1,721,015 research outputs found
Abstract B51: Tumor cell evolutionary strategies to overcome immune response
No full textAbstract
Introduction: The human immune system is complex, dynamic, and highly effective with system tools ranging from simplistic barrier formation to innate and adaptive cellular responses. In turn, the organisms subject to the immune response can evolve a number of different adaptive strategies. Here we examine these evolutionary dynamics in host immune response to cancer focusing on available strategies that permit cancer cells to evade the immune response.
Materials and Methods: Two rapidly proliferating human cell lines, SW620 colon cancer and MDA-MB-231 triple negative breast cancers were subjected to repeated exposure to either immune conditioned media created by lipopolysaccharide stimulated immune cells or intermittent direct culturing with human peripheral blood leucocytes. Resulting phenotypes were evaluated for alterations in growth dynamics, immune resistance, and gene expression.
Results: Conditioned media had only slight effects on tumor cell death. However, after 4 months selected cells have an increased resistance to T cell mediated killing. Co-culturing with immune cells at high effector to target ratios resulted in strong selection with greater than 50% tumor cell death. After 15 rounds we evolved cancer cells that were resistant to this killing. Interestingly, In-vitro selection of SW620, a more rapidly proliferating cell line, resulted in an anti-apoptotic strategy when confronted with immune cells while MDA-MB-231 cells increased fecundity.
Conclusion: Utilizing different arms of the immune system resulted in different styles and strengths of selection force. Additionally, we demonstrate that the two different cell lines employed distinctly different strategies to overcome host immune response. The MDA-MB-231 population adapts to immune attack by accelerating proliferation so that it exceeds the death rate imposed by the immune system. Interestingly, this has been observed clinically as some tumors show explosive growth during immunotherapy. In contrast, the SW620 cells upregulate anti-apoptotic cellular machinery which appears to be phenotypically costly so that proliferation of resistant cells is significantly diminished. As clinical applications of immunotherapy continue to grow it is imperative that we do not ignore the evolutionary consequences of immune selection on the tumor phenotype. While investigations of immune evasive strategies in tumor cells has led to a growing list of specific mechanisms, here we look to not only expand this list but to exploit it. Detailed understanding of the specific adaptive strategy for each tumor population may reveal phenotypic vulnerabilities to second line treatments.
Citation Format: Kimberly A. Luddy, Jan Poleszczuk, Arig Ibrahim Hashim, Mehdi Damaghi, Robert Gillies, Joel Brown, Robert Gatenby. Tumor cell evolutionary strategies to overcome immune response. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B51.</jats:p
Abstract 2695: Role of tumor generated acidity in immune stromal interactions during prostate carcinogenesis
No full textAbstract
Insufficiency in tumor perfusion and high rate glycolysis combine to reduce the pH of tumor microenvironment. In a TRAMP model of prostate cancer, we had shown that carcinogenesis is associated with increasing acidification of the microenvironment and that neutralization of this acidity can prevent cancer emergence or metastases. Carcinogenesis in the TRAMP model is also associated with increased fibrosis and immune cells infiltration. We thus sought to determine if fibrosis drives immune infiltration in early tumorigenesis or vice-versa; and whether this dynamics is affected by tumor acidity. To investigate this, we harvested prostates from TRAMP mice or their matching non-transgenic controls at different time points and stained serial prostate tissue sections with F4/80 (macrophages), SMA (cancer-associated fibroblasts, CAFs), and Masson’s Trichome (collagen). Quantitative image analysis reveals that increase in fibrosis occur prior to macrophage infiltration and that both events preceded tumor development. However, the relative amount of collagen fibers was unchanged across all time points. Notably, neither fibrosis nor macrophage infiltration occurred in mice treated with buffer, suggesting an involvement of acidity in this immune stromal interactions. Interestingly, macrophages isolated from latter time points in the untreated group as well as macrophages co-cultured with prostate tumor cells at acidic pH, possessed an M2-like phenotype by expressing immunosuppressive genes (e.g. Arginase 1, Arg1) and a range of scavenging receptors (e.g. mannose receptor, Cd206), as well as releasing more angiogenic factors (e.g. VEGF and MMPs). Similar results were recapitulated when M2 macrophages were stimulated at acidic pH by showing enhanced Cd206 and Arg1 expression. On the functional level, macrophages activated at acidic pH had a higher ability to uptake fluorescently labelled ovalbumin and collagen, as examples of mannosylated ligands that prevail the fibrotic microenvironment. In summary, these results suggest that tumor acidity may promote fibrosis, with subsequent macrophage infiltration and phenotypic switching, leading to increased collagen turnover. It is suspected that this extracellular matrix remodeling may be permissive for tumor progression.
