeled (ASL) magnetic resonance imaging (MRI) and dynamic contrast enhanced (DCE) MRI derived quantitative measures of vascularity in renal masses >2 cm and to correlate these with microvessel density (MVD) in clear cell renal cell carcinoma (ccRCC). Methods Informed written consent was obtained from all patients before imaging in this HIPAA-compliant, IRB-approved, prospective study. 36 consecutive patients scheduled for surgery of a known renal mass >2 cm underwent 3T ASL and DCE MRI. ASL measures (PASL) of mean, peak, and low perfusion areas within the mass were correlated to DCE-derived Ktrans, Kep, and Ve in the same locations using a region of interest analysis. MRI data were correlated to MVD measures in the same tumor regions in ccRCC. Spearman correlation was used to evaluate the correlation between PASL and DCE-derived measurements, and MVD. P<0.05 was considered statistically significant. Results Histopathologic diagnosis was obtained in 36 patients (25 men; mean age 58 ±12 years). PASL correlated with Ktrans (ρ=0.48, P=0.0091 for the entire tumor and ρ=0.43, P=0.03 for the high flow area, respectively) and Kep (ρ=0.46, P=0.01 for the entire tumor and ρ=0.52, P=0.008 for the high flow area, respectively). PASL (ρ=0.66, P=0.0002), Ktrans (ρ=0.61, P=0.001), and Kep (ρ=0.64, P=0.0006) also correlated with MVD in high and low perfusion areas in ccRCC. Conclusions PASL correlate with the DCE-derived measures of vascular permeability and flow, Ktrans and Kep, in renal masses >2cm in size. Both measures correlate to MVD in clear cell histology. MICROABSTRACT Arterial spin labeling (ASL) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) have been proposed to quantitatively assess vascularity in renal cell carcinoma (RCC). However there are intrinsic differences between these two imaging methods, such as the relative contribution of vascular permeability

  8. 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

  9. Plasminogen kringle 5-engineered glioma cells block migration of tumor-associated macrophages and suppress tumor vascularization and progression.

    PubMed

    Perri, Sabrina R; Nalbantoglu, Josephine; Annabi, Borhane; Koty, Zafiro; Lejeune, Laurence; François, Moïra; Di Falco, Marcos R; Béliveau, Richard; Galipeau, Jacques

    2005-09-15

    Angiostatin, a well-characterized angiostatic agent, is a proteolytic cleavage product of human plasminogen encompassing the first four kringle structures. The fifth kringle domain (K5) of human plasminogen is distinct from angiostatin and has been shown, on its own, to act as a potent endothelial cell inhibitor. We propose that tumor-targeted K5 cDNA expression may act as an effective therapeutic intervention as part of a cancer gene therapy strategy. In this study, we provide evidence that eukaryotically expressed His-tagged human K5 cDNA (hK5His) is exported extracellularly and maintains predicted disulfide bridging conformation in solution. Functionally, hK5His protein produced by retrovirally engineered human U87MG glioma cells suppresses in vitro migration of both human umbilical vein endothelial cells and human macrophages. Subcutaneous implantation of Matrigel-embedded hK5His-producing glioma cells in nonobese diabetic/severe combined immunodeficient mice reveals that hK5His induces a marked reduction in blood vessel formation and significantly suppresses the recruitment of tumor-infiltrating CD45+ Mac3+ Gr1- macrophages. Therapeutically, we show in a nude mouse orthotopic brain cancer model that tumor-targeted K5 expression is capable of effectively suppressing glioma growth and promotes significant long-term survival (>120 days) of test animals. These data suggest that plasminogen K5 acts as a novel two-pronged anticancer agent, mediating its inhibitory effect via its action on host-derived endothelial cells and tumor-associated macrophages, resulting in a potent, clinically relevant antitumor effect.

  10. Glutathione regulation of redox-sensitive signals in tumor necrosis factor-alpha-induced vascular endothelial dysfunction.

    PubMed

    Tsou, Tsui-Chun; Yeh, Szu Ching; Tsai, Feng-Yuan; Chen, Jein-Wen; Chiang, Huai-Chih

    2007-06-01

    We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-alpha)-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-alpha induces various biological effects on vascular cells, TNF-alpha dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-alpha concentrations, we adopted the lower TNF-alpha (0.2 ng/ml) to rule out the possible involvement of other TNF-alpha-induced biological effects. Inhibition of glutathione synthesis by l-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-alpha-induced adhesion molecule expression and monocyte-endothelial monolayer binding. BSO attenuated the TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-alpha. Inhibition of ERK, JNK, or NF-kappaB attenuates TNF-alpha-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-alpha induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-kappaB in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-alpha. Although AP-1 activation by the lower TNF-alpha was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-alpha-induced adhesion molecule expression.

  11. Hair follicle-derived blood vessels vascularize tumors in skin and are inhibited by Doxorubicin.

    PubMed

    Amoh, Yasuyuki; Li, Lingna; Yang, Meng; Jiang, Ping; Moossa, Abdool R; Katsuoka, Kensei; Hoffman, Robert M

    2005-03-15

    We have recently shown that the neural-stem cell marker nestin is expressed in hair follicle stem cells and the blood vessel network interconnecting hair follicles in the skin of transgenic mice with nestin regulatory element-driven green fluorescent protein (ND-GFP). The hair follicles were shown to give rise to the nestin-expressing blood vessels in the skin. In the present study, we visualized tumor angiogenesis by dual-color fluorescence imaging in ND-GFP transgenic mice after transplantation of the murine melanoma cell line B16F10 expressing red fluorescent protein. ND-GFP was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing tumor. Results of immunohistochemical staining showed that the blood vessel-specific antigen CD31 was expressed in ND-GFP-expressing nascent blood vessels. ND-GFP expression was diminished in the vessels with increased blood flow. Progressive angiogenesis during tumor growth was readily visualized during tumor growth by GFP expression. Doxorubicin inhibited the nascent tumor angiogenesis as well as tumor growth in the ND-GFP mice transplanted with B16F10-RFP. This model is useful for direct visualization of tumor angiogenesis and evaluation of angiogenic inhibitors.

  12. 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.

  13. Simultaneous Monitoring of Vascular Oxygenation and Tissue Oxygen Tension of Breast Tumors Under Hyperbaric Oxygen Exposure

    DTIC Science & Technology

    2008-04-01

    15. SUBJECT TERMS Technology Development, Near infrared spectroscopy , Hyperbaric Oxygen Treatment, Tumor Therapy Planning and Prognosis, Tumor...near-infrared spectroscopy and 19F magnetic resonance imaging in rats,” Physics in Medicine and Biology 51, 45-60 (2006). A2. Yueqing Gu, Wei R...infrared spectroscopy ,” Photochemistry and Photobiology 81(4), 1002– 1009 (2005). A3. Jae G. Kim, Mengna Xia, and Hanli Liu, “Hemoglobin extinction

  14. [An unusual primary vascular tumor: intimal sarcoma of the pulmonary artery].

    PubMed

    Brochériou, I; Quillard, A; Gatecel, C; Wassef, M

    2000-01-01

    Primary sarcomas of great vessels are rare and involve the aorta, pulmonary artery and inferior vena cava. The pathologic classification of these tumors can be made on the location of the sarcoma in relation to the vessel wall, luminal or mural. Luminal sarcomas are usually intimal sarcoma and mural sarcoma are most frequently leiomyosarcoma. The myofibroblastic or endothelial differentiation of these tumors is still debated. We report a case of intimal sarcoma of the pulmonary artery.

  15. Comparative proteome analysis of Tumor necrosis factor α-stimulated human Vascular Smooth Muscle Cells in response to melittin

    PubMed Central

    2013-01-01

    Background Bee venom has been used to relieve pain and to treat inflammatory diseases, including rheumatoid arthritis, in humans. To better understand the mechanisms of the anti-inflammatory and anti-atherosclerosis effect of bee venom, gel electrophoresis and mass spectrometry were used to identify proteins whose expression was altered in human Vascular Smooth Muscle Cells (hVSMCs) stimulated by tumor necrosis factor alpha after 12 h in the presence of melittin. Results To obtain valuable insights into the anti-inflammatory and anti-atherosclerosis mechanisms of melittin, two-dimensional (2-D) gel electrophoresis and MALDI-TOF/TOF were used. The proteome study, we showed 33 significant proteins that were differentially expressed in the cells treated with tumor necrosis factor alpha and melittin. Thirteen proteins were significantly increased in the cells treated with tumor necrosis factor alpha, and those proteins were reduced in the cells treated with melittin. Five of the proteins that showed increased expression in the cells treated with tumor necrosis factor alpha are involved in cell migration, including calreticulin, an essential factor of development that plays a role in transcription regulation. The proteins involved in cell migration were reduced in the melittin treated cells. The observed changes in the expression of GRP75, prohibitin, and a select group of other proteins were validated with reverse transcribed-PCR. It was confirmed that the observed change in the protein levels reflected a change in the genes level. In addition, the phosphorylation of EGFR and ERK was validated by analyzing the protein pathway. Conclusion Taken together, these data established that the expression of some proteins was significantly changed by melittin treatment in tumor necrosis factor alpha stimulated the cells and provided insights into the mechanism of the melittin function for its potential use as an anti-inflammatory agent. PMID:23651618

  16. Vascular CD39/ENTPD1 Directly Promotes Tumor Cell Growth by Scavenging Extracellular Adenosine Triphosphate12

    PubMed Central

    Feng, Lili; Sun, Xiaofeng; Csizmadia, Eva; Han, Lihui; Bian, Shu; Murakami, Takashi; Wang, Xin; Robson, Simon C; Wu, Yan

    2011-01-01

    Extracellular adenosine triphosphate (ATP) is known to boost immune responses in the tumor microenvironment but might also contribute directly to cancer cell death. CD39/ENTPD1 is the dominant ectonucleotidase expressed by endothelial cells and regulatory T cells and catalyzes the sequential hydrolysis of ATP to AMP that is further degraded to adenosine by CD73/ecto-5′-nucleotidase. We have previously shown that deletion of Cd39 results in decreased growth of transplanted tumors in mice, as a result of both defective angiogenesis and heightened innate immune responses (secondary to loss of adenosinergic immune suppression). Whether alterations in local extracellular ATP and adenosine levels as a result of CD39 bioactivity directly affect tumor growth and cytotoxicity has not been investigated to date. We show here that extracellular ATP exerts antitumor activity by directly inhibiting cell proliferation and promoting cancer cell death. ATP-induced antiproliferative effects and cell death are, in large part, mediated through P2X7 receptor signaling. Tumors in Cd39 null mice exhibit increased necrosis in association with P2X7 expression. We further demonstrate that exogenous soluble NTPDase, or CD39 expression by cocultured liver sinusoidal endothelial cells, stimulates tumor cell proliferation and limits cell death triggered by extracellular ATP. Collectively, our findings indicate that local expression of CD39 directly promotes tumor cell growth by scavenging extracellular ATP. Pharmacological or targeted inhibition of CD39 enzymatic activity may find utility as an adjunct therapy in cancer management. PMID:21390184

  17. 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.

  18. 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

  19. Hydrogels to Model 3D in vitro Microenvironment of Tumor Vascularization

    PubMed Central

    Song, Hyun-Ho Greco; Park, Kyung Min; Gerecht, Sharon

    2014-01-01

    A growing number of failing clinical trials for cancer therapy is substantiating the need to upgrade the current practice in culturing tumor cells and modeling tumor angiogenesis in vitro. Many attempts have been made to engineer vasculature in vitro by utilizing hydrogels, but the application of these tools in simulating in vivo tumor angiogenesis is still very new. In this review, we explore current use of hydrogels and their design parameters to engineer vasculogenesis and angiogenesis and to evaluate the angiogenic capability of cancerous cells and tissues. When coupled with other technologies such as lithography and three-dimensional printing, one can even create an advanced microvessel model as microfluidic channels to more accurately capture the native angiogenesis process. PMID:24969477

  20. Acute Temporal Changes of MRI-Tracked Tumor Vascular Parameters after Combined Anti-angiogenic and Radiation Treatments in a Rat Glioma Model: Identifying Signatures of Synergism.

    PubMed

    Elmghirbi, Rasha; Nagaraja, Tavarekere N; Brown, Stephen L; Panda, Swayamprava; Aryal, Madhava P; Keenan, Kelly A; Bagher-Ebadian, Hassan; Cabral, Glauber; Ewing, James R

    2017-01-01

    In this study we used magnetic resonance imaging (MRI) biomarkers to monitor the acute temporal changes in tumor vascular physiology with the aim of identifying the vascular signatures that predict response to combined anti-angiogenic and radiation treatments. Forty-three athymic rats implanted with orthotopic U-251 glioma cells were studied for approximately 21 days after implantation. Two MRI studies were performed on each animal, pre- and post-treatment, to measure tumor vascular parameters. Two animal groups received treatment comprised of Cilengitide, an anti-angiogenic agent and radiation. The first group received a subcurative regimen of Cilengitide 1 h before irradiation, while the second group received a curative regimen of Cilengitide 8 h before irradiation. Cilengitide was given as a single dose (4 mg/kg; intraperitoneal) after the pretreatment MRI study and before receiving a 20 Gy radiation dose. After irradiation, the post-treatment MRI study was performed at selected time points: 2, 4, 8 and 12 h (n = ≥5 per time point). Significant changes in vascular parameters were observed at early time points after combined treatments in both treatment groups (1 and 8 h). The temporal changes in vascular parameters in the first group (treated 1 h before exposure) resembled a previously reported pattern associated with radiation exposure alone. Conversely, in the second group (treated 8 h before exposure), all vascular parameters showed an initial response at 2-4 h postirradiation, followed by an apparent lack of response at later time points. The signature time point to define the "synergy" of Cilengitide and radiation was 4 h postirradiation. For example, 4 h after combined treatments using a 1 h separation (which followed the subcurative regimen), tumor blood flow was significantly decreased, nearly 50% below baseline (P = 0.007), whereas 4 h after combined treatments using an 8 h separation (which followed the curative regimen), tumor blood flow was only 10

  1. Proposal for future diagnosis and management of vascular tumors by using automatic software for image processing and statistic prediction

    PubMed Central

    Popescu, MD; Draghici, L; Secheli, I; Secheli, M; Codrescu, M; Draghici, I

    2015-01-01

    Rationale. Infantile Hemangiomas (IH) are the most frequent tumors of vascular origin, and the differential diagnosis from vascular malformations is difficult to establish. Specific types of IH due to the location, dimensions and fast evolution, can determine important functional and esthetic sequels. To avoid these unfortunate consequences it is necessary to establish the exact appropriate moment to begin the treatment and decide which the most adequate therapeutic procedure is. Objective. Based on clinical data collected by a serial clinical observations correlated with imaging data, and processed by a computer-aided diagnosis system (CAD), the study intended to develop a treatment algorithm to accurately predict the best final results, from the esthetical and functional point of view, for a certain type of lesion. Methods and Results. The preliminary database was composed of 75 patients divided into 4 groups according to the treatment management they received: medical therapy, sclerotherapy, surgical excision and no treatment. The serial clinical observation was performed each month and all the data was processed by using CAD. Discussions. The project goal was to create a software that incorporated advanced methods to accurately measure the specific IH lesions, integrated medical information, statistical methods and computational methods to correlate this information with that obtained from the processing of images. Based on these correlations, a prediction mechanism of the evolution of hemangioma, which helped determine the best method of therapeutic intervention to minimize further complications, was established. Abbreviations: Infantile Hemangiomas = IH, Computer Aided Diagnosis = CAD, Society for the Study of Vascular Anomalies = ISSVA, Color-coded duplex sonography = CCDS PMID:25914738

  2. Toxicity of Gamma Knife Radiosurgery in the Treatment of Intracranial Tumors in Patients With Collagen Vascular Diseases or Multiple Sclerosis

    SciTech Connect

    Lowell, Dot; Tatter, Stephen B.; Bourland, J. Daniel; Guzman, Allan F. de; Ekstrand, Kenneth E.; Ellis, Thomas L.; Lovato, James F.; McMullen, Kevin P.; Munley, Michael T.; Shaw, Edward G.; Urbanic, James J.; Chan, Michael D.

    2011-11-15

    Purpose: To assess toxicity in patients with either a collagen vascular disease (CVD) or multiple sclerosis (MS) treated with intracranial radiosurgery. Methods and Materials: Between January 2004 and April 2009, 6 patients with MS and 14 patients with a CVD were treated with Gamma Knife radiosurgery (GKRS) for intracranial tumors. Treated lesions included 15 total brain metastases in 7 patients, 11 benign brain tumors, 1 low grade glioma, and 1 cavernous malformation. Toxicities were graded by the Radiation Therapy Oncology Group Acute/Late Radiation Morbidity Scoring Criteria. 'Rare toxicities' were characterized as those reported in the scientific literature at an incidence of <5%. Results: Median follow-up time was 16 months. Median dose to the tumor margin was 13.0 Gy (range, 12-21 Gy). Median size of tumor was 5.0 cm{sup 3} (range, 0.14-7.8 cm{sup 3}). Of the 14 patients with CVD, none experienced a Grade 3 or 4 toxicity or a toxicity characterized as rare. Of the 6 patients with MS, 3 experienced rare toxicities, and two of these were Grade 3 toxicities. Rare complications included a patient experiencing both communicating hydrocephalus and facial nerve palsy, as well as 2 additional patients with motor cranial nerve palsy. High-grade toxicities included the patient with an acoustic neuroma requiring ventriculoperitoneal shunt placement for obstructive hydrocephalus, and 1 patient with a facial nerve schwannoma who experienced permanent facial nerve palsy. Interval between radiosurgery and high-grade toxicities ranged from 1 week to 4 months. Conclusions: Our series suggests that patients with MS who receive GKRS may be at increased risk of rare and high-grade treatment-related toxicity. Given the time course of toxicity, treatment-related edema or demyelination represent potential mechanisms.

  3. Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer

    PubMed Central

    Heist, Rebecca S.; Duda, Dan G.; Sahani, Dushyant V.; Ancukiewicz, Marek; Fidias, Panos; Sequist, Lecia V.; Temel, Jennifer S.; Shaw, Alice T.; Pennell, Nathan A.; Neal, Joel W.; Gandhi, Leena; Lynch, Thomas J.; Engelman, Jeffrey A.; Jain, Rakesh K.

    2015-01-01

    Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non–small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment—while reducing blood flow, volume, and permeability in the overall population—may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy. PMID:25605928

  4. Susceptibility Contrast Magnetic Resonance Imaging Determination of Fractional Tumor Blood Volume: A Noninvasive Imaging Biomarker of Response to the Vascular Disrupting Agent ZD6126

    SciTech Connect

    Robinson, Simon P. Howe, Franklyn A.; Griffiths, John R.; Ryan, Anderson J.; Waterton, John C.

    2007-11-01

    Purpose: To assess tumor fractional blood volume ({xi}), determined in vivo by susceptibility contrast magnetic resonance imaging (MRI) as a noninvasive imaging biomarker of tumor response to the vascular disrupting agent ZD6126. Methods and Materials: The transverse MRI relaxation rate R{sub 2}* of rat GH3 prolactinomas was quantified prior to and following injection of 2.5 mgFe/kg feruglose, an ultrasmall superparamagnetic iron oxide intravascular contrast agent, and {xi} (%) was determined from the change in R{sub 2}*. The rats were then treated with either saline or 50 mg/kg ZD6126, and {xi} measured again 24 hours later. Following posttreatment MRI, Hoechst 33342 (15 mg/kg) was administered to the rats and histological correlates from composite images of tumor perfusion and necrosis sought. Results: Irrespective of treatment, tumor volume significantly increased over 24 hours. Saline-treated tumors showed no statistically significant change in {xi}, whereas a significant (p = 0.002) 70% reduction in {xi} of the ZD6126-treated cohort was determined. Hoechst 33342 uptake was associated with viable tumor tissue and was significantly (p = 0.004) reduced and restricted to the rim of the ZD6126-treated tumors. A significant positive correlation between posttreatment {xi} and Hoechst 33342 uptake was obtained (r = 0.83, p = 0.002), providing validation of the MRI-derived measurements of fractional tumor blood volume. Conclusions: These data clearly highlight the potential of susceptibility contrast MRI with ultrasmall superparamagnetic iron oxide contrast agents to provide quantitative imaging biomarkers of fractional tumor blood volume at high spatial resolution to assess tumor vascular status and response to vascular disrupting agents.

  5. An engineered antibody-interleukin-12 fusion protein with enhanced tumor vascular targeting properties.

    PubMed

    Gafner, Verena; Trachsel, Eveline; Neri, Dario

    2006-11-01

    The antibody-mediated targeted delivery of interleukin-12 (IL12) to the EDB domain of fibronectin, a marker of angiogenesis, is a promising avenue for enhancing the therapeutic index of this anti-cancer cytokine. Previous experiments, based on sequential fusion of a single-chain IL12 derivative to the anti-EDB antibody fragment scFv(L19) had yielded a therapeutic fusion protein [IL12-scFv(L19)-FLAG], which displayed an impressive therapeutic activity in murine models of cancer, in spite of a tumor uptake, which was less efficient compared to the parental unmodified scFv(L19). In this article, we describe the comparative analysis of 3 recombinant fusion proteins comprising the scFv(L19) and IL12 moieties. One of them, in which the p40 and p35 form a covalent heterodimer and in which each subunit is fused to a molecule of scFv(L19), displays an excellent tumor targeting performance in vivo, as assessed by quantitative biodistribution analysis, and a potent anti-tumor effect, superior to the one of IL12-scFv(L19)-FLAG. These results may have a clinical impact, considering the fact that the tumor targeting ability of scFv(L19) in patients with cancer has been demonstrated using scintigraphic methods, and that 2 scFv(L19)-based antibody-cytokine fusion are currently entering clinical trials.

  6. Simultaneous Monitoring of Vascular Oxygenation and Tissue Oxygen Tension of Breast Tumors Under Hyperbaric Oxygen Exposure

    DTIC Science & Technology

    2007-04-01

    doxorubicin in an experimental model of pulmonary sarcoma [13]. HBO stimulated proliferation of an MCA-2 metastatic lung tumor cell line and induced...organ-cultured artery . British J of Pharm, 2001. 132: p. 1365-73. 35. Kanmura, Y., L. Raeymaekers, and R. Casteels, Effects of doxorubicin and

  7. Simultaneous Monitoring of Vascular Oxygenation and Tissue Oxygen Tension of Breast Tumors under Hyperbaric Oxygen Exposure

    DTIC Science & Technology

    2006-04-01

    FOXY system, on various rat breast tumor size (months 14- 30). Instead of single-channel NIRS, steady-state diffuse reflectance spectroscopy (SSDRS...combination of normobaric and hyperbaric oxygen interventions) simultaneously monitored by steady-state diffuse reflectance spectroscopy (SSDRS) and...simultaneously by steady-state diffuse reflectance spectroscopy (SSDRS) and FOXY oxygen sensor in response to normobaric and hyperbaric oxygen

  8. Endothelial Cell Death, Angiogenesis, and Microvascular Function after Castration in an Androgen-Dependent Tumor: Role of Vascular Endothelial Growth Factor

    NASA Astrophysics Data System (ADS)

    Jain, Rakesh K.; Safabakhsh, Nina; Sckell, Axel; Chen, Yi; Jiang, Ping; Benjamin, Laura; Yuan, Fan; Keshet, Eli

    1998-09-01

    The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone--ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone--ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.

  9. 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.

  10. 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

  11. Simultaneous Monitoring of Vascular Oxygenation and Tissue Oxygen Tension of Breast Tumors Under Hyperbaric Oxygen Exposure

    DTIC Science & Technology

    2005-04-01

    Following the same strategy, here, oxygen/carbogen induced tumor blood flow changes were estimated by fitting the Windkessel model ( Mandeville et al 1999...determined by the vasomotor control of arterioles, and that the capillaries and veins passively respond to arterial pressure changes ( Mandeville et al 1999...than normobaric oxygen. Reference: Boas D, Strangman G, Culver J, Hoge R, Jasdzewski G, Poldrack R, Rosen B and Mandeville J 2003 Can the cerebral

  12. 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

  13. Biodistribution Analysis of Oncolytic Adenoviruses in Patient Autopsy Samples Reveals Vascular Transduction of Noninjected Tumors and Tissues

    PubMed Central

    Koski, Anniina; Bramante, Simona; Kipar, Anja; Oksanen, Minna; Juhila, Juuso; Vassilev, Lotta; Joensuu, Timo; Kanerva, Anna; Hemminki, Akseli

    2015-01-01

    In clinical trials with oncolytic adenoviruses, there has been no mortality associated with treatment vectors. Likewise, in the Advanced Therapy Access Program (ATAP), where 290 patients were treated with 10 different viruses, no vector-related mortality was observed. However, as the patient population who received adenovirus treatments in ATAP represented heavily pretreated patients, often with very advanced disease, some patients died relatively soon after receiving their virus treatment mandating autopsy to investigate cause of death. Eleven such autopsies were performed and confirmed disease progression as the cause of death in each case. The regulatory requirement for investigating the safety of advanced therapy medical products presented a unique opportunity to study tissue samples collected as a routine part of the autopsies. Oncolytic adenoviral DNA was recovered in a wide range of tissues, including injected and noninjected tumors and various normal tissues, demonstrating the ability of the vector to disseminate through the vascular route. Furthermore, we recovered and cultured viable virus from samples of noninjected brain metastases of an intravenously treated patient, confirming that oncolytic adenovirus can reach tumors through the intravascular route. Data presented here give mechanistic insight into mode of action and biodistribution of oncolytic adenoviruses in cancer patients. PMID:26156245

  14. Assessment of Tumor Response to the Vascular Disrupting Agents 5,6-Dimethylxanthenone-4-Acetic Acid or Combretastatin-A4-Phosphate by Intrinsic Susceptibility Magnetic Resonance Imaging

    SciTech Connect

    McPhail, Lesley D. Griffiths, John R. D.Phil.; Robinson, Simon P.

