Cancer de l'ovaire

Résumé

Le est une forme de cancer affectant un ovaire. Il se développe généralement à partir du revêtement de surface des ovaires. La forme la plus fréquente est le carcinome épithélial de l'ovaire. Les formes rares, comme les tumeurs germinales de l'ovaire ou les tumeurs borderline , justifient d'une prise en charge spécifique. Le cancer de l'ovaire est en général de mauvais pronostic car découvert souvent tardivement. L'ovaire est situé dans le petit bassin et une lésion tumorale peut se développer lentement sans signes cliniques. Le traitement repose sur une chirurgie la plus complète possible associé à la chimiothérapie qui réduit le risque de récidive. Lorsque le cancer est très évolué, la chimiothérapie améliore la qualité de vie des patientes et augmente la durée de survie. Épidémiologie L'incidence est plus élevée en Europe et aux États-Unis, comparativement au Japon et aux pays peu industrialisés. En 2005, et en France, l'incidence du cancer de l'ovaire a été de 8,1/

Source officielle

https://fr.wikipedia.org/wiki/Cancer_de_l'ovaire

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ProblemDevelopment of platinum resistance in ovarian cancer is mediated by both cancer cells and tumor microenvironment. Activation of epithelial-mesenchymal transition program in cancer cells may lead to enrichment for resistant clones. These processes can be affected by tumor-associated macrophages, a highly plastic population of cells that participate in tumor progression and response to treatment by shaping the microenvironment. We aimed to study how platinum resistance influences the crosstalk between macrophages and ovarian cancer cells. Method of studyUsing cisplatin-sensitive ovarian cancer cell line A2780, we developed and characterized cisplatin-resistant A2780Cis and cisplatin and doxorubicin co-resistant A2780Dox cell lines. Next, we set up an indirect coculture system with THP-1 cell line-derived M0-type-, M1-type- and M2-type-like polarized macrophages. We monitored the expression of genes associated with cellular stemness, multidrug resistance, and epithelial-mesenchymal transition in cancer cells, and expression profile of M1/M2 markers in macrophages. ResultsDevelopment of drug resistance in ovarian cancer cell lines was accompanied by increased migration, clonogenicity, and upregulated expression of transcription factors, associated with cellular stemness and epithelial-mesenchymal transition. Upon coculture, we noted that the most relevant changes in gene expression profile occurred in A2780 cells. Moreover, M0- and M1-type macrophages, but not M2-type macrophages, showed significant transcriptional alterations. ConclusionOur results provide the evidence for bidirectional interplay between cancer cells and macrophages. Independent of platinum resistance status, ovarian cancer cells polarize macrophages toward M2-like type, whereas macrophages induce epithelial-mesenchymal transition and stemness-related gene expression profile in cisplatin-sensitive, but not cisplatin-resistant cancer cells.

WILEY2018

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The management of advanced ovarian cancer is challenging due to the high frequency of recurrence, often associated with the development of resistance to platinum-based chemotherapy. Molecular analyses revealed the complexity of ovarian cancer with particular emphasis on the immune system, which may contribute to disease progression and response to treatment. Cytokines and chemokines mediate the cross-talk between cancer and immune cells, and therefore, present as potential biomarkers, reflecting the tumor microenvironment. A panel of circulating C-C motif chemokine ligand (CCL) and C-X-C motif chemokine ligand (CXCL) chemokines were examined in the serum of 40 high-grade patients with ovarian cancer prior to primary surgery. The level of immune infiltration in tumors was also analyzed. The preoperative levels of chemokines differ between patients. Elevated levels of circulating CXCL4 + CCL20 + CXCL1 combination can discriminate patients with shorter recurrence-free survival and overall survival. The presence of tumor-infiltrating T lymphocytes was detected in half of the patients. The mRNA expression analysis suggests the presence of antitumoral and immunosuppressive elements in the tumor microenvironment. The combination of circulating CXCL9 + CXCL10 can distinguish immune-infiltrated tumors that will lead to shorter recurrence-free survival. The results suggest that preoperative profiling of circulating chemokines in patients with ovarian cancer may provide valuable information regarding tumor recurrence and immune infiltration. The findings demonstrate that combinations have better prognostic utility than single chemokines, and may serve as patient stratification tools.

SPANDIDOS PUBL LTD2019

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Controlling and Monitoring Intracellular Drug Delivery Using PHPMA-Based Polymer Nanomedicines

Claudia Battistella

Polymer nanomedicine is an attractive approach for the delivery of anticancer drugs. Firstly designed to increase drug bioavailability, polymer conjugates and polymer nanoparticles have rapidly emerged in the field of cancer therapy after the discovery of the enhanced permeation and retention (EPR) effect. The leaky and disordered tumor neovascularization provides opportunities to guide the accumulation of polymer nanomedicines to the tumor tissue therefore enhancing therapy selectivity and reducing off-target-associated side effects. However, since many chemotherapeutics act on targets that are located in well-defined subcellular compartments, controlling the intracellular fate of polymer nanomedicines and/or their payload is another important factor that contributes to therapy efficiency. Polymer conjugates and polymer nanoparticles generally access the cell interior via endocytosis. The physiochemical and biochemical parameters that distinguish the endolysosomal compartments from the extracellular environment have been widely exploited to trigger intracellular drug release from the polymer carriers. Amongst a range of other polymers and polymer nanoparticles that have been investigated over the past 30 years, poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-based conjugates have been extensively explored for the endolysosomal release of anticancer drugs. While the modern polymer chemistry toolbox provides many opportunities to tailor the molecular weight and functionality of PHPMA and to introduce features that allow the polymer to respond to the different endolysosomal environments, the development of tools and methods to monitor these processes is also crucial for the future development of advanced delivery systems. The aim of this Thesis is to design dual-functional PHPMA polymers that offer the possibility to control the endolysosomal release of anticancer drug combinations as well as to monitor the PHPMA endolysosomal trafficking. Chapter 1 of this Thesis provides an overview of the different approaches that have been described in literature to control and monitor the intracellular delivery of polymer nanomedicines. Chapter 2 describes a synthetic approach to prepare alpha- and alpha,omega-fluorine labeled pentafluorophenyl methacrylate (PPFMA) polymers via reversible addition fragmentation chain transfer (RAFT) polymerization. In Chapter 3 post-polymerization modification of the alpha-fluorine labeled PPFMA precursor will be used to prepare a series of PHPMA conjugates carrying either the anticancer drug doxorubicin (Dox) or the P-glycoprotein inhibitor zosuquidar (Zos) or both drugs at the polymer side chains. The ability of the conjugates to overcome doxorubicin efflux and therefore reverse P-gp-mediated multidrug resistance in resistant ovarian carcinoma cells will be assessed. Finally, Chapter 4 will study the cellular internalization and endolysosomal trafficking of PHPMA. The synthesis of a dual-labeled PHPMA polymer containing both a fluorescent as well as a fluorinated label will be used for flow cytometry and confocal fluorescence microscopy studies and to demonstrate the potential of nanoscale secondary ion mass spectrometry (NanoSIMS) to map and localize fluorine-containing polymers in cells.

EPFL2017

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Controlling and Monitoring Intracellular Drug Delivery Using PHPMA-Based Polymer Nanomedicines

Claudia Battistella

EPFL2017