Citation Format: Asmaa El-Kenawi, Jasreman Dhillon, Arig Ibrahim-Hashim, Dominique Abrahams, Shari Pilon-Thomas, Brian Ruffell, Robert Gatenby, Robert Gillies. Role of tumor generated acidity in immune stromal interactions during prostate carcinogenesis [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 2695. doi:10.1158/1538-7445.AM2017-2695</jats:p
Abstract 2929: Exploratory evolved strategies that limit cancer growth for possible new therapeutic strategies
No full textAbstract
Strong selection can promote mammalian evolution of a remarkably diverse phenotypic range over a short period of time. With appropriate selection forces, we tested the hypothesis that laboratory animals can evolve phenotypes that are resistant to the growth of implanted tumors. We propose that strong selection can produce evolution of different strategies to generate resistance to the growth of inoculated tumors,1. Changes in the supportive cell layer that decrease limited growth of cancer cell populations. 2. Increase of immunologic response to tumor antigens.
Hence, we examined the evolution of resistance in immuno-competent and immuno-deficient mice. Fixed number of cells from luciferase tagged LL/2 (Lewis lung carcinoma) cancer cells were implanted in groups of 10 male C57BL/6 and SCID mice. All tumor cells were obtained from frozen samples of a single large tumor population to eliminate any contribution from tumor cell evolution. Tumor growth in each animal was measured by calipers and luciferase imaging. The two animals that exhibited the slowest tumor growth in each cohort were bred with females from the same litter. Over 12 generations, the selection pressures resulted in emergence of SCID mice in which tumors grew at approximately 1/10th the rate compared their initial generation. The immunocompetent C57BL/6 mice evolved significant changes in immune-mediated parental tumor cell killing but this has yet resulted in significantly delayed tumor growth because the LL/2 cells rapidly evolve resistance strategies. Injection of the same tumor cells into unevolved wild type strains of both SCID and C57BL/6 mice produced rapid tumor growth identical to that seen in the first generation.
Using immunohistochemistry we observed decrease in blood supply among generations, proliferation, and apoptosis while no differences were observed in Glut-1 and CA-9 expression. To investigate this observation, first we examined changes in the molecular characteristics of the tumor cells during in-vivo growth by microarray on tumor cells isolated from “final” adapted cell population(s) in the animals that have been selected to decrease tumor growth compared to the wild type as well as normal cells in parallel. Our results showed that there are 158 genes different between tumors growing in the evolved and selected mice, among them are genes involved in extracellular matrix organization, hence we used second-harmonic generation (SHG) microscopy to image and quantify collagen,
our results showed significant increase in collagen at the edge as well as the core of the tumor of the evolved mice compared to wild type mice.
In conclusion our evolutionary study has reduced tumor growth in SCID mice but has had limited success in the C57BL/6. The SCID mice adaptation to tumor was likely through alteration in function of the supportive cell layer (Collagen), thus generating biomechanical forces and protective cellular events during tumor progression at early stages.
Citation Format: Dominique Abrahams, Arig Ibrahim Hashim, Kim Luddy, Robert Gillies, Robert Gatenby, Joel Brown. Exploratory evolved strategies that limit cancer growth for possible new therapeutic strategies [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 2929. doi:10.1158/1538-7445.AM2017-2929</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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