    2007-11-15

    Purpose: To investigate the use of the transverse magnetic resonance imaging (MRI) relaxation rate R{sub 2}* (s{sup -1}) as a biomarker of tumor vascular response to monitor vascular disrupting agent (VDA) therapy. Methods and Materials: Multigradient echo MRI was used to quantify R{sub 2}* in rat GH3 prolactinomas. R{sub 2}* is a sensitive index of deoxyhemoglobin in the blood and can therefore be used to give an index of tissue oxygenation. Tumor R{sub 2}* was measured before and up to 35 min after treatment, and 24 h after treatment with either 350 mg/kg 5,6-dimethylxanthenone-4-acetic acid (DMXAA) or 100 mg/kg combretastatin-A4-phosphate (CA4P). After acquisition of the MRI data, functional tumor blood vessels remaining after VDA treatment were quantified using fluorescence microscopy of the perfusion marker Hoechst 33342. Results: DMXAA induced a transient, significant (p < 0.05) increase in tumor R{sub 2}* 7 min after treatment, whereas CA4P induced no significant changes in tumor R{sub 2}* over the first 35 min. Twenty-four hours after treatment, some DMXAA-treated tumors demonstrated a decrease in R{sub 2}*, but overall, reduction in R{sub 2}* was not significant for this cohort. Tumors treated with CA4P showed a significant (p < 0.05) reduction in R{sub 2}* 24 h after treatment. The degree of Hoechst 33342 uptake was associated with the degree of R{sub 2}* reduction at 24 h for both agents. Conclusions: The reduction in tumor R{sub 2}* or deoxyhemoglobin levels 24 h after VDA treatment was a result of reduced blood volume caused by prolonged vascular collapse. Our results suggest that DMXAA was less effective than CA4P in this rat tumor model.

  15. 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.

  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 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

  17. Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors

    PubMed Central

    Oh, Do-Youn; Kim, Tae-Min; Han, Sae-Won; Shin, Dong-Yeop; Lee, Yun Gyoo; Lee, Keun-Wook; Kim, Jee Hyun; Kim, Tae-You; Jang, In-Jin; Lee, Jong-Seok; Bang, Yung-Jue

    2016-01-01

    Purpose CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. Materials and Methods Patients received CKD-516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1. Results Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m2/day (n=3), 2 mg/m2/day (n=3), 3.3 mg/m2/day (n=3), 5 mg/m2/day (n=3), 7 mg/m2/day (n=3), 9 mg/m2/day (n=6), and 12 mg/m2/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m2/day. The MTD was determined as 12 mg/m2/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose-linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days). Conclusion This study demonstrates feasibility of CKD-516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m2/day on D1 and D8 every 3 weeks. PMID:25715767

  18. 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.

  19. Expression of parathyroid-specific genes in vascular endothelial progenitors of normal and tumoral parathyroid glands.

    PubMed

    Corbetta, Sabrina; Belicchi, Marzia; Pisati, Federica; Meregalli, Mirella; Eller-Vainicher, Cristina; Vicentini, Leonardo; Beck-Peccoz, Paolo; Spada, Anna; Torrente, Yvan

    2009-09-01

    Parathyroid tissue is able to spontaneously induce angiogenesis, proliferate, and secrete parathyroid hormone when autotransplanted in patients undergoing total parathyroidectomy. Angiogenesis is also involved in parathyroid tumorigenesis. Here we investigated the anatomical and molecular relationship between endothelial and parathyroid cells within human parathyroid glands. Immunohistochemistry for CD34 antigen identified two subpopulations in normal and tumoral parathyroid glands: one constituted by cells lining small vessels that displayed endothelial antigens (factor VIII, isolectin, laminin, CD146) and the other constituted of single cells scattered throughout the parenchyma that did not express endothelial markers. These parathyroid-derived CD34(+) cells were negative for the hematopoietic and mesenchymal markers CD45, Thy-1/CD90, CD105, and CD117/c-kit; however, a subset of CD34(+) cells co-expressed the parathyroid specific genes glial cell missing B, parathyroid hormone, and calcium sensing receptor. When cultured, these cells released significant amount of parathyroid hormone. Parathyroid-derived CD34(+) cells, but not CD34(-) cells, proliferated slowly and differentiated into mature endothelial cells. CD34(+) cells from parathyroid tumors differed from those derived from normal parathyroid glands as: 1) they were more abundant and mainly scattered throughout the parenchyma; 2) they rarely co-expressed CD146; and 3) a fraction co-expressed nestin. In conclusion, we identified cells expressing endothelial and parathyroid markers in human adult parathyroid glands. These parathyroid/endothelial cells were more abundant and less committed in parathyroid tumors compared with normal glands, showing features of endothelial progenitors, which suggests that they might be involved in parathyroid tumorigenesis.

  20. Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy12

    PubMed Central

    Baker, Gregory J.; Yadav, Viveka Nand; Motsch, Sebastien; Koschmann, Carl; Calinescu, Anda-Alexandra; Mineharu, Yohei; Camelo-Piragua, Sandra Ines; Orringer, Daniel; Bannykh, Serguei; Nichols, Wesley S.; deCarvalho, Ana C.; Mikkelsen, Tom; Castro, Maria G.; Lowenstein, Pedro R.

    2014-01-01

    As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients. PMID:25117977

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. [A recurrent desmoid tumor of the popliteal fossa with vascular compromise].

    PubMed

    Díaz Hernández, M; Febles, G; Domínguez del Toro, M; Reboso Morales, L E; Llopart López, J R; Gambra Michel, L E

    1993-01-01

    We report a case of a 18-year-old male patient with his fourth relapse of a desmoid tumour of the left popliteal hollow after a traumatism in this area. Arterial displacement and extrinsic compression were showed by arteriography. Tumoration was extirpated including popliteal artery, in this way a terminal by-pass from distal femoral to peroneo-tibial trunks with contralateral great saphena was made. Diagnosis of intestinal polyposis and of the little osseous malformations, was discarded these pathologies frequently are related with these tumours. The research for 8 years and 4 months doesn't show any relapse, nor local neither multicentral. Furthermore, some considerations about this theme are reported.

  6. Evaluation of 225Ac for vascular targeted radioimmunotherapy of lung tumors.

    PubMed

    Kennel, S J; Chappell, L L; Dadachova, K; Brechbiel, M W; Lankford, T K; Davis, I A; Stabin, M; Mirzadeh, S

    2000-06-01

    Several alpha particle emitting radioisotopes have been studied for use in radioimmunotherapy. Ac-225 has the potential advantages of a relatively long half life of 10 days, and a yield of 4 alpha emissions in its decay chain with a total energy release of approximately 28 MeV. A new, 12 coordination site chelating ligand, HEHA, has been chemically modified for coupling to targeting proteins without loss of chelating ability. HEHA was coupled with MAb 201B which binds to thrombomodulin and accumulates efficiently in murine lung. Ac-225 was bound to the HEHA-MAb 201B conjugate and injected into BALB/c mice bearing lung tumor colonies of EMT-6 mammary carcinoma. Biodistribution data at 1 and 4 h postinjection indicated that, as expected, 225Ac was delivered to lung efficiently (> 300% ID/g). The 225Ac was slowly released from the lung with an initial t1/2 = 49 h, and the released 225Ac accumulated in the liver. Injection of free HEHA was only partially successful in scavenging free 225Ac. In addition to the slow release of 225Ac from the chelate, data indicated that decay daughters of 225Ac were also released from the lung. Immediately after organ harvest, the level of 213Bi, the third alpha-decay daughter, was found to be deficient in the lungs and to be in excess in the kidney, relative to equilibrium values. Injected doses of 225Ac MAb 201B of 1.0 microCi, delivering a minimum calculated absorbed dose of about 6 Gy to the lungs, was effective in killing lung tumors, but also proved acutely radiotoxic. Animals treated with 1.0 microCi or more of the 225Ac radioconjugate died of a wasting syndrome within days with a dose dependent relationship. We conclude that the potential for 225Ac as a radioimmunotherapeutic agent is compromised not only by the slow release of 225Ac from the HEHA chelator, but most importantly by the radiotoxicity associated with decay daughter radioisotopes released from the target organ.

  7. Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.

    PubMed

    Garcia, Emmanuel; Becker, Veronika G C; McCullough, Danielle J; Stabley, John N; Gittemeier, Elizabeth M; Opoku-Acheampong, Alexander B; Sieman, Dietmar W; Behnke, Bradley J

    2016-07-01

    Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes.

  8. Predictive value of tumor recurrence using urinary vascular endothelial factor levels in patients receiving radiation therapy for Glioblastoma Multiforme (GBM)

    PubMed Central

    2013-01-01

    Background Glioblastoma Multiforme (GBM) is the most common primary malignant tumor of the central nervous system. Standard of care includes maximal resection followed by chemoradiotherapy. Tumors need adequate perfusion and neovascularization to maintain oxygenation and for removal of wastes. Vascular endothelial growth factor (VEGF) is a well characterized pro-angiogenic factor. We hypothesized that the increases in urinary VEGF levels would occur early in the course of tumor recurrence or progression. We examine the feasibility of collecting and analyzing urinary VEGF levels in a prospective, multi-institutional trial (Radiation Therapy Oncology Group, RTOG, 0611) as well as the role of VEGF as a marker of tumor recurrence. Method We evaluated VEGF levels in urine specimens collected post-operatively, at the conclusion of radiation therapy (RT) and one month following RT. Urinary VEGF levels were correlated with tumor progression at one year. VEGF levels were measured by enzyme-linked immunosorbant assay in urine specimens and normalized to urinary creatinine levels. Sample size was determined based on a 50% 1-year recurrence rate. With a sensitivity and specificity of 80%, the expected 95% confidence interval was (0.69, 0.91) with 100 patients. A failure was defined as documented disease progression, recurrence or death before one year. Results 202 patients were enrolled between February-2006 and October-2007. Four patients were ineligible as they did not receive RT. Of the remaining 198 patients, 128 had all three samples collected. In this group, 35 patients (27.3%) did not progress, 89 (69.5%) had progression and 4 (3.1%) died without evidence of progression. Median VEGF levels at baseline were 52.9 pg/mg Cr (range 0.2- 15,034.4); on the last day of RT, 56.6 (range 0–2,377.1); and at one month follow-up, 70.0 (range 0.1-1813.2). In patients without progression at 1-year, both baseline VEGF level and end of RT VEGF level were lower than those of patients

  9. 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.

  10. 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 , ...

  11. Role of Endocrine Gland-Derived Vascular Endothelial Growth Factor (EG-VEGF) and Its Receptors in Adrenocortical Tumors.

    PubMed

    Heck, Dorothee; Wortmann, Sebastian; Kraus, Luitgard; Ronchi, Cristina L; Sinnott, Richard O; Fassnacht, Martin; Sbiera, Silviu

    2015-12-01

    Angiogenesis is essential for tumor growth and metastasis. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor predominantly expressed in steroidogenic organs like the adrenal gland, ovary, testes, and placenta. EG-VEGF has antiapoptotic, mitogenic, and chemoattractive properties mediated via the two G protein-coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). We investigated the expression of EG-VEGF and its receptors in a large number of normal adrenal glands (NAG), adrenocortical adenomas (ACA), and carcinomas (ACC) using real-time PCR (NAG, n = 12; ACA, n = 24; and ACC, n = 30) and immunohistochemistry (NAG, n = 9; ACA, n = 23; and ACC, n = 163) and evaluated its impact on patients' survival. EG-VEGF, PKR1, and PKR2 mRNA and protein are expressed in NAG and the vast majority of ACA and ACC samples. The mean EG-VEGF mRNA expression was significantly lower in ACC (606.5 ± 77.1 copies) compared to NAG (4,043 ± 1,111) and cortisol-producing adenomas (CPA) (4,433 ± 2,378) (p < 0.01 and p < 0.05, respectively). However, cytoplasmic and nuclear EG-VEGF protein expression was either significantly higher or similar in ACC (H score 2.4 ± 0.05, p < 0.05 and 1.7 ± 0.08, n.s., respectively) compared to NAG (1.8 ± 0.14 and 1.7 ± 0.2). Nuclear protein expression of either EG-VEGF or PKR1 or both is predictive for a higher mortality compared to patients without nuclear expression (hazard ratio (HR) = 5.15; 95% confidence interval (CI) = 1.24-21.36, n = 100, p = 0.02 independent of age, sex, and tumor stage). These findings suggest that EG-VEGF and its receptor PKR1 might play a role in the pathogenesis of adrenocortical tumors and could serve as prognostic markers for this rare malignant disease.

  12. Influence of Exposure to Chronic Persistent Low-Dose Ionizing Radiation on the Tumor Biology of Clear-Cell Renal-Cell Carcinoma. An Immunohistochemical and Morphometric Study of Angiogenesis and Vascular Related Factors.

    PubMed

    Ruiz-Saurí, Amparo; Valencia-Villa, Gerardo; Romanenko, Alina; Pérez, Jesús; García, Raúl; García, Heydi; Benavent, José; Sancho-Tello, María; Carda, Carmen; Llombart-Bosch, Antonio

    2016-10-01

    Increased angiogenesis is related to boosted growth and malignancy in carcinomas. "Chronic Persistent Low-Dose Ionizing Radiation" (CPLDIR) exposure increases incidence and aggressive behavior of clear-cell renal-cell carcinoma (CCRCC). The aim was to study the biology of angiogenesis, including microvessel density (MVD), in human clear-cell renal-cell carcinomas (CCRCC) originating from a radio-contaminated geographical area (Ukraine) and to compare with similar tumors diagnosed in non-contaminated regions of Europe (Spain, Valencia) and Latin America (Colombia, Barranquilla). MVD was comparatively examined in 124 patients diagnosed with CCRCC from three geographical areas by means of digital micro-imaging and computerized analysis. Additionally, 50 adult normal kidneys were used for controls (autopsy kidneys from Valencia and Barranquilla). Furthermore, an immunohistochemical study of several vascular related growth factors was undertaken using a similar methodology. MVD as well as VEFG are the most discriminating factors associated with an aggressive behavior of CCRCC. Their expression increased in proportion to the level of exposure to chronic low-dose ionizing radiation in Ukrainian patients in the 25 years since the Chernobyl accident substantiated by comparison with the two control groups of renal carcinomas present in non-irradiated areas (Spain and Colombia). No major biological differences relating to angiogenesis appear to exist between the CCRCC diagnosed in two distant geographical areas of the world. HIF-1α expression was similar in all groups, with no statistical significance. Present findings demonstrate the existence of a significant relationship between MVD and VEGF in CCRCC: an increased expression of VEGF is associated with a high level of angiogenesis.

  13. Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts

    PubMed Central

    Gerber, David E; Hao, Guiyang; Watkins, Linda; Stafford, Jason H; Anderson, Jon; Holbein, Blair; Öz, Orhan K; Mathews, Dana; Thorpe, Philip E; Hassan, Gedaa; Kumar, Amit; Brekken, Rolf A; Sun, Xiankai

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with 111In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of 111In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of 111In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of 111In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, 111In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of 111In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings. PMID:26550540

  14. A Platform to Monitor Tumor Cellular and Vascular Response to Radiation Therapy by Optical Coherence Tomography and Fluorescence Microscopy in vivo

    NASA Astrophysics Data System (ADS)

    Leung, Michael Ka Kit

    Radiotherapy plays a significant role in cancer treatment, and is thought to be curative by mainly killing tumor cells through damage to their genetic material. However, recent findings indicate that the tumor's vascular blood supply is also a major determinant of radiation response. The goals of this thesis are to: (1) develop an experimental platform for small animals to deliver ionizing radiation and perform high-resolution optical imaging to treatment targets, and (2) use this toolkit to longitudinally monitor the response of tumors and the associated vasculature. The thesis has achieved: (1) customization of a novel micro-irradiator for mice, (2) technical development of an improved optical coherence tomography imaging system, (3) comprehensive experimental protocol and imaging optimization for optical microscopy in a specialized animal model, and (4) completion of a feasibility study to demonstrate the capabilities of the experimental platform in monitoring the response of tumor and vasculature to radiotherapy.

  15. Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing

    PubMed Central

    Shah, Anuja; Miller, Clinton J.; Nast, Cynthia C.; Adams, Mark D.; Truitt, Barbara; Tayek, John A.; Tong, Lili; Mehtani, Parag; Monteon, Francisco; Sedor, John R.; Clinkenbeard, Erica L.; White, Kenneth; Mehrotra, Rajnish; LaPage, Janine; Dickson, Patricia; Adler, Sharon G.; Iyengar, Sudha K.

    2014-01-01

    Background Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. Methods We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. Results We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. Conclusions This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families. PMID:25378588

  16. [Primitive neuroectodermal tumor of the vagus nerve].

    PubMed

    Pegbessou, E; Diom, E S; Ndiaye, M; Dieng, P A; Nao, E E M; Thiam, A; Diouf, M S; Boube, D; Ndiaye, C; Kossinda, F; Tall, A; Diallo, B K; Ndiaye, I C; Diouf, R; Diop, E M

    2013-12-01

    Primitive neuroectodermal tumors are a rare type of malignant neuroectodermal tumor that is very aggressive. Cervicofacial location is rare, even exceptional. We report a case of a 4-month-old male infant, referred from the pediatric clinic for severe supralaryngeal dyspnea, a firm mass under the left mandibular angle, mobile and extended to the parotid area, painful, with a curve of the left side wall of the oropharynx. Cervical computed tomodensitometry showed a well-limited mass in the carotid area, enhanced by the contrast product. A vascularized mass, which had developed at the expense of the vagus nerve, was removed surgically. Histology found a primitive neuroectodermal tumor.

  17. 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

  18. Relationships between Micro-Vascular and Iodine-Staining Patterns in the Vicinity of the Tumor Front of Superficial Esophageal Squamous Carcinoma

    PubMed Central

    Ohta, Shunsuke; Kawada, Kenro; Swangsri, Jirawat; Fujiwara, Naoto; Saito, Katsumasa; Fujiwara, Hisashi; Ryotokuji, Tairo; Okada, Takuya; Miyawaki, Yutaka; Tohkairin, Yutaka; Nakajima, Yasuaki; Kumagai, Youichi; Nagai, Kagami; Ito, Takashi; Eishi, Yoshinobu; Kawano, Tatsuyuki

    2015-01-01

    Objective The aim of the present study was to clarify differences between micro-vascular and iodine-staining patterns in the vicinity of the tumor fronts of superficial esophageal squamous cell carcinomas (ESCCs). Methods Ten consecutive patients with ESCCs who were treated by endoscopic submucosal dissection (ESD) were enrolled. At the edge of the iodine-unstained area, we observed 183 sites in total using image-enhanced magnifying endoscopy. We classified the micro-vascular and iodine-staining patterns into three types: Type A, in which the line of vascular change matched the border of the iodine-unstained area; Type B, in which the border of the iodine-unstained area extended beyond the line of vascular change; Type C, in which the line of vascular change extended beyond the border of the iodine-unstained area. Then, by examining histopathological sections, we compared the diameter of intra-papillary capillary loops (IPCLs) in cancerous areas and normal squamous epithelium. Results We investigated 160 sites that the adequate quality of pictures were obtained. There was no case in which the line of vascular change completely matched the whole circumference of the border of an iodine-unstained area. Among the 160 sites, type A was recognized at 76 sites (47.5%), type B at 79 sites (49.4%), and type C at 5 sites (3.1%). Histological examination showed that the mean diameter of the IPCLs in normal squamous epithelium was 16.2±3.7μm, whereas that of IPCLs in cancerous lesions was 21.0±4.4μm. Conclusions The development of iodine-unstained areas tends to precede any changes in the vascularity of the esophageal surface epithelium. PMID:26301414

  19. 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.

  20. Niaspan inhibits diabetic retinopathy-induced vascular inflammation by downregulating the tumor necrosis factor-α pathway

    PubMed Central

    Wang, Yang; Meng, Xiangda; Yan, Hua

    2017-01-01

    Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and a major cause of blindness in the developing world. Early DR is characterized by vascular neuroinflammation, cell apoptosis and breakdown of the blood-retinal barrier (BRB). However, optimal treatment options and associated mechanisms remain unclear. Niaspan, which is widely used in the prevention and treatment of hyperlipidemia-associated diseases, has been reported to inhibit inflammation. However, the effects of Niaspan and the mechanisms underlying the anti-inflammatory effects of Niaspan on DR have yet to be reported. The present study aimed to investigate the anti-inflammatory effects and mechanisms of Niaspan in a rat model of DR. Rats with DR exhibited a significant increase in BRB breakdown, retinal apoptosis, and tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) expression. In addition, the expression levels of inducible nitric oxide synthase (iNOS) and intercellular cell adhesion molecule-1 (ICAM-1) were increased in the retinas of DR rats compared with in the normal control group. In conclusion, treatment with Niaspan significantly improved clinical and histopathological outcomes; decreased the expression levels of TNF-α, NF-κB, iNOS and ICAM-1; and decreased apoptosis and BRB breakdown, as compared with in the retinas of DR rats. The present study is the first, to the best of our knowledge, to demonstrate that Niaspan treatment ameliorates DR by inhibiting inflammation, and also suggests that the TNF-α pathway may contribute to the beneficial effects of Niaspan treatment. PMID:28138697

  1. 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.” ...

  2. Histological vascular invasion is a novel prognostic indicator in extranodal natural killer/T-cell lymphoma, nasal type

    PubMed Central

    Wang, Hua; Li, Pengfei; Zhang, Xinke; Xia, Zhongjun; Lu, Yue; Huang, Huiqiang

    2016-01-01

    Extranodal natural killer (NK)/T-cell lymphoma, (ENKTL), nasal type, is an aggressive lymphoma with no validated prognostic parameters, to date. In the present study, vascular invasion by this tumor was retrospectively analyzed in 214 patients with untreated ENKTL to evaluate its association with clinical features, treatment response and prognosis. Histological vascular invasion by the tumor was confirmed in 32.7% of patients with ENKTL. The presence of vascular invasion significantly correlated with poor performance status, B symptoms, extranodal involved sites, advanced stage, elevated serum lactate dehydrogenase, D-dimer and cluster of differentiation 68+ tumor-associated macrophages. Upon treatment termination, the complete remission (CR) rate and overall response rate were significantly lower for the vascular invasion group compared with the non-vascular invasion group. Furthermore, vascular invasion resulted in significantly reduced 5-year progression-free survival (PFS; 21.8 vs. 60.1%) and overall survival (OS; 36.8 vs. 77.0%) rates. Using the multivariate Cox regression model, vascular invasion, stage III/IV and CR after chemotherapy were independent prognostic factors for OS and PFS. Thus, histological vascular invasion by the tumor affected the response to treatment, and was also an independent prognostic factor for OS and PFS in ENKTL, nasal type, suggesting a role for vascular invasion in disease progression. PMID:27446357

  3. 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.

  4. Glucocorticoid Receptor Knockdown Decreases the Antioxidant Protection of B16 Melanoma Cells: An Endocrine System-Related Mechanism that Compromises Metastatic Cell Resistance to Vascular Endothelium-Induced Tumor Cytotoxicity

    PubMed Central

    Obrador, Elena; Valles, Soraya L.; Benlloch, María; Sirerol, J. Antoni; Pellicer, José A.; Alcácer, Javier; Coronado, Javier Alcácer-F.; Estrela, José M.

    2014-01-01

    We previously reported an interorgan system in which stress-related hormones (corticosterone and noradrenaline), interleukin-6, and glutathione (GSH) coordinately regulate metastatic growth of highly aggressive B16-F10 melanoma cells. Corticosterone, at levels measured in tumor-bearing mice, also induces apoptotic cell death in metastatic cells with low GSH content. In the present study we explored the potential role of glucocorticoids in the regulation of metastatic cell death/survival during the early stages of organ invasion. Glucocorticoid receptor (GCR) knockdown decreased the expression and activity of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting step in GSH synthesis, in metastatic cells in vivo independent of the tumor location (liver, lung, or subcutaneous). The decrease in γ-GCS activity was associated with lower intracellular GSH levels. Nrf2- and p53-dependent down-regulation of γ-GCS was associated with a decrease in the activities of superoxide dismutase 1 and 2, catalase, glutathione peroxidase, and glutathione reductase, but not of the O2−-generating NADPH oxidase. The GCR knockdown-induced decrease in antioxidant protection caused a drastic decrease in the survival of metastatic cells during their interaction with endothelial cells, both in vitro and in vivo; only 10% of cancer cells attached to the endothelium survived compared to 90% survival observed in the controls. This very low rate of metastatic cell survival was partially increased (up to 52%) in vivo by inoculating B16-F10 cells preloaded with GSH ester, which enters the cell and delivers free GSH. Taken together, our results indicate that glucocorticoid signaling influences the survival of metastatic cells during their interaction with the vascular endothelium. PMID:24802641

  5. Glucocorticoid receptor knockdown decreases the antioxidant protection of B16 melanoma cells: an endocrine system-related mechanism that compromises metastatic cell resistance to vascular endothelium-induced tumor cytotoxicity.

    PubMed

    Obrador, Elena; Valles, Soraya L; Benlloch, María; Sirerol, J Antoni; Pellicer, José A; Alcácer, Javier; Coronado, Javier Alcácer-F; Estrela, José M

    2014-01-01

    We previously reported an interorgan system in which stress-related hormones (corticosterone and noradrenaline), interleukin-6, and glutathione (GSH) coordinately regulate metastatic growth of highly aggressive B16-F10 melanoma cells. Corticosterone, at levels measured in tumor-bearing mice, also induces apoptotic cell death in metastatic cells with low GSH content. In the present study we explored the potential role of glucocorticoids in the regulation of metastatic cell death/survival during the early stages of organ invasion. Glucocorticoid receptor (GCR) knockdown decreased the expression and activity of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting step in GSH synthesis, in metastatic cells in vivo independent of the tumor location (liver, lung, or subcutaneous). The decrease in γ-GCS activity was associated with lower intracellular GSH levels. Nrf2- and p53-dependent down-regulation of γ-GCS was associated with a decrease in the activities of superoxide dismutase 1 and 2, catalase, glutathione peroxidase, and glutathione reductase, but not of the O2--generating NADPH oxidase. The GCR knockdown-induced decrease in antioxidant protection caused a drastic decrease in the survival of metastatic cells during their interaction with endothelial cells, both in vitro and in vivo; only 10% of cancer cells attached to the endothelium survived compared to 90% survival observed in the controls. This very low rate of metastatic cell survival was partially increased (up to 52%) in vivo by inoculating B16-F10 cells preloaded with GSH ester, which enters the cell and delivers free GSH. Taken together, our results indicate that glucocorticoid signaling influences the survival of metastatic cells during their interaction with the vascular endothelium.

  6. Investigation of the therapeutic efficacy of codelivery of psiRNA-vascular endothelial growth factor and pIL-4 into chitosan nanoparticles in the breast tumor model.

