NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas.

Abstract:

:Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionally, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.

journal_name

Int J Cancer

authors

Meder L,König K,Ozretić L,Schultheis AM,Ueckeroth F,Ade CP,Albus K,Boehm D,Rommerscheidt-Fuss U,Florin A,Buhl T,Hartmann W,Wolf J,Merkelbach-Bruse S,Eilers M,Perner S,Heukamp LC,Buettner R

doi

10.1002/ijc.29835

subject

Has Abstract

pub_date

2016-02-15 00:00:00

pages

927-38

issue

4

eissn

0020-7136

issn

1097-0215

journal_volume

138

pub_type

杂志文章
  • Impact of technology on cytology outcome in cervical cancer screening of young and older women.

    abstract::Little is known about age-dependent variation in outcomes of cervical cytology with modern technologies. This population-based study evaluated age-dependent changes after routine implementation of ThinPrep and SurePath technology in two independent laboratories, and controlled for time trends in a third laboratory usi...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.28532

    authors: Rask J,Lynge E,Franzmann M,Hansen B,Hjortebjerg A,Rygaard C,Schledermann D,Wåhlin A,Rebolj M

    更新日期:2014-05-01 00:00:00

  • Nicotine modulates the effects of retinoids on growth inhibition and RAR beta expression in lung cancer cells.

    abstract::Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives, retinoids, are effective agents in preventing the development of tobacco-associated cancers. Unfortunately, clinical trials of retinoids on cigarette smokers have shown lack of efficacy in preventing lung can...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.10304

    authors: Chen GQ,Lin B,Dawson MI,Zhang XK

    更新日期:2002-05-10 00:00:00

  • Physical inactivity, energy intake, obesity and the risk of rectal cancer in Canada.

    abstract::We conducted a population-based case-control study of 1,447 incident rectal cancer cases and 3,106 population controls aged 20-76 years to assess the effect of recreational physical activity, energy intake and obesity on rectal cancer risk in 7 of 10 Canadian provinces in 1994-97. After adjustment for the effect of va...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.11159

    authors: Mao Y,Pan S,Wen SW,Johnson KC,Canadian Cancer Registries Epidemiology Research Group.

    更新日期:2003-07-20 00:00:00

  • Gene expression profiling of peripheral blood mononuclear cells during treatment with a gene-modified allogeneic tumor cell vaccine in advanced renal cell cancer: tumor-induced immunosuppression and a possible role for NF-κB.

    abstract::Tumor-induced immunosuppression remains a major challenge for immunotherapy of cancer patients. To further elucidate why an allogeneic gene-modified [interleukin-7 (IL-7)/CD80-cotransfected] renal cell cancer (RCC) vaccine failed to induce clinically relevant TH-1-polarized immune responses, peripheral blood mononucle...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.29230

    authors: Flörcken A,Grau M,Wolf A,Weilemann A,Kopp J,Dörken B,Blankenstein T,Pezzutto A,Lenz P,Lenz G,Westermann J

    更新日期:2015-04-15 00:00:00

  • Dietary catechins and epithelial cancer incidence: the Zutphen elderly study.

    abstract::The flavonoids, a group of more than 4,000 polyphenolic antioxidants, are potential cancer preventive components of fruits and vegetables. Catechins, one of the 6 major groups of flavonoids, are present in high concentrations in tea as well. Our objective was to evaluate the association between intake of catechins and...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/1097-0215(200102)9999:9999<::aid-ijc1187>3

    authors: Arts IC,Hollman PC,Bueno De Mesquita HB,Feskens EJ,Kromhout D

    更新日期:2001-04-15 00:00:00

  • Lung cancer risk prediction: a tool for early detection.

    abstract::Although 45% of men and 39% of women will be diagnosed with cancer in their lifetime, it is difficult to predict which individuals will be affected. For some cancers, substantial progress in individual risk estimation has already been made. However, relatively few models have been developed to predict lung cancer risk...

    journal_title:International journal of cancer

    pub_type: 杂志文章,评审

    doi:10.1002/ijc.22331

    authors: Cassidy A,Duffy SW,Myles JP,Liloglou T,Field JK

    更新日期:2007-01-01 00:00:00

  • Benign breast disease increases breast cancer risk independent of underlying familial risk profile: Findings from a Prospective Family Study Cohort.

    abstract::Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort, we used Cox pr...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.32112

    authors: Zeinomar N,Phillips KA,Daly MB,Milne RL,Dite GS,MacInnis RJ,Liao Y,Kehm RD,Knight JA,Southey MC,Chung WK,Giles GG,McLachlan SA,Friedlander ML,Weideman PC,Glendon G,Nesci S,kConFab Investigators.,Andrulis IL,Buys SS

    更新日期:2019-07-15 00:00:00

  • Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis.

