X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 22 ( 2017-11-15), p. 6442-6452
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 22 ( 2017-11-15), p. 6442-6452
    Abstract: Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n = 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n = 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n = 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P = 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment. Cancer Res; 77(22); 6442–52. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-2006
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 2
    Online Resource
    Online Resource
    Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14 ( 2016-07-15), p. 4270-4282
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14 ( 2016-07-15), p. 4270-4282
    Abstract: Epithelial–mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTCs with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related procoagulant properties in the blood. TF blockade by antibody or shRNA diminished the procoagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties, and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT–TF regulatory axis that triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTCs. Cancer Res; 76(14); 4270–82. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-2263
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 3
    Online Resource
    Online Resource
    Author response
    eLife Sciences Publications, Ltd ; 2018
    In:  eLife Vol. 7 ( 2018-09-04)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 7 ( 2018-09-04)
    Abstract: Lymphoid and myeloid cells are abundant in the tumor microenvironment, can be quantified by immunohistochemistry and shape the disease course of human solid tumors. Yet, there is no comprehensive understanding of spatial immune infiltration patterns (‘topography’) across cancer entities and across various immune cell types. In this study, we systematically measure the topography of multiple immune cell types in 965 histological tissue slides from N = 177 patients in a pan-cancer cohort. We provide a definition of inflamed (‘hot’), non-inflamed (‘cold’) and immune excluded patterns and investigate how these patterns differ between immune cell types and between cancer types. In an independent cohort of N = 287 colorectal cancer patients, we show that hot, cold and excluded topographies for effector lymphocytes (CD8) and tumor-associated macrophages (CD163) alone are not prognostic, but that a bivariate classification system can stratify patients. Our study adds evidence to consider immune topographies as biomarkers for patients with solid tumors.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.7554/eLife.36967
    DOI: 10.7554/eLife.36967.001
    DOI: 10.7554/eLife.36967.002
    DOI: 10.7554/eLife.36967.003
    DOI: 10.7554/eLife.36967.004
    DOI: 10.7554/eLife.36967.005
    DOI: 10.7554/eLife.36967.006
    DOI: 10.7554/eLife.36967.007
    DOI: 10.7554/eLife.36967.008
    DOI: 10.7554/eLife.36967.009
    DOI: 10.7554/eLife.36967.010
    DOI: 10.7554/eLife.36967.011
    DOI: 10.7554/eLife.36967.012
    DOI: 10.7554/eLife.36967.013
    DOI: 10.7554/eLife.36967.014
    DOI: 10.7554/eLife.36967.015
    DOI: 10.7554/eLife.36967.016
    DOI: 10.7554/eLife.36967.017
    DOI: 10.7554/eLife.36967.018
    DOI: 10.7554/eLife.36967.019
    DOI: 10.7554/eLife.36967.020
    DOI: 10.7554/eLife.36967.021
    DOI: 10.7554/eLife.36967.023
    DOI: 10.7554/eLife.36967.024
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2018
    detail.hit.zdb_id: 2687154-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 4
    Online Resource
    Online Resource
    Abstract 3021: CCR5 inhibition: macrophage repolarization therapy for colorectal cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3021-3021
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3021-3021
    Abstract: In patients with metastatic colorectal cancer (CRC), the local immune response influences the clinical course. An in-depth analysis of the invasive margin of human CRC liver metastases revealed a distinct immunological microenvironment. Within this microenvironment, two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10. CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5, creating an exploitive loop. CCR5 was found on macrophages, lymphocytes and on the vast majority of tumor cells. Inhibition of CCR5 in patient-derived functional in vitro organotypic culture models showed a promising macrophage repolarization with anti-tumoral effects. These effects are mediated by activation of an antiviral program in macrophages, leading to interferon and reactive oxygen species production and subsequent selective tumor cell death. These anti-tumoral effects were confirmed in a phase I trial with a CCR5 antagonist in 14 patients with liver metastases of advanced refractory CRC. Treatment with the oral CCR5 Inhibitor was very well tolerated and objective responses were seen, especially in combination with previously ineffective chemotherapy. Biopsies revealed mitigation of tumor-promoting inflammation within the tumor tissue, confirming the validity of the explant model and highlighting the feasbility of this approach. It furthermore shows the proof-of-concept for macrophage repolarization in cancer patients. Citation Format: Niels Halama, Inka Zoernig, Anna Berthel, Christoph Kahlert, Fee Klupp, Meggy Suarez-Carmona, Karsten Brand, Juergen Krauss, Felix Lasitschka, Alexis Ulrich, Juergen Weitz, Martin Schneider, Markus Buechler, Laurence Zitvogel, Thomas Herrmann, Axel Benner, Christina Kunz, Stephan Luecke, Christoph Springfeld, Christine S. Falk, Dirk Jaeger. CCR5 inhibition: macrophage repolarization therapy for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3021. doi:10.1158/1538-7445.AM2017-3021
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3021
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 5
    Online Resource
    Online Resource
    Abstract 3954: Regulation of pro-angiogenic and pro-inflammatory cytokines in tumor cells: Implication of epithelial-to-mesenchymal transitions .