    PubMed

    Şalva, Emine; Turan, Suna O; Kabasakal, Levent; Alan, Saadet; Özkan, Naziye; Eren, Fatih; Akbuğa, Jülide

    2014-03-01

    Angiogenesis has been known to increase tumor growth and for its metastatic potential in human tumors. Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis and is a promising therapeutic target for breast cancer. VEGF is an essential target for RNAi-based gene therapy of breast cancer. Interleukin-4 (IL-4) may act as an anti-angiogenic molecule that inhibits tumor growth and migration in rats. The purpose of the present study was to improve therapeutic efficacy in breast cancer with the codelivery of siRNA-expressing plasmid targeting VEGF and IL-4-expressing plasmid encapsulating into chitosan nanoparticles (NPs). The codelivery of psiVEGF and pIL-4 plasmids greatly enhanced in vitro and in vivo gene-silencing efficiency. For the in vitro study, when psiVEGF and pIL-4 into chitosan NPs were combined (81%), the gene-silencing effect was higher than psiVEGF and pIL-4 NPs alone. The in vivo study breast tumor model demonstrated that the administration of coencapsulation of psiVEGF and pIL-4 into chitosan NPs caused an additive effect on breast tumor growth inhibition (97%), compared with containing NPs psiVEGF or pIL-4 alone. These results indicate that chitosan NPs can be effectively used for the codelivery of pIL-4 and siVEGF-expressing plasmid in a combination therapy against breast cancer.

  7. IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo.

    PubMed

    Drogat, Benjamin; Auguste, Patrick; Nguyen, Duc Thang; Bouchecareilh, Marion; Pineau, Raphael; Nalbantoglu, Josephine; Kaufman, Randal J; Chevet, Eric; Bikfalvi, Andréas; Moenner, Michel

    2007-07-15

    In solid tumors, cancer cells subjected to ischemic conditions trigger distinct signaling pathways contributing to angiogenic stimulation and tumor development. Characteristic features of tumor ischemia include hypoxia and glucose deprivation, leading to the activation of hypoxia-inducible factor-1-dependent signaling pathways and to complex signaling events known as the unfolded protein response. Here, we show that the activation of the endoplasmic reticulum stress sensor IRE1 is a common determinant linking hypoxia- and hypoglycemia-dependent responses to the up-regulation of vascular endothelial growth factor-A (VEGF-A). Tumor cells expressing a dominant-negative IRE1 transgene as well as Ire1alpha-null mouse embryonic fibroblasts were unable to trigger VEGF-A up-regulation upon either oxygen or glucose deprivation. These data correlated with a reduction of tumor angiogenesis and growth in vivo. Our results therefore suggest an essential role for IRE1-dependent signaling pathways in response to ischemia and identify this protein as a potential therapeutic target to control both the angiogenic switch and tumor development.

  8. The Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor Cediranib (Recentin; AZD2171) Inhibits Endothelial Cell Function and Growth of Human Renal Tumor Xenografts

    SciTech Connect

    Siemann, Dietmar W. Brazelle, W.D.; Juergensmeier, Juliane M.

    2009-03-01

    Purpose: The goal of this study was to examine the therapeutic potential of the vascular endothelial growth factor (VEGF) signaling inhibitor cediranib in a human model of renal cell carcinoma (Caki-1). Methods and Materials: The effects of cediranib treatment on in vitro endothelial cell function (proliferation, migration, and tube formation), as well as in vivo angiogenesis and tumor growth, were determined. Results: In vitro, cediranib significantly impaired the proliferation and migration of endothelial cells and their ability to form tubes, but had no effect on the proliferation of Caki-1 tumor cells. In vivo, cediranib significantly reduced Caki-1 tumor cell-induced angiogenesis, reduced tumor perfusion, and inhibited the growth of Caki-1 tumor xenografts. Conclusions: The present results are consistent with the notion that inhibition of VEGF signaling leads to an indirect (i.e., antiangiogenic) antitumor effect, rather than a direct effect on tumor cells. These results further suggest that inhibition of VEGF signaling with cediranib may impair the growth of renal cell carcinoma.

  9. Expression and correlation of CD44v6, vascular endothelial growth factor, matrix metalloproteinase-2, and matrix metalloproteinase-9 in Krukenberg tumor

    PubMed Central

    Lou, Ge; Gao, Ying; Ning, Xiao-Ming; Zhang, Qi-Fan

    2005-01-01

    AIM: To explore the expression and correlation of CD44v6, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and matrix metalloproteinase (MMP)-9 in Krukenberg and primary epithelial ovarian carcinoma. METHODS: The expressions of CD44v6, VEGF, MMP-2 and MMP-9 were detected by immunohistochemical method in 20 cases of normal ovarian tissues, 38 cases of Krukenberg tumor and 45 cases of primary epithelial ovarian carcinoma. RESULTS: The expression of CD44v6 (primary epithelial ovarian carcinoma tissue vs normal ovarian tissue: χ2 = 4.516, P = 0.034; Krukenberg tumor tissue vs normal ovarian tissue: χ2 = 19.537, P = 0.001) and VEGF (primary epithelial ovarian carcinoma tissue vs normal ovarian tissue: P = 0.026; Krukenberg tumor tissue vs normal ovarian tissue: χ2 = 22.895, P = 0.001) was significantly higher in primary epithelial ovarian carcinoma tissue and Krukenberg tumor tissue than in normal ovarian tissue. The positive expression rate of MMP-2 and MMP-9 was 0% in the normal ovarian tissue. The positive expression rate of CD44v6 (χ2 = 10.398, P = 0.001), VEGF (χ2 = 13.149, P = 0.001), MMP-2 (χ2 = 33.668, P = 0.001) and MMP-9 (χ2 = 38.839, P = 0.001) was remarkably higher in Krukenberg tumor than in primary epithelial ovarian carcinoma. The correlation of CD44v6, VEGF, MMP-2, and MMP-9 was observed in primary epithelial ovarian carcinoma and Krukenberg tumor. CONCLUSION: CD44v6, VEGF, MMP-2, and MMP-9 are involved in ovarian carcinoma, gastric cancer and Krukenberg tumor. Detection of CD44v6, VEGF, MMP-2 and MMP-9 may contribute to the diagnosis of ovarian carcinoma, gastric cancer, and Krukenberg tumor. PMID:16124061

  10. 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.

  11. A Cahn-Hilliard model of vascularized tumor growth in a complex evolving confinement using a diffuse domain approach

    NASA Astrophysics Data System (ADS)

    Chuang, Yao-Li; Cristini, Vittorio; Chen, Ying; Li, Xiangrong; Frieboes, Hermann; Lowengrub, John

    2012-02-01

    Understanding the spatiotemporal evolution of tumor growth is essential for developing effective strategies to treat cancers. Various studies have suggested that spatial heterogeneity during tumors growth is a key factor associated with subsequent tumor invasion and the effectiveness of chemotherapy. Spatial heterogeneity may arise due to morphological instability of the tumors and the complex tissue structure surrounding the tumors. In previous works, we have used a Cahn-Hilliard tumor growth model to study the morphological instability for tumors in non-resisting tissues. However, most tumors are surrounded by complex tissue structures and confined in the capsules of some organs or between certain basement membranes. The capsules and basement membranes may be distorted by interacting with the evolving tumors, affecting the morphological instability. Here we adopt a novel diffuse domain approach to adapt our previous Cahn-Hilliard model for tumor growth in such complex evolving environments. As an example, we apply the model to simulate the evolution of lymphoma in a lymph node, incorporating also the tumor-induced angiogenesis.

  12. Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor necrosis factor-alpha and oncostatin M derived from macrophages.

    PubMed

    Shioi, Atsushi; Katagi, Miwako; Okuno, Yasuhisa; Mori, Katsuhito; Jono, Shuichi; Koyama, Hidenori; Nishizawa, Yoshiki

    2002-07-12

    Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calcification associated with atherosclerosis and cardiac valvular disease. In particular, macrophages activated with cytokines derived from T lymphocytes such as interferon-gamma (IFN-gamma) may contribute to the development of vascular calcification. Moreover, we have shown the stimulatory effect of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) on in vitro calcification through increasing the expression of alkaline phosphatase (ALP), an ectoenzyme indispensable for bone mineralization, in vascular smooth muscle cells. Therefore, we hypothesized that macrophages may induce calcifying phenotype, especially the expression of ALP in human vascular smooth muscle cells (HVSMCs) in the presence of IFN-gamma and 1,25(OH)2D3. To test this hypothesis, we used cocultures of HVSMCs with human monocytic cell line (THP-1) or peripheral blood monocytes (PBMCs) in the presence of IFN-gamma and 1,25(OH)2D3. THP-1 cells or PBMCs induced ALP activity and its gene expression in HVSMCs and the cells with high expression of ALP calcified their extracellular matrix by the addition of beta-glycerophosphate. Thermostability and immunoassay showed that ALP induced in HVSMCs was bone-specific enzyme. We further identified tumor necrosis factor-alpha (TNF-alpha) and oncostatin M (OSM) as major factors inducing ALP in HVSMCs in the culture supernatants of THP-1 cells. TNF-alpha and OSM, only when applied together, increased ALP activities and in vitro calcification in HVSMCs in the presence of IFN-gamma and 1,25(OH)2D3. These results suggest that macrophages may contribute to the development of vascular calcification through producing various inflammatory mediators, especially TNF-alpha and OSM.

  13. In vivo phage display screening for tumor vascular targets in glioblastoma identifies a llama nanobody against dynactin-1-p150Glued

    PubMed Central

    Verhoeff, Joost J.C.; Mäkinen, Petri I.; Lappalainen, Jari P.; Ylä-Herttuala, Seppo; Raats, Jos; van Wijk, Erwin; Roepman, Ronald; Letteboer, Stef J.; Verrijp, Kiek; Leenders, William P.J.

    2016-01-01

    Diffuse gliomas are primary brain cancers that are characterised by infiltrative growth. Whereas high-grade glioma characteristically presents with perinecrotic neovascularisation, large tumor areas thrive on pre-existent vasculature as well. Clinical studies have revealed that pharmacological inhibition of the angiogenic process does not improve survival of glioblastoma patients. Direct targeting of tumor vessels may however still be an interesting therapeutic approach as it allows pinching off the blood supply to tumor cells. Such tumor vessel targeting requires the identification of tumor-specific vascular targeting agents (TVTAs). Here we describe a novel TVTA, C-C7, which we identified via in vivo biopanning of a llama nanobody phage display library in an orthotopic mouse model of diffuse glioma. We show that C-C7 recognizes a subpopulation of tumor blood vessels in glioma xenografts and clinical glioma samples. Additionally, C-C7 recognizes macrophages and activated endothelial cells in atherosclerotic lesions. By using C-C7 as bait in yeast-2-hybrid (Y2H) screens we identified dynactin-1-p150Glued as its binding partner. The interaction was confirmed by co-immunostainings with C-C7 and a commercial anti-dynactin-1-p150Glued antibody, and via co-immunoprecipitation/western blot studies. Normal brain vessels do not express dynactin-1-p150Glued and its expression is reduced under anti-VEGF therapy, suggesting that dynactin-1-p150Glued is a marker for activated endothelial cells. In conclusion, we show that in vivo phage display combined with Y2H screenings provides a powerful approach to identify tumor-targeting nanobodies and their binding partners. Using this combination of methods we identify dynactin-1-p150Glued as a novel targetable protein on activated endothelial cells and macrophages. PMID:27689404

  14. Inhibition of Vascular Endothelial Growth Factor A and Hypoxia-Inducible Factor 1α Maximizes the Effects of Radiation in Sarcoma Mouse Models Through Destruction of Tumor Vasculature

    SciTech Connect

    Lee, Hae-June; Yoon, Changhwan; Park, Do Joong; Kim, Yeo-Jung; Schmidt, Benjamin; Lee, Yoon-Jin; Tap, William D.; Eisinger-Mathason, T.S. Karin; Choy, Edwin; Kirsch, David G.; Simon, M. Celeste; and others

    2015-03-01

    Purpose: To examine the addition of genetic or pharmacologic inhibition of hypoxia-inducible factor 1α (HIF-1α) to radiation therapy (RT) and vascular endothelial growth factor A (VEGF-A) inhibition (ie trimodality therapy) for soft-tissue sarcoma. Methods and Materials: Hypoxia-inducible factor 1α was inhibited using short hairpin RNA or low metronomic doses of doxorubicin, which blocks HIF-1α binding to DNA. Trimodality therapy was examined in a mouse xenograft model and a genetically engineered mouse model of sarcoma, as well as in vitro in tumor endothelial cells (ECs) and 4 sarcoma cell lines. Results: In both mouse models, any monotherapy or bimodality therapy resulted in tumor growth beyond 250 mm{sup 3} within the 12-day treatment period, but trimodality therapy with RT, VEGF-A inhibition, and HIF-1α inhibition kept tumors at <250 mm{sup 3} for up to 30 days. Trimodality therapy on tumors reduced HIF-1α activity as measured by expression of nuclear HIF-1α by 87% to 95% compared with RT alone, and cytoplasmic carbonic anhydrase 9 by 79% to 82%. Trimodality therapy also increased EC-specific apoptosis 2- to 4-fold more than RT alone and reduced microvessel density by 75% to 82%. When tumor ECs were treated in vitro with trimodality therapy under hypoxia, there were significant decreases in proliferation and colony formation and increases in DNA damage (as measured by Comet assay and γH2AX expression) and apoptosis (as measured by cleaved caspase 3 expression). Trimodality therapy had much less pronounced effects when 4 sarcoma cell lines were examined in these same assays. Conclusions: Inhibition of HIF-1α is highly effective when combined with RT and VEGF-A inhibition in blocking sarcoma growth by maximizing DNA damage and apoptosis in tumor ECs, leading to loss of tumor vasculature.

  15. The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma

    SciTech Connect

    Zhou, Hua; Yang, Ying-Hua; Binmadi, Nada O.; Proia, Patrizia; Basile, John R.

    2012-08-15

    Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to such stresses as chemotherapy or radiotherapy-induced hypoxia, and it therefore has become a tempting target for neutralizing antibodies in the treatment of advanced neoplasms. Emerging evidence has shown that the semaphorins, proteins originally associated with control of axonal growth and immunity, are regulated by changes in oxygen tension as well and may play a role in tumor-induced angiogenesis. Through the use of RNA interference, in vitro and in vivo angiogenesis assays and tumor xenograft experiments, we demonstrate that expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors. -- Highlights: Black-Right-Pointing-Pointer Similar to VEGF, SEMA4D promotes angiogenesis in vitro and in vivo. Black-Right-Pointing-Pointer Both VEGF and SEMA4D are produced by OSCC cells in a HIF-dependent manner. Black-Right-Pointing-Pointer These factors combine to elicit a robust pro-angiogenic phenotype in OSCC. Black-Right-Pointing-Pointer Anti-SEMA4D

  16. The impact of including spatially longitudinal heterogeneities of vessel oxygen content and vascular fraction in 3D tumor oxygenation models on predicted radiation sensitivity

    SciTech Connect

    Lagerlöf, Jakob H.; Kindblom, Jon; Bernhardt, Peter

    2014-04-15

    Purpose: Oxygen distribution models have been used to analyze the influences of oxygen tensions on tissue response after radiotherapy. These distributions are often generated assuming constant oxygen tension in the blood vessels. However, as red blood cells progress through the vessels, oxygen is continuously released into the plasma and the surrounding tissue, resulting in longitudinally varying oxygen levels in the blood vessels. In the present study, the authors investigated whether a tumor oxygenation model that incorporated longitudinally varying oxygen levels would provide different predictions of necrotic fractions and radiosensitivity compared to commonly used models with a constant oxygen pressure. Methods: Our models simulated oxygen diffusion based on a Green's function approach and oxygen consumption according to the Michaelis-Menten equation. The authors constructed tumor models with different vascular fractions (VFs), from which they generated depth oxygenation curves and a look-up table of oxygen pressure gradients. The authors evaluated models of spherical tumors of various sizes, from 1 to 10{sup 4} mg. The authors compared the results from a model with constant vessel oxygen (CVO) pressure to those from models with longitudinal variations in oxygen saturation and either a constant VF (CVF) or variable VF (VVF) within the tumor tissue. The authors monitored the necrotic fractions, defined as tumor regions with an oxygen pressure below 1 mmHg. Tumor radiation sensitivity was expressed as D{sub 99,} the homogeneous radiation dose required for a tumor control probability of 0.99. Results: In the CVO saturation model, no necrosis was observed, and decreasing the VF could only decrease the D{sub 99} by up to 10%. Furthermore, the D{sub 99} vs VF dependence was similar for different tumor masses. Compared to the CVO model, the extended CVF and VVF models provided clearly different results, including pronounced effects of VF and tumor size on the necrotic

  17. Fcγ Receptor-induced Soluble Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) Production Inhibits Angiogenesis and Enhances Efficacy of Anti-tumor Antibodies*

    PubMed Central

    Justiniano, Steven E.; Elavazhagan, Saranya; Fatehchand, Kavin; Shah, Prexy; Mehta, Payal; Roda, Julie M.; Mo, Xiaokui; Cheney, Carolyn; Hertlein, Erin; Eubank, Timothy D.; Marsh, Clay; Muthusamy, Natarajan; Butchar, Jonathan P.; Byrd, John C.; Tridandapani, Susheela

    2013-01-01

    Monocytes/macrophages are potent mediators of antitumor antibody therapy, where they engage target cells via Fcγ receptors (FcγR). Binding of these cells to opsonized tumor targets elicits cytokine production, phagocytosis, and antibody-mediated cellular cytotoxicity. Here we show for the first time that activation of monocyte FcγR results in the secretion of soluble vascular endothelial growth factor receptor-1 (VEGFR-1/sFlt-1), which serves to antagonize VEGF-mediated angiogenesis and tumor growth. Consistent with this, using a murine solid tumor model of antibody therapy, we show that sFlt-1 is involved in restricting tumor growth. Analyzing the mechanism of induction of sFlt-1, we found that the Erk and PI3K pathways were required for transcription, and NF-κB was required for translation. Upon closer examination of the role of NF-κB, we found that a microRNA, miR181a, negatively regulates FcγR-mediated sFlt-1 production and that NF-κB serves to antagonize this microRNA. Taken together, these results demonstrate a novel and biologically important function of monocytes and macrophages during antibody therapy. PMID:23902770

  18. Fcγ receptor-induced soluble vascular endothelial growth factor receptor-1 (VEGFR-1) production inhibits angiogenesis and enhances efficacy of anti-tumor antibodies.

    PubMed

    Justiniano, Steven E; Elavazhagan, Saranya; Fatehchand, Kavin; Shah, Prexy; Mehta, Payal; Roda, Julie M; Mo, Xiaokui; Cheney, Carolyn; Hertlein, Erin; Eubank, Timothy D; Marsh, Clay; Muthusamy, Natarajan; Butchar, Jonathan P; Byrd, John C; Tridandapani, Susheela

    2013-09-13

    Monocytes/macrophages are potent mediators of antitumor antibody therapy, where they engage target cells via Fcγ receptors (FcγR). Binding of these cells to opsonized tumor targets elicits cytokine production, phagocytosis, and antibody-mediated cellular cytotoxicity. Here we show for the first time that activation of monocyte FcγR results in the secretion of soluble vascular endothelial growth factor receptor-1 (VEGFR-1/sFlt-1), which serves to antagonize VEGF-mediated angiogenesis and tumor growth. Consistent with this, using a murine solid tumor model of antibody therapy, we show that sFlt-1 is involved in restricting tumor growth. Analyzing the mechanism of induction of sFlt-1, we found that the Erk and PI3K pathways were required for transcription, and NF-κB was required for translation. Upon closer examination of the role of NF-κB, we found that a microRNA, miR181a, negatively regulates FcγR-mediated sFlt-1 production and that NF-κB serves to antagonize this microRNA. Taken together, these results demonstrate a novel and biologically important function of monocytes and macrophages during antibody therapy.

  19. Multifocal vascular lesions.

    PubMed

    Levin, Laura E; Lauren, Christine T

    2016-09-01

    Multifocal vascular lesions are important to recognize and appropriately diagnose. Generally first noticed on the skin, multifocal vascular lesions may have systemic involvement. Distinguishing among the different types of multifocal vascular lesions is often based on clinical features; however, radiological imaging and/or biopsy are frequently needed to identify distinct features and guide treatment. Knowledge of the systemic associations that can occur with different vascular anomalies may reduce life-threatening complications, such as coagulopathy, bleeding, cardiac compromise, and neurologic sequelae. This review provides a synopsis of the epidemiology, pathogenesis, presentation, workup, and treatment of several well-recognized multifocal vascular tumors and malformations.

  20. Andrographolide Inhibits Nuclear Factor-κB Activation through JNK-Akt-p65 Signaling Cascade in Tumor Necrosis Factor-α-Stimulated Vascular Smooth Muscle Cells

    PubMed Central

    Chen, Yu-Ying; Hsieh, Cheng-Ying; Lee, Lin-Wen; Sheu, Joen-Rong

    2014-01-01

    Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism. PMID:25114952

  1. 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).

  2. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody

    DTIC Science & Technology

    2013-05-01

    Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody PRINCIPAL INVESTIGATOR: Ulrich Bickel...of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody 5b. GRANT NUMBER W81XWH-12-1-0184 5c. PROGRAM ELEMENT NUMBER 6...tumors using a brain selective cell line, 231-BR, derived from human breast cancer . Therefore, the experimental model to be used must be immune

  3. Identification of vascular breast tumor markers by laser capture microdissection and label-free LC-MS.

    PubMed

    Hill, Jennifer J; Tremblay, Tammy-Lynn; Pen, Ally; Li, Jie; Robotham, Anna C; Lenferink, Anne E G; Wang, Edwin; O'Connor-McCourt, Maureen; Kelly, John F

    2011-05-06

    Blood vessels in tumors frequently show abnormal characteristics, such as tortuous morphology or leakiness, but very little is known about protein expression in tumor vessels. In this study, we have used laser capture microdissection (LCM) to isolate microvessels from clinical samples of invasive ductal carcinoma (IDC), the most common form of malignant breast cancer, and from patient-matched adjacent nonmalignant tissue. This approach eliminates many of the problems associated with the heterogeneity of clinical tumor tissues by controlling for differences in protein expression between both individual patients and different cell types. Proteins from the microvessels were trypsinized and the resulting peptides were quantified by a label-free nanoLC-MS method. A total of 86 proteins were identified that are overexpressed in tumor vessels relative to vessels isolated from the adjacent nonmalignant tissue. These proteins include well-known breast tumor markers such as Periostin and Tenascin C but also proteins with lesser-known or emerging roles in breast cancer and tumor angiogenesis (i.e., Serpin H1, Clic-1, and Transgelin 2). We also identified 40 proteins that were relatively under-expressed in IDC tumor vessels, including several components of the basement membrane whose lower expression could be responsible for weakening tumor vessels. Lastly, we show that a subset of 29 proteins, derived from our list of differentially expressed proteins, is able to predict survival in three publicly available clinical breast cancer microarray data sets, which suggests that this subset of proteins likely plays a functional role in cancer progression and outcome.

  4. Targeting T1 and T2 dual modality enhanced magnetic resonance imaging of tumor vascular endothelial cells based on peptides-conjugated manganese ferrite nanomicelles

    PubMed Central

    Gong, Mingfu; Yang, Hua; Zhang, Song; Yang, Yan; Zhang, Dong; Li, Zhaohui; Zou, Liguang

    2016-01-01

    Tumor angiogenesis plays very important roles for tumorigenesis, tumor development, metastasis, and prognosis. Targeting T1/T2 dual modality magnetic resonance (MR) imaging of the tumor vascular endothelial cells (TVECs) with MR molecular probes can greatly improve diagnostic sensitivity and specificity, as well as helping to make an early diagnosis of tumor at the preclinical stage. In this study, a new T1 and T2 dual modality nanoprobe was successfully fabricated. The prepared nanoprobe comprise peptides CL 1555, poly(ε-caprolactone)-block-poly(ethylene glycol) amphiphilic copolymer shell, and dozens of manganese ferrite (MnFe2O4) nanoparticle core. The results showed that the hydrophobic MnFe2O4 nanoparticles were of uniform spheroidal appearance and narrow size distribution. Due to the self-assembled nanomicelles structure, the prepared probes were of high relaxivity of 281.7 mM−1 s−1, which was much higher than that of MnFe2O4 nanoparticles (67.5 mM 1 s−1). After being grafted with the targeted CD105 peptide CL 1555, the nanomicelles can combine TVECs specifically and make the labeled TVECs dark in T2-weighted MR imaging. With the passage on, the Mn2+ ions were released from MnFe2O4 and the size decreased gradually, making the signal intensity of the second and third passage of labeled TVECs increased in T1-weighted MR imaging. Our results demonstrate that CL-poly(ethylene glycol)-MnFe2O4 can conjugate TVECs and induce dark and bright contrast in MR imaging, and act as a novel molecular probe for T1- and T2-enhanced MR imaging of tumor angiogenesis. PMID:27578974

  5. Coregistration of ultrasonography and magnetic resonance imaging with a preliminary investigation of the spatial colocalization of vascular endothelial growth factor receptor 2 expression and tumor perfusion in a murine tumor model.

    PubMed

    Loveless, Mary E; Whisenant, Jennifer G; Wilson, Kevin; Lyshchik, Andrej; Sinha, Tuhin K; Gore, John C; Yankeelov, Thomas E

    2009-01-01

    We present an ultrasonography (US)-magnetic resonance imaging (MRI) coregistration technique and examine its application in a preliminary multimodal, multiparametric study in a preclinical model of breast cancer. Nine mice were injected with 67NR breast cancer cells and imaged 6 and 9 days later with 4.7 T MRI and high-frequency US. Tumor volumes from each data set were segmented independently by two investigators and coregistered using an iterative closest point algorithm. In addition to anatomic images, vascular endothelial growth factor receptor 2 (VEGFR2) distribution images from the central tumor slice using VEGFR2-targeted ultrasound contrast agent (UCA) and measurements of perfusion and extravascular-extracellular volume fraction using dynamic contrast-enhanced MRI were acquired from five mice for multiparametric coregistration. Parametric maps from each modality were coregistered and examined for spatial correlation. Average registration root mean square (RMS) error was 0.36 +/- 0.11 mm, less than approximately two voxels. Segmented volumes were compared between investigators to minimize interobserver variability; the average RMS error was 0.23 +/- 0.09 mm. In the preliminary study, VEGFR2-targeted UCA data did not demonstrate direct spatial correlation with magnetic resonance measures of vascular properties. In summary, a method for accurately coregistering small animal US and MRI has been presented that allows for comparison of quantitative metrics provided by the two modalities.

