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Do cancer stem cells exist? A pilot study combining a systematic review with the hierarchy-of-hypotheses approach.

ABSTRACT: The phenomenon of cancer cell heterogeneity has been explained by different hypotheses, each entailing different therapy strategies. The most recent is the cancer stem cell model, which says that tumourigenicity and self-renewal are restricted to rare stem cell-like cancer cells. Since its conception, conflicting evidence has been published. In this study, we tested the applicability of a new approach developed in the field of ecology, the hierarchy-of-hypotheses approach, for the Cancer Stem Cell hypothesis. This approach allows to structure a broad concept into more specific sub-hypotheses, which in turn can be connected to available empirical studies. To generate a dataset with empirical studies, we conducted a systematic literature review in the Web of Science limited to the first 1000 publications returned by the search. From this pool, 51 publications were identified that tested whether a cell sub-population had cancer stem cell properties. By classifying the studies according to: (1) assessed indicators, (2) experimental assays and (3) model cancer cells used, we built a hierarchical structure of sub-hypotheses. The empirical tests from the selected studies were subsequently assigned to this hierarchy of hypotheses, and the percentage of supporting, undecided and questioning evidence was calculated for each sub-hypothesis, as well as additional experimental characteristics. Our approach successfully allowed us to determine that within our dataset, the empirical support for the CSC hypothesis was only 49.0%. The support of different sub-hypotheses was highly variable. Most noticeable, the conception that putative cancer stem cells are a rare subset of cells could not be confirmed by most studies (13.5% support). The empirical support varied also between types of cancer, animal models and cell isolation method used. For the first time, this study showed the applicability of the hierarchy-of-hypotheses approach for synthesizing and evaluating empirical evidence for a broad hypothesis in the field of bio-medical research.

SUBMITTER: Bartram I

PROVIDER: S-EPMC6910685 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Do cancer stem cells exist? A pilot study combining a systematic review with the hierarchy-of-hypotheses approach.

Bartram Isabelle I Jeschke Jonathan M JM

PloS one 20191213 12

The phenomenon of cancer cell heterogeneity has been explained by different hypotheses, each entailing different therapy strategies. The most recent is the cancer stem cell model, which says that tumourigenicity and self-renewal are restricted to rare stem cell-like cancer cells. Since its conception, conflicting evidence has been published. In this study, we tested the applicability of a new approach developed in the field of ecology, the hierarchy-of-hypotheses approach, for the Cancer Stem Ce ...[more]

PMID: 31834886

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Project description:Non-communicable disease (NCD) prevention strategies now prioritise four major risk factors: food, tobacco, alcohol and physical activity. Dietary salt intake remains much higher than recommended, increasing blood pressure, cardiovascular disease and stomach cancer. Substantial reductions in salt intake are therefore urgently needed. However, the debate continues about the most effective approaches. To inform future prevention programmes, we systematically reviewed the evidence on the effectiveness of possible salt reduction interventions. We further compared "downstream, agentic" approaches targeting individuals with "upstream, structural" policy-based population strategies.We searched six electronic databases (CDSR, CRD, MEDLINE, SCI, SCOPUS and the Campbell Library) using a pre-piloted search strategy focussing on the effectiveness of population interventions to reduce salt intake. Retrieved papers were independently screened, appraised and graded for quality by two researchers. To facilitate comparisons between the interventions, the extracted data were categorised using nine stages along the agentic/structural continuum, from "downstream": dietary counselling (for individuals, worksites or communities), through media campaigns, nutrition labelling, voluntary and mandatory reformulation, to the most "upstream" regulatory and fiscal interventions, and comprehensive strategies involving multiple components.After screening 2,526 candidate papers, 70 were included in this systematic review (49 empirical studies and 21 modelling studies). Some papers described several interventions. Quality was variable. Multi-component strategies involving both upstream and downstream interventions, generally achieved the biggest reductions in salt consumption across an entire population, most notably 4g/day in Finland and Japan, 3g/day in Turkey and 1.3g/day recently in the UK. Mandatory reformulation alone could achieve a reduction of approximately 1.45g/day (three separate studies), followed by voluntary reformulation (-0.8g/day), school interventions (-0.7g/day), short term dietary advice (-0.6g/day) and nutrition labelling (-0.4g/day), but each with a wide range. Tax and community based counselling could, each typically reduce salt intake by 0.3g/day, whilst even smaller population benefits were derived from health education media campaigns (-0.1g/day). Worksite interventions achieved an increase in intake (+0.5g/day), however, with a very wide range. Long term dietary advice could achieve a -2g/day reduction under optimal research trial conditions; however, smaller reductions might be anticipated in unselected individuals.Comprehensive strategies involving multiple components (reformulation, food labelling and media campaigns) and "upstream" population-wide policies such as mandatory reformulation generally appear to achieve larger reductions in population-wide salt consumption than "downstream", individually focussed interventions. This 'effectiveness hierarchy' might deserve greater emphasis in future NCD prevention strategies.

Project description:Mesenchymal stem cells (MSC) comprise a heterogeneous population of rapidly proliferating cells that can be isolated from adult (e.g., bone marrow, adipose tissue) as well as fetal (e.g., umbilical cord) tissues (termed bone marrow (BM)-, adipose tissue (AT)-, and umbilical cord (UC)-MSC, respectively) and are capable of differentiation into a wide range of non-hematopoietic cell types. An additional, unique attribute of MSC is their ability to home to tumor sites and to interact with the local supportive microenvironment which rapidly conceptualized into MSC-based experimental cancer cytotherapy at the turn of the century. Towards this purpose, both naïve (unmodified) and genetically modified MSC (GM-MSC; used as delivery vehicles for the controlled expression and release of antitumorigenic molecules) have been employed using well-established in vitro and in vivo cancer models, albeit with variable success. The first approach is hampered by contradictory findings regarding the effects of naïve MSC of different origins on tumor growth and metastasis, largely attributed to inherent biological heterogeneity of MSC as well as experimental discrepancies. In the second case, although the anti-cancer effect of GM-MSC is markedly improved over that of naïve cells, it is yet apparent that some protocols are more efficient against some types of cancer than others. Regardless, in order to maximize therapeutic consistency and efficacy, a deeper understanding of the complex interaction between MSC and the tumor microenvironment is required, as well as examination of the role of key experimental parameters in shaping the final cytotherapy outcome. This systematic review represents, to the best of our knowledge, the first thorough evaluation of the impact of experimental anti-cancer therapies based on MSC of human origin (with special focus on human BM-/AT-/UC-MSC). Importantly, we dissect the commonalities and differences as well as address the shortcomings of work accumulated over the last two decades and discuss how this information can serve as a guide map for optimal experimental design implementation ultimately aiding the effective transition into clinical trials.

Dataset Information

Do cancer stem cells exist? A pilot study combining a systematic review with the hierarchy-of-hypotheses approach.

Publications

Do cancer stem cells exist? A pilot study combining a systematic review with the hierarchy-of-hypotheses approach.

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