    abstract::The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50%...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.20297

    authors: Sheng Y,Hua J,Pinney KG,Garner CM,Kane RR,Prezioso JA,Chaplin DJ,Edvardsen K

    更新日期:2004-09-10 00:00:00

  • A five-microRNA model (pCaP) for predicting prostate cancer aggressiveness using cell-free urine.

    abstract::Improved biomarkers for prostate cancer (PC) risk stratification are urgently needed. Here, we aimed to develop a novel multimarker model for prediction of biochemical recurrence (BCR) after curatively intended radical prostatectomy (RP), based on minimally invasive sampling of blood and urine. We initially measured t...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.32296

    authors: Fredsøe J,Rasmussen AKI,Mouritzen P,Borre M,Ørntoft T,Sørensen KD

    更新日期:2019-11-01 00:00:00

  • Molecular basis and current strategies of therapeutic arginine depletion for cancer.

    abstract::Renewed interest in the use of therapeutic enzymes combined with an improved knowledge of cancer cell metabolism, has led to the translation of several arginine depletion strategies into early phase clinical trials. Arginine auxotrophic tumors are reliant on extracellular arginine, due to the downregulation of arginos...

    journal_title:International journal of cancer

    pub_type: 杂志文章,评审

    doi:10.1002/ijc.30051

    authors: Fultang L,Vardon A,De Santo C,Mussai F

    更新日期:2016-08-01 00:00:00

  • A bispecific transmembrane antibody simultaneously targeting intra- and extracellular epitopes of the epidermal growth factor receptor inhibits receptor activation and tumor cell growth.

    abstract::Epidermal growth factor receptor (EGFR) plays an important role in essential cellular processes such as proliferation, survival and migration. Aberrant activation of EGFR is frequently found in human cancers of various origins and has been implicated in cancer pathogenesis. The therapeutic antibody cetuximab (Erbitux)...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.28585

    authors: Müller N,Hartmann C,Genssler S,Koch J,Kinner A,Grez M,Wels WS

    更新日期:2014-06-01 00:00:00

  • Toward understanding nonparticipation in sigmoidoscopy screening for colorectal cancer.

    abstract::Understanding the reasons for nonparticipation in cancer screening may give clues about how to improve compliance. However, limited cooperation has hampered research on nonparticipant profiles. We took advantage of Sweden's comprehensive demographic and health care registers to investigate characteristics of all parti...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.23208

    authors: Blom J,Yin L,Lidén A,Dolk A,Jeppsson B,Påhlman L,Holmberg L,Nyrén O

    更新日期:2008-04-01 00:00:00

  • Health impact of delayed implementation of cervical cancer screening programs in India: A modeling analysis.

    abstract::India has the highest burden of cervical cancer in the world. To estimate the consequences of delaying implementation of organized cervical cancer screening, we projected the avertable burden of disease under different implementation scenarios of a screening program. We used an individual-based microsimulation model o...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.31823

    authors: Campos NG,Tsu V,Jeronimo J,Regan C,Resch S,Clark A,Sy S,Kim JJ

    更新日期:2019-02-15 00:00:00

  • Decrease of human pancreatic cancer cell tumorigenicity by alpha1,3galactosyltransferase gene transfer.

    abstract::The enzyme alpha1,3galactosyltransferase synthesizes the alphaGal epitope, a carbohydrate structure (Galalpha1,3Galbeta1,4GlcNAc-R), on glycoconjugates in lower mammals. The enzyme is absent in humans but large amounts of natural antibodies that recognize alphaGal epitopes are present in human serum. It is likely that...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.11470

    authors: Aubert M,Crotte C,Bernard JP,Lombardo D,Sadoulet MO,Mas E

    更新日期:2003-12-20 00:00:00

  • BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy.

    abstract::Heat shock protein 90 (Hsp90) is a molecular chaperone that promotes the conformational maturation of numerous client proteins, many of which play critical roles in tumor cell growth and survival. The ansamycin-based Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in Phase III clinical tes...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.24815

    authors: Yin X,Zhang H,Lundgren K,Wilson L,Burrows F,Shores CG

    更新日期:2010-03-01 00:00:00

  • c-Jun NH2-terminal kinase pathway is involved in constitutive matrix metalloproteinase-1 expression in a hepatocellular carcinoma-derived cell line.

    abstract::Transcription factor c-Jun serves for cellular proliferation, survival, differentiation and transformation and is recognized as an important factor in cancer development, including hepatocellular carcinoma (HCC). The purpose of present study is to determine the involvement of c-Jun in matrix metalloproteinase-1 (MMP-1...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.20095

    authors: Sugioka Y,Watanabe T,Inagaki Y,Kushida M,Niioka M,Endo H,Higashiyama R,Okazaki I