  6. Prophylactic Administration of Fucoidan Represses Cancer Metastasis by Inhibiting Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinases (MMPs) in Lewis Tumor-Bearing Mice

    PubMed Central

    Huang, Tse-Hung; Chiu, Yi-Han; Chan, Yi-Lin; Chiu, Ya-Huang; Wang, Hang; Huang, Kuo-Chin; Li, Tsung-Lin; Hsu, Kuang-Hung; Wu, Chang-Jer

    2015-01-01

    Fucoidan, a heparin-like sulfated polysaccharide, is rich in brown algae. It has a wide assortment of protective activities against cancer, for example, induction of hepatocellular carcinoma senescence, induction of human breast and colon carcinoma apoptosis, and impediment of lung cancer cells migration and invasion. However, the anti-metastatic mechanism that fucoidan exploits remains elusive. In this report, we explored the effects of fucoidan on cachectic symptoms, tumor development, lung carcinoma cell spreading and proliferation, as well as expression of metastasis-associated proteins in the Lewis lung carcinoma (LLC) cells-inoculated mice model. We discovered that administration of fucoidan has prophylactic effects on mitigation of cachectic body weight loss and improvement of lung masses in tumor-inoculated mice. These desired effects are attributed to inhibition of LLC spreading and proliferation in lung tissues. Fucoidan also down-regulates expression of matrix metalloproteinases (MMPs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and vascular endothelial growth factor (VEGF). Moreover, the tumor-bearing mice supplemented with fucoidan indeed benefit from an ensemble of the chemo-phylacticity. The fact is that fucoidan significantly decreases viability, migration, invasion, and MMPs activities of LLC cells. In summary, fucoidan is suitable to act as a chemo-preventative agent for minimizing cachectic symptoms as well as inhibiting lung carcinoma metastasis through down-regulating metastatic factors VEGF and MMPs. PMID:25854641

  7. Prophylactic administration of fucoidan represses cancer metastasis by inhibiting vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in Lewis tumor-bearing mice.

    PubMed

    Huang, Tse-Hung; Chiu, Yi-Han; Chan, Yi-Lin; Chiu, Ya-Huang; Wang, Hang; Huang, Kuo-Chin; Li, Tsung-Lin; Hsu, Kuang-Hung; Wu, Chang-Jer

    2015-04-03

    Fucoidan, a heparin-like sulfated polysaccharide, is rich in brown algae. It has a wide assortment of protective activities against cancer, for example, induction of hepatocellular carcinoma senescence, induction of human breast and colon carcinoma apoptosis, and impediment of lung cancer cells migration and invasion. However, the anti-metastatic mechanism that fucoidan exploits remains elusive. In this report, we explored the effects of fucoidan on cachectic symptoms, tumor development, lung carcinoma cell spreading and proliferation, as well as expression of metastasis-associated proteins in the Lewis lung carcinoma (LLC) cells-inoculated mice model. We discovered that administration of fucoidan has prophylactic effects on mitigation of cachectic body weight loss and improvement of lung masses in tumor-inoculated mice. These desired effects are attributed to inhibition of LLC spreading and proliferation in lung tissues. Fucoidan also down-regulates expression of matrix metalloproteinases (MMPs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and vascular endothelial growth factor (VEGF). Moreover, the tumor-bearing mice supplemented with fucoidan indeed benefit from an ensemble of the chemo-phylacticity. The fact is that fucoidan significantly decreases viability, migration, invasion, and MMPs activities of LLC cells. In summary, fucoidan is suitable to act as a chemo-preventative agent for minimizing cachectic symptoms as well as inhibiting lung carcinoma metastasis through down-regulating metastatic factors VEGF and MMPs.

  8. Desmoplastic small round cell tumor of the lung: A case report and literature review

    PubMed Central

    Ariza-Prota, Miguel Angel; Pando-Sandoval, Ana; Fole-Vázquez, David; Casan, Pere

    2015-01-01

    Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive and malignant tumor that is characterized by nests of small tumor cells surrounded by a cellular and vascular collagenous stroma and predominantly affects young adolescent males. This tumor most commonly originates in the abdomen; however, in rare cases, DSRCT can originate in other body regions. The main manifestations of DSRCT are chest pain and respiratory symptoms, and patients' average survival after diagnosis is less than two years. In this report, we describe a case involving DSRCT of the lung that proved to be difficult to diagnose, and we conduct a literature review. PMID:26744673

  9. Radioimmunotherapy with radioactive nanoparticles: Biological doses and treatment efficiency for vascularized tumors with or without a central hypoxic area

    SciTech Connect

    Bouchat, V.; Nuttens, V. E.; Michiels, C.; and others

    2010-04-15

    Purpose: Radioactive atoms attached to monoclonal antibodies are used in radioimmunotherapy to treat cancer while limiting radiation to healthy tissues. One limitation of this method is that only one radioactive atom is linked to each antibody and the deposited dose is often insufficient to eradicate solid and radioresistant tumors. In a previous study, simulations with the Monte Carlo N-Particle eXtended code showed that physical doses up to 50 Gy can be delivered inside tumors by replacing the single radionuclide by a radioactive nanoparticle of 5 nm diameter containing hundreds of radioactive atoms. However, tumoral and normal tissues are not equally sensitive to radiation, and previous works did not take account the biological effects such as cellular repair processes or the presence of less radiosensitive cells such as hypoxic cells. Methods: The idea is to adapt the linear-quadratic expression to the tumor model and to determine biological effective doses (BEDs) delivered through and around a tumor. This BED is then incorporated into a Poisson formula to determine the shell control probability (SCP) which predicts the cell cluster-killing efficiency at different distances ''r'' from the center of the tumor. BED and SCP models are used to analyze the advantages of injecting radioactive nanoparticles instead of a single radionuclide per vector in radioimmunotherapy. Results: Calculations of BED and SCP for different distances r from the center of a solid tumor, using the non-small-cell lung cancer as an example, were investigated for {sup 90}Y{sub 2} O{sub 3} nanoparticles. With a total activity of about 3.5 and 20 MBq for tumor radii of 0.5 and 1.0 cm, respectively, results show that a very high BED is deposited in the well oxygenated part of the spherical carcinoma. Conclusions: For either small or large solid tumors, BED and SCP calculations highlight the important benefit in replacing the single {beta}-emitter {sup 90}Y attached to each antibody by a {sup

  10. Aggressive thyroid cancer: targeted therapy with sorafenib.

    PubMed

    Corrado, Alda; Ferrari, Silvia M; Politti, Ugo; Mazzi, Valeria; Miccoli, Mario; Materazzi, Gabriele; Antonelli, Alessandro; Ulisse, Salvatore; Fallahi, Poupak; Miccoli, Paolo

    2017-03-01

    Sorafenib (Nexavar), is a multikinase inhibitor, which has demonstrated both antiproliferative and antiangiogenic properties in vitro and in vivo, inhibiting the activity of targets present in the tumoral cells (c-RAF [proto-oncogene serine/threonine-protein kinase], BRAF, (V600E)BRAF, c-KIT, and FMS-like tyrosine kinase 3) and in tumor vessels (c-RAF, vascular endothelial growth factor receptor [VEGFR]-2, VEGFR-3, and platelet-derived growth factor receptor β). Sorafenib was initially approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma. Experimental studies have demonstrated that sorafenib has both antiproliferative and antiangiogenic properties in vitro and in vivo, against thyroid cancer cells. Furthermore, several completed (or ongoing) studies have evaluated the long-term efficacy and tolerability of sorafenib in patients with papillary, follicular and medullary aggressive thyroid cancer. The results of the different studies showed good clinical responses and stabilization of the disease and suggested that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies (such as radioiodine). Currently, USA Food and Drug Administration has approved the use of sorafenib for metastatic differentiated thyroid cancer.

  11. 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 ...

  12. 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.

  13. Vascular dementia

    PubMed Central

    Korczyn, Amos D; Vakhapova, Veronika; Grinberg, Lea T

    2012-01-01

    The epidemic grow of dementia causes great concern for the society. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, followed by vascular dementia (VaD). This dichotomous view of a neurodegenerative disease as opposed to brain damage caused by extrinsic factors led to separate lines of research in these two entities. Indeed, accumulated data suggest that the two disorders have additive effects and probably interact; however it is still unknown to what degree. Furthermore, epidemiological studies have shown “vascular” risk factors to be associated with AD. Therefore, a clear distinction between AD and VaD cannot be made in most cases, and is furthermore unhelpful. In the absence of efficacious treatment for the neurodegenerative process, special attention must be given to vascular component, even in patients with presumed mixed pathology. Symptomatic treatment of VaD and AD are similar, although the former is less effective. For prevention of dementia it is important to treat aggressively all factors, even in stroke survivors who do not show evidence of cognitive decline,. In this review, we will give a clinical and pathological picture of the processes leading to VaD and discuss it interaction with AD. PMID:22575403

  14. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis.

    PubMed Central

    Yoshida, S; Ono, M; Shono, T; Izumi, H; Ishibashi, T; Suzuki, H; Kuwano, M

    1997-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors were increased after the treatment of human microvascular endothelial cells with TNF-alpha (100 U/ml). TNF-alpha-dependent tubular morphogenesis in vascular endothelial cells was inhibited by the administration of anti-IL-8, anti-VEGF, and anti-bFGF antibodies, and coadministration of all three antibodies almost completely abrogated tubular formation. Moreover, treatment with Sp1, NF-kappaB, and c-Jun antisense oligonucleotides inhibited TNF-alpha-dependent tubular morphogenesis by microvascular endothelial cells. Administration of a NF-kappaB antisense oligonucleotide almost completely inhibited TNF-alpha-dependent IL-8 production and partially abrogated TNF-alpha-dependent VEGF production, and an Sp1 antisense sequence partially inhibited TNF-alpha-dependent production of VEGF. A c-Jun antisense oligonucleotide significantly inhibited TNF-alpha-dependent bFGF production but did not affect the production of IL-8 and VEGF. Administration of an anti-IL-8 or anti-VEGF antibody also blocked TNF-alpha-induced neovascularization in the rabbit cornea in vivo. Thus, angiogenesis by TNF-alpha appears to be modulated through various angiogenic factors, both in vitro and in vivo, and this pathway is controlled through paracrine and/or autocrine mechanisms. PMID:9199336

  15. Vascular Cures

    MedlinePlus

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  16. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody

    DTIC Science & Technology

    2014-05-01

    endothelial cells using a TCR mimic antibody. J Cell Physiol. 2010;225(3):664-672. 3. Verma B, Jain R, Caseltine S, Rennels A, Bhattacharya R, Markiewski MM...Rawat A, Neethling F, Bickel U, Weidanz JA. TCR Mimic Monoclonal Antibodies Induce Apoptosis of Tumor Cells via Immune Effector- Independent

  17. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T Cell Receptor Mimic Antibody

    DTIC Science & Technology

    2015-05-01

    REPORT U b. ABSTRACT U c. THIS PAGE U U 5 19b. TELEPHONE NUMBER (include area code ) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18...Thorsheim HR, Gaasch JA, Huang S, Palmieri D, Steeg PS, Smith QR . Heterogeneous blood-tumor barrier permeability determines drug efficacy in

  18. Vascular Targeted Radioimmunotherapy for the Treatment of Glioblastoma

    PubMed Central

    Maguire, William F.; López Puebla, José Carlos; Sprinkle, Shanna R.; Ruggiero, Alessandro; O'Donoghue, Joseph; Gutin, Philip H.; Scheinberg, David A.

    2016-01-01

    Glioblastoma is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 mo despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium of glioblastoma with cytotoxic short-range, high-energy α-particles would be an effective therapeutic approach. Methods: E4G10, an antibody directed at an epitope of monomeric vascular endothelium cadherin that is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow, was labeled with α-particle-emitting 225Ac. Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac-E4G10 radioimmunoconstruct in a transgenic Nestin-tumor virus A (Ntva) mouse model of high-grade glioblastoma. Histologic analysis was used to demonstrate local therapeutic effects in treated brain tumor sections. Radioimmunotherapy with 225Ac-E4G10 was performed in Ntva mice to assess overall survival alone and in combination with temozolomide, the standard-of-care chemotherapeutic agent. Results: 225Ac-E4G10 was found to accumulate in tissues expressing the target antigen. Antivascular α-particle therapy of glioblastoma in the transgenic Ntva model resulted in significantly improved survival compared with controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 d (vs. 9 d for vehicle-treated animals). Histologic analyses showed a remodeled glioblastoma vascular microenvironment. Conclusion: Targeted α-particle antivascular therapy is shown for the first time to be effective in increasing overall survival in a solid tumor in a clinically relevant transgenic glioblastoma mouse model. PMID:27127217

  19. 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

  20. A Novel Tumor-Promoting Function Residing in the 5′ Non-coding Region of vascular endothelial growth factor mRNA

    PubMed Central

    Masuda, Kiyoshi; Teshima-Kondo, Shigetada; Mukaijo, Mina; Yamagishi, Naoko; Nishikawa, Yoshiko; Nishida, Kensei; Kawai, Tomoko; Rokutan, Kazuhito

    2008-01-01

    Background Vascular endothelial growth factor-A (VEGF) is one of the key regulators of tumor development, hence it is considered to be an important therapeutic target for cancer treatment. However, clinical trials have suggested that anti-VEGF monotherapy was less effective than standard chemotherapy. On the basis of the evidence, we hypothesized that vegf mRNA may have unrecognized function(s) in cancer cells. Methods and Findings Knockdown of VEGF with vegf-targeting small-interfering (si) RNAs increased susceptibility of human colon cancer cell line (HCT116) to apoptosis caused with 5-fluorouracil, etoposide, or doxorubicin. Recombinant human VEGF165 did not completely inhibit this apoptosis. Conversely, overexpression of VEGF165 increased resistance to anti-cancer drug-induced apoptosis, while an anti-VEGF165-neutralizing antibody did not completely block the resistance. We prepared plasmids encoding full-length vegf mRNA with mutation of signal sequence, vegf mRNAs lacking untranslated regions (UTRs), or mutated 5′UTRs. Using these plasmids, we revealed that the 5′UTR of vegf mRNA possessed anti-apoptotic activity. The 5′UTR-mediated activity was not affected by a protein synthesis inhibitor, cycloheximide. We established HCT116 clones stably expressing either the vegf 5′UTR or the mutated 5′UTR. The clones expressing the 5′UTR, but not the mutated one, showed increased anchorage-independent growth in vitro and formed progressive tumors when implanted in athymic nude mice. Microarray and quantitative real-time PCR analyses indicated that the vegf 5′UTR-expressing tumors had up-regulated anti-apoptotic genes, multidrug-resistant genes, and growth-promoting genes, while pro-apoptotic genes were down-regulated. Notably, expression of signal transducers and activators of transcription 1 (STAT1) was markedly repressed in the 5′UTR-expressing tumors, resulting in down-regulation of a STAT1-responsive cluster of genes (43 genes). As a result, the

  1. Successful management of aggressive fibromatosis of the neck using wide surgical excision: a case report

    PubMed Central

    2011-01-01

    Introduction Aggressive fibromatosis is a benign tumor, thought to arise from deep musculoaponeurotic structures, rarely found in the head or neck. However, when it does occur in the head and neck region, it tends to be more aggressive and associated with significant morbidity, which may be attributed to the vital vascular, neurological or anatomical structures in close proximity. Case presentation We report the case of a 39-year-old Pakistani man who presented with a two-month history of a lump on the right side of his neck. The mass was excised and histopathological analysis revealed a case of aggressive fibromatosis. Conclusion Due to the rarity of the condition no guidelines are available on the indications and extent of each modality. Due to its aggressive behavior and tendency to invade local structures and recur, a multi-modality management strategy is usually employed. On the basis of this case, we suggest that aggressive surgery is a viable management option and may be successfully used as a single modality treatment. PMID:21707981

  2. Multiphoton imaging reveals that nanosecond pulsed electric fields collapse tumor and normal vascular perfusion in human glioblastoma xenografts

    PubMed Central

    Bardet, Sylvia M.; Carr, Lynn; Soueid, Malak; Arnaud-Cormos, Delia; Leveque, Philippe; O’Connor, Rodney P.

    2016-01-01

    Despite the biomedical advances of the last century, many cancers including glioblastoma are still resistant to existing therapies leaving patients with poor prognoses. Nanosecond pulsed electric fields (nsPEF) are a promising technology for the treatment of cancer that have thus far been evaluated in vitro and in superficial malignancies. In this paper, we develop a tumor organoid model of glioblastoma and apply intravital multiphoton microscopy to assess their response to nsPEFs. We demonstrate for the first time that a single 10 ns, high voltage electric pulse (35–45 kV/cm), collapses the perfusion of neovasculature, and also alters the diameter of capillaries and larger vessels in normal tissue. These results contribute to the fundamental understanding of nsPEF effects in complex tissue environments, and confirm the potential of nsPEFs to disrupt the microenvironment of solid tumors such as glioblastoma. PMID:27698479

  3. Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect.

    PubMed

    Kasuya, Kazuhiko; Nagakawa, Yuichi; Suzuki, Minako; Tanaka, Hiroaki; Ohta, Hiroshi; Itoi, Takao; Tsuchida, Akihiko

    2011-11-01

    At present, no effective chemotherapy for pancreatic neuroendocrine carcinoma (PNEC) exists. However, anti-angiogenic therapy is expected to be effective for PNEC, a hypervascular tumor. We treated PNEC and hypovascular pancreatic ductal cell carcinoma (DCC) cell lines with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, and compared the antitumor effect between the two different types of cell lines. The PNEC cell line QGP-1 and the DCC cell lines BxPC-3 and AsPC-1 were used. We evaluated the ability of the cell lines to proliferate and secrete VEGF in vitro, the antitumor effect of bevacizumab administration in vivo and the side effects of bevacizumab on the pancreas in a caerulein-induced pancreatitis model. Comparison of the QGP-1 and DCC cell lines showed that QGP-1 secreted a higher level of VEGF under a hypoxic environment than the DCC cell line, and bevacizumab exerted the most marked growth-inhibitory effect on QGP-1; the number of intratumoral blood vessels decreased and the percentage of proliferating cells was approximately the same. In the pancreatitis model, bevacizumab administration did not adversely affect the pancreatitis or the associated hypoxic environment. Bevacizumab does not affect the pancreas itself; therefore, its potent inhibitory effect on the growth of pancreatic neuroendocrine tumors alone can be expected.

  4. Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect

    PubMed Central

    KASUYA, KAZUHIKO; NAGAKAWA, YUICHI; SUZUKI, MINAKO; TANAKA, HIROAKI; OHTA, HIROSHI; ITOI, TAKAO; TSUCHIDA, AKIHIKO

    2011-01-01

    At present, no effective chemotherapy for pancreatic neuroendocrine carcinoma (PNEC) exists. However, anti-angiogenic therapy is expected to be effective for PNEC, a hypervascular tumor. We treated PNEC and hypovascular pancreatic ductal cell carcinoma (DCC) cell lines with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, and compared the antitumor effect between the two different types of cell lines. The PNEC cell line QGP-1 and the DCC cell lines BxPC-3 and AsPC-1 were used. We evaluated the ability of the cell lines to proliferate and secrete VEGF in vitro, the antitumor effect of bevacizumab administration in vivo and the side effects of bevacizumab on the pancreas in a caerulein-induced pancreatitis model. Comparison of the QGP-1 and DCC cell lines showed that QGP-1 secreted a higher level of VEGF under a hypoxic environment than the DCC cell line, and bevacizumab exerted the most marked growth-inhibitory effect on QGP-1; the number of intratumoral blood vessels decreased and the percentage of proliferating cells was approximately the same. In the pancreatitis model, bevacizumab administration did not adversely affect the pancreatitis or the associated hypoxic environment. Bevacizumab does not affect the pancreas itself; therefore, its potent inhibitory effect on the growth of pancreatic neuroendocrine tumors alone can be expected. PMID:22977618

  5. 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.

  6. 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

  7. 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; ...

  8. Simple modifications to Methimazole that enhance its inhibitory effect on Tumor Necrosis Factor-α-induced Vascular Cell Adhesion Molecule-1 expression by human endothelial cells

    PubMed Central

    Alapati, Anuja; Deosarkar, Sudhir P.; Lanier, Olivia L.; Qi, Chunyan; Carlson, Grady E.; Burdick, Monica M.; Schwartz, Frank L.; McCall, Kelly D.; Bergmeier, Stephen C.; Goetz, Douglas J.

    2015-01-01

    The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be increased by pro-inflammatory cytokines [e.g. tumor necrosis factor – α (TNF-α)]. VCAM-1 contributes to leukocyte adhesion to, and emigration from, the vasculature which is a key aspect of pathological inflammation. As such, a promising therapeutic approach for pathological inflammation is to inhibit the expression of VCAM-1. Methimazole [3-methyl-1, 3 imidazole-2 thione (MMI)] is routinely used for the treatment of Graves’ disease and patients treated with MMI have decreased levels of circulating VCAM-1. In this study we used cultured human umbilical vein endothelial cells (HUVEC) to investigate the effect of MMI structural modifications on TNF-α induced VCAM-1 expression. We found that addition of a phenyl ring at the 4-nitrogen of MMI yields a compound that is significantly more potent than MMI at inhibiting 24 h TNF-α-induced VCAM-1 protein expression. Addition of a para methoxy to the appended phenyl group increases the inhibition while substitution of a thiazole ring for an imidazole ring in the phenyl derivatives yields no clear difference in inhibition. Addition of the phenyl ring to MMI appears to increase toxicity as does substitution of a thiazole ring for an imidazole ring in the phenyl MMI derivatives. Each of the compounds reduced TNF-α-induced VCAM-1 mRNA expression and had a functional inhibitory effect, i.e. each inhibited monocytic cell adhesion to 24 h TNF-α-activated HUVEC under fluid flow conditions. Combined, these studies provide important insights into the design of MMI-related anti-inflammatory compounds. PMID:25641748

  9. Simple modifications to methimazole that enhance its inhibitory effect on tumor necrosis factor-α-induced vascular cell adhesion molecule-1 expression by human endothelial cells.

    PubMed

    Alapati, Anuja; Deosarkar, Sudhir P; Lanier, Olivia L; Qi, Chunyan; Carlson, Grady E; Burdick, Monica M; Schwartz, Frank L; McCall, Kelly D; Bergmeier, Stephen C; Goetz, Douglas J

    2015-03-15

    The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be increased by pro-inflammatory cytokines [e.g. tumor necrosis factor-α (TNF-α)]. VCAM-1 contributes to leukocyte adhesion to, and emigration from, the vasculature which is a key aspect of pathological inflammation. As such, a promising therapeutic approach for pathological inflammation is to inhibit the expression of VCAM-1. Methimazole [3-methyl-1, 3 imidazole-2 thione (MMI)] is routinely used for the treatment of Graves׳ disease and patients treated with MMI have decreased levels of circulating VCAM-1. In this study we used cultured human umbilical vein endothelial cells (HUVEC) to investigate the effect of MMI structural modifications on TNF-α induced VCAM-1 expression. We found that addition of a phenyl ring at the 4-nitrogen of MMI yields a compound that is significantly more potent than MMI at inhibiting 24h TNF-α-induced VCAM-1 protein expression. Addition of a para methoxy to the appended phenyl group increases the inhibition while substitution of a thiazole ring for an imidazole ring in the phenyl derivatives yields no clear difference in inhibition. Addition of the phenyl ring to MMI appears to increase toxicity as does substitution of a thiazole ring for an imidazole ring in the phenyl MMI derivatives. Each of the compounds reduced TNF-α-induced VCAM-1 mRNA expression and had a functional inhibitory effect, i.e. each inhibited monocytic cell adhesion to 24h TNF-α-activated HUVEC under fluid flow conditions. Combined, these studies provide important insights into the design of MMI-related anti-inflammatory compounds.

  10. Molecular Targeted Therapies of Aggressive Thyroid Cancer

    PubMed Central

    Ferrari, Silvia Martina; Fallahi, Poupak; Politti, Ugo; Materazzi, Gabriele; Baldini, Enke; Ulisse, Salvatore; Miccoli, Paolo; Antonelli, Alessandro

    2015-01-01

    Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in

  11. [Practice guideline for diagnosis and treatment of craniopharyngioma and parasellar tumors of the pituitary gland].

    PubMed

    Venegas, Eva; Concepcion, Blanco; Martin, Tomas; Soto, Alfonso

    2015-01-01

    Craniopharyngiomas are rare, locally aggressive epithelial tumors usually located in the sellar and suprasellar region. Diagnosis of craniopharyngioma is usually suggested by clinical and radiological findings that should be confirmed histologically. Surgery is the treatment of choice for most patients. The goal of surgery is to relieve compressive symptoms and to remove as much tumor as safely possible. Radiation therapy is the usual treatment to control postoperative tumor remnants and local recurrences. Parasellar lesions are low prevalent lesions and include neoplastic, inflammatory, infectious, developmental, and vascular diseases. Both their diagnosis and treatment depend on the type of lesion.

  12. Effectiveness of evaluating tumor vascularization using 3D power Doppler ultrasound with high-definition flow technology in the prediction of the response to neoadjuvant chemotherapy for T2 breast cancer: a preliminary report

    NASA Astrophysics Data System (ADS)

    Shia, Wei-Chung; Chen, Dar-Ren; Huang, Yu-Len; Wu, Hwa-Koon; Kuo, Shou-Jen

    2015-10-01

    The aim of this study was to evaluate the effectiveness of advanced ultrasound (US) imaging of vascular flow and morphological features in the prediction of a pathologic complete response (pCR) and a partial response (PR) to neoadjuvant chemotherapy for T2 breast cancer. Twenty-nine consecutive patients with T2 breast cancer treated with six courses of anthracycline-based neoadjuvant chemotherapy were enrolled. Three-dimensional (3D) power Doppler US with high-definition flow (HDF) technology was used to investigate the blood flow in and morphological features of the tumors. Six vascularity quantization features, three morphological features, and two vascular direction features were selected and extracted from the US images. A support vector machine was used to evaluate the changes in vascularity after neoadjuvant chemotherapy, and pCR and PR were predicted on the basis of these changes. The most accurate prediction of pCR was achieved after the first chemotherapy cycle, with an accuracy of 93.1% and a specificity of 85.5%, while that of a PR was achieved after the second cycle, with an accuracy of 79.31% and a specificity of 72.22%. Vascularity data can be useful to predict the effects of neoadjuvant chemotherapy. Determination of changes in vascularity after neoadjuvant chemotherapy using 3D power Doppler US with HDF can generate accurate predictions of the patient response, facilitating early decision-making.

