6 research outputs found
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Use of preclinical models for malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is an aggressive cancer most commonly caused by prior exposure to asbestos. Median survival is 12-18 months, since surgery is ineffective and chemotherapy offers minimal benefit. Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development of new treatments. The most commonly used models of MPM are two-dimensional cell lines established from primary tumours or pleural fluid. While these have provided some important insights into MPM biology, these cell models have significant limitations. In order to address some of these limitations, spheroids and microfluidic chips have more recently been used to investigate the role of the three-dimensional environment in MPM. Efforts have also been made to develop animal models of MPM, including asbestos-induced murine tumour models, MPM-prone genetically modified mice and patient-derived xenografts. Here, we discuss the available in vitro and in vivo models of MPM and highlight their strengths and limitations. We discuss how newer technologies, such as the tumour-derived organoids, might allow us to address the limitations of existing models and aid in the identification of effective treatments for this challenging-to-treat disease.MS and JO are supported by BLF-Papworth Fellowships from the British Lung Foundation and the Victor Dahdaleh Foundation. MJG and HEF is supported by the British Lung Foundation and Wellcome Trust grant 206194. RCR is supported by the Cambridge Biomedical Research Centre, Cancer Research UK Cambridge Centre, British Lung Foundation and Royal Papworth Hospital. SJM is supported by the Medical Research Council, British Lung Foundation, Cambridge BRC, Royal Papworth Hospital, and the Alpha1-Foundatio
Biological basis for novel mesothelioma therapies
Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351Funder: Royal Society through a University Research Fellowship and the Engineering and Physical Sciences Research Council (EPRSC)Funder: China Scholarship Council (CSC); doi: https://doi.org/10.13039/501100004543Abstract: Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies
Progestins used for hormonal contraception in Switzerland: study of their effects on the breast epithelium
Breast cancer is the most commonly diagnosed cancer and the most common cause of cancer death among women. Hormones have been shown to have a key role in breast development and carcinogenesis. Repeated activation of progesterone receptor (PR) signaling as it occurs during menstrual cycles is important in cancer risk. Through hormonal contraception many women are exposed to synthetic PR agonists, progestins, either on their own or in combination with the synthetic estrogen receptor (ER) agonist, ethinyl estradiol (EE). Progestins vary in their chemical structures and biological activities. Epidemiological studies show that hormonal contraceptions increase the risk of breast cancer but to date there have been few studies that analyze specific progestins regarding the breast cancer risk they confer.
We hypothesized that different progestins have distinct abilities to induce cell proliferation and to modulate gene expression in the breast epithelium and this may ultimately have different effects on breast cancer risk.
To test the hypothesis that different progestins currently used in hormonal contraceptions in Switzerland have distinct abilities to induce the expression of important mediators of PR action, receptor activator of NF-ĂŽÂşB ligand (RANKL) and Wnt4, we employed mouse mammary gland organoids and human breast tissue microstructures. We find that androgenic progestins strongly induce RANKL and Wnt4 whereas anti-androgenic progestins fail to do so.
To test the ability of different progestins currently used in hormonal contraceptions in Switzerland to induce cell proliferation in human breast epithelium, we humanized mouse mammary gland using intraductal injection of human breast epithelial cells obtained from reduction mammoplasty surgery. We show that breast epithelial cells maintain hormone receptor expression and remain hormone responsive in this approach. We find that the androgenic progestins, Gestodene and Levonorgestrel, promote cell proliferation over two months more than progesterone.
Furthermore, we show that Androgen receptor (AR) inhibition abrogates promegestone-induced RANKL induction and reduces cell proliferation induced by androgenic progestin, LNG. We also show that activation of AR signaling through DHT exposure is sufficient to induce proliferation of human breast epithelial cells.
Thus, different progestins have different biological effects on the breast epithelium that appear to be related to their androgenic activities
Variably Scaled Kernels Improve Classification of Hormonally-Treated Patient-Derived Xenografts
Little is known about the biological functions which are exerted by hormone receptors in physiological conditions. Here, we made use of the Mouse INtraDuctal (MIND) model, an innovative patient-derived xenograft (PDX) model, to characterize global gene expression changes, which are triggered by stimulation of dihydrotestosterone (DHT) and progesterone (P4) in vivo. Fast and clever mathematical tools are needed to analyze increasing numbers of complex datasets. We generated hormone receptor-specific list of genes which were then used to test the classification performance obtained by different machine-learning algorithms in the frame of our labelled PDXs RNAseq dataset. Next to other standard techniques, we consider the variably scaled kernel (VSK) setting in the framework of support vector machines. Our results show that mixed schemes obtained via VSKs can outperform standard classification methods in the considered task
Dermal quercetin lipid nanocapsules: Influence of the formulation on antioxidant activity and cellular protection against hydrogen peroxide
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The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche
Estrogens and progesterone control breast development and carcinogenesis via their cognate receptors expressed in a subset of luminal cells in the mammary epithelium. How they control the extracellular matrix, important to breast physiology and tumorigenesis, remains unclear. Here we report that both hormones induce the secreted protease Adamts18 in myoepithelial cells by controlling Wnt4 expression with consequent paracrine canonical Wnt signaling activation. Adamts18 is required for stem cell activation, has multiple binding partners in the basement membrane and interacts genetically with the basal membrane-specific proteoglycan, Col18a1, pointing to the basement membrane as part of the stem cell niche. In vitro, ADAMTS18 cleaves fibronectin; in vivo, Adamts18 deletion causes increased collagen deposition during puberty, which results in impaired Hippo signaling and reduced Fgfr2 expression both of which control stem cell function. Thus, Adamts18 links luminal hormone receptor signaling to basement membrane remodeling and stem cell activation. How hormonal signaling in the mammary epithelium controls the surrounding extracellular matrix is unclear. Here, the authors show that a secreted protease, Adamts18, induced by upstream estrogen-progesterone activated Wnt4 in myoepithelial cells, remodels the basement membrane and contributes to mammary epithelial stemness