Hypoxia has been shown to increase the aggressiveness and severity of tumor progression. Along with chronic and acute hypoxic regions, solid tumors contain regions of cycling hypoxia (also called ...intermittent hypoxia or IH). Cyclic hypoxia is mimicked
and
by periodic exposure to cycles of hypoxia and reoxygenation (H-R cycles). Compared to chronic hypoxia, cyclic hypoxia has been shown to augment various hallmarks of cancer to a greater extent: angiogenesis, immune evasion, metastasis, survival etc. Cycling hypoxia has also been shown to be the major contributing factor in increasing the risk of cancer in obstructive sleep apnea (OSA) patients. Here, we first compare and contrast the effects of acute, chronic and intermittent hypoxia in terms of molecular pathways activated and the cellular processes affected. We highlight the underlying complexity of these differential effects and emphasize the need to investigate various combinations of factors impacting cellular adaptation to hypoxia: total duration of hypoxia, concentration of oxygen (O
), and the presence of and frequency of H-R cycles. Finally, we summarize the effects of cycling hypoxia on various hallmarks of cancer highlighting their dependence on the abovementioned factors. We conclude with a call for an integrative and rigorous analysis of the effects of varying extents and durations of hypoxia on cells, including tools such as mechanism-based mathematical modelling and microfluidic setups.
Epithelial-mesenchymal heterogeneity implies that cells within the same tumor can exhibit different phenotypes-epithelial, mesenchymal, or one or more hybrid epithelial-mesenchymal phenotypes. This ...behavior has been reported across cancer types, both in vitro and in vivo, and implicated in multiple processes associated with metastatic aggressiveness including immune evasion, collective dissemination of tumor cells, and emergence of cancer cell subpopulations with stem cell-like properties. However, the ability of a population of cancer cells to generate, maintain, and propagate this heterogeneity has remained a mystifying feature. Here, we used a computational modeling approach to show that epithelial-mesenchymal heterogeneity can emerge from the noise in the partitioning of biomolecules (such as RNAs and proteins) among daughter cells during the division of a cancer cell. Our model captures the experimentally observed temporal changes in the fractions of different phenotypes in a population of murine prostate cancer cells, and describes the hysteresis in the population-level dynamics of epithelial-mesenchymal plasticity. The model is further able to predict how factors known to promote a hybrid epithelial-mesenchymal phenotype can alter the phenotypic composition of a population. Finally, we used the model to probe the implications of phenotypic heterogeneity and plasticity for different therapeutic regimens and found that co-targeting of epithelial and mesenchymal cells is likely to be the most effective strategy for restricting tumor growth. By connecting the dynamics of an intracellular circuit to the phenotypic composition of a population, our study serves as a first step towards understanding the generation and maintenance of non-genetic heterogeneity in a population of cancer cells, and towards the therapeutic targeting of phenotypic heterogeneity and plasticity in cancer cell populations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties ...such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the ‘fittest’ for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.
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The cancer stem cell (CSC) concept stands for undifferentiated tumor cells with the ability to initiate heterogeneous tumors. It is also relevant in metastasis and can explain how metastatic tumors ...mirror the heterogeneity of primary tumors. Cellular plasticity, including the epithelial-to-mesenchymal transition (EMT), enables the generation of CSCs at different steps of the metastatic process including metastatic colonization. In this review, we update the concept of CSCs and provide evidence of the existence of metastatic stem cells (MetSCs). In addition, we highlight the nuanced understanding of EMT that has been gained recently and the association of mesenchymal-to-epithelial transition (MET) with the acquisition of CSCs properties during metastasis. We also comment on the computational approaches that have profoundly influenced our understanding of CSCs and EMT; and how these studies and new experimental technologies can yield a deeper understanding of the biological aspects of metastasis.
The epithelial-mesenchymal transition (EMT) is a process by which cells lose epithelial traits, such as cell-cell adhesion and apico-basal polarity, and acquire migratory and invasive traits. EMT is ...crucial to embryonic development and wound healing. Misregulated EMT has been implicated in processes associated with cancer aggressiveness, including metastasis. Recent experimental advances such as single-cell analysis and temporal phenotypic characterization have established that EMT is a multistable process wherein cells exhibit and switch among multiple phenotypic states. This is in contrast to the classical perception of EMT as leading to a binary choice. Mathematical modeling has been at the forefront of this transformation for the field, not only providing a conceptual framework to integrate and analyze experimental data, but also making testable predictions. In this article, we review the key features and characteristics of EMT dynamics, with a focus on the mathematical modeling approaches that have been instrumental to obtaining various useful insights.