  13. Expression of Tumor-Derived Vascular Endothelial Growth Factor and Its Receptors Is Associated With Outcome in Early Squamous Cell Carcinoma of the Lung

    PubMed Central

    Pajares, María J.; Agorreta, Jackeline; Larrayoz, Marta; Vesin, Aurélien; Ezponda, Teresa; Zudaire, Isabel; Torre, Wenceslao; Lozano, María D.; Brambilla, Elisabeth; Brambilla, Christian; Wistuba, Ignacio I.; Behrens, Carmen; Timsit, Jean-Francois; Pio, Ruben; Field, John K.; Montuenga, Luis M.

    2012-01-01

    Purpose Antiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non–small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Patients and Methods We evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC. Results The combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC. Conclusion Our results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC. PMID:22355056

  14. RGD-conjugated two-photon absorbing near-IR emitting fluorescent probes for tumor vascular imaging (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Belfield, Kevin D.; Yue, Xiling; Morales, Alma R.; Githaiga, Grace W.; Woodward, Adam W.; Tang, Simon; Sawada, Junko; Komatsu, Masanobu; Liu, Xuan

    2016-03-01

    Observation of the activation and inhibition of angiogenesis processes is important in the progression of cancer. Application of targeting peptides, such as a small peptide that contains adjacent L-arginine (R), glycine (G) and L-aspartic acid (D) residues can afford high selectivity and deep penetration in vessel imaging. To facilitate deep tissue vasculature imaging, probes that can be excited via two-photon absorption (2PA) in the near-infrared (NIR) and subsequently emit in the NIR are essential. In this study, the enhancement of tissue image quality with RGD conjugates was investigated with new NIR-emitting pyranyl fluorophore derivatives in two-photon fluorescence microscopy. Linear and nonlinear photophysical properties of the new probes were comprehensively characterized; significantly the probes exhibited good 2PA over a broad spectral range from 700-1100 nm. Cell and tissue images were then acquired and examined, revealing deep penetration and high contrast with the new pyranyl RGD-conjugates up to 350 μm in tumor tissue.

  15. Tumor necrosis factor gene expression in human vascular intimal smooth muscle cells detected by in situ hybridization.

    PubMed Central

    Barath, P.; Fishbein, M. C.; Cao, J.; Berenson, J.; Helfant, R. H.; Forrester, J. S.

    1990-01-01

    We used immunohistochemistry to detect tumor necrosis factor (TNF) and in situ hybridization to detect TNF messenger RNA (mRNA) in the intimal mesenchymal-appearing cells and in the medial smooth muscle cells of human atherosclerotic arteries. Medial smooth muscle cells showed localization of immunoreactive TNF on the cell surface and did not express TNF mRNA. Conversely, in intimal mesenchymal-appearing cells, TNF was localized in the cytoplasm and TNF mRNA was expressed by in situ hybridization. Thus 89% of intimal cells were immunohistochemically positive for TNF, 96% of them were positive by in situ hybridization, and 76% were positive for the smooth muscle cell marker, HHF35. Our results suggest that intimal mesenchymal-appearing cells are mostly, but not exclusively, derived from smooth muscle cells. These cells express TNF, whereas the medial smooth muscle cells in the atherosclerotic human arteries do not. The expression of TNF by these mesenchymal-appearing cells may have implications regarding the evolution of the atherosclerotic plaque. Images Figure 1 to Figure 4 Figure 3 PMID:1698022

  16. Analysis and Quantitation of NF-[kappa]B Nuclear Translocation in Tumor Necrosis Factor Alpha (TNF-[alpha]) Activated Vascular Endothelial Cells

    NASA Astrophysics Data System (ADS)

    Fuseler, John W.; Merrill, Dana M.; Rogers, Jennifer A.; Grisham, Matthew B.; Wolf, Robert E.

    2006-07-01

    Nuclear factor kappa B (NF-[kappa]B) is a heterodimeric transcription factor typically composed of p50 and p65 subunits and is a pleiotropic regulator of various inflammatory and immune responses. In quiescent cells, p50/p65 dimers are sequestered in the cytoplasm bound to its inhibitors, the I-[kappa]Bs, which prevent entry into the nucleus. Following cellular stimulation, the I-[kappa]Bs are rapidly degraded, activating NF-[kappa]B. The active form of NF-[kappa]B rapidly translocates into the nucleus, binding to consensus sequences in the promoter/enhancer region of various genes, promoting their transcription. In human vascular endothelial cells activated with tumor necrosis factor-alpha, the activation and translocation of NF-[kappa]B is rapid, reaching maximal nuclear localization by 30 min. In this study, the appearance of NF-[kappa]B (p65 subunit, p65-NF-[kappa]B) in the nucleus visualized by immunofluorescence and quantified by morphometric image analysis (integrated optical density, IOD) is compared to the appearance of activated p65-NF-[kappa]B protein in the nucleus determined biochemically. The appearance of p65-NF-[kappa]B in the nucleus measured by fluorescence image analysis and biochemically express a linear correlation (R2 = 0.9477). These data suggest that localization and relative protein concentrations of NF-[kappa]B can be reliably determined from IOD measurements of the immunofluorescent labeled protein.

  17. Congenital tumors of the central nervous system.

    PubMed

    Severino, Mariasavina; Schwartz, Erin S; Thurnher, Majda M; Rydland, Jana; Nikas, Ioannis; Rossi, Andrea

    2010-06-01

    Congenital tumors of the central nervous system (CNS) are often arbitrarily divided into "definitely congenital" (present or producing symptoms at birth), "probably congenital" (present or producing symptoms within the first week of life), and "possibly congenital" (present or producing symptoms within the first 6 months of life). They represent less than 2% of all childhood brain tumors. The clinical features of newborns include an enlarged head circumference, associated hydrocephalus, and asymmetric skull growth. At birth, a large head or a tense fontanel is the presenting sign in up to 85% of patients. Neurological symptoms as initial symptoms are comparatively rare. The prenatal diagnosis of congenital CNS tumors, while based on ultrasonography, has significantly benefited from the introduction of prenatal magnetic resonance imaging studies. Teratomas constitute about one third to one half of these tumors and are the most common neonatal brain tumor. They are often immature because of primitive neural elements and, rarely, a component of mixed malignant germ cell tumors. Other tumors include astrocytomas, choroid plexus papilloma, primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, and medulloblastomas. Less common histologies include craniopharyngiomas and ependymomas. There is a strong predilection for supratentorial locations, different from tumors of infants and children. Differential diagnoses include spontaneous intracranial hemorrhage that can occur in the presence of coagulation factor deficiency or underlying vascular malformations, and congenital brain malformations, especially giant heterotopia. The prognosis for patients with congenital tumors is generally poor, usually because of the massive size of the tumor. However, tumors can be resected successfully if they are small and favorably located. The most favorable outcomes are achieved with choroid plexus tumors, where aggressive surgical treatment leads to disease-free survival.

  18. Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results.

    PubMed

    Sorace, Anna G; Quarles, C Chad; Whisenant, Jennifer G; Hanker, Ariella B; McIntyre, J Oliver; Sanchez, Violeta M; Yankeelov, Thomas E

    2016-01-01

    To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter K (trans) ) and the extravascular extracellular volume fraction (v e ) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in K (trans) (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in v e (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging

  19. Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results

    PubMed Central

    Quarles, C. Chad; Whisenant, Jennifer G.; Hanker, Ariella B.; McIntyre, J. Oliver; Sanchez, Violeta M.; Yankeelov, Thomas E.

    2016-01-01

    To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter Ktrans) and the extravascular extracellular volume fraction (ve) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in Ktrans (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in ve (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging method

  20. 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

  1. A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis

    SciTech Connect

    Kim, Su Jin; Chang, Suhwan; Lee, Yangsoon; Kim, Na Young; Hwang, Yeonsil; Min, Hye Jin; Yoo, Kyung-Sook; Park, Eun Hye; Kim, Seokho; Chung, Young-Hwa; Park, Young Woo; Koh, Sang Seok

    2014-11-07

    Highlights: • PMAb83, a human monoclonal antibody against PAUF, impaired tumor progression in vivo. • PMAb83 attenuated aggressiveness of tumor cells and suppressed angiogenesis. • PMAb83 in combination with gemcitabine conferred improved survival of mouse model. - Abstract: Pancreatic adenocarcinoma up-regulated factor (PAUF) is expressed in pancreatic ductal adenocarcinoma (PDAC) and plays an important role in tumor progression and metastasis. Here we evaluate the anti-tumor efficacy of a human monoclonal antibody against PAUF, PMAb83, to provide a therapeutic intervention to treat the disease. PMAb83 reduced tumor growth and distant metastasis in orthotopically xenografted mice of human PDAC cells. PMAb83 treatment retarded proliferation along with weakened aggressiveness traits of the carcinoma cells. AKT/β-catenin signaling played a role in the carcinoma cell proliferation and the treated xenograft tumors exhibited reduced levels of β-catenin and cyclin D1. Moreover PMAb83 abrogated the PAUF-induced angiogenic responses of endothelial cells, reducing the density of CD31{sup +} vessels in the treated tumors. In combination with gemcitabine, PMAb83 conferred enhanced survival of xenografted mice by about twofold compared to gemcitabine alone. Taken together, our findings show that PMAb83 treatment decreases the aggressiveness of carcinoma cells and suppresses tumor vascularization, which culminates in mitigated tumor growth and metastasis with improved survival in PDAC mouse models.

  2. 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.

  3. Lung tumorigenesis induced by human vascular endothelial growth factor (hVEGF)-A165 overexpression in transgenic mice and amelioration of tumor formation by miR-16.

    PubMed

    Tung, Yu-Tang; Huang, Pin-Wu; Chou, Yu-Ching; Lai, Cheng-Wei; Wang, Hsiu-Po; Ho, Heng-Chien; Yen, Chih-Ching; Tu, Chih-Yen; Tsai, Tung-Chou; Yeh, Dah-Cherng; Wang, Jiun-Long; Chong, Kowit-Yu; Chen, Chuan-Mu

    2015-04-30

    Many studies have shown that vascular endothelial growth factor (VEGF), especially the human VEGF-A165 (hVEGF-A165) isoform, is a key proangiogenic factor that is overexpressed in lung cancer. We generated transgenic mice that overexpresses hVEGF-A165 in lung-specific Clara cells to investigate the development of pulmonary adenocarcinoma. In this study, three transgenic mouse strains were produced by pronuclear microinjection, and Southern blot analysis indicated similar patterns of the foreign gene within the genomes of the transgenic founder mice and their offspring. Accordingly, hVegf-A165 mRNA was expressed specifically in the lung tissue of the transgenic mice. Histopathological examination of the lung tissues of the transgenic mice showed that hVEGF-A165 overexpression induced bronchial inflammation, fibrosis, cysts, and adenoma. Pathological section and magnetic resonance imaging (MRI) analyses demonstrated a positive correlation between the development of pulmonary cancer and hVEGF expression levels, which were determined by immunohistochemistry, qRT-PCR, and western blot analyses. Gene expression profiling by cDNA microarray revealed a set of up-regulated genes (hvegf-A165, cyclin b1, cdc2, egfr, mmp9, nrp-1, and kdr) in VEGF tumors compared with wild-type lung tissues. In addition, overexpressing hVEGF-A165 in Clara cells increases CD105, fibrogenic genes (collagen α1, α-SMA, TGF-β1, and TIMP1), and inflammatory cytokines (IL-1, IL-6, and TNF-α) in the lungs of hVEGF-A165-overexpressing transgenic mice as compared to wild-type mice. We further demonstrated that the intranasal administration of microRNA-16 (miR-16) inhibited lung tumor growth by suppressing VEGF expression via the intrinsic and extrinsic apoptotic pathways. In conclusion, hVEGF-A165 transgenic mice exhibited complex alterations in gene expression and tumorigenesis and may be a relevant model for studying VEGF-targeted therapies in lung adenocarcinoma.

  4. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1.

    PubMed Central

    Bevilacqua, M P; Pober, J S; Majeau, G R; Fiers, W; Cotran, R S; Gimbrone, M A

    1986-01-01

    Human recombinant tumor necrosis factor (rTNF) was found to act directly on cultured human vascular endothelium to induce a tissue factor-like procoagulant activity (PCA). After a 4-hr incubation in rTNF (100 units/ml), serially passaged endothelial cells isolated from umbilical veins, saphenous veins, iliac arteries, and thoracic aortae demonstrated a dramatic increase (4- to 15-fold, 21 experiments) in total cellular PCA as measured with a one-stage clotting assay. rTNF-induced PCA was also expressed at the surface of intact viable endothelial monolayers. Induction of PCA by rTNF was concentration dependent (maximum, 500 units/ml), time dependent, reversible, and blocked by cycloheximide and actinomycin D, and it occurred without detectable endothelial cell damage. Actions of rTNF were compared with those of natural human interleukin 1 (IL-1) derived from stimulated monocytes and two distinct species of recombinant IL-1, each of which also induced endothelial PCA. The use of recombinant polypeptides and specific neutralizing antisera established the distinct natures of the mediators. The kinetics of the endothelial PCA responses to TNF and IL-1 were similar, demonstrating a rapid rise to peak activity at approximately equal to 4 hr, and a decline toward basal levels by 24 hr. This characteristic decline in PCA after prolonged incubation with TNF or IL-1 was accompanied by selective endothelial hyporesponsiveness to the initially stimulating monokine. Interestingly, the effects of TNF and IL-1 were found to be additive even at apparent maximal doses of the individual monokines. Endothelial-directed actions of TNF, alone or in combination with other monokines, may be important in the initiation of coagulation and inflammatory responses in vivo. PMID:3487091

  5. Aqueous Humor Levels of Different Interleukins 1-β, 2, 6 and 10, Tumor Necrosis Factor-α and Vascular Endothelial Growth Factor in Uveitis Treated with Adalimumab

    PubMed Central

    Hernández Garfella, María Luisa; Palomares Fort, Paula; Román Ivorra, José Andrés; Cervera Taulet, Enrique

    2015-01-01

    Purpose: To assess changes in aqueous humor levels of different interleukins (IL), tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) in patients with uveitis treated with adalimumab. Methods: In this study, 24 aqueous humor samples including 12 pre- and post-treatment samples from 6 patients with uveitis treated with subcutaneous adalimumab and 12 samples from patients with cataracts (serving as controls) were evaluated. The levels of IL-1β, IL-2, IL-6, IL-10, TNF-α and VEGF were measured using a Luminex® 200™ flow cytometer (Merckmillipore, Merck KGaA, Darmstadt, Alemania) and a highly sensitive ELISA system. Results: The levels of IL-1β, IL-2, IL-6 and IL-10 in the aqueous humor before and after treatment with adalimumab did not show significant differences. Aqueous VEGF levels significantly reduced after treatment with adalimumab (P = 0.028). Aqueous TNF-α levels did not significantly change after treatment with adalimumab, however the post-treatment level was significantly higher in patients as compared to control subjects (P = 0.032). IL-2 showed significantly higher levels in uveitis patients before treatment as compared to controls (P = 0.024), while its post-treatment levels were almost normalized. Conclusion: Decrease in the aqueous humor levels of VEGF and IL-2 after treatment with systemic adalimumab indicates that anti-TNF-α therapy induces modifications of some inflammatory mediators involved in the pathogenesis of uveitis. Aqueous humor samples may be useful to assess the effect of adalimumab on intraocular inflammation through measurement of cytokines. PMID:26005553

  6. Radiology of the spine: Tumors

    SciTech Connect

    Jeanmart, L.

    1986-01-01

    This book deals with tumors of the spinal cord and various aspects of primary and secondary osseous tumors of the spine. Included in discussion are tumors, chordoma hemangioma, vascular malformation and the terms angioma and hemangiomas.

  7. PEI-g-PEG-RGD/Small Interference RNA Polyplex-Mediated Silencing of Vascular Endothelial Growth Factor Receptor and Its Potential as an Anti-Angiogenic Tumor Therapeutic Strategy

    PubMed Central

    Kim, Jihoon; Kim, Sung Wan

    2011-01-01

    Tumor angiogenesis appears to be achieved by the expression of vascular endothelial growth factor (VEGF) within solid tumors that stimulate host vascular endothelial cell mitogenesis and possibly chemotaxis. VEGF's angiogenic actions are mediated through its high-affinity binding to 2 endothelium-specific receptor tyrosine kinase, Flt-1 (VEGFR1), and Flk-1/KDR (VEGFR2). RNA interference-mediated knockdown of protein expression at the messenger RNA level provides a new therapeutic strategy to overcome various diseases. To achieve high efficacy in RNA interference-mediated therapy, it is critical to develop an efficient delivering system to deliver small interference RNA (siRNA) into tissues or cells site-specifically. We previously reported an angiogenic endothelial cell-targeted polymeric gene carrier, PEI-g-PEG-RGD. This targeted carrier was developed by the conjugation of the ανβ3/ανβ5 integrin-binding RGD peptide (ACDCRGDCFC) to the cationic polymer, branched polyethylenimine, with a hydrophilic polyethylene glycol (PEG) spacer. In this study, we used PEI-g-PEG-RGD to deliver siRNA against VEGFR1 into tumor site. The physicochemical properties of PEI-g-PEG-RGD/siRNA complexes was evaluated. Further, tumor growth profile was also investigated after systemic administration of PEI-g-PEG-RGD/siRNA complexes. PMID:21375397

  8. 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.

  9. 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

  10. Inferior vena cava leiomyosarcoma: vascular reconstruction is not always mandatory

    PubMed Central

    Slimane, Maher; Yahia, Nada Belhaj; Bouaziz, Hanene; Bouzaine, Hatem; Benhassouna, Jamel; Dhieb, Tarek Ben; Hechiche, Monia; Gammoudi, Amor; Rahal, Khaled

    2016-01-01

    Leiomyosarcoma (LMS) of inferior vena cava is a rare and aggressive tumor, arising from the smooth muscle cells in the vessel wall. A large complete surgical resection is the essential treatment. The need of vascular reconstruction is not always mandatory. It’s above all to understand the place of the reconstruction with artificial vascular patch prosthetics of vena cave after a large resection of the tumor. We rapport two cases of LMS of inferior vena cava in two women who underwent successful large resection of tumor and lower segment of inferior vena cava. In first case, reconstruction of the inferior vena cava was not performed because of the development of venous collaterals derivation. In the second case reconstruction was done using Dacron interposition graft. The necessity of a large resection in management of primary leiomyosarcoma of vena cave makes sometimes unavoidable the sacrifice of a portion of the vena. Indeed, a better comprehension of the development of venous derivation may render unnecessary the reconstruction. PMID:28154642

  11. 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…

  12. Vascular ring

    MedlinePlus

    ... with aberrant subclavian and left ligamentum ateriosus; Congenital heart defect - vascular ring; Birth defect heart - vascular ring ... accounts for less than 1% of all congenital heart problems. The condition occurs as often in males ...

  13. 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

  14. [Retinal vascular tumors in the material of the Department of Ophthalmology and Ocular Oncology of Jagiellonian University Collegium Medicum in Cracow].

    PubMed

    Leśniak, Anna; Karska-Basta, Izabella; Kobylarz, Joanna; Romanowska-Dixon, Bożena

    2015-01-01

    Retinal vascular tumours are congenital and acquired lesions of variable clinical manifestation. They are classified as benign, but their presence leads to vision impairment due to the development of complications. Each retinal vascular tumour possesses characteristic clinical features and is often associated with certain systemic disorders. Thus, a correct diagnosis is crucial for providing individualised treatment and expanded diagnostic management as well as prognostic assessment. The aim of the study was to present retinal vascular tumour cases of patients treated at the Department of Ophtalmology and Ocular Oncology of Jagiellonian University Collegium Medicum in Cracow.

  15. Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2.

    PubMed Central

    Ishii, Y; Partridge, C A; Del Vecchio, P J; Malik, A B

    1992-01-01

    We examined the effects of tumor necrosis factor-alpha (TNF alpha) stimulation of endothelial cells on the increase in endothelial permeability induced by H2O2. Bovine pulmonary microvascular endothelial cells (BPMVEC) were grown to confluence on a microporous filter and the 125I-albumin clearance rate across the monolayer was determined. Pretreatment with TNF alpha (100 U/ml) for 6 h had no direct effect on transendothelial 125I-albumin permeability. However, TNF alpha pretreatment enhanced the susceptibility of BPMVEC to H2O2; that is, H2O2 (10 microM) alone had no direct effect, whereas H2O2 increased 125I-albumin permeability more than threefold when added to monolayers pretreated for 6 h with TNF alpha. Determination of lactate dehydrogenase release indicated that increased permeability was not due to cytolysis. We measured the intracellular contents of GSH and catalase to determine their possible role in mediating the increased susceptibility to H2O2. TNF alpha treatment (100 U/ml for 6 h) decreased total GSH content and concomitantly increased the oxidized GSH content, but did not alter the cellular catalase activity. The role of GSH was examined by pretreating endothelial cells with 2 mM GSH for 3 h, which produced an 80% increase in intracellular GSH content. GSH repletion inhibited the increased sensitivity of the TNF alpha-treated endothelial cells to H2O2. We tested the effects of xanthine oxidase (XO) inhibition since XO activation may be a source of oxidants responsible for the decrease in cellular GSH content. Pretreatment with 0.5 mM oxypurinol attenuated the synergistic effect of TNF alpha and H2O2 on endothelial permeability. The results indicate that decreased oxidant buffering capacity secondary to TNF alpha-induced reduction in intracellular GSH content mediates the increased susceptibility of endothelial cells to H2O2. This mechanism may contribute to oxidant-dependent vascular endothelial injury in septicemia associated with TNF alpha release

  16. Hemangiomas and Vascular Malformations: Current Theory and Management

    PubMed Central

    Richter, Gresham T.; Friedman, Adva B.

    2012-01-01

    Vascular anomalies are a heterogeneous group of congenital blood vessel disorders more typically referred to as birthmarks. Subcategorized into vascular tumors and malformations, each anomaly is characterized by specific morphology, pathophysiology, clinical behavior, and management approach. Hemangiomas are the most common vascular tumor. Lymphatic, capillary, venous, and arteriovenous malformations make up the majority of vascular malformations. This paper reviews current theory and practice in the etiology, diagnosis, and treatment of these more common vascular anomalies. PMID:22611412

  17. 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.

  18. 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

  19. Automated image analysis of intra-tumoral and peripheral endocrine organ vascular bed regression using 'Fibrelength' as a novel structural biomarker.

    PubMed

    Hargreaves, Adam; Bigley, Alison; Price, Shirley; Kendrew, Jane; Barry, Simon T

    2017-02-10

    The study of vascular modulation has received a great deal of attention in recent years as knowledge has increased around the role of angiogenesis within disease contexts such as cancer. Despite rapidly expanding insights into the molecular processes involved and the concomitant generation of a number of anticancer vascular modulating chemotherapeutics, techniques used in the measurement of structural vascular change have advanced more modestly, particularly with regard to the preclinical quantification of off-target vascular regression within systemic, notably endocrine, blood vessels. Such changes translate into a number of major clinical side effects and there remains a need for improved preclinical screening and analysis. Here we present the generation of a novel structural biomarker, which can be incorporated into a number of contemporary image analysis platforms and used to compare tumour versus systemic host tissue vascularity. By contrasting the measurements obtained, the preclinical efficacy of vascular modulating chemotherapies can be evaluated in light of the predicted therapeutic window. Copyright © 2017 John Wiley & Sons, Ltd.

  20. [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.

  1. Megakaryocytes, malignancy and bone marrow vascular niches.

    PubMed

    Psaila, B; Lyden, D; Roberts, I

    2012-02-01

    Dynamic interactions between hematopoietic cells and their specialized bone marrow microenvironments, namely the vascular and osteoblastic 'niches', regulate hematopoiesis. The vascular niche is conducive for thrombopoiesis and megakaryocytes may, in turn, regulate the vascular niche, especially in supporting vascular and hematopoietic regeneration following irradiation or chemotherapy. A role for platelets in tumor growth and metastasis is well established and, more recently, the vascular niche has also been implicated as an area for preferential homing and engraftment of malignant cells. This article aims to provide an overview of the dynamic interactions between cellular and molecular components of the bone marrow vascular niche and the potential role of megakaryocytes in bone marrow malignancy.

  2. Shiga toxin-associated hemolytic-uremic syndrome: combined cytotoxic effects of Shiga toxin, interleukin-1 beta, and tumor necrosis factor alpha on human vascular endothelial cells in vitro.

