RESUMO
Localization of activated natural killer (A-NK) cells in the microvasculature of growing tumors is the result of recognition of the intracellular and vascular cell-adhesion molecules ICAM-1 and VCAM-1 on the tumor endothelium, mediated by lymphocyte function-associated protein LFA-1 and vascular lymphocyte function-associated protein VLA-4. In vitro and in vivo studies of A-NK cell adhesion to endothelial cells showed that vascular endothelial growth factor (VEGF) promotes adhesion, whereas basic fibroblast growth factor (bFGF) inhibits adhesion through the regulation of these molecules on tumor vasculature. Thus, some angiogenic factors may facilitate lymphocyte recognition of angiogenic vessels, whereas others may provide such vessels with a mechanism that protects them from cytotoxic lymphocytes.
Assuntos
Adesão Celular , Fatores de Crescimento Endotelial/fisiologia , Endotélio Vascular/imunologia , Fator 2 de Crescimento de Fibroblastos/fisiologia , Células Matadoras Ativadas por Linfocina/imunologia , Linfocinas/fisiologia , Neoplasias Experimentais/irrigação sanguínea , Neovascularização Patológica/imunologia , Animais , Selectina E/fisiologia , Humanos , Molécula 1 de Adesão Intercelular/fisiologia , Antígeno-1 Associado à Função Linfocitária/fisiologia , Camundongos , Camundongos SCID , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/imunologia , Selectina-P/fisiologia , Células Tumorais Cultivadas , Molécula 1 de Adesão de Célula Vascular/fisiologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Magnetic resonance (MR) tracking of magnetically labeled stem and progenitor cells is an emerging technology, leading to an urgent need for magnetic probes that can make cells highly magnetic during their normal expansion in culture. We have developed magnetodendrimers as a versatile class of magnetic tags that can efficiently label mammalian cells, including human neural stem cells (NSCs) and mesenchymal stem cells (MSCs), through a nonspecific membrane adsorption process with subsequent intracellular (non-nuclear) localization in endosomes. The superparamagnetic iron oxide nanocomposites have been optimized to exhibit superior magnetic properties and to induce sufficient MR cell contrast at incubated doses as low as 1 microg iron/ml culture medium. When containing between 9 and 14 pg iron/cell, labeled cells exhibit an ex vivo nuclear magnetic resonance (NMR) relaxation rate (1/T2) as high as 24-39 s-1/mM iron. Labeled cells are unaffected in their viability and proliferating capacity, and labeled human NSCs differentiate normally into neurons. Furthermore, we show here that NSC-derived (and LacZ-transfected), magnetically labeled oligodendroglial progenitors can be readily detected in vivo at least as long as six weeks after transplantation, with an excellent correlation between the obtained MR contrast and staining for beta-galactosidase expression. The availability of magnetodendrimers opens up the possibility of MR tracking of a wide variety of (stem) cell transplants.
Assuntos
Endossomos/metabolismo , Magnetismo , Células-Tronco/citologia , Células 3T3 , Adsorção , Animais , Encéfalo/patologia , Divisão Celular , Linhagem Celular , Sobrevivência Celular , Células HeLa , Humanos , Mesoderma/citologia , Camundongos , Sensibilidade e Especificidade , Fatores de Tempo , Transfecção , Células Tumorais Cultivadas , beta-Galactosidase/metabolismoRESUMO
Tumor necrosis factor alpha (TNF-alpha) can lead to tumor regression when injected locally or when used in an isolated limb perfusion, and it can enhance the tumoricidal effect of various therapies. TNF-alpha can also up-regulate adhesion molecules, and thus, facilitate the binding of leukocytes to normal vessels. The present study was designed to investigate the extent to which the host leukocytes roll and adhere to vessels of different tumors (MCaIV, a murine mammary adenocarcinoma; HGL21, a human malignant astrocytoma) at a given site or to the same tumor at different sites (dorsal skin and cranium), in different mouse strains [C3H and severe combined immunodeficient (SCID)], both with and without TNF-alpha-activation. There was no significant difference in hemodynamic parameters such as RBC velocity, diameter, or shear rate between PBS-treated control groups and corresponding TNF-alpha-treated groups. Under PBS control conditions, the leukocyte rolling count in MCaIV tumor vessels in the dorsal chamber in C3H and SCID mice and in the cranial window in C3H mice was significantly lower than that in normal vessels (P < 0.05), but stable cell adhesion was similar between normal and tumor vessels. TNF-alpha led to an increase (P < 0.05) in leukocyte-endothelial interaction in vessels in the following cases: normal tissue regardless of sites and strains, MCaIV tumor in the cranial window in C3H mice, and HGL21 tumor in the cranial window in SCID mice. However, the increase in rolling and adhesion in the MCaIV tumor in response to TNF-alpha was significantly lower than in the corresponding normal vessels (P < 0.05) in the dorsal chamber in C3H and SCID mice and in the cranial window in C3H mice. The HGL21 tumor in the cranial window in SCID mice showed leukocyte rolling and adhesion comparable to that in normal pial vessels. These findings suggest that (a) in general, basal leukocyte rolling is lower in tumor vessels than in normal vessels; (b) leukocyte rolling and adhesion in tumors can be enhanced by TNF-alpha-mediated activation; and (c) the TNF-alpha response is dependent on tumor type, transplantation site, and host strain. These results have significant implications in the gene therapy of cancer using TNF-alpha-gene-transfected cancer cells or lymphocytes.
