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1.
《Molecular medicine today》1996,2(10):432-438
The nerve growth factor receptor TrkA was initially isolated as a transforming oncogene, trk, in which most of the extracellular receptor part is replaced by the coding sequence for a tropomyosin-encoding gene. The impact that the identification of the first neurotrophin receptor has made on the entire field of developmental neurobiology cannot be overstated. Following a brief introduction to the biology of neurotrophins and their receptors, this review will focus on oncogenic Trk in human malignant disorders, discuss putative tumorigenic involvement of Trk family members in the childhood malignancy neuroblastoma, and point out potential neurotrophin-based treatment modalities for this and other neuroendocrine tumors. 相似文献
2.
Morikane K Tempero RM Sivinski CL Nomoto M Van Lith ML Muto T Hollingsworth MA 《Cancer immunology, immunotherapy : CII》1999,47(5):287-296
We established a model of orthotopic injection of a syngeneic pancreatic tumor cell line in C57BL/6 mice and evaluated the
effects of organ site on induction of immunity to a tumor-specific antigen, MUC1. Mice were challenged with a syngeneic pancreatic
adenocarcinoma cell line that expressed MUC1 (Panc02-MUC1) by orthotopic injection into the pancreas, or by subcutaneous injection.
Tumor cells injected into the pancreas grew much faster than those injected subcutaneously. Mice challenged subcutaneously
with Panc02-MUC1 rejected tumors or developed slowly growing tumors that were negative for MUC1 expression. In contrast, mice
challenged orthotopically into the pancreas developed progressive tumors that were positive for MUC1 expression. Sera from
mice that rejected Panc02-MUC1 (tumor-immune mice) showed no detectable IgG1 and IgM titers against the MUC1 tandem-repeat
peptide, whereas mice with progressive tumor growth had significant titers of IgG1 and IgM specific for MUC1. This suggests
that the humoral immune response was ineffective in mediating tumor rejection. The results show that the growth properties
and immunological rejection of pancreatic tumors is affected by the organ site at which the tumor grows.
Received: 25 April 1998 / Accepted: 7 October 1998 相似文献
3.
A model of tumor growth and tumor response to radiation is introduced in which each tumor cell is taken into account individually. Each cell is assigned a set of radiobiological parameters, and the status of each cell is checked in discrete intervals. Tumor proliferation is governed by the cell cycle times of tumor cells, the growth fraction, the apoptotic capacity of the tumor, and the degree of tumor angiogenesis. The response of tumor cells to radiation is determined by the radiosensitivities and the oxygenation status. Computer simulation is performed on a 3D rigid cubic lattice, starting out from a single tumor cell. Random processes are simulated by Monte Carlo methods. Short cell cycle time, high growth fraction, and tumor angiogenesis all increase tumor proliferation rates. Accelerated time-dose patterns result in lower total doses needed for tumor control, but the extent of dose reduction depends on the kinetics and the radiosensitivities of tumor cells. Tumor angiogenesis alters fully oxygenated and hypoxic fractions within the tumor and subsequently affects the radiation response. It is demonstrated for selected radiobiological parameters that the simulation tools are suitable to quantitatively assess the total doses needed for tumor control. Using the simulation tools, it is feasible to simulate time-dependent effects during fractionated radiotherapy and to compare different time-dose patterns in terms of their tumor control. 相似文献
4.
PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma 总被引:9,自引:0,他引:9
Ostman A 《Cytokine & growth factor reviews》2004,15(4):275-286
PDGFs and their cognate tyrosine kinase alpha- and beta-receptors are involved in multiple tumor-associated processes including autocrine growth stimulation of tumor cells, stimulation of tumor angiogenesis and recruitment and regulation of tumor fibroblasts. The recent development of clinically useful PDGF antagonists, like STI571/Glivec, has increased the interest in PDGF receptors as cancer drug targets. Autocrine PDGF receptor signaling occurs in certain malignancies characterized by mutational activation of PDGF or PDGF receptors, for instance, dermatofibrosaracoma protuberans, gastrointestinal stromal tumors, and hypereosinophilic syndrome. The roles of PDGF in regulation of tumor angiogenesis and tumor fibroblasts are more general, and probably occur in most common solid tumors. Concerning tumor angiogenesis recent studies have predominantly focused on the importance of PDGF receptor signaling for tumor pericyte recruitment. PDGF receptors in the tumor stroma have also attracted attention as interesting drug targets because of their function as regulators of tumor interstitial fluid pressure, tumor transvascular transport and tumor drug uptake. In summary, the improved understanding of the role of PDGF signaling in tumor biology, and the introduction of PDGF antagonists, has set the stage for a continued development of PDGF antagonists as novel cancer drugs. 相似文献
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Naoki Watanabe Hiroshi Neda Yoshiki Ohtusuka Hisao Sone Naofumi Yamauchi Masahiro Maeda Hiroshi Kuriyama Yoshiro Niitsu 《Cancer immunology, immunotherapy : CII》1989,28(3):157-163
Summary Several aspects of the activity and effects of tumor necrosis factor (TNF) were investigated to gain further insight into its cytotoxic mechanism. The relation between number of TNF receptors and TNF susceptibility of both tumor cells and normal cells was studied, utilizing a specific binding assay. Among the tumor cells, a fairly close correlation (r=0.855) was observed between receptor number and sensitivity to TNF. No cytotoxic effect by TNF was observed on any of the normal cells tested, even though TNF receptors were shown to be present, and cell proliferation was apparently stimulated by TNF in some cases. TNF internalization and intracellular distribution were studied by pulse-labelling and Percoll density gradient centrifugation. In L-M (murine tumorigenic fibroblasts, highly sensitive to TNF cytotoxicity) cells and HEL (human embryonic lung cells, non-sensitive to TNF cytotoxicity) cells, receptor-bound 125I-labelled recombinant human TNF was rapidly internalized and delivered to lysosomes within 15–30 min, and this was followed by degradation and release into the culture medium. The presence of either a cytoskeletal disrupting agent or a lysosomotropic agent was observed to inhibit the cytotoxic effect of TNF, thus also indicating that TNF internalization, followed by delivery to lysosomes, is essential in the cytolytic mechanism of TNF.As observed by [3H]uridine incorporation, TNF did not affect RNA synthesis in L-R cells (TNF-resistant cell lines derived from L-M cells) and HEL cells, but markedly stimulated (by 3.5 times) RNA synthesis in L-M cells. 相似文献
9.
Deregulation of tumor angiogenesis and blockade of tumor growth in PPARbeta-deficient mice 总被引:1,自引:0,他引:1
Müller-Brüsselbach S Kömhoff M Rieck M Meissner W Kaddatz K Adamkiewicz J Keil B Klose KJ Moll R Burdick AD Peters JM Müller R 《The EMBO journal》2007,26(15):3686-3698
The peroxisome proliferator-activated receptor-beta (PPARbeta) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb(-/-) mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb(-/-) mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57(Kip2) as a PPARbeta target gene and a mediator of the PPARbeta-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb(-/-) mice. Our data point to an unexpected essential role for PPARbeta in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels. 相似文献
10.
Bo-Duan Xiao Yu-Jia Zhao Xiao-Yuan Jia Jiong Wu Yi-Gang Wang Fang Huang 《World journal of stem cells》2020,12(6):481-487
Cancer cells possess metabolic properties that are different from those of benign cells. p21, encoded by CDKN1A gene, also named p21Cip1/WAF1, was first identified as a cyclin-dependent kinase regulator that suppresses cell cycle G1/S phase and retinoblastoma protein phosphorylation. CDKN1A (p21) acts as the downstream target gene of TP53 (p53), and its expression is induced by wild-type p53 and it is not associated with mutant p53. p21 has been characterized as a vital regulator that involves multiple cell functions, including G1/S cell cycle progression, cell growth, DNA damage, and cell stemness. In 1994, p21 was found as a tumor suppressor in brain, lung and colon cancer by targeting p53 and was associated with tumorigenesis and metastasis. Notably, p21 plays a significant role in tumor development through p53-dependent and p53-independent pathways. In addition, expression of p21 is closely related to the resting state or terminal differentiation of cells. p21 is also associated with cancer stem cells and acts as a biomarker for such cells. In cancer therapy, given the importance of p21 in regulating the G1/S and G2 check points, it is not surprising that p21 is implicated in response to many cancer treatments and p21 promotes the effect of oncolytic virotherapy. 相似文献
11.
Rasmussen Markus Sundström Magnus Kultima Hanna Göransson Botling Johan Micke Patrick Birgisson Helgi Glimelius Bengt Isaksson Anders 《Genome biology》2011,12(10):1-1
We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors. 相似文献
12.