    PubMed Central

    Louise, C B; Obrig, T G

    1991-01-01

    This study explores the relationship between Shiga toxin-producing Shigella or Escherichia coli strains and the development of vascular complications in humans following bacillary dysentery. We propose that endotoxin-elicited interleukin-1 or tumor necrosis factor alpha (TNF) may combine with Shiga toxin to facilitate vascular damage characteristic of hemolytic-uremic syndrome. This study examines the cytotoxic effects of Shiga toxin, interleukin-1, and TNF on cultured human umbilical vein endothelial cells (HUVEC). Both Shiga toxin and TNF were cytotoxic to HUVEC, although HUVEC obtained from individual umbilical cords differed in their sensitivities to these agents. With Shiga toxin-sensitive HUVEC, combinations of TNF with Shiga toxin resulted in a synergistic cytotoxic effect. In contrast, interleukin-1 was not cytotoxic to HUVEC, nor did it enhance cell death in combination with Shiga toxin. The synergistic cytotoxic response of HUVEC to Shiga toxin and TNF was dose and time dependent for both agents and could be neutralized by monoclonal antibodies directed against either Shiga toxin or TNF. This synergistic response was delayed, being maximal on day 2. Preincubation (24 h) of HUVEC with TNF sensitized the cells to Shiga toxin. TNF alone had no effect on HUVEC protein synthesis but enhanced the inhibitory activity of Shiga toxin. These results are consistent with a role for Shiga toxin in the development of hemolytic-uremic syndrome at the level of the vascular endothelium in humans. PMID:1937774

  3. Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro

    PubMed Central

    2012-01-01

    Background Obesity is associated with prostate cancer aggressiveness and mortality. The contribution of periprostatic adipose tissue, which is often infiltrated by malignant cells, to cancer progression is largely unknown. Thus, this study aimed to determine if periprostatic adipose tissue is linked with aggressive tumor biology in prostate cancer. Methods Supernatants of whole adipose tissue (explants) or stromal vascular fraction (SVF) from paired fat samples of periprostatic (PP) and pre-peritoneal visceral (VIS) anatomic origin from different donors were prepared and analyzed for matrix metalloproteinases (MMPs) 2 and 9 activity. The effects of those conditioned media (CM) on growth and migration of hormone-refractory (PC-3) and hormone-sensitive (LNCaP) prostate cancer cells were measured. Results We show here that PP adipose tissue of overweight men has higher MMP9 activity in comparison with normal subjects. The observed increased activities of both MMP2 and MMP9 in PP whole adipose tissue explants, likely reveal the contribution of adipocytes plus stromal-vascular fraction (SVF) as opposed to SVF alone. MMP2 activity was higher for PP when compared to VIS adipose tissue. When PC-3 cells were stimulated with CM from PP adipose tissue explants, increased proliferative and migratory capacities were observed, but not in the presence of SVF. Conversely, when LNCaP cells were stimulated with PP explants CM, we found enhanced motility despite the inhibition of proliferation, whereas CM derived from SVF increased both cell proliferation and motility. Explants culture and using adipose tissue of PP origin are most effective in promoting proliferation and migration of PC-3 cells, as respectively compared with SVF culture and using adipose tissue of VIS origin. In LNCaP cells, while explants CM cause increased migration compared to SVF, the use of PP adipose tissue to generate CM result in the increase of both cellular proliferation and migration. Conclusions Our

  4. 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.

  5. Primary Vascular Leiomyosarcoma: Clinical Observations and Molecular Variables

    PubMed Central

    Roland, Christina L.; Boland, Genevieve M.; Demicco, Elizabeth G.; Lusby, Kristelle; Ingram, Davis; May, Caitlin D.; Kivlin, Christine M.; Watson, Kelsey; Al Sannaa, Ghadah A.; Wang, Wei-Lien; Ravi, Vinod; Pollock, Raphael E.; Lev, Dina; Cormier, Janice N.; Hunt, Kelly K.; Feig, Barry W.; Lazar, Alexander J.; Torres, Keila E.

    2016-01-01

    Importance Vascular leiomyosarcomas (vLMS) are a rare subtype of leiomyosarcomas (LMS) most commonly affecting the inferior vena cava and accounting for 5% of all LMS. These tumors are aggressive malignancies for which adjuvant modalities have not shown increased efficacy compared over surgery. Our study evaluates potential molecular markers that should be evaluated in prospective studies to determine their prognostic and therapeutic utility. Objective To evaluate the outcomes of patients with vLMS and associations with immunohistochemical prognostic markers. Design Retrospective chart review Setting Single institution Participants A cohort of 77 patients that presented to MDACC from 1993–2012 was analyzed. All of the cases had a confirmed diagnosis of vascular leiomyosarcoma. Immunohistochemical studies for biomarkers were performed on a tissue microarray that included 26 primary vLMS specimens. Main Outcomes and Measures Demographic, and clinical factors were evaluated to assess clinical course, patterns of recurrence and survival outcomes for patients with primary vLMS. Univariate Cox proportional hazards model was utilized to correlate DSS and time to recurrence with potential prognostic indicators. Results Five year disease-specific survival (DSS) rates after tumor resection was 65%. Median time to local recurrence was 43 months, versus 25 months for distant recurrence versus 15 months for concurrent local and distant recurrences; p=0.04. Strong cytoplasmic β-catenin (p=0.06) and IGF-1R (p=0.04) expression were associated with inferior DSS. Conclusions and Relevance vLMS are aggressive malignancies, with high recurrence rates. Expression of β-catenin and IGF-1R were associated with poor DSS. Prospective studies should evaluate their clinical and therapeutic utility. PMID:26629783

  6. 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 ...

  7. 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

  8. 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

  9. 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

  10. Current medical treatment of pancreatic neuroendocrine tumors.

    PubMed

    Yalcin, Suayib; Oyan, Basak; Bayraktar, Yusuf

    2007-01-01

    Pancreatic neuroendocrine tumors (NETs) consist of a wide group of neoplasms, with different biological behaviors in terms of aggressiveness and hormone production. In the last two decades, significant progress has been observed in our understanding of their biology, diagnosis and treatment. Surgery remains to be the only curative approach, but unfortunately the diagnosis is often delayed due to the slow growth of these tumors and the difficulty in identifying the symptoms related to the tumor-released hormones. In addition to surgery, other approaches to control the disease are biological therapy consisting of somatostatin analogs and interferon (IFN), systemic chemotherapy, radioligand therapy and local therapy with chemoembolization. Several newer cytotoxic agents, including irinotecan, gemcitabine, taxanes, oxaliplatin, capecitabine and PS-341 have been studied in metastatic patients. Considering the high vascularity of these tumors, antiangiogenic agents like endostatin and thalidomide have also been evaluated in advanced NETs. Although these agents seem to have potential activity in NETs and may increase progression free survival, none of these currently available medical therapeutic options are curative. While more efficient novel strategies are to be developed, the rationale use of the current therapeutic options may improve quality of life, control the symptoms related to the hypersecretion of hormones and/or peptides, control tumor proliferation and prolong survival in patients suffering from NETs.

  11. 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…

  12. 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…

  13. 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

  14. 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…

  15. 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…

  16. Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness

    PubMed Central

    Zhang, Tao; Shen, Xiaopei; Liu, Rengyun; Zhu, Guangwu; Bishop, Justin; Xing, Mingzhao

    2017-01-01

    How the BRAF V600E mutation promotes the pathogenesis and aggressiveness of papillary thyroid cancer (PTC) is not completely understood. Here we explored a novel mechanism involving WASP interacting protein family member 1 (WIPF1). In PTC tumors, compared with the wild-type BRAF, BRAF V600E was associated with over-expression and hypomethylation of the WIPF1 gene. In thyroid cancer cell lines with wild-type BRAF, WIPF1 expression was robustly upregulated upon introduced expression of BRAF V600E (P=0.03) whereas the opposite was seen upon BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E. Methylation of a functionally critical region of the WIPF1 promoter was decreased by expressing BRAF V600E in cells harboring the wild-type BRAF and increased by BRAF knockdown or treatment with BRAF V600E or MEK inhibitors in cells harboring BRAF V600E mutation. Under-expression and hypermethylation of WIPF1 induced by stable BRAF knockdown was reversed by DNA demethylating agent 5′-azadeoxycytidine. Knockdown of WIPF1 robustly inhibited anchorage-independent colony formation, migration, and invasion of thyroid cancer cells and suppressed xenograft thyroid cancer tumor growth and vascular invasion, mimicking the effects of BRAF knockdown. In human PTC tumors, WIPF1 expression was associated with extrathyroidal invasion (P=0.01) and lymph node metastasis (P=2.64E-05). In summary, BRAF V600E-activated MAP kinase pathway causes hypomethylation and overexpression of WIPF1; WIPF1 then functions like an oncoprotein to robustly promote aggressive cellular and tumor behaviors of PTC. This represents a novel mechanism in BRAF V600E-promoted PTC aggressiveness and identifies WIPF1 as a novel therapeutic target for thyroid cancer. PMID:27863429

  17. 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

  18. 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.].

  19. 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.

  20. Ultrasound -- Vascular

    MedlinePlus

    ... plan for their effective treatment. detect blood clots (deep venous thrombosis (DVT) in the major veins of ... What are the limitations of Vascular Ultrasound? Vessels deep in the body are harder to see than ...

  1. Vascular Dementia

    MedlinePlus

    ... attack) may increase your risk of developing dementia. Atherosclerosis. This condition occurs when deposits of cholesterol and ... in your arteries and narrow your blood vessels. Atherosclerosis can increase your risk of vascular dementia — and ...

  2. 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…

  3. Primo Vascular System Accompanying a Blood Vessel from Tumor Tissue and a Method to Distinguish It from the Blood or the Lymph System

    PubMed Central

    Lim, Jaekwan; Lee, Sungwoo; Su, Zhendong; Kim, Hong Bae; Yoo, Jung Sun; Soh, Kwang-Sup; Kim, Sungchul; Ryu, Yeon Hee

    2013-01-01

    A primo vessel was observed in the abdominal cavity in the lung cancer mouse model, and its function as an extra metastatic path was observed. In this work, we found a primo vessel accompanying a blood vessel emanating from a tumor in the skin. We also presented simple and efficient criteria to distinguish a primo vessel from a blood or a lymph vessel and from a nerve. The criteria for using DAPI and Phalloidin will be useful in clinical situations to find and identify the primo vessels among the blood vessels, lymph vessels, or nerves in the tissue surrounding a tumor such as a melanoma or breast cancer. PMID:23737856

  4. Primo vascular system accompanying a blood vessel from tumor tissue and a method to distinguish it from the blood or the lymph system.

    PubMed

    Lim, Jaekwan; Lee, Sungwoo; Su, Zhendong; Kim, Hong Bae; Yoo, Jung Sun; Soh, Kwang-Sup; Kim, Sungchul; Ryu, Yeon Hee

    2013-01-01

    A primo vessel was observed in the abdominal cavity in the lung cancer mouse model, and its function as an extra metastatic path was observed. In this work, we found a primo vessel accompanying a blood vessel emanating from a tumor in the skin. We also presented simple and efficient criteria to distinguish a primo vessel from a blood or a lymph vessel and from a nerve. The criteria for using DAPI and Phalloidin will be useful in clinical situations to find and identify the primo vessels among the blood vessels, lymph vessels, or nerves in the tissue surrounding a tumor such as a melanoma or breast cancer.

  5. Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.

    PubMed

    Zhang, Lei; Kundu, Soumi; Feenstra, Tjerk; Li, Xiujuan; Jin, Chuan; Laaniste, Liisi; El Hassan, Tamador Elsir Abu; Ohlin, K Elisabet; Yu, Di; Olofsson, Tommie; Olsson, Anna-Karin; Pontén, Fredrik; Magnusson, Peetra U; Nilsson, Karin Forsberg; Essand, Magnus; Smits, Anja; Dieterich, Lothar C; Dimberg, Anna

    2015-12-08

    Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.

  6. Prognostic value of vascular mimicry in patients with urothelial carcinoma of the bladder after radical cystectomy.

    PubMed

    Zhou, Lin; Chang, Yuan; Xu, Le; Hoang, Son Tung Nguyen; Liu, Zheng; Fu, Qiang; Lin, Zongming; Xu, Jiejie

    2016-11-15

    Vascular mimicry (VM) refers to the plasticity of aggressive cancer cells forming de novo vascular networks, which promoted tumor metastasis. The aim of this study was evaluate the impact of VM on recurrence-free survival (RFS) in urothelial carcinoma of the bladder (UCB). Records from 202 patients treated with radical cystectomy (RC) for UCB at Zhongshan Hospital between 2002 and 2014 were reviewed. The presence of VM was identified by CD31-PAS double staining. Positive VM staining occurred in 19.3% (39 of 202) UCB cases, and it was associated with increased risks of recurrence (Log-Rank p<0.001). VM was identified as an independent prognostic factor (p=0.002). In the cohort with MIBC, patients with VM negative got CSS benefit from the use of ACT (p = 0.048). As for lung metastasis, the combination of VM and TNM stage (AUC 0.792) showed a better prognostic value than TNM stage alone (AUC 0.748, p = 0.008) or VM alone (AUC 0.714, p = 0.023). Vascular mimicry could be a potential prognosticator for recurrence-free survival in patients with UCB after RC. Vascular mimicry seems to predict risk of developing lung metastases after RC. The presence of VM identified a subgroup of patients with MIBC who appeared to benefit from adjuvant chemotherapy.

  7. Prognostic value of vascular mimicry in patients with urothelial carcinoma of the bladder after radical cystectomy

    PubMed Central

    Hoang, Son Tung Nguyen; Liu, Zheng; Fu, Qiang; Lin, Zongming; Xu, Jiejie

    2016-01-01

    Vascular mimicry (VM) refers to the plasticity of aggressive cancer cells forming de novo vascular networks, which promoted tumor metastasis. The aim of this study was evaluate the impact of VM on recurrence-free survival (RFS) in urothelial carcinoma of the bladder (UCB). Records from 202 patients treated with radical cystectomy (RC) for UCB at Zhongshan Hospital between 2002 and 2014 were reviewed. The presence of VM was identified by CD31-PAS double staining. Positive VM staining occurred in 19.3% (39 of 202) UCB cases, and it was associated with increased risks of recurrence (Log-Rank p<0.001). VM was identified as an independent prognostic factor (p=0.002). In the cohort with MIBC, patients with VM negative got CSS benefit from the use of ACT (p = 0.048). As for lung metastasis, the combination of VM and TNM stage (AUC 0.792) showed a better prognostic value than TNM stage alone (AUC 0.748, p = 0.008) or VM alone (AUC 0.714, p = 0.023). Vascular mimicry could be a potential prognosticator for recurrence-free survival in patients with UCB after RC. Vascular mimicry seems to predict risk of developing lung metastases after RC. The presence of VM identified a subgroup of patients with MIBC who appeared to benefit from adjuvant chemotherapy. PMID:27776348

  8. An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation.

    PubMed

    Perrin, George Q; Li, Hua; Fishbein, Lauren; Thomson, Susanne A; Hwang, Min S; Scarborough, Mark T; Yachnis, Anthony T; Wallace, Margaret R; Mareci, Thomas H; Muir, David

    2007-11-01

    Malignant peripheral nerve sheath tumors (MPNST) are the most aggressive cancers associated with neurofibromatosis type 1 (NF1). Here we report a practical and reproducible model of intraneural NF1 MPNST, by orthotopic xenograft of an immortal human NF1 tumor-derived Schwann cell line into the sciatic nerves of female scid mice. Intraneural injection of the cell line sNF96.2 consistently produced MPNST-like tumors that were highly cellular and showed extensive intraneural growth. These xenografts had a high proliferative index, were angiogenic, had significant mast cell infiltration and rapidly dominated the host nerve. The histopathology of engrafted intraneural tumors was consistent with that of human NF1 MPNST. Xenograft tumors were readily examined by magnetic resonance imaging, which also was used to assess tumor vascularity. In addition, the intraneural proliferation of sNF96.2 cell tumors was decreased in ovariectomized mice, while replacement of estrogen or progesterone restored tumor cell proliferation. This suggests a potential role for steroid hormones in supporting tumor cell growth of this MPNST cell line in vivo. The controlled orthotopic implantation of sNF96.2 cells provides for the precise initiation of intraneural MPNST-like tumors in a model system suitable for therapeutic interventions, including inhibitors of angiogenesis and further study of steroid hormone effects on tumor cell growth.

  9. 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

  10. Activation of the Kinin B1 Receptor Attenuates Melanoma Tumor Growth and Metastasis

    PubMed Central

    Dillenburg-Pilla, Patricia; Maria, Andrea G.; Reis, Rosana I.; Floriano, Elaine Medeiros; Pereira, Cacilda Dias; De Lucca, Fernando Luiz; Ramos, Simone Gusmão; Pesquero, João B.; Jasiulionis, Miriam G.; Costa-Neto, Claudio M.

    2013-01-01

    Melanoma is a very aggressive tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies. Furthermore, acquiring the ability to metastasize in melanoma and many other tumor types is directly related to incurable disease. The B1 kinin receptor participates in a variety of cancer-related pathophysiological events, such as inflammation and angiogenesis. Therefore, we investigated whether this G protein-coupled receptor plays a role in tumor progression. We used a murine melanoma cell line that expresses the kinin B1 receptor and does not express the kinin B2 receptor to investigate the precise contribution of activation of the B1 receptor in tumor progression and correlated events using various in vitro and in vivo approaches. Activation of the kinin B1 receptor in the absence of B2 receptor inhibits cell migration in vitro and decreases tumor formation in vivo. Moreover, tumors formed from cells stimulated with B1-specific agonist showed several features of decreased aggressiveness, such as smaller size and infiltration of inflammatory cells within the tumor area, higher levels of pro-inflammatory cytokines implicated in the host anti-tumor immune response, lower number of cells undergoing mitosis, a poorer vascular network, no signs of invasion of surrounding tissues or metastasis and increased animal survival. Our findings reveal that activation of the kinin B1 receptor has a host protective role during murine melanoma tumor progression, suggesting that the B1 receptor could be a new anti-tumor GPCR and provide new opportunities for therapeutic targeting. PMID:23691222

  11. Activation of the kinin B1 receptor attenuates melanoma tumor growth and metastasis.

    PubMed

    Dillenburg-Pilla, Patricia; Maria, Andrea G; Reis, Rosana I; Floriano, Elaine Medeiros; Pereira, Cacilda Dias; De Lucca, Fernando Luiz; Ramos, Simone Gusmão; Pesquero, João B; Jasiulionis, Miriam G; Costa-Neto, Claudio M

    2013-01-01

    Melanoma is a very aggressive tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies. Furthermore, acquiring the ability to metastasize in melanoma and many other tumor types is directly related to incurable disease. The B1 kinin receptor participates in a variety of cancer-related pathophysiological events, such as inflammation and angiogenesis. Therefore, we investigated whether this G protein-coupled receptor plays a role in tumor progression. We used a murine melanoma cell line that expresses the kinin B1 receptor and does not express the kinin B2 receptor to investigate the precise contribution of activation of the B1 receptor in tumor progression and correlated events using various in vitro and in vivo approaches. Activation of the kinin B1 receptor in the absence of B2 receptor inhibits cell migration in vitro and decreases tumor formation in vivo. Moreover, tumors formed from cells stimulated with B1-specific agonist showed several features of decreased aggressiveness, such as smaller size and infiltration of inflammatory cells within the tumor area, higher levels of pro-inflammatory cytokines implicated in the host anti-tumor immune response, lower number of cells undergoing mitosis, a poorer vascular network, no signs of invasion of surrounding tissues or metastasis and increased animal survival. Our findings reveal that activation of the kinin B1 receptor has a host protective role during murine melanoma tumor progression, suggesting that the B1 receptor could be a new anti-tumor GPCR and provide new opportunities for therapeutic targeting.

  12. A small interfering RNA targeting vascular endothelial growth factor efficiently inhibits growth of VX2 cells and VX2 tumor model of hepatocellular carcinoma in rabbit by transarterial embolization-mediated siRNA delivery

    PubMed Central

    Zou, Yu; Guo, Chuan-Gen; Yang, Zheng-Gang; Sun, Jun-Hui; Zhang, Min-Ming; Fu, Cai-Yun

    2016-01-01

    Introduction Hepatocellular carcinoma is currently the second leading cause of cancer-related deaths worldwide with an increasing incidence. Objective The objective of this study is to investigate the effect of vascular endothelial growth factor small interfering RNA (VEGF-siRNA) on rabbit VX2 carcinoma cell viability in vitro and the effect of transarterial embolization (TAE)-mediated VEGF-siRNA delivery on the growth of rabbit VX2 liver-transplanted model in vivo. Methods Quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot technologies were used to detect the expression level of VEGF. TAE and computed tomography scan were used to deliver the VEGF-siRNA and detect the tumor volume in vivo, respectively. Microvessel density was detected by immunohistochemistry with CD34 antibody. A biochemical autoanalyzer was used to evaluate the hepatic and renal toxicity. Results The designed VEGF-siRNAs could effectively decrease the expression levels of VEGF mRNA and protein in vitro and in vivo. In vitro, the viability of rabbit VX2 carcinoma cells was reduced by 38.5%±7.3% (VEGF-siRNA no 1) and 30.0%±5.8% (VEGF-siRNA no 3) at 48 hours after transfection. Moreover, in rabbit VX2 liver-transplanted model, the growth ratios of tumors at 28 days after TAE-mediated siRNA delivery were 155.18%±19.42% in the control group, 79.67%±19.63% in the low-dose group, and 36.09%±15.73% in the high-dose group, with significant differences among these three groups. Microvessel density dropped to 34.22±4.01 and 22.63±4.07 in the low-dose group and high-dose group, respectively, compared with the control group (57.88±5.67), with significant differences among these three groups. Furthermore, inoculation of VX2 tumor into the liver itself at later stage induced significant increase in alanine aminotransferase and aspartate aminotransferase, indicating an obvious damage of liver functions, while treatment of VX2 tumor via TAE

  13. What Is Vascular Disease?

    MedlinePlus

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  14. Vascular Disease Foundation

    MedlinePlus

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  15. 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.

  16. BENIGN BONE TUMORS AND TUMOR-LIKE BONE LESIONS: TREATMENT UPDATE AND NEW TRENDS

    PubMed Central

    Nogueira Drumond, José Marcos

    2015-01-01

    The treatment of benign bone tumors (BBT) and tumor-like bone lesions (TBL) has observed the introduction of new drugs, such as intravenous bisphosphonates, which have ossified bone lesions caused by fibrous dysplasia. Aneurismal bone cyst has been treated with sclerosing agents by percutaneous injection, yielding good results. Adjuvants allow joint salvage, maintenance of movements and function, with low rates of recurrence. Among them, the most used ones are bone cement (PMMA), phenol, nitrogen-based cryotherapy, hydrogen peroxide, ethanol and radiotherapy. New methods of treatment include thermal ablation with radiofrequency and laser, mainly utilized for treating osteoid osteoma. Arthroscopy allows resection of benign intra-joint lesions and assists the surgery of subchondral tumors. A great advance is the utilization of synthetic bone substitutes, which are a mixture of osteoinductive growth factors and osteoconductive ceramics, and have presented comparable results to autogenous bone grafts. There is a recent trend for closed treatments, with percutaneous injection of demineralized bone matrix (DBM) and calcium sulfate. Autogenous cancellous bone graft remains as the gold standard. Vascularized fibula graft, on the other hand, incorporates faster in the treatment of large destructive lesions. Also, allogenic cortical support allows structural augmentation for aggressive tumors. Freeze-dried allografts are used to fill contained defects and as expanders of autografts. Joint endoprosthesis may be used in large destructive lesions of the distal femur, hip and shoulder. PMID:27004184

  17. STAT3 Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer

    PubMed Central

    Nagathihalli, Nagaraj S.; Castellanos, Jason A.; Shi, Chanjuan; Beesetty, Yugandhar; Reyzer, Michelle L.; Caprioli, Richard; Chen, Xi; Walsh, Alex J.; Skala, Melissa C.; Moses, Harold L.; Merchant, Nipun B.

    2015-01-01

    BACKGROUND & AIMS A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified STAT3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. METHODS Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by MALDI-imaging mass spectrometry. Collagen second harmonic generation (SHG) imaging quantified tumor collagen alignment and density. RESULTS STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma and downregulation of cytidine deaminase (Cda). CONCLUSIONS Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and downregulation of Cda without depletion of tumor stromal content. PMID:26255562

  18. A Review of Vascular Anomalies: Genetics and Common Syndromes

    PubMed Central

    Killion, Elizabeth; Mohan, Kriti; Lee, Edward I.

    2014-01-01

    Vascular tumors and malformations are unique in that affected cells exhibit disrupted angiogenesis. The current treatment options often yield suboptimal results. New insight into the genetics and molecular basis of vascular anomalies may pave the way for potential development of targeted therapy. The authors review the genetic and molecular basis of vascular anomalies and common associated syndromes. PMID:25045331

  19. 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

  20. 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…

  1. 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…

  2. 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…

  3. 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…

  4. 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…

  5. 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…

  6. Automated Voxel-Based Analysis of Volumetric Dynamic Contrast-Enhanced CT Data Improves Measurement of Serial Changes in Tumor Vascular Biomarkers

    SciTech Connect

    Coolens, Catherine; Driscoll, Brandon; Chung, Caroline; Shek, Tina; Gorjizadeh, Alborz; Ménard, Cynthia; Jaffray, David

    2015-01-01

    Objectives: Development of perfusion imaging as a biomarker requires more robust methodologies for quantification of tumor physiology that allow assessment of volumetric tumor heterogeneity over time. This study proposes a parametric method for automatically analyzing perfused tissue from volumetric dynamic contrast-enhanced (DCE) computed tomography (CT) scans and assesses whether this 4-dimensional (4D) DCE approach is more robust and accurate than conventional, region-of-interest (ROI)-based CT methods in quantifying tumor perfusion with preliminary evaluation in metastatic brain cancer. Methods and Materials: Functional parameter reproducibility and analysis of sensitivity to imaging resolution and arterial input function were evaluated in image sets acquired from a 320-slice CT with a controlled flow phantom and patients with brain metastases, whose treatments were planned for stereotactic radiation surgery and who consented to a research ethics board-approved prospective imaging biomarker study. A voxel-based temporal dynamic analysis (TDA) methodology was used at baseline, at day 7, and at day 20 after treatment. The ability to detect changes in kinetic parameter maps in clinical data sets was investigated for both 4D TDA and conventional 2D ROI-based analysis methods. Results: A total of 7 brain metastases in 3 patients were evaluated over the 3 time points. The 4D TDA method showed improved spatial efficacy and accuracy of perfusion parameters compared to ROI-based DCE analysis (P<.005), with a reproducibility error of less than 2% when tested with DCE phantom data. Clinically, changes in transfer constant from the blood plasma into the extracellular extravascular space (K{sub trans}) were seen when using TDA, with substantially smaller errors than the 2D method on both day 7 post radiation surgery (±13%; P<.05) and by day 20 (±12%; P<.04). Standard methods showed a decrease in K{sub trans} but with large uncertainty (111.6 ± 150.5) %. Conclusions

  7. Pleiotrophin is a driver of vascular abnormalization in glioblastoma.

    PubMed

    Zhang, Lei; Dimberg, Anna

    2016-01-01

    In a recent report by Zhang et al., pleiotrophin (PTN) was demonstrated to enhance glioma growth by promoting vascular abnormalization. PTN stimulates glioma vessels through anaplastic lymphoma kinase (Alk)-mediated perivascular deposition of vascular endothelial growth factor (VEGF). Targeting of Alk or VEGF signaling normalizes tumor vessels in PTN-expressing tumors.