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3954-3954
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3954-3954
    Abstract: Increasing data suggest a contribution of epithelial-to-mesenchymal transitions in specific steps of the metastatic cascade, particularly in tumor invasion and intravasation, and in the release of circulating tumor cells (CTCs) in the blood stream. The completion of these steps largely relies on interactions disseminating tumor cells establish with host cells. Because cytokines are particularly implicated in tumor-host cross-talks, we have examined whether EMT programs could be involved in the regulation of pro-inflammatory and pro-angiogenic cytokines which could favor angiogenesis, intravasation and CTC release. To investigate EMT implication in cytokine regulation, we used two cell lines, MDA-MB-468 (a mammary adenocarcinoma cell line) and A549 (a lung carcinoma cell line). These cell lines were shown to undergo EMT-changes following EGF and TGF-β treatment respectively, characterized by an upregulation of vimentin, snail and slug, and a downregulation of E-cadherin. A cytokine array on cell supernatant showed that EMT induction in these cell lines is associated with the upregulation of a consistant panel of cytokines. We then confirmed that interleukin-8 (IL-8), interleukin-6 (IL-6) and Granulocyte Monocyte-Colony Stimulating Factor (GM-CSF) are upregulated during EMT in the two carcinoma cell lines by RT-qPCR and ELISA. Emphasizing a functional role of such regulations, conditioned medium from EMT-induced MDA-468 cells was shown to stimulate HUVEC cell migration in a boyden chamber assay. In order to investigate whether slug and snail EMT transcription factors are involved in the regulation of IL-8, IL-6 and GM-CSF, we used both siRNA and cDNA transfection approaches. Combined repression of snail and slug inhibited the EMT-associated upregulation of IL-8, IL-6 and GM-CSF, suggesting that snail and slug are necessary for this process. Ectopic expression of each transcription factor was not sufficient to induce cytokines expression. However, ectopic expression of a proteasome degradation-resistant mutant of snail was sufficient to induce expression of IL-6, IL-8 and GM-CSF, suggesting that the stabilization of snail is necessary to regulate the expression of these cytokines. We thus here demonstrate that EMT is associated with an overexpression of specific pro-angiogenic and pro-inflammatory cytokines. We further emphasize a role of snail and slug transcription factors in this regulatory process. These data suggest that EMT programs could directly contribute to the stimulation of angiogenesis and inflammatory cell recruitment in the tumor microenvironment. The impact of such regulations on angiogenesis and the metastatic spread is currently under investigation. Citation Format: Meggy Suarez-Carmona, Morgane Bourcy, Jean-Michel Foidart, Philippe Delvenne, Agnès Noël, Myriam Polette, Christine Gilles. Regulation of pro-angiogenic and pro-inflammatory cytokines in tumor cells: Implication of epithelial-to-mesenchymal transitions . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3954. doi:10.1158/1538-7445.AM2013-3954
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3954
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 6
    Online Resource
    Online Resource
    Proteomic signatures reveal a dualistic and clinically relevant classification of anal canal carcinoma
    Wiley ; 2017
    In:  The Journal of Pathology Vol. 241, No. 4 ( 2017-03), p. 522-533
    Details
    In: The Journal of Pathology, Wiley, Vol. 241, No. 4 ( 2017-03), p. 522-533
    Abstract: Aetiologically linked to HPV infection, malignancies of the anal canal have substantially increased in incidence over the last 20 years. Although most anal squamous cell carcinomas (SCCs) respond well to chemoradiotherapy, about 30% of patients experience a poor outcome, for undetermined reasons. Despite cumulative efforts for discovering independent predictors of overall survival, both nodal status and tumour size are still the only reliable factors predicting patient outcome. Recent efforts have revealed that the biology of HPV‐related lesions in the cervix is strongly linked to the originally infected cell population. To address the hypothesis that topography also influences both gene expression profile and behaviour of anal (pre)neoplastic lesions, we correlated both proteomic signatures and clinicopathological features of tumours arising from two distinct portions of the anal canal: the lower part (squamous zone) and the more proximal anal transitional zone. Although microdissected cancer cells appeared indistinguishable by morphology (squamous