Abstract：
BACKGROUND:Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor pathway that may mediate this interaction is the HGF-c-MET pathway. METHODS:Effects of HGF inhibition (using a neutralising antibody AMG102) alone or in combination with gemcitabine were assessed (i) in vivo using an orthotopic model of PC, and (ii) in vitro using cultured PC cells (AsPC-1) and human PSCs. RESULTS:We have shown that human PSCs (hPSCs) secrete HGF but do not express the receptor c-MET, which is present predominantly on cancer cells. HGF inhibition was as effective as standard chemotherapy in inhibiting local tumour growth but was significantly more effective than gemcitabine in reducing tumour angiogenesis and metastasis. HGF inhibition has resulted in reduced metastasis; however, interestingly this antimetastatic effect was lost when combined with gemcitabine. This suggests that gemcitabine treatment selects out a subpopulation of cancer cells with increased epithelial-mesenchymal transition (EMT) and stem-cell characteristics, as supported by our findings of increased expression of EMT and stem-cell markers in tumour sections from our animal model. In vitro studies showed that hPSC secretions induced proliferation and migration, but inhibited apoptosis, of cancer cells. These effects were countered by pretreatment of hPSC secretions with a HGF-neutralising antibody but not by gemcitabine, indicating a key role for HGF in PSC-PC interactions. CONCLUSIONS:Our studies suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC that will require careful modelling for optimal integration with existing treatment modalities.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Pothula SP,Xu Z,Goldstein D,Biankin AV,Pirola RC,Wilson JS,Apte MVdoi
10.1038/bjc.2015.478subject
Has Abstractpub_date
2016-02-02 00:00:00pages
269-80issue
3eissn
0007-0920issn
1532-1827pii
bjc2015478journal_volume
114pub_type
杂志文章abstract：BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/s41416-020-0892-9
更新日期：2020-07-01 00:00:00
abstract：:There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculat...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6604101
更新日期：2008-01-15 00:00:00
abstract：:P-glycoprotein (P-gp) pumps multiple types of drugs out of the cell, using energy generated from ATP, and confers multidrug resistance (MDR) on cancer cells. ZD6474 is an orally active, selective inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during trans...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6603985
更新日期：2007-10-08 00:00:00
abstract：:Nabilone, a synthetic cannabinoid, and Prochlorperazine were compared in a double-blind crossover study of 34 patients with lung cancer undergoing a 3-day schedule of chemotherapy with Cyclophosphamide, Adriamycin and Etoposide. Symptom scores were significantly better for patients on nabilone for nausea, retching and...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/bjc.1983.247
更新日期：1983-11-01 00:00:00
abstract：:This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability an...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/sj.bjc.6602173
更新日期：2004-10-18 00:00:00
abstract：:Peripheral blood mononuclear cells (PBMCs) were obtained from patients receiving radioactive murine monoclonal antibody (MAb) therapy for malignant epithelial tumours, as well as normal controls, and were tested for the ability of T cells to proliferate in vitro in the presence of the MAb administered for therapy (HMF...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1991.337
更新日期：1991-09-01 00:00:00
abstract：:In adults, the haemolytic-uraemic syndrome (HUS) is associated with probable causative factors in the minority of all cases. Cytotoxic drugs are one of these potential causative agents. Although metastatic cancer by itself is a recognized risk-factor for the development of HUS, therapy with mitomycin-C, with cis-plati...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6690242
更新日期：1999-03-01 00:00:00
abstract：:High levels of loss of distal markers on 17p13.3 in breast cancer suggested the presence within the region of at least one tumour-suppressor gene. Here we describe the derivation of two biallelic polymorphisms from the 17p telomeric yeast artificial chromosome (YAC) TYAC98. Polymerase chain reaction-restriction fragme...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.449
更新日期：1996-09-01 00:00:00