  8. 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…

  9. 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…

  10. Vascular Hyperpermeability, Angiogenesis, and Stroma Generation

    PubMed Central

    Nagy, Janice A.; Dvorak, Ann M.; Dvorak, Harold F.

    2012-01-01

    It has been known for more than half a century that the tumor microvasculature is hyperpermeable to plasma proteins. However, the identity of the leaky vessels and the consequences of vascular hyperpermeability have received little attention. This article places tumor vascular hyperpermeability in a broader context, relating it to (1) the low-level “basal” permeability of the normal vasculature; (2) the “acute,” short-term hyperpermeability induced by vascular permeability factor/vascular endothelial growth factor (VPF/VEGF-A) and other vascular permeabilizing agents; and (3) the “chronic” hyperpermeability associated with longer-term exposure to agents such as VPF/VEGF-A that accompanies many types of pathological angiogenesis. Leakage of plasma protein-rich fluids is important because it activates the clotting system, depositing an extravascular fibrin gel provisional matrix that serves as the first step in stroma generation. PMID:22355795

  11. Vascular effect of photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Fyodorov, Svyatoslav N.; Kopayeva, V. G.; Andreev, J. B.; Ponomarev, Gelii V.; Stranadko, Eugeny P.; Suchin, H. M.

    1996-01-01

    Vascular effect of PDT has been studied in patients with corneal vascularized leucomas (10 patients) and in patients with corneal neovascularized transplant (3 patients). For vascularized leucomas the method of photodynamic therapy consisted of the local injection of dimegin (deiteroporphyrin derivative) into the space of the newly-formed vessels under operating microscope (opton) with the microneedle (diameter 200 microns) and corneal irradiation by the operating microscope light. For corneal neovascularized transplant the injection of photogem (hematoporphyrin derivative) intravenously were made with subsequent irradiation by light of dye laser (5 hours after the injection) with light density of 150 mW/cm2 for 15 minutes. In all the cases at the time of irradiation the aggregated blood flow was appeared, followed by blood flow stasis. In postoperative period the vessels disintegrated into separate fragments which disappeared completely after 10 - 15 days. Taking into account the data of light microscopy, the disappearance of the vessels took place as a result of the vascular endothelium lisis along the vascular walls. Neovascularized cornea and newly-formed vessels in tumor stroms have much in common. The vessel alterations study presented in this paper, may serve to specify the mechanism of photodynamic destruction of neovascularized stroma of tumor.

  12. NADPH Oxidases in Vascular Pathology

    PubMed Central

    Konior, Anna; Schramm, Agata; Czesnikiewicz-Guzik, Marta

    2014-01-01

    Abstract Significance: Reactive oxygen species (ROS) play a critical role in vascular disease. While there are many possible sources of ROS, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases play a central role. They are a source of “kindling radicals,” which affect other enzymes, such as nitric oxide synthase endothelial nitric oxide synthase or xanthine oxidase. This is important, as risk factors for atherosclerosis (hypertension, diabetes, hypercholesterolemia, and smoking) regulate the expression and activity of NADPH oxidases in the vessel wall. Recent Advances: There are seven isoforms in mammals: Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2. Nox1, Nox2, Nox4, and Nox5 are expressed in endothelium, vascular smooth muscle cells, fibroblasts, or perivascular adipocytes. Other homologues have not been found or are expressed at very low levels; their roles have not been established. Nox1/Nox2 promote the development of endothelial dysfunction, hypertension, and inflammation. Nox4 may have a role in protecting the vasculature during stress; however, when its activity is increased, it may be detrimental. Calcium-dependent Nox5 has been implicated in oxidative damage in human atherosclerosis. Critical Issues: NADPH oxidase-derived ROS play a role in vascular pathology as well as in the maintenance of normal physiological vascular function. We also discuss recently elucidated mechanisms such as the role of NADPH oxidases in vascular protection, vascular inflammation, pulmonary hypertension, tumor angiogenesis, and central nervous system regulation of vascular function and hypertension. Future Directions: Understanding the role of individual oxidases and interactions between homologues in vascular disease is critical for efficient pharmacological regulation of vascular NADPH oxidases in both the laboratory and clinical practice. Antioxid. Redox Signal. 20, 2794–2814. PMID:24180474

  13. 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 ...

  14. Tumor Endothelial Cells

    PubMed Central

    Dudley, Andrew C.

    2012-01-01

    The vascular endothelium is a dynamic cellular “organ” that controls passage of nutrients into tissues, maintains the flow of blood, and regulates the trafficking of leukocytes. In tumors, factors such as hypoxia and chronic growth factor stimulation result in endothelial dysfunction. For example, tumor blood vessels have irregular diameters; they are fragile, leaky, and blood flow is abnormal. There is now good evidence that these abnormalities in the tumor endothelium contribute to tumor growth and metastasis. Thus, determining the biological basis underlying these abnormalities is critical for understanding the pathophysiology of tumor progression and facilitating the design and delivery of effective antiangiogenic therapies. PMID:22393533

  15. Ocular surface tumors

    PubMed Central

    Othman, Ihab Saad

    2009-01-01

    Tumors of the conjunctiva and cornea comprise a large and varied spectrum of conditions. These tumors are grouped into two major categories of congenital and acquired lesions. The acquired lesions are further subdivided based on origin of the mass into surface epithelial, mucoepidermoid, melanocytic, vascular, fibrous, neural, histiocytic, myxoid, myogenic, lipomatous, lymphoid, leukemic, metastatic and secondary tumors. Ocular surface tumors include a variety of neoplasms originating from squamous epithelium, melanocytic tumors and lymphocytic resident cells of the conjunctival stroma. In this review, we highlight clinical features of these lesions, important diagnostic and investigative tools and standard care of management. PMID:21234217

  16. A randomized Phase II trial of the tumor vascular disrupting agent CA4P (fosbretabulin tromethamine) with carboplatin, paclitaxel, and bevacizumab in advanced nonsquamous non-small-cell lung cancer

    PubMed Central

    Garon, Edward B; Neidhart, Jeffrey D; Gabrail, Nashat Y; de Oliveira, Moacyr R; Balkissoon, Jai; Kabbinavar, Fairooz

    2016-01-01

    Introduction Combretastatin A4-phosphate, fosbretabulin tromethamine (CA4P) is a vascular disrupting agent that targets tumor vasculature. This study evaluated the safety of CA4P when combined with carboplatin, paclitaxel, and bevacizumab in chemotherapy-naïve subjects with advanced nonsquamous, non-small-cell lung cancer. Methods Adult subjects with confirmed American Joint Committee on Cancer six stage IIIB/IV non-small-cell lung cancer and an Eastern Cooperative Oncology Group performance score of 0 or 1 were randomized to receive six cycles (treatment phase) of paclitaxel (200 mg/m2), carboplatin (area under the concentration versus time curve 6), and bevacizumab (15 mg/kg) on day 1 and repeated every 21 days, or this regimen plus CA4P (60 mg/m2) on days 7, 14, and 21 of each cycle. Subjects could then receive additional maintenance treatment (excluding carboplatin and paclitaxel) for up to 1 year. Results Sixty-three subjects were randomized, 31 to control and 32 to CA4P, and 19 (61.3%) and 17 (53.1%), respectively, completed the treatment phase. Exposure to study treatment and dose modifications were comparable between the randomized groups. The overall incidence of treatment-emergent adverse events was similar between groups, with increased neutropenia, leukopenia, and hypertension in the CA4P group. Deaths, serious adverse events, and early discontinuations from treatment were comparable between the randomized treatment groups. The overall tumor response rate with CA4P was 50% versus 32% in controls. Overall and progression-free survival rates were comparable between the groups. Conclusion CA4P plus carboplatin, paclitaxel, and bevacizumab appears to be a tolerable regimen with an acceptable toxicity profile in subjects with advanced non-small-cell lung cancer. PMID:27942221

  17. Pathophysiological Basis for the Formation of the Tumor Microenvironment

    PubMed Central

    Horsman, Michael R.; Vaupel, Peter

    2016-01-01

    Poor microenvironmental conditions are a characteristic feature of solid tumors. Such conditions occur because the tumor vascular supply, which develops from the normal host vasculature by the process of angiogenesis, is generally inadequate in meeting the oxygen and nutrient demands of the growing tumor mass. Regions of low oxygenation (hypoxia) is believed to be the most critical deficiency, since it has been well documented to play a significant role in influencing the response to conventional radiation and chemotherapy treatments, as well as influencing malignant progression in terms of aggressive growth and recurrence of the primary tumor and its metastatic spread. As a result, significant emphasis has been placed on finding clinically applicable approaches to identify those tumors that contain hypoxia and realistic methods to target this hypoxia. However, most studies consider hypoxia as a single entity, yet we now know that it is multifactorial. Furthermore, hypoxia is often associated with other microenvironmental parameters, such as elevated interstitial fluid pressure, glycolysis, low pH, and reduced bioenergetic status, and these can also influence the effects of hypoxia. Here, we review the various aspects of hypoxia, but also discuss the role of the other microenvironmental parameters associated with hypoxia. PMID:27148472

  18. Rectal carcinoid tumor metastasis to a skull base meningioma

    PubMed Central

    Huang, Jennifer; Gupta, Amit; Badve, Chaitra; Cohen, Mark L; Wolansky, Leo J

    2016-01-01

    Carcinoid tumors are rare, slow-growing neuroendocrine tumors that most frequently develop in the gastrointestinal tract or lungs and have high potential for metastasis. Metastasis to the brain is rare, but to another intracranial tumor is extremely rare. Of the intracranial tumors, meningiomas are the most common to host metastases, which may be related to its rich vascularity and E-cadherin expression. We describe the case of a 65-year-old female with active chemotherapy-treated neuroendocrine carcinoma who presented with left-sided facial numbness, headaches, and blurry vision. Initial imaging revealed a 1 cm irregular dural-based left petrous apex mass suggestive of a meningioma that was re-imaged four months later as a rapidly enlarging, extra-axial, mass extending into the cavernous sinus, effacing Meckel’s cave that resembled a trigeminal schwannoma. Pathology revealed a carcinoid tumor metastatic to meningioma. While the mass displayed characteristic imaging findings of a schwannoma, rapid growth in the setting of known active malignancy should prompt the clinician to consider mixed pathology from metastatic disease or a more aggressive meningioma. PMID:26825133

  19. Enrichment of regulatory T cells in invasive breast tumor correlates with the upregulation of IL-17A expression and invasiveness of the tumor.

    PubMed

    Benevides, Luciana; Cardoso, Cristina R B; Tiezzi, Daniel G; Marana, Heitor R C; Andrade, Jurandyr M; Silva, João S

    2013-06-01

    Breast cancer is a leading cause of neoplasia-associated death in women worldwide. Regulatory T (Treg) and Th17 cells are enriched within some tumors, but the role these cells play in invasive ductal carcinoma (IDC) of the breast is unknown. We show that CD25(+) CD4(+) T cells from PBMCs and tumor express high levels of Foxp3, GITR, CTLA-4, and CD103, indicating that tumor-infiltrating Treg cells are functional and possibly recruited by CCL22. Additionally, we observed upregulation of Th17-related molecules (IL-17A, RORC, and CCR6) and IL-17A produced by tumor-infiltrating CD4(+) and CD8(+) T lymphocytes. The angiogenic factors CXCL8, MMP-2, MMP-9, and vascular endothelial growth factor detected within the tumor are possibly induced by IL-17 and indicative of poor disease prognosis. Treg and Th17 cells were synchronically increased in IDC patients, with positive correlation between Foxp3, IL-17A, and RORC expression, and associated with tumor aggressiveness. Therefore, Treg and Th17 cells can affect disease progression by Treg-cell-mediated suppression of the effector T-cell response, as indicated by a decrease in the proliferation of T cells isolated from PBMCs of IDC patients and induction of angiogenic factors by IL-17-producing Th17. The understanding of regulation of the Treg/Th17 axis may result in novel perspectives for the control of invasive tumors.

  20. 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.

  1. 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.

  2. 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

  3. Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)benzo[b]furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Properties

    PubMed Central

    Flynn, Bernard L.; Gill, Gurmit S.; Grobelny, Damian W.; Chaplin, Jason H.; Paul, Dharam; Leske, Annabell F.; Lavranos, Tina C.; Chalmers, David K.; Charman, Susan A.; Kostewicz, Edmund; Shackleford, David M.; Morizzi, Julia; Hamel, Ernest; Jung, M. Katherine; Kremmidiotis, Gabriel

    2011-01-01

    A structure–activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo-[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P). PMID:21774499

  4. 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

  5. SLT-VEGF reduces lung metastases, decreases tumor recurrence, and improves survival in an orthotopic melanoma model.

    PubMed

    Ackerman, Rachel; Backer, Joseph M; Backer, Marina; Skariah, Sini; Hamby, Carl V

    2010-09-01

    SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 10(6) cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007), reduced the incidence of lung metastasis (p = 0.038), and improved survival (p = 0.002). These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions.

  6. 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…

  7. 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

  8. [Pathogenesis and genetics of vascular anomalies].

    PubMed

    Vikkula, M

    2006-01-01

    Vascular anomalies, divided into vascular tumors and vascular malformations, are localized defects of angiogenesis. Hemangiomas appear soon after birth, grow quickly, and then spontaneously, but slowly, disappear. In contrast, vascular malformations are congenital defects of vascular development that grow proportionately with the child. Most vascular anomalies are considered non-hereditary. However, due to detailed analysis inherited forms have been observed, which has led to identify mutations in three genes causing familial vascular malformations: in the angiopoietin receptor TIE2 in mucocutaneous venous malformations (VMCM), in glomulin in glomuvenous malformations (GVM) and in RASA1 in the newly recognized phenotype capillary malformation-arteriovenous malformation (CM-AVM). Identification of the causative genes has permitted more precise diagnosis and differential diagnosis, evaluation of phenotypic variability among patients with a proven mutation, study of used treatments in more homogeneous patient groups, and elucidation of the etiopathogenic mechanisms behind vascular malformations. Further studies are needed to unravel the role of genetic variations in the various vascular malformations and to unravel the precise molecular mechanisms that lead to development of these vascular lesions. This should provide development of new-targeted therapies.

  9. 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

  10. Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis

    PubMed Central

    Agrawal, Vijayendra; Kim, Dong Young; Kwon, Young-Guen

    2017-01-01

    Tumor growth is governed by the coordinated action of various types of cells that are present in the tumor environment. Fibroblasts, which constitute a major fraction of the stroma, participate actively in various signaling events and regulate tumor development and metastasis. The Hedgehog (Hh) pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood. Here we implanted B16F10 tumors in hhip+/− mice to study the tumor growth characteristics and the vascular phenotype. Furthermore, the mechanism involved in the observed phenomena was explored to reveal the role of hhip in tumor growth. The tumors that were implanted in hhip+/− mice exhibited accelerated growth and increased tumor angiogenesis. Although we observed a decrease in hypoxia, blood vessels still had abnormal phenotype. We found that increased Hh signaling in tumor fibroblasts induced a high expression of vascular endothelial growth factor (VEGF), which subsequently resulted in an increased proliferation of endothelial cells. Thus, the heterozygous knockdown of hhip in mice could affect Hh signaling in tumor fibroblasts, which could cause the increased production of the growth factor VEGF. This signaling, via a paracrine effect on endothelial cells, increased tumor vascular density. PMID:28127049

  11. Superior sulcus tumors (Pancoast tumors)

    PubMed Central

    Battistella, Lucia; Mammana, Marco; Calabrese, Francesca; Rea, Federico

    2016-01-01

    Superior Sulcus Tumors, frequently termed as Pancoast tumors, are a wide range of tumors invading the apical chest wall. Due to its localization in the apex of the lung, with the potential invasion of the lower part of the brachial plexus, first ribs, vertebrae, subclavian vessels or stellate ganglion, the superior sulcus tumors cause characteristic symptoms, like arm or shoulder pain or Horner’s syndrome. The management of superior sulcus tumors has dramatically evolved over the past 50 years. Originally deemed universally fatal, in 1956, Shaw and Paulson introduced a new treatment paradigm with combined radiotherapy and surgery ensuring 5-year survival of approximately 30%. During the 1990s, following the need to improve systemic as well as local control, a trimodality approach including induction concurrent chemoradiotherapy followed by surgical resection was introduced, reaching 5-year survival rates up to 44% and becoming the standard of care. Many efforts have been persecuted, also, to obtain higher complete resection rates using appropriate surgical approaches and involving multidisciplinary team including spine surgeon or vascular surgeon. Other potential treatment options are under consideration like prophylactic cranial irradiation or the addition of other chemotherapy agents or biologic agents to the trimodality approach. PMID:27429965

  12. Frontal Bone Hemangioma in an 8-year-old Female: A Common Tumor in a Rare Location

    PubMed Central

    Sharma, Abhimanyu; Singh, Usha Rani; Sihag, Prateek

    2016-01-01

    Intraosseous hemangioma is a rare bone tumor accounting for 0.7%–1.0% of all bone tumors. In the skull, frontal bone is the commonly involved bone. An 8-year-old female presented to our outpatient department with complaints of pain and swelling over forehead for 4 months. X-ray revealed a lytic expansile lesion involving frontal bone with sunburst pattern of bony spicules radiating to periphery of the lesion. Magnetic resonance imaging revealed the presence of a well-circumscribed lesion with both intra as well as extracranial components. Histopathology revealed a vascular tumor consisting of both small (capillary) and large (cavernous) sized vessels. A diagnosis of mixed type of hemangioma of the frontal bone was given. Recognition of hemangioma on radiology and confirmation by histopathology is essential for proper management as it might be confused clinically with other locally aggressive/malignant lesions. PMID:28163515

  13. 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.

  14. 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.

  15. Overexpression of homeobox B-13 correlates with angiogenesis, aberrant expression of EMT markers, aggressive characteristics and poor prognosis in pancreatic carcinoma.

    PubMed

    Zhai, Lu-Lu; Wu, Yang; Cai, Chong-Yang; Tang, Zhi-Gang

    2015-01-01

    To investigate the expression of homeobox B (Hoxb)-13 and analyze its relationship with tumor angiogenesis, epithelial-mesenchymal transition (EMT)-associated markers (E-cadherin and vimentin), clinicopathologic data and prognosis in pancreatic carcinoma. Immunohistochemistry was applied to determine the level of Hoxb-13 expression in tumor tissues and surrounding non-tumor tissues from 85 subjects with pancreatic carcinoma. Besides, vascular endothelial growth factor (VEGF), CD31, E-cadherin and vimentin were also detected in tumor tissues by immunostaining. We found that the level of Hoxb-13 expression was significantly higher in pancreatic carcinoma tissues than in paracarcinomatous tissues (P < 0.05). Hoxb-13 staining was positively correlated with VEGF (r = 0.429, P < 0.001) and microvessel density (MVD) (r = 0.454, P < 0.001). Likewise, Hoxb-13 staining was positively correlated with vimentin (r = 0.448, P < 0.001); while it was negatively correlated with E-cadherin (r = -0.405, P < 0.001). High Hoxb-13 expression was associated with aggressive clinicopathological characteristics, worse disease-free survival (DFS) (P < 0.001) and worse overall survival (OS) (P < 0.001). Multivariate analysis showed that Hoxb-13 was an independent predictor for poor DFS (P < 0.001) and OS (P = 0.002). In conclusion, our data show that overexpressed Hoxb-13 is correlated with tumor angiogenesis, aberrant expression of EMT-associated markers and aggressive clinicopathological characteristics, and serves as a promising marker for unfavourable prognosis in pancreatic carcinoma.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. Palmitic acid exerts pro-inflammatory effects on vascular smooth muscle cells by inducing the expression of C-reactive protein, inducible nitric oxide synthase and tumor necrosis factor-α.

    PubMed

    Wu, Di; Liu, Juntian; Pang, Xiaoming; Wang, Shuyue; Zhao, Jingjing; Zhang, Xiaolu; Feng, Liuxin

    2014-12-01

    Atherosclerosis is a chronic inflammatory disease in the vessel, and inflammatory cytokines play an important role in the inflammatory process of atherosclerosis. A high level of free fatty acids (FFAs) produced in lipid metabolism disorders are known to participate in the formation of atherosclerosis through multiple bioactivities. As the main saturated fatty acid in FFAs, palmitic acid stimulates the expression of inflammatory cytokines in macrophages. However, it is unclear whether palmitic acid exerts a pro-inflammatory effect on vascular smooth muscle cells (VSMCs). The purpose of the present study was to observe the effect of palmitic acid on the expression of C-reactive protein (CRP), tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) in VSMCs. Rat VSMCs were cultured, and palmitic acid was used as a stimulant for CRP, TNF-α and iNOS expression. mRNA expression was assayed with reverse transcription-polymerase chain reaction, and protein expression was detected with western blot analysis and immunocytochemistry. The results showed that palmitic acid significantly stimulated mRNA and protein expression of CRP, TNF-α and iNOS in VSMCs in time- and concentration-dependent manners, and therefore, palmitic acid is able to exert a pro-inflammatory effect on VSMCs via stimulating CRP, TNF-α and iNOS expression. The findings provide a novel explanation for the direct pro-inflammatory and atherogenic effects of palmitic acid, and for the association with metabolic syndrome, such as type 2 diabetes mellitus, obesity and atherosclerosis. Therefore, the intervention with anti-inflammatory agents may effectively delay the formation and progression of atherosclerosis in patients with metabolic syndrome.

  2. Berberine inhibits tumor necrosis factor-α-induced expression of inflammatory molecules and activation of nuclear factor-κB via the activation of AMPK in vascular endothelial cells.

    PubMed

    Liu, Su-Jian; Yin, Cai-Xia; Ding, Ming-Chao; Wang, Yi-Zhong; Wang, Hong

    2015-10-01

    Berberine, which is a well‑known drug used in traditional medicine, has been demonstrated to exert diverse pharmacological effects, including anti‑inflammatory effects. However, whether berberine can affect the production of inflammatory molecules in vascular endothelial cells remains to be elucidated. Therefore, the present study aimed to determine the effects of berberine, and the underlying molecular mechanisms of these effects. The effect of berberine on tumor necrosis factor (TNF)‑α‑induced inflammatory molecule expression was examined in cultured human aortic endothelial cells (HAECs). The HAECs were stimulated with TNF‑α and incubated with or without berberine. The activation of nuclear factor (NF)‑κB and adenosine monophosphate‑activated protein kinase (AMPK) were analyzed using western blotting, and the protein secretion of intercellular adhesion molecule (ICAM)‑1 and monocyte chemoattractant protein (MCP)‑1 was measured using ELISA kits. The mRNA expression levels of ICAM‑1 and MCP‑1 were analyzed using reverse transcription‑quantitative polymerase chain reaction. The results of the present study demonstrated that berberine significantly inhibited the TNF‑α‑induced expression of ICAM‑1 and MCP‑1, as well as the activation of NF‑κB in the HAECs. These effects were attenuated following co‑treatment with AMPK inhibitor compound C, or specific small interfering RNAs. In conclusion, the results of the present study indicated that berberine inhibits the TNF‑α‑induced expression of ICAM‑1 and MCP‑1, and the activation of NF‑κB in HAECs in vitro, possibly through the AMPK‑dependent pathway.

  3. Two Susceptibility Loci Identified for Prostate Cancer Aggressiveness

    PubMed Central

    Berndt, Sonja I.; Wang, Zhaoming; Yeager, Meredith; Alavanja, Michael C.; Albanes, Demetrius; Amundadottir, Laufey; Andriole, Gerald; Freeman, Laura Beane; Campa, Daniele; Cancel-Tassin, Geraldine; Canzian, Federico; Cornu, Jean-Nicolas; Cussenot, Olivier; Diver, W. Ryan; Gapstur, Susan M.; Grönberg, Henrik; Haiman, Christopher A.; Henderson, Brian; Hutchinson, Amy; Hunter, David J.; Key, Timothy J.; Kolb, Suzanne; Koutros, Stella; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Machiela, Mitchell J.; Ostrander, Elaine A.; Riboli, Elio; Schumacher, Fred; Siddiq, Afshan; Stanford, Janet L.; Stevens, Victoria L.; Travis, Ruth C.; Tsilidis, Konstantinos K.; Virtamo, Jarmo; Weinstein, Stephanie; Wilkund, Fredrik; Xu, Jianfeng; Zheng, S. Lilly; Yu, Kai; Wheeler, William; Zhang, Han; Sampson, Joshua; Black, Amanda; Jacobs, Kevin; Hoover, Robert N; Tucker, Margaret; Chanock, Stephen J.

    2015-01-01

    Most men diagnosed with prostate cancer will experience indolent disease; hence discovering genetic variants that distinguish aggressive from non-aggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49×10-9) and rs78943174 at 3q26.31 (NAALADL2, P=4.18×10-8). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85×10-5) with no association for non-aggressive prostate cancer compared to controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation. PMID:25939597

  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. Novel Treatment Shrinks Ovarian Tumors in Mice

    Cancer.gov

    Researchers have developed a new approach for treating tumors that express mutant versions of the p53 protein, which are present in more than half of all cancers, including an aggressive and common subtype of ovarian cancer.

  6. Emerging Insights into Barriers to Effective Brain Tumor Therapeutics

    PubMed Central

    Woodworth, Graeme F.; Dunn, Gavin P.; Nance, Elizabeth A.; Hanes, Justin; Brem, Henry

    2014-01-01

    There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM. PMID:25101239

  7. Reduction of Aggressive Behavior in the School.

    ERIC Educational Resources Information Center

    Petermann, Ulrike

    1988-01-01

    Discusses what may be considered aggressive behavior, what motivates aggressive students, and possible teacher responses to aggressive behavior. Describes four points on which teachers can focus to diminish the attractiveness of aggression and ensure that it is not rewarded. Identifies learning activities which provide aggressive students with the…

  8. The Effects of Pornography on Aggressive Behavior.

    ERIC Educational Resources Information Center

    Stacy, Lauri L.

    This document reviews existing empirical research on the effect of pornography on aggressive behavior. Two types of pornography are distinguished: aggressive pornography and non-aggressive pornography. Conclusions drawn from the research review are presented, including: (1) aggressive pornograpy consistently increases aggressive attitudes and…

  9. Vascular permeability, vascular hyperpermeability and angiogenesis

    PubMed Central

    Nagy, Janice A.; Benjamin, Laura; Zeng, Huiyan; Dvorak, Ann M.

