RESUMEN
Several studies have shown that cancer cells can be "phenotypically reversed", thus achieving a "tumor reversion", by losing malignant hallmarks as migrating and invasive capabilities. These findings suggest that genome activity can switch to assume a different functional configuration, i.e. a different Gene Regulatory Network pattern. Indeed, once "destabilized", cancer cells enter into a critical transition phase that can be adequately "oriented" by yet unidentified morphogenetic factors - acting on both cells and their microenvironment - that trigger an orchestrated array of structural and epigenetic changes. Such process can bypass genetic abnormalities, through rerouting cells toward a benign phenotype. Oocytes and embryonic tissues, obtained by animals and humans, display such "reprogramming" capability, as a number of yet scarcely identified embryo-derived factors can revert the malignant phenotype of several types of tumors. Mechanisms involved in the reversion process include the modification of cell-microenvironment cross talk (mostly through cytoskeleton reshaping), chromatin opening, demethylation, and epigenetic changes, modulation of biochemical pathways, comprising TCTP-p53, PI3K-AKT, FGF, Wnt, and TGF-ß-dependent cascades. Results herein discussed promise to open new perspectives not only in the comprehension of cancer biology but also toward different therapeutic options, as suggested by a few preliminary clinical studies.
Asunto(s)
Técnicas de Reprogramación Celular , Reprogramación Celular/genética , Epigénesis Genética/genética , Neoplasias/genética , Neoplasias/terapia , Transformación Celular Neoplásica/efectos de los fármacos , Ensamble y Desensamble de Cromatina/genética , Citoesqueleto/genética , Desmetilación del ADN , Humanos , Neoplasias/patología , Microambiente Tumoral/fisiologíaRESUMEN
Some yet unidentified factors released by both oocyte and embryonic microenvironments demonstrated to be non-permissive for tumor development and display the remarkable ability to foster cell/tissue reprogramming, thus ultimately reversing the malignant phenotype. In the present study we observed how molecular factors extracted from Zebrafish embryos during specific developmental phases (20 somites) significantly antagonize proliferation of breast cancer cells, while reversing a number of prominent aspects of malignancy. Embryo extracts reduce cell proliferation, enhance apoptosis, and dramatically inhibit both invasiveness and migrating capabilities of cancer cells. Counteracting the invasive phenotype is a relevant issue in controlling tumor spreading and metastasis. Moreover, such effect is not limited to cancerous cells as embryo extracts were also effective in inhibiting migration and invasiveness displayed by normal breast cells undergoing epithelial-mesenchymal transition upon TGF-ß1 stimulation. The reversion program involves the modulation of E-cadherin/ß-catenin pathway, cytoskeleton remodeling with dramatic reduction in vinculin, as well as downregulation of TCTP and the concomitant increase in p53 levels. Our findings highlight that-contrary to the prevailing current "dogma", which posits that neoplastic cells are irreversibly "committed"-the malignant phenotype can ultimately be "reversed", at least partially, in response to environmental morphogenetic influences.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Embrión no Mamífero/química , Extractos de Tejidos/farmacología , Animales , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo , Humanos , Fenotipo , Proteína Tumoral Controlada Traslacionalmente 1 , Pez Cebra , beta Catenina/metabolismoRESUMEN
Different experimental models reveal that malignant cancer cells can be induced to change their phenotype into a benign one. This phenotypic transformation, confirmed both in vitro and in vivo, currently is known as 'tumor reversion'. This evidence raises a radical question among current cancer models: Is cancer reversible? How do genetic and epigenetic alterations hierarchically relate? Understanding the mechanisms of 'tumor reversion' represents a key point in order to evolve the actual cancer models and develop new heuristic models that can possibly lead to drugs that target epigenetic mechanisms, for example epigenetic drugs. Even though evidence of tumor reversion dates back to the 1950s, this remains a completely new field of research recently rediscovered thanks to the interest in cell reprogramming research, developmental biology and the increasing understanding of epigenetic mechanisms. In the current review, a comprehensive review of all the main experimental models on tumor reversion was presented.
