Experimental evidence accumulated over decades has implicated epithelial-mesenchymal plasticity (EMP), which collectively encompasses epithelial-mesenchymal transition and the reverse process of ...mesenchymal-epithelial transition, in tumour metastasis, cancer stem cell generation and maintenance, and therapeutic resistance. However, the dynamic nature of EMP processes, the apparent need to reverse mesenchymal changes for the development of macrometastases and the likelihood that only minor cancer cell subpopulations exhibit EMP at any one time have made such evidence difficult to accrue in the clinical setting. In this Perspectives article, we outline the existing preclinical and clinical evidence for EMP and reflect on recent controversies, including the failure of initial lineage-tracing experiments to confirm a major role for EMP in dissemination, and discuss accumulating data suggesting that epithelial features and/or a hybrid epithelial-mesenchymal phenotype are important in metastasis. We also highlight strategies to address the complexities of therapeutically targeting the EMP process that give consideration to its spatially and temporally divergent roles in metastasis, with the view that this will yield a potent and broad class of therapeutic agents.
Deep learning is a subdiscipline of artificial intelligence that uses a machine learning technique called artificial neural networks to extract patterns and make predictions from large data sets. The ...increasing adoption of deep learning across healthcare domains together with the availability of highly characterised cancer datasets has accelerated research into the utility of deep learning in the analysis of the complex biology of cancer. While early results are promising, this is a rapidly evolving field with new knowledge emerging in both cancer biology and deep learning. In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools. We provide specific examples of how deep learning may be applied in cancer diagnosis, prognosis and treatment management. We also assess the current limitations and challenges for the application of deep learning in precision oncology, including the lack of phenotypically rich data and the need for more explainable deep learning models. Finally, we conclude with a discussion of how current obstacles can be overcome to enable future clinical utilisation of deep learning.
Leptin is a hormone associated with satiety, lipid oxidation, energy expenditure, and energy homeostasis. To date, the current body of research examining the effect of chronic exercise training on ...leptin has yielded inconsistent results.
The purpose of this meta-analysis was to provide a quantitative estimate of the magnitude of change in leptin levels following participation in exercise interventions lasting ≥ 2 weeks.
All studies included were peer-reviewed and published in English. To be included, studies randomized human participants to an exercise training group or non-exercise comparison group for an exercise training intervention. Leptin levels were measured at baseline, during, and/or after completion of the exercise training program. Random-effects models were used to aggregate a mean effect size (ES) and 95% confidence intervals (CIs), and identify potential moderators.
Seventy-two randomized controlled trials met the inclusion criteria and resulted in 107 effects (n = 3826). The mean ES of 0.24 (95% CI 0.16-0.32, p < 0.0001) indicated a decrease in leptin following an exercise training program. A decrease in %Fat (β = - 0.07, p < 0.01) was associated with a decrease in leptin after accounting for the type of control group (β = - 0.38, p < 0.0001) used in each study.
These results suggest that engaging in chronic exercise training (≥ 2 weeks) is associated with a decrease in leptin levels for individuals regardless of age and sex. However, a greater decrease in leptin occurred with a decreased percentage of body fat.
Shotgun sequence read data derived from xenograft material contains a mixture of reads arising from the host and reads arising from the graft. Classifying the read mixture to separate the two allows ...for more precise analysis to be performed.
We present a technique, with an associated tool Xenome, which performs fast, accurate and specific classification of xenograft-derived sequence read data. We have evaluated it on RNA-Seq data from human, mouse and human-in-mouse xenograft datasets.
Xenome is available for non-commercial use from http://www.nicta.com.au/bioinformatics.
The existence of the exclusion zone (EZ), a layer of water in which plastic microspheres are repelled from hydrophilic surfaces, has now been independently demonstrated by several groups. A better ...understanding of the mechanisms which generate EZs would help with understanding the possible importance of EZs in biology and in engineering applications such as filtration and microfluidics. Here we review the experimental evidence for EZ phenomena in water and the major theories that have been proposed. We review experimental results from birefringence, neutron radiography, nuclear magnetic resonance, and other studies. Pollack theorizes that water in the EZ exists has a different structure than bulk water, and that this accounts for the EZ. We present several alternative explanations for EZs and argue that Schurr's theory based on diffusiophoresis presents a compelling alternative explanation for the core EZ phenomenon. Among other things, Schurr's theory makes predictions about the growth of the EZ with time which have been confirmed by Florea et al. and others. We also touch on several possible confounding factors that make experimentation on EZs difficult, such as charged surface groups, dissolved solutes, and adsorbed nanobubbles.