abstract：:A case-control study of lung cancer involving interviews with 965 female patients and 959 controls in Shenyang and Harbin, two industrial cities which have among the highest rates of lung cancer in China, revealed that cigarette smoking is the main causal factor and accounted for about 35% of the tumours among women. ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1990.421
更新日期：1990-12-01 00:00:00
abstract：:The mechanism of down-regulation of c-myc RNA associated with androgen-induced suppression of the transformed phenotype in the human prostate carcinoma cell line LNCaP was investigated. The synthetic androgen mibolerone (7 alpha-17 alpha-Dimethyl-19-nortestosterone) reversibly inhibits the proliferation of LNCaP cells...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1992.76
更新日期：1992-03-01 00:00:00
abstract：:Chromosome 9p21 gene copy number in Ewing's sarcoma family of tumour (ESFT) cell lines and primary ESFT has been evaluated using Multiplex Ligation-dependent probe amplification, and the clinical significance of CDKN2A loss and p16/p14(ARF) expression investigated. Homozygous deletion of CDKN2A was identified in 4/9 (...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6603819
更新日期：2007-06-18 00:00:00
abstract：:Bryostatin 1 is a novel antitumour agent derived from Bugula neritina of the marine phylum Ectoprocta. Nineteen patients with advanced solid tumours were entered into a phase I study to evaluate the toxicity and biological effects of bryostatin 1. Bryostatin 1 was given as a one hour intravenous infusion at the beginn...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/bjc.1993.352
更新日期：1993-08-01 00:00:00
abstract：BACKGROUND:Identification of promising biomarkers that predict the prognosis of patients with breast cancer is needed. In this study, we hypothesised that the expression of the epithelial-mesenchymal transition-related biomarker plastin3 (PLS3) in peripheral blood could be a prognostic factor in breast cancer. METHODS...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2015.132
更新日期：2015-04-28 00:00:00
abstract：:The lability of cell surface histocompatibility antigens of 2 murine lymphomata was examined. These 2 tumours differ greatly in their capacity to metastasize in syngeneic hosts. Cells of the metastatic lymphoma released histocompatibility antigens in vivo and in vitro at a greater rate than cells of the non-metastasiz...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1976.2
更新日期：1976-01-01 00:00:00
abstract：BACKGROUND:A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency. High-level microsatellite instability (MSI-H) is currently the best predictor of responsiveness towards immune checkpoint blockade. Data about the prevalence of high-level microsatellite instability in cholangiocarc...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/s41416-018-0199-2
更新日期：2019-01-01 00:00:00
abstract：:To investigate the association between medullary carcinoma of the thyroid (MCT) and carcinoembryonic antigen (CEA), we assayed 78 sera from patients with thyroid diseases for CEA, employing the radioimmunoassay of double antibody technique. All 13 sera from patients with MCT had high levels of CEA, ranging from 14 to ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1976.133
更新日期：1976-08-01 00:00:00
abstract：:In the present study we have used flow cytometric DNA measurements on synchronised human NHIK 3025 cells to measure cell cycle progression under various conditions of reduced oxygenation. Our data indicate that addition of 0.1 mM deoxycytidine or uridine has no effect on the oxygen-dependent arrest in late G1 or on th...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1994.411
更新日期：1994-11-01 00:00:00
abstract：:The levels of polyamines (putrescine, spermidine and spermine) in erythrocytes and plasma were studied using Cloudman S-91 melanoma grown in the lungs of DBA/2 mice. Polyamine levels and the numbers of tumour-cell colonies in the lungs were determined at weekly intervals. Putrescine levels in both erythrocytes and pla...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1980.137
更新日期：1980-05-01 00:00:00
abstract：:Three hundred and nineteen patients with primary adenocarcinoma of the ovary were studied to define those factors, many of them histopathological, which influence survival. The paper considers the stage of spread at the time of operation, the histological type of the tumour, its grade and in particular its mitotic act...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1971.30
更新日期：1971-06-01 00:00:00