Rasmussen M Sundström M Göransson Kultima H Botling J Micke P Birgisson H Glimelius B Isaksson A 《Genome biology》2011,12(10):R108
We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy
numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics
and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS
can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as
30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity,
which is commonly found in many types of solid tumors. 相似文献
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Kenneth V. Honn Richard S. Bockman Lawrence J. Marnett 《Prostaglandins & other lipid mediators》1981,21(5):833-864
Prostaglandin is a term applied to a series of compounds derived enzymatically and nonenzymatically from 20 carbon fatty acids such as arachidonic acid (20:4). Research over the past 20 years has identified the prostaglandins as products of almost every cell although the amount and class of prostaglandin produced varies considerably with cell type. Within the last ten years additional, related products of 20:4 metabolism (operationally termed eicosanoids) have been discovered, eg. prostacyclin, thromboxanes, malondialdehyde, leukotrienes, hydroperoxy and hydroxy fatty acids. The role of these 20:4 metabolites in physiological and pathological states is currently under intensive investigation and the biological action of these compounds have been implicated in many key regulatory processes. Therefore, it is not unreasonable to predict that these potent bioregulatory compounds may have a central role in the initiation and regulation (positive and negative) of the spectrum of diseases which we functionally term “cancer”. 相似文献
15.
《European journal of cell biology》2020,99(6):151098
Metastasis, a process that requires tumor cell dissemination followed by tumor growth, is the primary cause of death in cancer patients. An essential step of tumor cell dissemination is intravasation, a process by which tumor cells cross the blood vessel endothelium and disseminate to distant sites. Studying this process is of utmost importance given that intravasation in the primary tumor, as well as the secondary and tertiary metastases, is the key step in the systemic spread of tumor cells, and that this process continues even after removal of the primary tumor. High-resolution intravital imaging of the tumor microenvironment of breast carcinoma has revealed that tumor cell intravasation exclusively occurs at doorways, termed “Tumor MicroEnvironment of Metastasis” (TMEM), composed of three different cell types: a Tie2high/VEGFhigh perivascular macrophage, a Mena overexpressing tumor cell, and an endothelial cell, all in direct contact. In this review article, we discuss the interactions between these cell types, the subsequent signaling events which lead to tumor cell intravasation, and the role of invadopodia in supporting tumor cell invasion and dissemination. We end our review by discussing how the knowledge acquired from the use of intravital imaging is now leading to new clinical trials targeting tumor cell dissemination and preventing metastatic progression. 相似文献
16.
The role of cytokines in modulating the formation of new tumors is mediated by their ability to regulate antigen-specific anti-tumor responses and by the activation of non-specific mechanisms, including those involved in the processes of inflammation and innate resistance. Cytokines may influence the growth of tumors by acting directly on tumor cells as growth promoting or growth inhibiting factors or indirectly by attracting inflammatory cell types and affecting angiogenesis. Due to the potency and complexity of cytokine activity against tumor growth, the improvement of cloning techniques and the availability of recombinant forms of different cytokines, a great effort has been made in the recent years to exploit this anti-tumor potential for cancer therapy. This important goal has been difficult to achieve in most cases due to toxicity of most cytokines which could not be dissociated from their anti-tumoral functions. Nevertheless, if well designed, treatment protocols and/or modifications of the cytokine molecules may in some situations augment the anti-tumor effects while limiting the toxicity. One of these molecular approaches could be the design of peptides containing the functional domain of certain cytokines, exemplified by IT9302, a peptide homologous to the functional domain of IL-10, which has demonstrated to increase tumor NK cell sensitivity. 相似文献
17.
CTL adoptive immunotherapy concurrently mediates tumor regression and tumor escape 总被引:11,自引:0,他引:11
Liu K Caldwell SA Greeneltch KM Yang D Abrams SI 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(6):3374-3382
Tumor escape and recurrence are major impediments for successful immunotherapy. It is well-documented that the emergence of Ag-loss variants, as well as regulatory mechanisms suppressing T cell function, have been linked to inadequate antitumor activity. However, little is known regarding the role of Fas-mediated cytotoxicity by tumor-specific CD8(+) CTL in causing immune evasion of Fas resistant variants during adoptive immunotherapy. In this study, we made use of an adoptive transfer model of experimental lung metastasis using tumor-specific CTL as a relevant immune-based selective pressure, and wherein the Fas ligand pathway was involved in the antitumor response. Surviving tumor cells were recovered and examined for alterations in antigenic, functional, and biologic properties. We showed that diminished susceptibility to Fas-mediated cytotoxicity in vivo was an important determinant of tumor escape following CTL-based immunotherapy. Tumor escape variants (TEV) recovered from the lungs of CTL-treated mice exhibited more aggressive behavior in vivo. However, these TEV retained relevant MHC class I and tumor Ag expression and sensitivity to CTL via the perforin pathway but reduced susceptibility to Fas-mediated lysis. Moreover, TEV were significantly less responsive to eradication by CTL adoptive immunotherapy paradigms as a consequence of increased Fas resistance. Overall, we identified that Fas(low)-TEV emerged as a direct consequence of CTL-tumor interactions in vivo, and that such an altered neoplastic Fas phenotype compromised immunotherapy efficacy. Together, these findings may have important implications for both tumor progression and the design of immunotherapeutic interventions to confront these selective pressures or escape mechanisms. 相似文献
18.
Angiogenesis is crucial to tumor growth and metastasis, and interruption of this process is a prime avenue for therapeutic intervention of tumor proliferation. The present study has made use of the S180 tumor-bearing mouse model to investigate the polysaccharopeptide, PSP, isolated from the edible mushroom Coriolus versicolor, a herbal medicine known for its anti-angiogenesis properties. Quantitative analysis of microcorrosion casting of the tumor tissue showed more angiogenic features such as dense sinusoids and hot spots, in control (untreated) than in PSP-treated animals. Immunostaining of tumor tissues with antibody against the endothelial cell marker (Factor VIII) demonstrated a positive correlation in that both the vascular density and tumor weight were lower in mice treated with PSP. Morphometric analysis of corrosion casts revealed that, even though the total amount of new vessel production was reduced, the basic tumor type-specific vascular architecture was retained. However, the expression of vascular endothelial cell growth factor (VEGF) in these tumors was suppressed. In conclusion, anti-angiogenesis should be one of the pathways through which PSP mediated its anti-tumor activity. 相似文献
19.
Background
Pten functionally acts as a tumor suppressor gene. Lately, tissue-specific ablation of Pten gene in mice has elucidated the role of Pten in different tumor progression models. However, a temporally controlled Pten loss in all adult tissues to examine susceptibility of various tissues to Pten-deficient tumorigenesis has not been addressed yet. Our goal was to explore the genesis of Pten-deficient malignancies in multiple tissue lineages of the adult mouse.Methods and Findings
We utilized an inducible Cre/loxP system to delete Pten exon 5 in the systemic organs of ROSA26 (R26)-CreERT;Ptenfx/fx mice. On reaching 45 weeks 4OHT-induced Pten loss, we found that the R26-CreERT;Ptenfx/fx mice developed a variety of malignancies. Overall tumor mean latency was 17 weeks in the Pten-deficient mice. Interestingly, mutant females developed malignancies more quickly at 10∼11 weeks compared with a tumor latency of 21 weeks for mutant males. Lymphoma incidence (76.9% in females; 40.0% in males) was higher than the other malignancies found in the mutant mice. Mutant males developed prostate (20.0%), intestinal cancer (35.0%) and squamous cell carcinoma (10.0%), whereas the mutant females developed squamous cell carcinoma (15.4%) and endometrial cancer (46.1%) in addition to lymphomas. Furthermore, we tested the pharmacological inhibition of the PTEN downstream effectors using on Pten-deficient prostate hyperplasia. Our data revealed that, indeed, the prostate hyperplasia resulting from the induced Pten loss was significantly suppressed by LY294002 (p = 0.007). LY294002Conclusions
Through monitoring a variety of Pten-deficient tumor formation, our results revealed that the lymphoid lineages and the epithelium of the prostate, endometrium, intestine and epidermis are highly susceptible to tumorigenesis after the Pten gene is excised. Therefore, this R26-CreERT; Ptenfx/fx mouse model may provide an entry point for understanding the role of Pten in the tumorigenesis of different organs and extend the search for potential therapeutic approaches to prevent Pten-deficient malignancies. 相似文献20.
Hyaluronan promotes tumor lymphangiogenesis and intralymphantic tumor growth in xenografts 总被引:2,自引:0,他引:2
Hyaluronan (HA), a high molecular weight glycosaminoglycan in the extracellular matrix, has been implicated in the promotion of malignant phenotypes, including tumor angiogenesis. However, little is known about the effect of HA on tumor-associated lymphangiogenesis. In this study, mouse hepatocellular carcinoma Hca-F cells combined with or without HA were injected subcutaneously into C3H/Hej mice, then angiogenesis and lymphangiogenesis of implanted tumors were examined by immunostaining for plateletendothelial cell adhesion molecule-1 and lymphatic vascular endothelial hyaluronan receptor-1 respectively. Interestingly, we found HA promotes tumor lymphangiogenesis and the occurrence of intratumoral lymphatic vessels, but has little effect on tumor angiogenesis. Moreover, HA also promotes intralymphatic tumor growth, although it is not sufficient to potentiate lymphatic metastasis. These results suggest that HA, which is elevated in most malignant tumor stroma, may also play a role in tumor progression by promoting lymphangiogenesis. 相似文献