While prostate cancer (PCa) cells most often metastasize to bone in men, species-specific differences between human and mouse bone marrow mean that this pattern is not faithfully replicated in mice. ...Herein we evaluated the impact of partially humanizing mouse bone marrow with human bone marrow-derived stromal cells (BMSC, also known as "mesenchymal stem cells") on human PCa cell behaviour.
BMSC are key cellular constituents of marrow. We used intrafemoral injection to transplant 5 × 10
luciferase (Luc) and green fluorescence protein (GFP) expressing human BMSC (hBMSC-Luc/GFP) into the right femur of non-obese diabetic (NOD)-severe combined immunodeficiency (scid) interleukin (IL)-2γ
(NSG) mice. Two weeks later, 2.5 × 10
PC-3 prostate cancer cells expressing DsRed (PC-3-DsRed) were delivered into the mice via intracardiac injection. PC-3-DsRed cells were tracked over time using an In Vivo Imaging System (IVIS) live animal imaging system, X-ray and IVIS imaging performed on harvested organs, and PC-3 cell numbers in femurs quantified using flow cytometry and histology.
Flow cytometry analysis revealed greater PC-3-DsRed cell numbers within femurs of the mice that received hBMSC-Luc/GFP. However, while there were overall greater PC-3-DsRed cell numbers in these animals, there were not more PC-3-DsRed in the femurs injected with hBMSC-Luc/GFP than in contralateral femurs. A similar proportion of mice in with or without hBMSC-Luc/GFP had bone lessions, but the absolute number of bone lesions was greater in mice that had received hBMSC-Luc/GFP.
PC-3-DsRed cells preferentially populated bones in mice that had received hBMSC-Luc/GFP, although PC-3-DsRed cells not specifically localize in the bone marrow cavity where hBMSC-Luc/GFP had been transplanted. hBMSC-Luc/GFP appear to modify mouse biology in a manner that supports PC-3-DsRed tumor development, rather than specifically influencing PC-3-DsRed cell homing. This study provides useful insights into the role of humanizing murine bone marrow with hBMSC to study human PCa cell biology.
Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial ...growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood.
Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration.
Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.
Abstract Remodelling of the extracellular matrix (ECM) has emerged as a key factor in cancer progression. Proteoglycans, including versican and other hyalectans, represent key structural elements of ...the ECM where they interact with other important molecules, including the glycosaminoglycan hyaluronan and the CD44 cell surface receptor. The hyalectan proteoglycans are regulated through cleavage by the proteolytic actions of A D isintegrin-like A nd M etalloproteinase domain with T hrombo s pondin-1 motif (ADAMTS) family members. Alteration in the balance between hyalectan proteoglycans and ADAMTS enzymes has been proposed to be a key factor in cancer progression either in a positive or negative manner depending on the context. Further complexity arises due to the formation of bioactive cleavage products, such as versikine, which may also play a role, and non-enzymatic roles for ADAMTS proteins. This research is providing fresh insights into cancer biology and opportunities for the development of new diagnostic and treatment strategies.
Bladder cancer is associated with high recurrence and mortality rates due to metastasis. The elucidation of metastasis suppressors may offer therapeutic opportunities if their mechanisms of action ...can be elucidated and tractably exploited. In this study, we investigated the clinical and functional significance of the transcription factor activating transcription factor 3 (ATF3) in bladder cancer metastasis. Gene expression analysis revealed that decreased ATF3 was associated with bladder cancer progression and reduced survival of patients with bladder cancer. Correspondingly, ATF3 overexpression in highly metastatic bladder cancer cells decreased migration in vitro and experimental metastasis in vivo. Conversely, ATF3 silencing increased the migration of bladder cancer cells with limited metastatic capability in the absence of any effect on proliferation. In keeping with their increased motility, metastatic bladder cancer cells had increased numbers of actin filaments. Moreover, ATF3 expression correlated with expression of the actin filament severing protein gelsolin (GSN). Mechanistic studies revealed that ATF3 upregulated GSN, whereas ATF3 silencing reduced GSN levels, concomitant with alterations in the actin cytoskeleton. We identified six ATF3 regulatory elements in the first intron of the GSN gene confirmed by chromatin immunoprecipitation analysis. Critically, GSN expression reversed the metastatic capacity of bladder cancer cells with diminished levels of ATF3. Taken together, our results indicate that ATF3 suppresses metastasis of bladder cancer cells, at least in part through the upregulation of GSN-mediated actin remodeling. These findings suggest ATF3 coupled with GSN as prognostic markers for bladder cancer metastasis.
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