Asunto(s)
Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Epigénesis Genética , Fenotipo , Reprogramación CelularRESUMEN
INTRODUCTION: Actinic keratoses (AKs) are humans' most common keratinocyte-derived precancerous lesions. They can be observed predominantly in fair-skinned individuals on sun-exposed surfaces. Another name for AKs is solar keratosis. The primary risk factor for AKs is cumulative UV exposure from sunlight and/or tanning salons. AKs may present on a patient as a few detectable lesions. Clinically, they present as scaly erythema lesions with various pigmentations. Surgery treatment is the only approach that can definitively resolve the illness. METHOD: The research aims to demonstrate the effectiveness of treating relapsing AKs through the use of factors present during organogenesis extracted from zebrafish caviar conveyed through a cryopass therapy device (cryolaser phoresis). These factors are peptides present during specific phases of organogenesis and have shown the capacity to reverse cancer and neurodegeneration processes through gene, transcriptional, translational, and post-translational regulation. RESULT: We found that 90% of patients responded. The percentage of responding patients was 100% among females and 80% among men. CONCLUSION: Our results confirm previous findings about the effectiveness of stem cell differentiation stage factors (SCDFs) in cancer and open new ways to integrate treatment.
RESUMEN
A growing number of studies shows that it is possible to induce a phenotypic transformation of cancer cells from malignant to benign. This process is currently known as "tumor reversion". However, the concept of reversibility hardly fits the current cancer models, according to which gene mutations are considered the primary cause of cancer. Indeed, if gene mutations are causative carcinogenic factors, and if gene mutations are irreversible, how long should cancer be considered as an irreversible process? In fact, there is some evidence that intrinsic plasticity of cancerous cells may be therapeutically exploited to promote a phenotypic reprogramming, both in vitro and in vivo. Not only are studies on tumor reversion highlighting a new, exciting research approach, but they are also pushing science to look for new epistemological tools capable of better modeling cancer.
Asunto(s)
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/patología , Carcinogénesis/genética , Carcinógenos , MutaciónRESUMEN
Most drugs have a natural compound 'ancestor' acting as the lead molecule. Classic pharmacology does not explicitly take into consideration the peculiarities of natural origin compounds, the mechanism of action of which is interpreted by the same target-specific mode of action used for synthetic molecules. Over the past few decades, this approach has entered a crisis of efficacy, requiring general reconsideration of the nature of chemobiological interactions. Taking both the unique properties of natural compounds and their original presence in complex mixtures into account pushes researchers to enlarge the range of mechanisms of action well beyond the drug-receptor interaction and has the potential to overcome the current drug discovery crisis.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Animales , Descubrimiento de Drogas/métodos , HumanosRESUMEN
The fall of reductionist approaches to explanation leaves biology with an unescapable challenge: how to decipher complex systems. This entails a number of very critical questions, the most basic ones being: "What do we mean by 'complex'?" and "What is the system we should look for?" In complex systems, constraints belong to a higher level that the molecular one and their effect reduces and constrains the manifold of the accessible internal states of the system itself. Function is related but not deterministically imposed by the underlying structure. It is quite unlikely that such kind of complexity could be grasped by current approaches focusing on a single organization scale. The natural co-emergence of systems, parts and properties can be adopted as a hypothesis-free conceptual framework to understand functional integration of organisms, including their hierarchical or multilevel patterns, and including the way scientific practice proceeds in approaching such complexity. External, "driving" factors - order parameters and control parameters provided by the surrounding microenvironment - are always required to "push" the components' fate into well-defined developmental directions. In the negative, we see that in pathological processes such as cancer, organizational fluidity, collapse of levels and dynamic heterogeneity make it hard to even find a level of observation for a stable explanandum to persist in scientific practice. Parts and the system both lose their properties once the system is destabilized. The mesoscopic approach is our proposal to conceptualizing, investigating and explaining in biology. "Mesoscopic way of thinking" is increasingly popular in the epistemology of biology and corresponds to looking for an explanation (and possibly a prediction) where "non-trivial determinism is maximal": the "most microscopic" level of organization is not necessarily the place where "the most relevant facts do happen." A fundamental re-thinking of the concept of causality is also due for order parameters to be carefully and correctly identified. In the biological realm, entities have relational properties only, as they depend ontologically on the context they happen to be in. The basic idea of a relational ontology is that, in our inventory of the world, relations are somehow prior to the relata (i.e., entities).