abstract：:The 5-year relative survival rates of women diagnosed with breast cancer between 1992 and 1994 were compared among the 99 Health Authorities (1999 boundaries) of England. Substantial variation, with evidence of geographical clustering was observed. Part of this variation was explained by differences in deprivation bet...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6601812
更新日期：2004-06-01 00:00:00
abstract：:Basal cell carcinoma (BCC) is a common malignancy with a good prognosis in the majority of cases. However, some BCC patients develop a more advanced disease that poses significant management challenges. Such cases include locally advanced, recurrent or metastatic BCC, or tumours that occur in anatomical sites where su...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2014.270
更新日期：2014-10-14 00:00:00
abstract：:We retrospectively analysed neuromuscular toxicity associated with paclitaxel 210 mg m(-2) given by 3-h infusion in 247 patients. The severity correlated significantly with total cumulative dose, but could not be predicted by the pretreatment clinical variables or by pharmacokinetic parameters. The toxicity tended to ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1998.278
更新日期：1998-05-01 00:00:00
abstract：BACKGROUND:Thyroid function has been suggested to interfere with tumour biology and prognosis in different cancers. The present study was performed to investigate the impact of pre-therapeutic serum thyroid-stimulating hormone (TSH) levels on the prognosis of patients with endometrial cancer. METHODS:Pre-therapeutic s...
journal_title：British journal of cancer
pub_type： 杂志文章,多中心研究
doi：10.1038/bjc.2013.282
更新日期：2013-07-09 00:00:00
abstract：BACKGROUND:Immunoscore have shown a promising prognostic value in many cancers. We aimed to establish and validate an immune classifier to predict survival after curative resection of hepatocellular carcinoma (HCC) patients who have undergone curative resection. METHODS:The immunohistochemistry (IHC) classifier assay ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/s41416-020-0864-0
更新日期：2020-07-01 00:00:00
abstract：:Tumour-associated cell-surface glycoprotein is associated with tumour progression in gastric cancer. We investigated the biological significance of tumour-associated cell-surface glycoprotein, determined by the binding of Helix pomatia agglutinin (HPA), with regard to survival time and to the malignant potential of ca...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1995.192
更新日期：1995-05-01 00:00:00
abstract：:Both misonidazole (MISO) and hyperthermia are known to enhance the radiation response of hypoxic cells, and to be selectively cytotoxic against cells in a hypoxic and acidic environment. The ability of these conditions to modify the effect of irradiation and their individual relationship was studied in a C3H mammary c...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1980.2
更新日期：1980-01-01 00:00:00
abstract：:The objective of this study was to examine the relationship between educational level and mortality from cancer in the city of Barcelona. The data were derived from a record linkage between the Barcelona Mortality Registry and the Municipal Census. The relative risks (RR) of death and 95% confidence intervals (CIs) ac...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6690108
更新日期：1999-02-01 00:00:00
abstract：:Molecular and immunohistochemical studies of genetic events on chromosome 17p were prospectively compared with conventional clinical and pathological parameters and disease behaviour at a minimum of 72 months follow-up. In a series of 91 patients with primary operable breast cancer, 37 out of 91 (41%) patients had dis...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1998.129
更新日期：1998-03-01 00:00:00
abstract：BACKGROUND:To quantify the benefits (cancer prevention and down-staging) and harms (recall and excess treatment) of cervical screening starting from age 20 years rather than from age 25 years. METHODS:We use routine screening and cancer incidence statistics from Wales (for screening from age 20 years) and England (scr...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2014.65
更新日期：2014-04-02 00:00:00
abstract：:To test the hypothesis that steroid hormone receptor expression is particularly pronounced in breast tumours when compared with non-neoplastic tissue, mastectomy samples were divided into 16 sectors. Multifocal tumours, of varying receptor phenotype were found in 4 patients and in addition different regions of large t...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1987.90
更新日期：1987-04-01 00:00:00