Assuntos
Endotélio Vascular/citologia , Glioblastoma/irrigação sanguínea , Leucócitos/citologia , Neoplasias Mamárias Experimentais/irrigação sanguínea , Fator de Necrose Tumoral alfa/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Endotélio Vascular/efeitos dos fármacos , Eritrócitos/fisiologia , Glioblastoma/sangue , Humanos , Leucócitos/efeitos dos fármacos , Neoplasias Mamárias Experimentais/sangue , Camundongos , Camundongos Endogâmicos C3H , Camundongos SCID , Transplante de Neoplasias , Pele , CrânioRESUMO
BACKGROUND: We describe a case of an intramedullary metastasis to the cervical spinal cord from a temporal gliosarcoma. CASE DESCRIPTION: A 48-year-old man with known temporal lobe gliosarcoma presented with a new onset of ipsilateral hemiparesis. A MRI scan revealed the presence of an intramedullary lesion in the spinal cord behind the body of C2. Despite repeated craniotomy, radiation, and chemotherapy, the patient succumbed to a rapidly progressive disease. CONCLUSION: The case illustrates the ability of gliosarcoma to metastasize to other locations in the neuroaxis. We believe this to be the first case report of an intramedullary spinal cord metastasis from a gliosarcoma. The pathological features and available literature are reviewed.
Assuntos
Neoplasias Encefálicas/patologia , Gliossarcoma/secundário , Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/secundário , Lobo Temporal , Neoplasias Encefálicas/complicações , Vértebras Cervicais , Diagnóstico Diferencial , Progressão da Doença , Evolução Fatal , Gliossarcoma/complicações , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Paresia/etiologia , Neoplasias da Medula Espinal/complicaçõesRESUMO
The aquaporins represent a family of transmembrane water channel proteins that are widely distributed in various tissues throughout the body and play a major role in transcellular and transepithelial water movement. Most tumors have been shown to exhibit high vascular permeability and high interstitial fluid pressure, but the transport pathways for water within tumors remain unknown. In this study, we examined the distribution of the aquaporin 1 (AQP1) water channel protein in several types of transplanted tumor. Two mammary carcinomas, MCaIV and R3230AC, and three glioblastomas, HGL21, U87, and F98, were implanted in rats and mice. Two sites of implantation in rodents were chosen: a cranial window (CW) region and a subcutaneous (SC) region. Tissues were studied using immunoblot analysis and immunofluorescence staining. In the mammary carcinomas, AQP1 was localized in vascular structures; no differences between CW and SC regions were observed. Among the three glioblastomas, HGL21 and U87 exhibited similar AQP1 localization in vascular structures, whereas the center of F98 did not show vascular staining. Cell membranes of normal epithelial cells did not show AQP1 expression, while membranes of most tumor cells exhibited significant AQP1 expression. Interestingly, however, HGL21 and F98 in the CW locations showed no AQP1 expression on tumor cell membranes. These results show that the AQP1 water channel is heterogeneously expressed in tumor cells and their vasculature, and that the level of expression is determined not only by the specific cellular origin of the tumor, but also by the location of the tumor in the host animal.
Assuntos
Aquaporinas/metabolismo , Glioblastoma/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Animais , Aquaporina 1 , Antígenos de Grupos Sanguíneos , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Permeabilidade Capilar , Feminino , Glioblastoma/irrigação sanguínea , Humanos , Neoplasias Mamárias Experimentais/irrigação sanguínea , Camundongos , Camundongos Endogâmicos C3H , Camundongos SCID , Microscopia de Fluorescência , Ratos , Ratos Endogâmicos F344 , Neoplasias de Tecidos Moles/irrigação sanguínea , Neoplasias de Tecidos Moles/metabolismo , Distribuição Tecidual , Água/metabolismoRESUMO
Fluid transport parameters in intracranial tumours influence the delivery of therapeutic agents and the resolution of peritumoral oedema. The tumour and cortex interstitial fluid pressure (IFP) and the cerebrospinal fluid pressure (CSFP) were measured during the growth of brain and pial surface tumours [R3230AC mammary adenocarcinoma (R3230AC) and F98 glioma (F98)] in rats. Intratumoral and intracranial pressures were also measured in rodents and patients treated with dexamethasone, mannitol and furosemide (DMF), and hypocapnia. The results show that (1) for the R3230AC on the pial surface, IFP increased with tumour volume and CSFP increased exponentially for tumours occupying a brain volume of 5% or greater; (2) in F98 with volumes of approximately 10 mm3, IFP decreased from the tumour to the cortex, whereas for tumour volumes > 16 mm3 IFP equilibrates between F98 and the cortex; (3) DMF treatment reduced the IFP of intraparenchymal tumours significantly and induced a pressure gradient from the tumour to the cortex; and (4) in 11 patients with intracranial tumours, the mean IFP was 2.0 +/- 2.5 mmHg. In conclusion, the IFP gradient between intraparenchymal tumours and the cortex decreases with tumour growth, and treatment with DMF can increase the pressure difference between the tumour and surrounding brain. The results also suggest that antioedema therapy in patients with brain tumours is responsible in part for the low tumour IFP.
Assuntos
Neoplasias Encefálicas/fisiopatologia , Encéfalo/fisiopatologia , Espaço Extracelular/fisiologia , Pressão Intracraniana/fisiologia , Adulto , Idoso , Animais , Anti-Inflamatórios/farmacologia , Astrocitoma/fisiopatologia , Dexametasona/farmacologia , Diuréticos/farmacologia , Espaço Extracelular/efeitos dos fármacos , Feminino , Furosemida/farmacologia , Glioblastoma/fisiopatologia , Humanos , Hipocapnia/fisiopatologia , Pressão Intracraniana/efeitos dos fármacos , Masculino , Manitol/farmacologia , Manometria/métodos , Meningioma/fisiopatologia , Pessoa de Meia-Idade , RatosRESUMO
A prerequisite for the development of novel angiogenic and anti-angiogenic agents is the availability of routine in vivo assays that permit 1) repeated, long-term quantitation of angiogenesis and 2) physiological characterization of angiogenic vessels. We report here the development of such an assay in mice. Using this assay, we tested the hypothesis that the physiological properties of angiogenic vessels governed by the microenvironment and vessel origin rather than the initial angiogenic stimulus. Gels containing basic fibroblast growth factor (bFGF) or vascular endothelial growth (VEGF) were implanted in transparent windows in the dorsal skin or cranium of mice. Vessels could be continuously and non-invasively monitored and easily quantified for more than 5 weeks after gel implantation. Newly formed vessels were first visible on day 4 in the cranial window and day 10 in the dorsal skinfold chamber, respectively. The number of vessels was dependent on the dose of bFGF and VEGF. At 3000 ng/ml, bFGF- and VEGF-induced blood vessels had similar diameters, red blood cell velocities, and microvascular permeability to albumin. However, red blood cell velocities and microvascular permeability to albumin were higher in the cranial window than in the dorsal skinfold chamber. Leukocyte-endothelial interaction was nearly zero in both sites. Thus, newly grown microvessels resembled vessels of granulation and neoplastic tissue in many aspects. Their physiological properties were mainly determined by the microenvironment, whereas the initial angiogenic response was stimulated by growth factors.