    2008-01-01

    The vascular system has the critical function of supplying tissues with nutrients and clearing waste products. To accomplish these goals, the vasculature must be sufficiently permeable to allow the free, bidirectional passage of small molecules and gases and, to a lesser extent, of plasma proteins. Physiologists and many vascular biologists differ as to the definition of vascular permeability and the proper methodology for its measurement. We review these conflicting views, finding that both provide useful but complementary information. Vascular permeability by any measure is dramatically increased in acute and chronic inflammation, cancer, and wound healing. This hyperpermeability is mediated by acute or chronic exposure to vascular permeabilizing agents, particularly vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A). We demonstrate that three distinctly different types of vascular permeability can be distinguished, based on the different types of microvessels involved, the composition of the extravasate, and the anatomic pathways by which molecules of different size cross-vascular endothelium. These are the basal vascular permeability (BVP) of normal tissues, the acute vascular hyperpermeability (AVH) that occurs in response to a single, brief exposure to VEGF-A or other vascular permeabilizing agents, and the chronic vascular hyperpermeability (CVH) that characterizes pathological angiogenesis. Finally, we list the numerous (at least 25) gene products that different authors have found to affect vascular permeability in variously engineered mice and classify them with respect to their participation, as far as possible, in BVP, AVH and CVH. Further work will be required to elucidate the signaling pathways by which each of these molecules, and others likely to be discovered, mediate the different types of vascular permeability. PMID:18293091

  10. Lunar Influences on Human Aggression.

    ERIC Educational Resources Information Center

    Russell, Gordon W.; Dua, Manjula

    1983-01-01

    Used league records of all Canadian hockey games (N=426) played during a season to test a lunar-aggression hypothesis. Despite the use of multiple measures of lunar phase and interpersonal aggression, support for lunar influence was not forthcoming. Supplemental data revealed that beliefs in lunar influence are fairly common. (JAC)

  11. Traumatic Brain Injury and Aggression.

    ERIC Educational Resources Information Center

    Miller, Laurence

    1994-01-01

    Persons who have suffered traumatic injury to the brain may subsequently display aggressive behavior. Three main syndromes of aggression following traumatic brain injury are described: (1) episodic dyscontrol; (2) frontal lobe disinhibition; and (3) exacerbation of premorbid antisociality. The neuropsychological substrates of these syndromes are…

  12. Neuroblastoma-targeted nanocarriers improve drug delivery and penetration, delay tumor growth and abrogate metastatic diffusion.

    PubMed

    Cossu, Irene; Bottoni, Gianluca; Loi, Monica; Emionite, Laura; Bartolini, Alice; Di Paolo, Daniela; Brignole, Chiara; Piaggio, Francesca; Perri, Patrizia; Sacchi, Angelina; Curnis, Flavio; Gagliani, Maria Cristina; Bruno, Silvia; Marini, Cecilia; Gori, Alessandro; Longhi, Renato; Murgia, Daniele; Sementa, Angela Rita; Cilli, Michele; Tacchetti, Carlo; Corti, Angelo; Sambuceti, Gianmario; Marchiò, Serena; Ponzoni, Mirco; Pastorino, Fabio

    2015-11-01

    Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive neuroblastoma, a childhood tumor mostly refractory to current therapies. Here we validated the specific binding of HSYWLRS to neuroblastoma cell suspensions obtained either from cell lines, animal models, or Schwannian-stroma poor, stage IV neuroblastoma patients. Binding of the biotinylated peptide and of HSYWLRS-functionalized fluorescent quantum dots or liposomal nanoparticles was dose-dependent and inhibited by an excess of free peptide. In animal models obtained by the orthotopic implant of either MYCN-amplified or MYCN single copy human neuroblastoma cell lines, treatment with HSYWLRS-targeted, doxorubicin-loaded Stealth Liposomes increased tumor vascular permeability and perfusion, enhancing tumor penetration of the drug. This formulation proved to exert a potent antitumor efficacy, as evaluated by bioluminescence imaging and micro-PET, leading to (i) delay of tumor growth paralleled by decreased tumor glucose consumption, and (ii) abrogation of metastatic spreading, accompanied by absence of systemic toxicity and significant increase in the animal life span. Our findings are functional to the design of targeted nanocarriers with potentiated therapeutic efficacy towards the clinical translation.

  13. The Neurobiology of Impulsive Aggression.

    PubMed

    Blair, Robert J R

    2016-02-01

    This selective review provides a model of the neurobiology of impulsive aggression from a cognitive neuroscience perspective. It is argued that prototypical cases of impulsive aggression, those associated with anger, involve the recruitment of the acute threat response system structures; that is, the amygdala, hypothalamus, and periaqueductal gray. It is argued that whether the recruitment of these structures results in impulsive aggression or not reflects the functional roles of ventromedial frontal cortex and dorsomedial frontal and anterior insula cortex in response selection. It is also argued that impulsive aggression may occur because of impaired decision making. The aggression may not be accompanied by anger, but it will reflect disrupted evaluation of the rewards/benefits of the action.

  14. The Neurobiology of Impulsive Aggression

    PubMed Central

    2016-01-01

    Abstract This selective review provides a model of the neurobiology of impulsive aggression from a cognitive neuroscience perspective. It is argued that prototypical cases of impulsive aggression, those associated with anger, involve the recruitment of the acute threat response system structures; that is, the amygdala, hypothalamus, and periaqueductal gray. It is argued that whether the recruitment of these structures results in impulsive aggression or not reflects the functional roles of ventromedial frontal cortex and dorsomedial frontal and anterior insula cortex in response selection. It is also argued that impulsive aggression may occur because of impaired decision making. The aggression may not be accompanied by anger, but it will reflect disrupted evaluation of the rewards/benefits of the action. PMID:26465707

  15. False memories for aggressive acts.

    PubMed

    Laney, Cara; Takarangi, Melanie K T

    2013-06-01

    Can people develop false memories for committing aggressive acts? How does this process compare to developing false memories for victimhood? In the current research we used a simple false feedback procedure to implant false memories for committing aggressive acts (causing a black eye or spreading malicious gossip) or for victimhood (receiving a black eye). We then compared these false memories to other subjects' true memories for equivalent events. False aggressive memories were all too easy to implant, particularly in the minds of individuals with a proclivity towards aggression. Once implanted, the false memories were indistinguishable from true memories for the same events, on several dimensions, including emotional content. Implications for aggression-related memory more generally as well as false confessions are discussed.

  16. Beliefs about aggression moderate alcohol's effects on aggression.

    PubMed

    Levinson, Cheri A; Giancola, Peter R; Parrott, Dominic J

    2011-02-01

    The goal of this investigation was to determine whether permissive beliefs about aggression moderate the relation between acute alcohol intoxication and aggression in two large experiments. Participants in Study 1 were 328 (163 men and 165 women) social drinkers and those in Study 2 were 518 (252 men and 266 women) social drinkers. Beliefs about aggression were assessed using a well-validated self-report measure. Following the consumption of either an alcohol or a placebo beverage, participants were tested on a laboratory task in which electric shocks were received from, and administered to, a fictitious opponent under the guise of a competitive reaction-time task. Aggression was operationalized as the combined mean responses for shock intensity and duration across all trials. Our central finding was that alcohol increased aggression in persons with more approving beliefs about aggression than in those who did not hold such beliefs. Our results are discussed within the context of Huesmann's (1988) cognitive script model of aggression. Suggestions for violence prevention efforts are put forth as well.

  17. Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer

    PubMed Central

    Seeley, Todd W; Sternlicht, Mark D; Klaus, Stephen J; Neff, Thomas B; Liu, David Y

    2017-01-01

    The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neundl-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592). In NeuYD mice, HIF-PHI treatments elevated erythropoiesis markers, but no differences were detected in tumor onset or the phenotypes of established tumors. PMID:28331872

  18. Aggressive Erotica and Violence against Women.

    ERIC Educational Resources Information Center

    Donnerstein, Edward

    1980-01-01

    Examines the effects of aggressive-erotic stimuli on male aggression toward females. Male subjects' deliveries of electric shocks to males or females after viewing either a neutral, erotic, or aggressive-erotic film were measured. (Author/SS)

  19. [The effect of media violence on aggression: is aggressive behavior mediated by aggressive cognitions and emotions?].

    PubMed

    Yukawa, S; Yoshida, F

    1999-06-01

    This study investigated whether cognitions and emotions elicited by media violence mediate aggressive behavior. Eighty undergraduates, 40 men and 40 women, participated in the experiment. First, subjects were exposed to one of four violent videos which varied in levels of violence and entertainment. Subjects' heart rate and eyeblink rate were continuously recorded while they watched the video. After watching it, subjects described their thoughts which occurred while watching it and rated their affective reactions to it. Finally, their aggressive behavior was measured. Results showed that (1) videos high in violence elicited more aggressive thoughts, more thoughts of negative affect, stronger negative affects, and stronger empty-powerless affects, whereas videos high in entertainment elicited stronger positive affects; (2) no significant differences were found among the videos in terms of physiological reactions and aggressive behavior; and (3) cognitions and emotions elicited by media violence did not mediate aggressive behavior.

  20. Characterization of the Primo-Vascular System in the Abdominal Cavity of Lung Cancer Mouse Model and Its Differences from the Lymphatic System

    PubMed Central

    Kim, Hong Bae; Zhang, Wei-bo; Soh, Kwang-Sup

    2010-01-01

    Cancer growth and dissemination have been extensively studied for a long time. Nevertheless, many new observations on anatomy and histopathology of cancer events are still reported such as formation of a vasculogenic-like network inside aggressive tumors. In this research, new kinds of micro-conduits, named primo-vessels, were found inside the abdominal cavity of NCI-H460 lung cancer murine xenograft models. These vascular threads were largely distributed on the surfaces of various organs and were often connected to peritoneal tumor nodules. Histological and immunofluorescent investigations showed that the primo-vessels had characteristic features that were distinctively different from those of similar-looking lymphatic vessels. They had multiple channels surrounded with loose collageneous matrices, which is in contrast to the single-channel structure of other vascular systems. The rod-shaped nuclei aligned longitudinally along the channels were assumed to be the endothelial cells of the primo-vessels, but LYVE-1, a specific marker of lymphatics, was not expressed, which indicates a clear difference from lymphatic endothelial cells. Taken together these findings on and characterization of the novel threadlike vascular structures in cancer models may have important implications for cancer prognosis and for therapy. PMID:20376343

  1. Characterization of the primo-vascular system in the abdominal cavity of lung cancer mouse model and its differences from the lymphatic system.

    PubMed

    Yoo, Jung Sun; Ayati, M Hossein; Kim, Hong Bae; Zhang, Wei-bo; Soh, Kwang-Sup

    2010-04-01

    Cancer growth and dissemination have been extensively studied for a long time. Nevertheless, many new observations on anatomy and histopathology of cancer events are still reported such as formation of a vasculogenic-like network inside aggressive tumors. In this research, new kinds of micro-conduits, named primo-vessels, were found inside the abdominal cavity of NCI-H460 lung cancer murine xenograft models. These vascular threads were largely distributed on the surfaces of various organs and were often connected to peritoneal tumor nodules. Histological and immunofluorescent investigations showed that the primo-vessels had characteristic features that were distinctively different from those of similar-looking lymphatic vessels. They had multiple channels surrounded with loose collageneous matrices, which is in contrast to the single-channel structure of other vascular systems. The rod-shaped nuclei aligned longitudinally along the channels were assumed to be the endothelial cells of the primo-vessels, but LYVE-1, a specific marker of lymphatics, was not expressed, which indicates a clear difference from lymphatic endothelial cells. Taken together these findings on and characterization of the novel threadlike vascular structures in cancer models may have important implications for cancer prognosis and for therapy.

  2. Aggression Can be Contagious: Longitudinal Associations between Proactive Aggression and Reactive Aggression Among Young Twins

    PubMed Central

    Dickson, Daniel J.; Richmond, Ashley; 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. PMID:25683448

  3. From aggressiveness to creativity.

    PubMed

    Mrevlje, Gorazd V

    2004-02-01

    Psychology has a long tradition of considering human creativity as a distinct human characteristic and a special kind of human activity. After explaining the key motives for such an attitude, the author discusses those forms of healthy aggressiveness that stand out as necessary and constitutive elements of the creative process. Taking the well-known statement of C. G. Jung's 'The person who does not build (create), will demolish and destroy' as a starting point, the author compares the basic premises for understanding the process of human creativity, at the same time drawing on Freud's psychology of the individual and Jung's principle of the collective unconscious as well as his notion of 'complexes'. In doing so, the author somewhat boldly paraphrases Jung's dictum: 'In order to be creative, rather than just constructive, one must occasionally also destroy'. With reference to Wallas, Taylor and Neumann (Wallas 1926; Taylor 1959;;Neumann 2001), the author goes on to explore those concepts which help us to investigate the phenomenon of human creativity, drawing distinctions between emergent, expressive, productive, inventive and innovative creativity. The second part of the article discusses the importance of intelligence, originality, nonconformity, subversiveness and free-mindedness for the creative process of human beings. The author concludes with a further explanation of Erich Neumann's argument that human creativity cannot be understood solely as a result of sociogenetic factors, and argues that it is only by taking into consideration Jung's perception of creativity that a global ontological understanding of these processes can be achieved.

  4. More aggressive cartoons are funnier.

    PubMed

    McCauley, C; Woods, K; Coolidge, C; Kulick, W

    1983-04-01

    Independent rankings of humor and aggressiveness were obtained for sets of cartoons drawn randomly from two different magazines. The correlation of median humor and median aggressiveness rankings ranged from .49 to .90 in six studies involving six different sets of cartoons and six different groups of subjects, including children and adults, high and low socioeconomic status (SES) individuals, and native- and foreign-born individuals. This correlation is consistent with Freudian, arousal, and superiority theories of humor. Another prediction of Freudian theory, that high-SES subjects should be more appreciative of aggressive humor than low-SES subjects, was not supported.

  5. Predicting workplace aggression and violence.

    PubMed

    Barling, Julian; Dupré, Kathryne E; Kelloway, E Kevin

    2009-01-01

    Consistent with the relative recency of research on workplace aggression and the considerable media attention given to high-profile incidents, numerous myths about the nature of workplace aggression have emerged. In this review, we examine these myths from an evidence-based perspective, bringing greater clarity to our understanding of the predictors of workplace aggression. We conclude by pointing to the need for more research focusing on construct validity and prevention issues as well as for methodologies that minimize the likelihood of mono-method bias and that strengthen the ability to make causal inferences.

  6. Plant Vascular Biology 2013: vascular trafficking.

    PubMed

    Ursache, Robertas; Heo, Jung-Ok; Helariutta, Ykä

    2014-04-01

    About 200 researchers from around the world attended the Third International Conference on Plant Vascular Biology (PVB 2013) held in July 2013 at the Rantapuisto Conference Center, in Helsinki, Finland (http://www.pvb2013.org). The plant vascular system, which connects every organ in the mature plant, continues to attract the interest of researchers representing a wide range of disciplines, including development, physiology, systems biology, and computational biology. At the meeting, participants discussed the latest research advances in vascular development, long- and short-distance vascular transport and long-distance signalling in plant defence, in addition to providing a context for how these studies intersect with each other. The meeting provided an opportunity for researchers working across a broad range of fields to share ideas and to discuss future directions in the expanding field of vascular biology. In this report, the latest advances in understanding the mechanism of vascular trafficking presented at the meeting have been summarized.

  7. Label-free detection of fibrillar collagen deposition associated with vascular elements in glioblastoma multiforme by using multiphoton microscopy.

    PubMed

    Jiang, L W; Wang, X F; Wu, Z Y; Lin, P H; DU, H P; Wang, S; Li, L H; Fang, N; Zhuo, S M; Kang, D Z; Chen, J X

    2017-02-01

    Glioblastoma multiforme (GBM-WHO grade IV) is the most common and the most aggressive form of brain tumors in adults with the median survival of 10-12 months. The diagnostic detection of extracellular matrix (ECM) component in the tumour microenvironment is of prognostic value. In this paper, the fibrillar collagen deposition associated with vascular elements in GBM were investigated in the fresh specimens and unstained histological slices by using multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG). Our study revealed the existence of fibrillar collagen deposition in the adventitia of remodelled large blood vessels and in glomeruloid vascular structures in GBM. The degree of fibrillar collagen deposition can be quantitatively evaluated by measuring the adventitial thickness of blood vessels or calculating the ratio of SHG pixel to the whole pixel of glomeruloid vascular structure in MPM images. These results indicated that MPM can not only be employed to perform a retrospective study in unstained histological slices but also has the potential to apply for in vivo brain imaging to understand correlations between malignancy of gliomas and fibrillar collagen deposition.

  8. 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

  9. [Pathophysiology of aggressive behavior: evaluation and management of pathological aggression].

    PubMed

    Pompili, E; Carlone, C; Silvestrini, C; Nicolò, G

    2016-01-01

    This work aims to define the aggression in all its forms, with notes on management and rapid tranquilization. The pathological aggression is described as a non-homogeneous phenomenon, it is variable in according to social, psychological and biological agents. The distinction of violence between affective aggression and predatory aggression can be functional to the prediction of outcome of any treatment. In general, a pattern of predatory violence tend to match with patients unresponsive and not compliant to treatment, a low probability to predict future violence and, therefore, a difficulty in managing risk. The affective aggressor, however, shows increased probability of treatment response, with more predictability of violent actions in reaction to situations perceived as threatening and, therefore, greater management of future violence risk. Those who act affective violence tend to show a wide range of emotional and cognitive problems, while those who act with predatory patterns show greater inclination to aggression and antisocial behavior. Aggression that occurs in psychiatry mostly appears to be affective, therefore susceptible to modulation through treatments.

  10. Radiographic Findings Associated with Vascular Anomalies

    PubMed Central

    Masand, Prakash

    2014-01-01

    Imaging of patients with vascular tumors and malformations has been sufficiently refined to answer pertinent questions when making treatment decisions in this challenging subgroup of pediatric patients. The imaging modalities at hand include conventional radiography, Doppler ultrasound, and magnetic resonance imaging with time-resolved, contrast-material enhanced magnetic resonance angiography. This review article will focus on the characteristic imaging features of some focal and diffuse vascular lesions, which have been classified by their clinical history and physical exam, and further labeled as a vascular tumor or slow-flow versus high-flow vascular malformation based on the updated classification system proposed by the International Society for the Study of Vascular Anomalies. The recent advances in knowledge regarding the biology of these vascular anomalies have led to increased awareness of the current nomenclature. Moreover, with better understanding of the imaging features, the radiologist has become a key player in the multidisciplinary approach offered at various institutions where appropriate treatment algorithms and interventional strategies are put together. This is crucial in avoiding misdiagnosis and improper management. PMID:25045332

  11. Non-functioning pituitary tumors: 2012 update.

    PubMed

    Cámara Gómez, Rosa

    2014-03-01

    Non-functioning pituitary adenomas are the most common pituitary macroadenomas in adults, accounting for approximately 14%-28% of all clinically relevant pituitary tumors. They are a heterogeneous group of tumors that cause symptoms by compression and/or hormone deficiencies. The possibility of tumor growth is increased in macroadenomas and solid tumors as compared to microadenomas and cystic tumors. Diagnosis is based on imaging procedures (magnetic resonance imaging), but there are studies reporting promising potential biomarkers. Transsphenoidal surgery remains the first therapeutic option for large tumors with compressive symptoms. There is no evidence that endoscopic procedures improve outcomes, but they decrease morbidity. There is no unanimity in finding prognostic predictors of recurrence. Radiosurgery achieves tumor control and, sometimes, adenoma size reduction. Its adverse effects increase with higher doses and tumor sizes>4cm(3). Drug treatment is of little value. In aggressive non-functioning tumors, temozolomide (TMZ) may be used with caution because no controlled studies are available. TMZ achieves tumor control in 38%-40% of aggressive non-functioning tumors. The optimal treatment regimen and duration have not been defined yet. Lack of response to TMZ after 3 cycles predicts for treatment resistance, but initial response does not ensure optimal mid or long-term results. O6-methylguanine-DNA methyltransferase expression has a limited predictive value of response to treatment with TMZ in aggressive non-functioning tumors. It should therefore not be a determinant factor in selection of patients to be treated with TMZ.

  12. The function of vascular endothelial growth factor.

    PubMed

    Nieves, Bonnie J; D'Amore, Patricia A; Bryan, Brad A

    2009-01-01

    Vascular endothelial growth factor (VEGF) is considered the master regulator of angiogenesis during growth and development, as well as in disease states such as cancer, diabetes, and macular degeneration. This review details our current understanding of VEGF signaling and discusses the benefits and unexpected side effects of promising anti-angiogenic therapeutics that are currently being used to inhibit neovacularization in tumors.

  13. Aggressiveness Niche: Can It Be the Foster Ground for Cancer Metastasis Precursors?

    PubMed Central

    2016-01-01

    The relationship between tumor initiation and tumor progression can follow a linear projection in which all tumor cells are equally endowed with the ability to progress into metastasis. Alternatively, not all tumor cells are equal genetically and/or epigenetically, and only few cells are induced to become metastatic tumor cells. The location of these cells within the tumor can also impact the fate of these cells. The most inner core of a tumor where an elevated pressure of adverse conditions forms, such as necrosis-induced inflammation and hypoxia-induced immunosuppressive environment, seems to be the most fertile ground to generate such tumor cells with metastatic potential. Here we will call this necrotic/hypoxic core the “aggressiveness niche” and will present data to support its involvement in generating these metastatic precursors. Within this niche, interaction of hypoxia-surviving cells with the inflammatory microenvironment influenced by newly recruited mesenchymal stromal cells (MSCs), tumor-associated macrophages (TAMs), and other types of cells and the establishment of bidirectional interactions between them elevate the aggressiveness of these tumor cells. Additionally, immune evasion properties induced in these cells most likely contribute in the formation and maintenance of such aggressiveness niche. PMID:27493669

  14. Quantifying Aggressive Behavior in Zebrafish.

    PubMed

    Teles, Magda C; Oliveira, Rui F

    2016-01-01

    Aggression is a complex behavior that influences social relationships and can be seen as adaptive or maladaptive depending on the context and intensity of expression. A model organism suitable for genetic dissection of the underlying neural mechanisms of aggressive behavior is still needed. Zebrafish has already proven to be a powerful vertebrate model organism for the study of normal and pathological brain function. Despite the fact that zebrafish is a gregarious species that forms shoals, when allowed to interact in pairs, both males and females express aggressive behavior and establish dominance hierarchies. Here, we describe two protocols that can be used to quantify aggressive behavior in zebrafish, using two different paradigms: (1) staged fights between real opponents and (2) mirror-elicited fights. We also discuss the methodology for the behavior analysis, the expected results for both paradigms, and the advantages and disadvantages of each paradigm in face of the specific goals of the study.

  15. Vasopressin/oxytocin and aggression.

    PubMed

    Ferris, Craig F

    2005-01-01

    Vasopressin/oxytocin and related peptides comprise a phylogenetically old superfamily of chemical signals in both vertebrates and invertebrates. Each peptide isoform has its own distinct receptor subtype and specific cellular action. The conservation and dispersion of vasopressin/oxytocin signalling systems across the animal kingdom attests to their functional significance in evolution. Indeed, they are involved in the physiology of fluid balance, carbohydrate metabolism, thermoregulation, immunity and reproduction. In addition, these peptides evolved a role in social behaviours related to aggression and affiliation. The focus of this chapter is the role of vasopressin/oxytocin as chemical signals in the brain altering aggressive responding in a context- and species-dependent manner. There is compelling evidence from several mammalian species including humans that vasopressin enhances aggression. The activity of the vasopressin appears linked to the serotonin system providing a mechanism for enhancing and suppressing aggressive behaviour.

  16. Environmental factors and aggressive behavior

    SciTech Connect

    Anderson, A.C.

    1982-07-01

    This paper briefly reviews some of the research areas which indicate a correlation between environmental factors and initiation of aggressive behavior. Environmental factors including lunar influences, month of birth, climate and the effects of crowding and certain chemicals are discussed.

  17. Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p): inhibition of bladder cancer cell aggressiveness

    PubMed Central

    Matsushita, Ryosuke; Yoshino, Hirofumi; Enokida, Hideki; Goto, Yusuke; Miyamoto, Kazutaka; Yonemori, Masaya; Inoguchi, Satoru; Nakagawa, Masayuki; Seki, Naohiko

    2016-01-01

    In microRNA (miRNA) biogenesis, the guide-strand of miRNA integrates into the RNA induced silencing complex (RISC), whereas the passenger-strand is inactivated through degradation. Analysis of our miRNA expression signature of bladder cancer (BC) by deep-sequencing revealed that microRNA (miR)-145-5p (guide-strand) and miR-145-3p (passenger-strand) were significantly downregulated in BC tissues. It is well known that miR-145-5p functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p on cancer cells is still ambiguous. The aim of the present study was to investigate the functional significance of miR-145-3p and BC oncogenic pathways and targets regulated by miR-145-5p/miR-145-3p. Ectopic expression of either miR-145-5p or miR-145-3p in BC cells significantly suppressed cancer cell growth, migration and invasion and it also induced apoptosis. The gene encoding ubiquitin-like with PHD and ring finger domains 1 (UHRF1) was a direct target of these miRNAs. Silencing of UHRF1 induced apoptosis and inhibited cancer cell proliferation, migration, and invasion in BC cells. In addition, overexpressed UHRF1 was confirmed in BC clinical specimens, and the high UHRF1 expression group showed a significantly poorer cause specific survival rate in comparison with the low expression group. Taken together, our present data demonstrated that both strands of miR-145 (miR-145-5p: guide-strand and miR-145-3p: passenger-strand) play pivotal roles in BC cells by regulating UHRF1. The identification of the molecular target of a tumor suppressive miRNAs provides novel insights into the potential mechanisms of BC oncogenesis and suggests novel therapeutic strategies. PMID:27072587

  18. Role of Radiotherapy in Aggressive Digital Papillary Adenocarcinoma.

    PubMed

    Feldmeyer, Laurence; Prieto, Victor G; Ivan, Doina; Nagarajan, Priyadharsini; Tetzlaff, Michael T; Curry, Jonathan L; Bell, Diana; Moon, Bryan S; Torres-Cabala, Carlos A; Aung, Phyu P

    2016-01-01

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