Cancer du poumon | EPFL Graph Search

vignette|upright=1|Représentation en coupe tridimensionnelle par tomodensitométrie d'un poumon présentant une tumeur. vignette|upright=1|Radiographie de face du thorax montrant un probable cancer du poumon (taches claires sur le côté externe de chaque poumon). Les expressions cancer du poumon et cancer bronchique désignent au sens strict une tumeur maligne du poumon, et par extension les carcinomes pulmonaires, qui regroupent les tumeurs malignes épithéliales du poumon. Selon l'OMS, c'est la cause la plus fréquente de décès par cancer chez les hommes, mais aussi chez les femmes. Il est la cause de 1,3 million de décès par an dans le monde. Les symptômes les plus fréquents sont le souffle court, la toux (éventuellement les crachements de sang), et l'amaigrissement. Les principaux types de cancers du poumon sont le carcinome à petites cellules et les cancers non à petites cellules. Cette distinction est importante, les traitements et pronostics étant très différents. Les cancers non

Role of RIP4 in lung adenocarcinoma differentiation

Jawahar Kopparam

Various studies have attributed NF-kB activation to promote KRAS mediated non-small cell lung cancer progression. In order to identify key genes regulating NF-kB activation and cell survival in lung adenocarcinoma, a synthetic lethal partner screen for KRAS was conducted in cell lines expressing mutant or wildtype KRAS. This screen identified an important role of Receptor-interacting serine/threonine protein kinase 4 (RIP4) in KRAS mediated oncogenesis. But altering RIP4 expression did not affect the viability of KRAS mutant cells, however a novel role of RIP4 in maintaining tumor differentiation was observed. Loss of epithelial differentiation and extracellular matrix remodeling are known to facilitate cancer progression and are associated with poor prognosis in patients with lung cancer. Bioinformatics analyses of human lung adenocarcinoma samples showed that poorly differentiated tumors express low levels of RIP4, whereas high levels are associated with better overall survival. Interleukin 6 (IL6) signaling is activated in lung adenocarcinoma expressing oncogenic KRAS and contributes to cancer invasiveness. Knockdown of RIP4 using shRNA in vitro enhanced activation of IL-6 signaling and also the ability of the cells to invade through collagen. In contrast, overexpression of RIP4 inhibited IL6-mediated Signal Transducer and activator of Transcription 3 (STAT3) activation, which abrogated IL6-dependent induction of lysyl oxidase, a collagen cross-linking enzyme. Tumor-specific Rip4 knockdown in an autochthonous mouse model of lung adenocarcinoma initiated by Kras(G12D) expression with loss of p53, progressed to a poorly differentiated state marked by an increase in Hmga2, reduced Ttf1 and enrichment of genes regulating extracellular matrix (ECM) remodeling and JAK-STAT signaling. Activated STAT3 can enhance NF-kB activation by interacting with NF-kB and promoting its nuclear retention. Tumors with RIP4 knockdown also exhibited enhanced STAT3- NF-kB interaction suggesting a cross talk between the two pathways. Tail vein injections of cells overexpressing RIP4 showed a reduced potential to invade and form tumors. Analysis of factors regulating RIP4 expression revealed that RIP4 is induced in a p53 dependent manner in response to chemotherapy. Altering the induced RIP4 levels in vitro had a modest effect on chemotherapy induced cell death. Our work has identified that loss of RIP4 enhances IL6 signaling in lung cancer cells, promoting the expression of ECM remodeling genes and cancer dedifferentiation.

EPFL2016

Liposome nano-formulation with cationic polar lipid DOTAP and cholesterol as a suitable pH-responsive carrier for molecular therapeutic drug (all-trans retinoic acid) delivery to lung cancer cells

Lucia Bonati

The molecular targeted drug ATRA demands a suitable carrier that delivers to the cancer site due to its poor bioavailability and drug resistance. ATRA, being a lipid with carboxylic acid, has been nano-formulated as a cationic lipo-ATRA with DOTAP:cholesterol:ATRA (5:4:1) and its pH-responsive release, intracellular drug accumulation, and anticancer effect on human lung cancer (A549) cell line analysed. The analysis of the physicochemical characteristics of the developed lipo-ATRA (0.8 mu mol) revealed that the size of 231 +/- 2.35 d.nm had a zeta potential of 6.4 +/- 1.19 and an encapsulation efficiency of 93.7 +/- 3.6%. The ATRA release from lipo-ATRA in vitro was significantly (p

WILEY2021

Repurposed drug combination via high-throughput screening and dual drug delivery system development for the treatment of retinoblastoma

Po-Jen Tseng

The goal of retinoblastoma (RB) treatment is to save the child's life, eyes and functional vision, with that order of priority. The management of RB is complex and involves strategically chosen methods of surgical enucleation, external beam radiotherapy, intravenous chemoreduction and focal therapy. Local administration routes of chemotherapy, intra-arterial (IAC) and intravitreal (IVC), have emerged as promising methods to salvage the eyes and vision. New improvements in the chemotherapy of RB are geared towards reducing side effects of the drugs employed. Emerging strategies includes alternative chemotherapeutic agents, drug combinations, and novel drug delivery systems. Most successful examples of drug repurposing so far have been serendipitous. The systematic approach here was identified candidate drugs by strategic high-throughput screening methods. In this thesis, hit drugs were screened from a drug library of primarily FDA-approved drugs, and the synergistic effect of selected drug combinations was investigated. The hit drug gemcitabine, known to be an effective clinical treatment for non-small cell lung cancers, in combination with carboplatin, was discovered to have the highest cytotoxicity of the hits identified, and appeared as a potential alternative therapeutic agent for RB treatment.Polymeric nanoparticles (NPs) as an improved drug delivery system were investigated with gemcitabine. The nanoprecipitation synthesis of a poly(lactic-co-glycolic acid), as known as PLGA, nanoparticle was developed for drug encapsulation. The characterization of PLGA NPs within various active pharmaceutical ingredients were studied using dynamic light scattering and scanning electron microscopy, revealing that spherical NPs ranging in size from 150 to 200 nm could be successfully prepared. The tumor cells proliferation inhibition was observed after treatment with this novel nanoformulation. Furthermore, the possibility of a dual drug delivery system was explored. Gemcitabine and carboplatin were encapsulated together in PLGA NPs and found to show a synergistic effect after dual drug release. Additionally, gemcitabine combined with the light-activated agent indocyanine green was prepared, and laser-induced photothermal therapy (PTT) was explored.

EPFL2022