phenotype), unsupervised clustering analysis of the whole proteome significantly highlighted the heterogeneity that exists within anal canal tumours. More importantly, two region‐specific subtypes of SCC were revealed. The expression profile (sensitivity/specificity) of several selected biomarkers (keratin filaments) further confirmed the subclassification of anal (pre)cancers based on their cellular origin. Less commonly detected compared to their counterparts located in the squamous mucosa, SCCs originating in the transitional zone more frequently displayed a poor or basaloid differentiation, and were significantly correlated with reduced disease‐free and overall survivals. Taken together, we present direct evidence that anal canal SCC comprises two distinct entities with different cells of origin, proteomic signatures, and survival rates. This study forms the basis for a dualistic classification of anal carcinoma, with implications for management, outcome expectations, and possibly therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2017.241.issue-4
    DOI: 10.1002/path.4858
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1475280-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 7
    Online Resource
    Online Resource
    Abstract A069: NIM15 blockade – A new stroma-targeting approach for the treatment of epithelial ovarian cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Immunology Research Vol. 7, No. 2_Supplement ( 2019-02-01), p. A069-A069
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 2_Supplement ( 2019-02-01), p. A069-A069
    Abstract: Despite the immense research over the past decade in the cancer immunology field, which has led to several clinical trials and FDA and EMA approvals of biologicals for the reinvigoration of T-cell-mediated cancer cell killing in diverse tumor entities, the long-term survival of patients with advanced epithelial ovarian cancer is still devastating. These results therefore imply the need for a more intensive investigation of the tumor microenvironment in this cancer type in order to enhance disease outcome and improve the effectiveness of current immunotherapeutics. We herein show for the first time efficacy data of a novel treatment approach for the specific targeting of the stromal tumor compartment in a human tissue explant culture model of high-grade serous ovarian cancer. Antibody-mediated blockade of NIM15, a protein suspected to be predominantly expressed by tumor-associated macrophages and cancer-associated-fibroblasts in ovarian cancer, has the potential to polarize the immune landscape in a subset of patients from a stromal-dense and immunosuppressive one into a Th1-M1-supportive microenvironment, as measured by cytokine pattern analyses and semiautomated immune cell quantification. Abrogating the effects of secreted NIM15 unleashes in vitro proliferation of T-cell subsets and increases the production of cytokines and chemokines involved in innate and adaptive antitumor immune responses in our tissue culture explant model. In order to unravel the mechanistic relations behind the observed effects, we plan further experiments to prove whether these might be due to a disruption of the collagen-dense tumor stroma and a repolarization of the secretory profile of tumor-associated macrophages and fibroblasts. In summary, we hope to develop a pharmacologic tool that converts immune-depleted, “cold” cancer types into T-cell infiltrated ones and therewith provide a rationale for combination treatment approaches, like anti-PD1 blockade or adoptive cell transfer, to further ameliorate the so far poor response of metastasized, refractory ovarian cancer. Citation Format: Dyke Ferber, Meggy Suarez-Carmona, Frank Momburg, Marten Meyer, Rebecca Rothenheber, Bénédicte M.A. Lenoir, Sarah Schott, Inka Zoernig, Dirk Jäger, Niels Halama. NIM15 blockade – A new stroma-targeting approach for the treatment of epithelial ovarian cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A069.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A069
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2732517-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 8
    Online Resource
    Online Resource
    Unique recurrence patterns of cervical intraepithelial neoplasia after excision of the squamocolumnar junction
    Wiley ; 2015
    In:  International Journal of Cancer Vol. 136, No. 5 ( 2015-03), p. 1043-1052
    Details
    In: International Journal of Cancer, Wiley, Vol. 136, No. 5 ( 2015-03), p. 1043-1052