    更新日期:2004-05-10 00:00:00

  • Relationships among tumor responsiveness, cell sensitivity, doxorubicin cellular pharmacokinetics and drug-induced DNA alterations in two human small-cell lung cancer xenografts.

    abstract::In an attempt to understand the underlying cellular/biochemical factors of sensitivity/resistance in human small-cell lung cancer (SCLC), 2 SCLC tumor lines were compared with respect to tumor responsiveness to drug treatment, cell sensitivity, cellular doxorubicin accumulation, and DNA topoisomerase-II-mediated DNA c...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910460420

    authors: Pratesi G,Capranico G,Binaschi M,De Isabella P,Pilotti S,Supino R,Zunino F

    更新日期:1990-10-15 00:00:00

  • Comparison of immediate colposcopy, repeat conventional cytology and hrHPV testing for the clinical management of ASC-US cytology in routine health services of Medellin, Colombia: The ASCUS-COL Trial.

    abstract::In the context of opportunistic cervical cancer screening settings of low-and-middle-income countries, little is known about the benefits of high-risk human papillomavirus (hrHPV) testing on high-grade cervical abnormality detection among women with atypical squamous cells of undetermined significance (ASC-US) cytolog...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.33318

    authors: Baena A,Agudelo MC,Lopez C,Ramírez AT,Castañeda KM,Bedoya AM,Riveros M,Posada G,Borrero M,Buitrago CA,Suescun D,Gomez LJ,Ochoa JC,Stoler M,Gage J,Castle PE,Sasieni P,Almonte M,Herrero R,Sanchez GI,ASCUS-COL Trial

    更新日期:2020-10-02 00:00:00

  • Measurement of a pancreatic cancer-associated antigen (DU-PAN-2) detected by a monoclonal antibody in sera of patients with digestive cancers.

    abstract::DU-PAN-2 is a high-molecular-weight glycoprotein defined by a murine monoclonal antibody (MAb) against a pancreatic ductal adenocarcinoma cell line. In order to evaluate the usefulness of this antigen as a tumor marker, we determined the serum level of the antigen by competitive inhibition radioimmunoassay in sera fro...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910370509

    authors: Sawabu N,Toya D,Takemori Y,Hattori N,Fukui M

    更新日期:1986-05-15 00:00:00

  • Breast cancer risk in BRCA1 and BRCA2 mutation carriers and polyglutamine repeat length in the AIB1 gene.

    abstract::Marked variation in phenotypic expression among BRCA1 and BRCA2 mutation carriers may be partly explained by modifier genes that influence mutation penetrance. Variation in CAG/CAA repeat lengths coding for stretches of glutamines in the C-terminus of the AIB1 protein (amplified in breast cancer 1, a steroid receptor ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.21176

    authors: Hughes DJ,Ginolhac SM,Coupier I,Barjhoux L,Gaborieau V,Bressac-de-Paillerets B,Chompret A,Bignon YJ,Uhrhammer N,Lasset C,Giraud S,Sobol H,Hardouin A,Berthet P,Peyrat JP,Fournier J,Nogues C,Lidereau R,Muller D,Fricke

    更新日期:2005-11-01 00:00:00

  • Thymidine kinase in epithelial ovarian cancer: relationship with the other pyrimidine pathway enzymes.

    abstract::TK is a pyrimidine metabolic pathway enzyme involved in salvage DNA synthesis. What roles TK may play in epithelial ovarian cancer and the relationships between TK and the other pyrimidine pathway enzymes remain unclear. We examined TK1 gene expression by RT-PCR and related it to gene expression of TS, TP and DPD in 6...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.10319

    authors: Fujiwaki R,Hata K,Nakayama K,Moriyama M,Iwanari O,Katabuchi H,Okamura H,Sakai E,Miyazaki K

    更新日期:2002-05-20 00:00:00

  • Ectopic expression of herpes simplex virus-thymidine kinase gene in human non-small cell lung cancer cells conferred caspase-activated apoptosis sensitized by ganciclovir.

    abstract::Human non-small cell lung cancer (NSCLC) cells were transfected with recombinant prodrug herpes simplex virus type I thymidine kinase (HSV-tk) cDNA, and the selected clones underwent apoptosis in response to induction by antiviral ganciclovir (GCV). The efficiency of GCV-induced growth inhibition and the extent of the...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.10701

    authors: Chiu CC,Kang YL,Yang TH,Huang CH,Fang K

    更新日期:2002-12-01 00:00:00

  • Novel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial-mesenchymal transition and colorectal cancer aggressiveness.

    abstract::Epithelial-mesenchymal transition (EMT) is a cell plasticity process required for metastasis and chemoresistance of carcinoma cells. We report a crucial role of the signal adaptor proteins CRK and CRKL in promoting EMT and tumor aggressiveness, as well as resistance against chemotherapy in colorectal and pancreatic ca...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.32955

    authors: Franke FC,Slusarenko BO,Engleitner T,Johannes W,Laschinger M,Rad R,Nitsche U,Janssen KP

    更新日期:2020-09-15 00:00:00

  • Clonal analysis of tumor-infiltrating lymphocytes from human primary and metastatic liver tumors.

    abstract::Phenotypic and functional characteristics of tumor-infiltrating lymphocytes (TIL) obtained from human primary and metastatic liver tumors were studied. Lymphocytes isolated from 18 tumors and autologous (A) peripheral blood (6 cases) were phenotyped by 2-color flow cytometry and cloned in a limiting dilution system, w...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910460521

    authors: Shimizu Y,Iwatsuki S,Herberman RB,Whiteside TL

    更新日期:1990-11-15 00:00:00

  • Gallstones and incident colorectal cancer in a large pan-European cohort study.

    abstract::Gallstones, a common gastrointestinal condition, can lead to several digestive complications and can result in inflammation. Risk factors for gallstones include obesity, diabetes, smoking and physical inactivity, all of which are known risk factors for colorectal cancer (CRC), as is inflammation. However, it is unclea...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.32090

    authors: Ward HA,Murphy N,Weiderpass E,Leitzmann MF,Aglago E,Gunter MJ,Freisling H,Jenab M,Boutron-Ruault MC,Severi G,Carbonnel F,Kühn T,Kaaks R,Boeing H,Tjønneland A,Olsen A,Overvad K,Merino S,Zamora-Ros R,Rodríguez-Barranc

    更新日期:2019-09-15 00:00:00

  • Characteristics and prognostic significance of profiling the peripheral blood T-cell receptor repertoire in patients with advanced lung cancer.

    abstract::Lung cancer is one of the greatest threats to human health, and is initially detected and attacked by the immune system through tumor-reactive T cells. The aim of this study was to determine the basic characteristics and clinical significance of the peripheral blood T-cell receptor (TCR) repertoire in patients with ad...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.32145

    authors: Liu YY,Yang QF,Yang JS,Cao RB,Liang JY,Liu YT,Zeng YL,Chen S,Xia XF,Zhang K,Liu L

    更新日期:2019-09-01 00:00:00

  • The melanoma-associated 24 base pair duplication in p16INK4a is functionally impaired.

    abstract::Melanoma-associated germline mutations affecting the tumor suppressor and cyclin-dependent kinase (CDK) inhibitor, CDKN2A/p16INK4a, have been identified in over 100 melanoma-prone families worldwide. To predict the melanoma risk for carriers of specific mutations, mutant p16INK4a can be tested in biochemical and cellu...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.21265

    authors: Becker TM,Ayub AL,Kefford RF,Mann GJ,Rizos H

    更新日期:2005-11-20 00:00:00

  • Acid ceramidase-mediated production of sphingosine 1-phosphate promotes prostate cancer invasion through upregulation of cathepsin B.

    abstract::Invasiveness is one of the key features of aggressive prostate cancer; however, our understanding of the precise mechanisms effecting invasion remains limited. The ceramide hydrolyzing enzyme acid ceramidase (AC), overexpressed in most prostate tumors, causes an aggressive and invasive phenotype through downstream eff...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.27480

    authors: Beckham TH,Lu P,Cheng JC,Zhao D,Turner LS,Zhang X,Hoffman S,Armeson KE,Liu A,Marrison T,Hannun YA,Liu X

    更新日期:2012-11-01 00:00:00

  • Mouse mammary tumor virus production stimulated by hormones and polyamines in cells grown in semi-synthetic in vitro conditions.

    abstract::Hormonal regulation of mouse mammary tumor virus (MMTV) synthesis was studied in the CCL-51-SF cell subline derived from the Sykes' mammary tumor cell line CCL-51 and adapted to grow in semi-synthetic in vitro conditions. The virus was quantitated by measuring the supernatant reverse transcriptase activity in exogenou...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910190215

    authors: Svec J,Links J

    更新日期:1977-02-15 00:00:00

  • Characterization of a small-cell-lung-carcinoma cell line from a patient with cancer-associated retinopathy.

    abstract::We examined the biologic properties of a small-cell-lung-carcinoma (SCLC) cell line (designated MN-1112) established from a patient with SCLC who showed paraneoplastic retinopathy syndrome. Morphologic and immunocytochemical analyses showed that MN-1112 cells possess features of the classic type of SCLC. MN-1112 cells...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/(SICI)1097-0215(19960301)65:5<671::AID-IJC

    authors: Yamaji Y,Matsubara S,Yamadori I,Sato M,Fujita T,Fujita J,Takahara J

    更新日期:1996-03-01 00:00:00