Abstract：
:Emerging evidence supporting the activation of the Akt-mammalian target of rapamycin (mTOR) signaling network in head and neck squamous cell carcinoma (HNSCC) progression has provided the rationale for exploring the therapeutic potential of inhibiting this pathway for HNSCC treatment. Indeed, rapamycin, a clinically relevant mTOR inhibitor, promotes the rapid regression of HNSCC-tumor xenografts in mice. However, rapamycin does not affect the growth of HNSCC cells in vitro, thus raising the possibility that, as for other cancer types, rapamycin may not target cancer cells directly but may instead act on a component of the tumor microenvironment, such as tumor-associated vasculature. Here, we used a retroinhibition approach to assess the contribution of cancer cell-autonomous actions of rapamycin to its antitumor activity in HNSCC. A rapamycin-resistant form of mTOR (mTOR-RR) was expressed in HNSCC cells while retaining the wild-type (rapamycin-sensitive) mTOR (mTOR-WT) alleles in host-derived endothelial and stromal cells. Expression of mTOR-RR prevented the decrease in phospho-S6 levels caused by rapamycin through mTOR in HNSCC cells but not in stromal cells, and rendered HNSCC xenografts completely resistant to the antitumoral activity of rapamycin. This reverse pharmacology strategy also enabled monitoring the direct consequences of inhibiting mTOR in cancer cells within the complex tumor microenvironment, which revealed that mTOR controls the accumulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and the consequent expression of vascular endothelial growth factor and a glucose transporter, Glut-1, in HNSCC cells. These findings indicate that HNSCC cells are the primary target of rapamycin in vivo, and provide evidence that its antiangiogenic effects may represent a downstream consequence of mTOR inhibition in HNSCC cells.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Amornphimoltham P,Patel V,Leelahavanichkul K,Abraham RT,Gutkind JSdoi
10.1158/0008-5472.CAN-07-1756subject
Has Abstractpub_date
2008-02-15 00:00:00pages
1144-53issue
4eissn
0008-5472issn
1538-7445pii
68/4/1144journal_volume
68pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract：:CXCL16 is a new member of the chemokine superfamily, which exists in a transmembrane as well as a soluble form. Its receptor CXCR6 is detected on CD4(+) T cells, CD8(+) T cells, and natural killer T cells. Here, we report a significant correlation of CXCL16 expression by tumor cells with the infiltration of T cells an...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-3424
更新日期：2007-05-15 00:00:00
abstract：:Little is known about the genetic and molecular events leading to the early stages of human astrocytoma formation. To examine this issue, we analyzed the significance of sequential accumulation of two somatic point mutations (R267W and E258D) in the TP53 gene during the initiation of astrocytoma in a patient born with...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2002-05-15 00:00:00
abstract：:A tetracosapeptide (peptide-24) corresponding to the amino-terminal sequence of the carcinoembryonic antigen (CEA) was synthesized and characterized. Antisera were produced to the peptide-24, and a radioimmunoassay was developed utilizing peptide-24 with a tyrosine residue on the amino-terminal end (Tyr-peptide-24). I...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1981-06-01 00:00:00
abstract：:Elevated oxidative stress is observed more frequently in cancer cells than in normal cells. It is therefore expected that additional exposure to a low level of reactive oxygen species (ROS) will push cancer cells toward death, whereas normal cells might maintain redox homeostasis through adaptive antioxidant responses...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-12-4297
更新日期：2013-07-15 00:00:00
abstract：:As with many types of cancer, cell motility is an important factor in the progression and metastasis of hepatocellular carcinomas (HCC). HCC is associated with significant fibrosis in the liver. The fibrotic microenvironment in the liver is characterized by an altered composition of the extracellular matrix (ECM) and ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2003-12-01 00:00:00