    Abstract: What's new? A discrete population of cells at the squamo‐columnar junction (SCJ) of the cervix may house the cells of origin—the first to become genetically altered in cancer initiation—for cervical intraepithelial neoplasia (CIN) and cervical cancer. In the present comparison of excision margins, timing of recurrence, CIN grade, HPV types, p16 immunophenotype, and SCJ immunophenotype for recurrent and initial CIN, recurrences were found to be invariably low grade and within the ectocervix or metaplastic epithelium. Hence, successful SCJ excision appears to reduce the risk of new CIN 2/3 lesions, suggesting that SCJ cryoablation could be effective in preventing cervical cancer.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v136.5
    DOI: 10.1002/ijc.28978
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 9
    Online Resource
    Online Resource
    EMT and inflammation: inseparable actors of cancer progression
    Wiley ; 2017
    In:  Molecular Oncology Vol. 11, No. 7 ( 2017-07), p. 805-823
    Details
    In: Molecular Oncology, Wiley, Vol. 11, No. 7 ( 2017-07), p. 805-823
    Abstract: Tumors can be depicted as wounds that never heal, and are infiltrated by a large array of inflammatory and immune cells. Tumor‐associated chronic inflammation is a hallmark of cancer that fosters progression to a metastatic stage, as has been extensively reviewed lately. Indeed, inflammatory cells persisting in the tumor establish a cross‐talk with tumor cells that may result in a phenotype switch into tumor‐supporting cells. This has been particularly well described for macrophages and is referred to as tumor‐associated ‘M2’ polarization. Epithelial‐to‐mesenchymal transition (EMT), the embryonic program that loosens cell–cell adherence complexes and endows cells with enhanced migratory and invasive properties, can be co‐opted by cancer cells during metastatic progression. Cancer cells that have undergone EMT are more aggressive, displaying increased invasiveness, stem‐like features, and resistance to apoptosis. EMT programs can also stimulate the production of proinflammatory factors by cancer cells. Conversely, inflammation is a potent inducer of EMT in tumors. Therefore, the two phenomena may sustain each other, in an alliance for metastasis. This is the focus of this review, where the interconnections between EMT programs and cellular and molecular actors of inflammation are described. We also recapitulate data linking the EMT/inflammation axis to metastasis.
    Type of Medium: Online Resource
    ISSN: 1574-7891 , 1878-0261
    URL: Issue
    URL: Article
    DOI: 10.1002/mol2.2017.11.issue-7
    DOI: 10.1002/1878-0261.12095
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2322586-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 10
    Online Resource
    Online Resource
    Carcinogenic HPV infection in the cervical squamo‐columnar junction
    Wiley ; 2015
    In:  The Journal of Pathology Vol. 236, No. 3 ( 2015-07), p. 265-271
    Details
    In: The Journal of Pathology, Wiley, Vol. 236, No. 3 ( 2015-07), p. 265-271
    Abstract: Recent studies have suggested the involvement of a unique population of cells at the cervical squamo‐columnar junction ( SCJ ) in the pathogenesis of early (squamous intraepithelial lesion or SIL ) and advanced (squamous cell and adeno‐carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to (1) determine if normal‐appearing SCJ cells contained evidence of carcinogenic HPV infection and (2) trace their transition to early SIL . Sections of cervix from high‐risk reproductive age women were selected and SCJ cells were analysed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/ RNA ( PCR ), immunostaining for HPV16 E2 (an early marker of HPV infection), p16 ink4 , Ki67, and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from eight of ten with visible SCJ cells, six of which were HPV16 /18 DNA ‐positive. In five of these latter cases, the SCJ cells were positive for p16 ink4 and/or HPV E2 . Transcriptionally active HPV infection ( E6 / E7 mRNAs ) was also detected in microdissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16 ink4 immunoreactivity, elevated proliferative index, and rare L1 antigen positivity. We present for the first time direct evidence that normal‐appearing SCJ cells can be infected by carcinogenic HPV . They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16 ink4 expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high‐grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ . Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2015.236.issue-3
    DOI: 10.1002/path.4533
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1475280-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
Nothing or not found what you are looking for? Please check your search query or use the Interlibrary Loan Search.
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages