Treatment of cancer

Résumé

Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series of separate treatments (e.g. chemotherapy before surgery). The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). Cancer genome sequencing helps in determining which cancer the patient exactly has for determining the best therapy for the cancer. A number of experimental cancer treatments are also under development. Under current estimates, two in five people will have cancer at some point in their lifetime. Complete removal of the cancer without damage to the rest of the body (that is, achieving cure with near-zero adverse effects) is the ideal, if rarely achieved, goal of treatment and is often the goal in practice. Sometimes this can be accomplished by surgery,

Source officielle

https://en.wikipedia.org/wiki/Treatment_of_cancer

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Expression of E-Cadherin in Epithelial Cancer Cells Increases Cell Motility and Directionality through the Localization of ZO-1 during Collective Cell Migration

Hwanseok Jang

Collective cell migration of epithelial tumor cells is one of the important factors for elucidating cancer metastasis and developing novel drugs for cancer treatment. Especially, new roles of E-cadherin in cancer migration and metastasis, beyond the epithelial-mesenchymal transition, have recently been unveiled. Here, we quantitatively examined cell motility using micropatterned free edge migration model with E-cadherin re-expressing EC96 cells derived from adenocarcinoma gastric (AGS) cell line. EC96 cells showed increased migration features such as the expansion of cell islands and straightforward movement compared to AGS cells. The function of tight junction proteins known to E-cadherin expression were evaluated for cell migration by knockdown using sh-RNA. Cell migration and straight movement of EC96 cells were reduced by knockdown of ZO-1 and claudin-7, to a lesser degree. Analysis of the migratory activity of boundary cells and inner cells shows that EC96 cell migration was primarily conducted by boundary cells, similar to leader cells in collective migration. Immunofluorescence analysis showed that tight junctions (TJs) of EC96 cells might play important roles in intracellular communication among boundary cells. ZO-1 is localized to the base of protruding lamellipodia and cell contact sites at the rear of cells, indicating that ZO-1 might be important for the interaction between traction and tensile forces. Overall, dynamic regulation of E-cadherin expression and localization by interaction with ZO-1 protein is one of the targets for elucidating the mechanism of collective migration of cancer metastasis.

MDPI2021

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Targeted cancer therapy is a very promising concept; however, small molecule inhibitors only exist for a limited number of oncoproteins and resistance development limits their clinical use. Different engineered non-antibody scaffolds are being explored to develop potent protein-based inhibitors of oncoproteins, which can overcome these hurdles. The first goal of this thesis was to characterize monobodies, engineered binders based on the fibronectin type 3 domain, which were selected to bind the SH2 domains of 6 members of the Src kinase family that play a role in different types of cancer. I have shown that the monobodies bind specifically to their target in cells by performing tandem affinity purifications with subsequent mass spectrometry analysis. When expressed in T cells, the Lck-targeting monobodies ML1 and ML3 inhibit the phosphorylation of Zap70, a kinase which is activated downstream of T cell activation. Moreover, the fusion of ML1 or ML3 to VHL, the substrate receptor of an E3 ubiquitin ligase, resulted in the targeted degradation of Lck. The selected monobodies therefore have great potential to interfere with cancer cell signaling and to be used in therapeutic approaches. The development of protein-based inhibitors is currently limited to extracellular targets due to the inability of proteins to cross the cell membrane. Many approaches to achieve cellular delivery are hampered by non-selective cytotoxicity or endosomal entrapment of the protein cargo. The second aim of my thesis was to explore different methods to deliver functional monobodies into cancer cells. Firstly, I tested cell penetrating poly-disulfides (CPDs). CPD-monobody adducts showed toxic effects on the tested cell line, and mainly followed an endocytic uptake route leading to lysosomal degradation, when used at subtoxic concentrations. Secondly, bacterial toxins have naturally evolved to deliver their payload into the cytoplasm of host cells. Both Shiga-like toxins and Exotoxin A from Pseudomonas aeruginosa are taken up into the cytosol via a retrograde trafficking route, avoiding endosomal entrapment. To deliver monobodies to the cytosol, we have tested a combination of their non-toxic subunits: The B subunit of Shiga-like toxin (Stx2B), binding to the sphingolipid Gb3 in the cell membrane, and the translocation domain of Exotoxin A (TDP). We could show that recombinant Stx2B-TDP-Monobody fusion proteins are taken up in HeLa cells, which naturally express Gb3. Colocalization analyses with markers for endocytic compartments demonstrated that the major part of the monobodies escape early endosomes and are not degraded in lysosomes. A recombinant fusion protein of the Stx2B-TDP construct with the monobody AS25, which allosterically inhibits Bcr-Abl kinase, leads to apoptosis in Bcr-Abl-dependent chronic myeloid leukemia cells. Furthermore, the delivery of the VHL-ML3 fusion protein into Jurkat T cells results in decreased Lck levels. The delivery of both constructs is dependent on Gb3 on the cell surface as well as the Stx2B-TDP subunits. These results demonstrate that functional monobodies can be delivered to the cytosol and bind to their target protein in cells. This method could facilitate the development of protein-based inhibitors of intracellular proteins for cancer treatment.

EPFL2018

Chargement

New dendritic silica/titania mesoporous nanoparticles (DSTNs) loaded with curcumin (CUR) were synthesized and coated with polyethylenimine-folic acid groups (PEI-FA) for an ultrasound (US)-triggered drug release and combined chemo-sonodynamic therapy. The PEI-FA groups play a gatekeeper role, strongly encapsulate the CUR molecules inside the nanocarrier, and prevent the unwanted premature release by blocking the mesoporous channels. The results showed that the specific cancer cell uptake is improved by FA groups on the surfaces of DSTNs via receptor-mediated endocytosis. The TiO2 layer as a sonosensitizer agent coated on the mesoporous silica nanoparticles generates reactive oxygen species. Following the US irradiation, the PEI molecules were cut off by free radicals, including OH center dot and O-2(-), on the exterior surface of DSTNs, and the CUR loaded in the nanocarrier was then released into the cancer cell cytosol. The release profiles of the CUR@PEI-FA-DSTN system showed that the amount of CUR released from DSTNs is controlled by tuning the US radiation time. The results of the MTT cytotoxicity tests of free CUR, free PEI-FADSTN nanocarrier, and CUR@PEI-FA-DSTNs against A549 (human lung carcinoma cell lines) and HeLa (human cervical carcinoma cell lines ( showed that the toxicity of CUR@PEI-FA-DSTNs is higher than those of CUR and PEI-FA-DSTNs alone. In addition, the specific targeting ability, the cellular uptake, and the anticancer activity of the synthesized compounds for targeted cancer treatment were investigated using different staining methods and fluorescence microscopy. The results revealed that the new system, CUR@PEI-FA-DSTNs, can be considered as a potent drug delivery system for increasing effectiveness of the anticancer activity of curcumin in the combined chemo-sonodynamic therapy.

2019

Chargement

EPFL2018