Migration from the primary tumor is a crucial step in the metastatic cascade. Cells with various degrees of adhesion and motility migrate and are launched into the bloodstream as single circulating ...tumor cells (CTC) or multicellular CTC clusters. The frequency and size distributions of these clusters have been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood. We present a biophysical model that couples the phenotypic plasticity enabled by the epithelial-mesenchymal transition (EMT) and cell migration to explain the modes of individual and collective cancer cell migration. This reduced physical model captures how cells undergo a transition from individual migration to collective cell migration and robustly recapitulates CTC cluster fractions and size distributions observed experimentally across several cancer types, thus suggesting the existence of common features in the mechanisms underlying cancer cell migration. Furthermore, we identify mechanisms that can maximize the fraction of CTC clusters in circulation. First, mechanisms that prevent a complete EMT and instead increase the population of hybrid epithelial/mesenchymal (E/M) cells are required to recapitulate CTC size distributions with large clusters of 5 to 10 cells. Second, multiple intermediate E/M states give rise to larger and heterogeneous clusters formed by cells with different epithelial-mesenchymal traits. Overall, this biophysical model provides a platform to continue to bridge the gap between the molecular and biophysical regulation of cancer cell migration and highlights that a complete EMT might not be required for metastasis. SIGNIFICANCE: A biophysical model of cancer cell invasion integrates phenotypic heterogeneity and cell migration to interpret experimental observations of circulating tumor cell clusters and provides new predictions.
http://cancerres.aacrjournals.org/content/canres/79/21/5527/F1.large.jpg.
Transitions between epithelial and mesenchymal phenotypes - the epithelial to -mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) - are hallmarks of cancer ...metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a "three-way" switch giving rise to three distinct phenotypes - E, M and hybrid E/M - and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell-cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary "bad actors" of metastasis.
Metastasis is a significant contributor to morbidity and mortality for many cancer patients and remains a major obstacle for effective treatment. In many tissue types, metastasis is fueled by the ...epithelial-to-mesenchymal transition (EMT)-a dynamic process characterized by phenotypic and morphologic changes concomitant with increased migratory and invasive potential. Recent experimental and theoretical evidence suggests that cells can be stably halted en route to EMT in a hybrid E/M phenotype. Cells in this phenotype tend to move collectively, forming clusters of circulating tumor cells that are key tumor-initiating agents. Here, we developed an inferential model built on the gene expression of multiple cancer subtypes to devise an EMT metric that characterizes the degree to which a given cell line exhibits hybrid E/M features. Our model identified drivers and fine-tuners of epithelial-mesenchymal plasticity and recapitulated the behavior observed in multiple
experiments across cancer types. We also predicted and experimentally validated the hybrid E/M status of certain cancer cell lines, including DU145 and A549. Finally, we demonstrated the relevance of predicted EMT scores to patient survival and observed that the role of the hybrid E/M phenotype in characterizing tumor aggressiveness is tissue and subtype specific. Our algorithm is a promising tool to quantify the EMT spectrum, to investigate the correlation of EMT score with cancer treatment response and survival, and to provide an important metric for systematic clinical risk stratification and treatment.
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The epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance, and cancer metastasis. Recent experiments ...show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics in the tumor microenvironment, however, remain largely unexplored. Here, we show through a mechanism-based dynamical model that the diffusion of EMT-inducing signals such as TGF-β, together with noncell autonomous control of EMT and CSC decision making via the Notch signaling pathway, can explain experimentally observed disparate localization of subsets of CSCs with varying EMT phenotypes in the tumor. Our simulations show that the more mesenchymal CSCs lie at the invasive edge, while the hybrid epithelial/mesenchymal (E/M) CSCs reside in the tumor interior. Further, motivated by the role of Notch-Jagged signaling in mediating EMT and stemness, we investigated the microenvironmental factors that promote Notch-Jagged signaling. We show that many inflammatory cytokines such as IL-6 that can promote Notch-Jagged signaling can (i) stabilize a hybrid E/M phenotype, (ii) increase the likelihood of spatial proximity of hybrid E/M cells, and (iii) expand the fraction of CSCs. To validate the predicted connection between Notch-Jagged signaling and stemness, we knocked down JAG1 in hybrid E/M SUM149 human breast cancer cells in vitro. JAG1 knockdown significantly restricted tumor organoid formation, confirming the key role that Notch-Jagged signaling can play in tumor progression. Together, our integrated computational–experimental framework reveals the underlying principles of spatiotemporal dynamics of EMT and CSCs.
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