abstract：:Transfection of C3H/10T1/2 cells with either a c-myc or an activated c-Ha-ras gene decreased the cellular dependence for serum-derived factors to proliferate in monolayer. The c-myc-transfected cells did, however, require a high plasma concentration for significant growth, while the ras transfectants grew extremely we...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1989-05-01 00:00:00
abstract：:Phorbol diester (PDE) tumor promoters affect cells by interacting with specific receptors on the plasma membrane. Cells are known to regulate their receptor populations in response to many external and internal stimuli, including differentiation. The human promyelocytic leukemia cell line HL-60, which can be induced b...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1986-08-01 00:00:00
abstract：:Molecular insights into how chronic stress affects lung tumorigenesis may offer new routes to chemoprevention. In this study, we show that chronic stress in mice chemically or genetically initiated for lung cancer leads to the release of norepinephrine and other catecholamines, thereby promoting lung tumorigenesis. Me...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-16-0990
更新日期：2016-11-15 00:00:00
abstract：:Gene transfer and expression of methotrexate (MTX)-resistant variants of dihydrofolate reductase (DHFR) in normal hematopoietic cells is a potential strategy to permit administration of larger doses of MTX by alleviating drug toxicity in normal cells and tissues that are drug sensitive. We have previously demonstrated...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-02-15 00:00:00
abstract：:The Inflammation and Cancer Think Tank Meeting was organized by the National Cancer Institute with the purpose of identifying research advances, gaps, and opportunities for the study and clinical application of the role of inflammation on tumorigenesis. The format of this meeting consisted of brief presentations that ...
journal_title：Cancer research
pub_type：
doi：10.1158/0008-5472.CAN-05-1777
更新日期：2005-10-01 00:00:00
abstract：:The relative amounts of HLA-A,B,C antigens, beta 2-microglobulin (beta 2m), and trophoblast antigens (Trop-1 and Trop-2) were determined on nine choriocarcinoma cell lines including seven lines of gestational origin and two lines of nongestational origin (from ovary and stomach) by quantitative immunofluorescence anal...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1984-09-01 00:00:00
abstract：:Diethyldithiocarbamate (DDTC) has been shown to protect against the toxicity of cis-diamminedichloroplatinum(II) (DDP) without inhibition of antitumor effect. We report here that DDTC is unreactive toward DDP complexes in which both chlorides have been replaced by guanine residues but removes platinum from a variety o...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1986-06-01 00:00:00
abstract：:Angiogenesis is one of the crucial events for cancer development and growth. Two members of the vascular endothelial growth factor (VEGF) family, VEGF-A and placental growth factor (PlGF), which are able to heterodimerize if coexpressed in the same cell, are both required for pathologic angiogenesis. We have generated...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-09-2609
更新日期：2010-03-01 00:00:00
abstract：:50C10 and 52H10 are two DNA clones previously reported by us to be overexpressed in human colonic mucosa at high risk for development of colonic tumors. This report presents sequencing data that reveal that these clones contain repetitive Alu elements. Each Alu sequence is associated with a 3'-oligoadenylate [oligo(A)...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1995-01-01 00:00:00
abstract：:The inactivation of the tumor suppressor gene p53 has been demonstrated in a variety of human tumors. In this study, we present a p53 gene analysis of 13 uterine carcinoma cell lines. Sequencing analysis of the entire coding region revealed mutations changing the p53 amino acid composition in all six endometrial carci...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1991-12-15 00:00:00
abstract：:4-Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effective treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of aromatase and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OH...
