Lucie Laplane

The clonal evolution (CE) model and the cancer stem cell (CSC) model are two independent models of cancers, yet recent data shows intersections between the two models. This article explores the impacts of the CSC model on the CE model. I show that CSC restriction, which depends on CSC frequency in cancer cell populations and on the probability of dedifferentiation of cancer non-stem cells (non-CSC) into CSCs, can favor or impede some patterns of evolution (linear or branched evolution) and some processes of evolution (drift, evolution by natural selection, complex adaptations). Taking CSC restriction into account for the CE model thus has implications for the way in which we understand the patterns and processes of evolution, and can also provide new leads for therapeutic interventions.

Qu’est-ce qu’une cellule souche ? La propriété souche est-elle une propriété intrinsèque ou extrinsèque ? Quel rôle joue le microenvironnement tumoral dans l’identité de la propriété souche ? En fonction des réponses à ces questions, nous distinguons quatre identités pour les cellules souches normales et cancéreuses et explorons leur impact sur le choix de la stratégie thérapeutique en oncologie. L’acquisition d’altérations génétiques et épigénétiques au cours de la transformation maligne et de la progression remet en question la stabilité de l’identité de la propriété souche dans les cancers.

Similar to seemingly maladaptive genes in general, the persistence of inherited cancer-causing mutant alleles in populations remains a challenging question for evolutionary biologists. In addition to traditional explanations like senescence or antagonistic pleiotropy, here we put forward a new hypothesis to explain the retention of oncogenic mutations. We propose that while natural defenses evolve to prevent neoplasm formation and progression thus increasing organismal fitness, they also conceal the effects of cancer-causing mutant alleles on fitness and concomitantly protect inherited ones from purging by purifying selection. We also argue for the importance of the ecological contexts experienced by individuals and/or species. These contexts determine the locally predominant fitness-reducing risks, and hence can aid the prediction of how natural selection will influence cancer outcomes. This article is protected by copyright. All rights reserved.

Reprogramming technologies show that cellular identity can be reprogrammed, challenging the classical conception of cell differentiation as an irreversible process. If non-stem cells can be reprogrammed into stem cells, then what is it to be a stem cell, and what kind of property is stemness? This article addresses this question both philosophically and biologically, states the different possibilities, and illustrates their potential consequences for science with the example of anti-cancer therapies

The demonstration that pluripotent stem cells could be generated by somatic cell reprogramming led to wonder if these so-called induced pluripotent stem (iPS) cells would extend our
investigation capabilities in the cancer research field. The first iPS cells derived from cancer cells have now revealed the benefits and potential pitfalls of this new model. iPS cells appear to be an innovative approach to decipher the steps of cell transformation as well as to screen the activity and toxicity of anticancer drugs. A better understanding of the impact of reprogramming on cancer cell-specific features as well as improvements in culture conditions to integrate the role of the microenvironment in their behavior may strengthen the epistemic interest of iPS cells as model systems in oncology.

This chapter brings a philosophical perspective to the concept of stem cell. Three general questions both clarify the concept of stem cell and emphasize its ambiguities: (1) How should we define stem cells? (2) What makes them different from non-stem cells? (3) What is their ontology? (i.e. what kind of property is “stemness?”) Following this last question, the Chapter distinguishes four conceptions of stem cells and highlights their respective consequences for the cancer stem cell theory. Determining what kind of property stemness is, in what context, is an urgent question, at least for therapeutic strategies against cancers. I hope that this chapter also illustrates how philosophy can be useful to biology.
What is a stem cell? The traditional answer to this question is that a stem cell has two properties: the ability to self-renew and the potential of differentiation. This traditional characterization of stem cells raises two questions. First, what do we mean by “ability to self-renew” and “potential of differentiation?” Second, can these two properties distinguish stem cells from non-stem cells? The first question is a problem of definition whereas the second one is a problem of classification. Together, they raise a third question about stem cells: what is their ontology? That is to say, do they belong to a common natural kind? Does the concept of stem cell refer to the cells that belong to a ‘stem cell’ natural kind or does it refer to a reversible and transient cell state? And what difference does that make?
This chapter will review the philosophical, theoretical and biological studies that have given insights on these questions. The first part of the Chapter will clarify the notions of self-renewal and differentiation. This will lead to the question “can we (and if so, how) distinguish stem cells from non-stem cells through these two properties?” From that will follow an interrogation on whether stem cells belong to a natural kind. On this issue, biologists and philosophers have framed the following alternative: either the concept of stem cell refers to entities (the cells that belong to the stem cell natural kind) or it refers to a transient and reversible cell state. I will argue that four conceptions of stemness should be distinguished rather than two. Finally, I will develop the case of the cancer stem cell (CSC) theory in order to show why it is crucial to answer the ontological question: some therapies might or might not be efficient depending on what stemness is.

Like most bilaterian animals, the annelid Platynereis dumerilii generates the majority of its body axis in an anterior to posterior temporal progression with new segments added sequentially. This process relies on a posterior subterminal proliferative body region, known as the “segment addition zone” (SAZ). We explored some of the molecular and cellular aspects of posterior elongation in Platynereis, in particular to test the hypothesis that the SAZ contains a specific set of stem cells dedicated to posterior elongation. We cloned and characterized the developmental expression patterns of orthologs of 17 genes known to be involved in the formation, behavior, or maintenance of stem cells in other metazoan models. These genes encode RNA-binding proteins (e.g., tudor, musashi, pumilio) or transcription factors (e.g., myc, id, runx) widely conserved in eumetazoans. Most of these genes are expressed both in the migrating primordial germ cells and in overlapping ring-like patterns in the SAZ, similar to some previously analyzed genes (piwi, vasa). The SAZ patterns are coincident with the expression of proliferation markers cyclin B and PCNA. EdU pulse and chase experiments suggest that new segments are produced through many rounds of divisions from small populations of teloblast-like posterior stem cells. The shared molecular signature between primordial germ cells and posterior stem cells in Platynereis thus corresponds to an ancestral “stemness” program.

The tacit standard view that development ends once reproductive capacity is acquired (reproductive boundary, or “RB,” thesis) has recently been challenged by biologists and philosophers of biology arguing that development continues until death (death boundary, or “DB,” thesis). The relevance of these two theses is difficult to assess because the fact that there is no precise definition of development makes the determination of its temporal boundaries problematic. Taking into account this difficulty, this article tries to develop a new species-dependent perspective on temporal boundaries of development. This species-dependent account stands against both RB and DB theses since neither of them reflects the differences between species in the temporality of their development. In this perspective, I propose to use stem cells as a tool to analyze (1) the different developmental capacities of an organism during its life; and (2) the different developmental temporal capacities between species. In particular, I will show that stem cells enable four distinct temporal developmental patterns to be distinguished, i.e., four distinct temporal boundaries of development in the living. I show how these four patterns can be interpreted differently depending on the perspective one has on the definition of development.

... En tant qu'objet on aura toujours à faire à une cellule souche de tel cancer de tel individu (il faut préciser toutefois, qu'aucune cellule souche d'aucun cancer n'a encore jamais été isolée, faute de marqueurs si l'on s'en tient aux discours ... [ 11] Wicha MS, Liu S, Dontu G. “Cancer ...