journal_title：Cancer research
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：1989-03-01 00:00:00
abstract：:Severe immunodeficiency characterized by lymphopenia was found in two siblings, one of whom was examined in detail. The calcium flux, pattern of tyrosine phosphorylation of proteins, and interleukin 2 (IL-2) production and proliferation in response to mitogens suggested that the peripheral blood T cells activated norm...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1999-07-15 00:00:00
abstract：:Although targeting the Ras/Raf/MEK pathway remains a promising anticancer strategy, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors in clinical development are likely to be limited in their ability to produce durable clinical responses due to the emergence of acquired drug...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-4351
更新日期：2011-08-15 00:00:00
abstract：:The combinations of amphotericin B (AmB) with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) or 2-cyclohexyl isocyanate, the carbamoylating decomposition product of CCNU, were more potent in lysing HL-60 cells than the combinations of AmB with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) or 2-chloroethyl isocyana...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1990-06-01 00:00:00
abstract：:Clonal variants of mouse epidermal JB6 cells that are genetically susceptible (P+) or resistant (P-) to tumor promoter-induced neoplastic transformation exhibit differential activator protein-1 (AP-1) response. Transactivation of AP-1 appears to be necessary but not sufficient to promote transformation in JB6 cells. I...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-05-15 00:00:00
abstract：:Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-15-2325-T
更新日期：2016-04-01 00:00:00
abstract：:We examined the role of constitutional genetic variation at the UDP-glucuronosyltransferase (UGT) 1A1 locus in breast cancer susceptibility. The UGT1A1 enzyme is a major UGT involved in estradiol glucuronidation. To date, four UGT1A1 variant alleles characterized by a variation in the number of TA from five through ei...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2000-02-15 00:00:00
abstract：:The present study investigated an immunotherapeutic strategy for rearranged during transfection proto-oncogene (ret)-associated carcinomas in a transgenic MT/ret 304/B6 mouse model in which spontaneous tumors develop due to overexpression of the ret gene. A Ret peptide vaccine comprising an extracellular fragment of R...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-08-2476
更新日期：2009-05-01 00:00:00
abstract：:Dissemination of tumor to the leptomeninges and cerebrospinal fluid represents a common pattern of metastasis for many cancers; however, few chemotherapeutic agents are available for intrathecal (i.t.) use and treatment results are often poor. We studied the neurotoxicity and pharmacokinetics of i.t. 4-hydroperoxycycl...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1992-11-15 00:00:00
abstract：:The calcium channel blocker verapamil has been shown to reverse multidrug resistance (T. Tsuruo et al., Cancer Res. 41: 1967-1972, 1981), but the mechanism of action of this agent has not been fully elucidated. A radioactive photoactive analogue of verapamil, N-[benzoyl-3,5-3H-(+/-)-5-[(3,4-dimethoxyphenetyl)methylami...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1989-09-15 00:00:00
abstract：:Pharmacokinetic studies of 5-fluorouracil (5-FUra) were performed on 18 patients divided into three groups: seven patients were given 5-FUra i.v. by rapid injection; five patients received the drug p.o.; and six patients were treated by continuous i.v. infusion for 96 hr. The results showed rapid i.v. injection to be ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1980-07-01 00:00:00
abstract：:Antineoplastic drug resistance is a major obstacle to improved treatment of most adult cancers in humans. Novobiocin, an antibacterial agent which inhibits the eukaryotic topoisomerase II enzyme, increases the cytotoxicity of several alkylating agents in vitro by the formation of lethal DNA-DNA interstrand cross-links...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1991-01-15 00:00:00
abstract：:Cancer patients and tumor-bearing animals excrete high levels of modified purines and pyrimidines some of which, e.g., N2,N2-dimethylguanosine, can originate only from transfer RNA (tRNA). Until recently, it could not be ascertained whether the high level of excretion of such compounds is due to cell death or specific...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1977-09-01 00:00:00
abstract：:Verapamil and a number of other Ca2+ antagonists were found to potentiate DNA damage induced by 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucop yra noside (VP-16) in L1210 cells in vitro. The potentiating effect of verapamil on DNA single-strand breaks in vitro was concentration dependent, relevant to ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1984-08-01 00:00:00
abstract：:The Na+/I- symporter (NIS) present in the membranes of thyroid cells is responsible for the capacity of the thyroid to concentrate iodide. This allows treatment of thyroid cancers with 131I. We propose to enlarge this therapeutic strategy to nonthyroid tumors by using an adenoviral vector to deliver the NIS gene into ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2000-07-01 00:00:00
