https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Molecular mechanisms of epithelial–mesenchymal transition

https://web.stanford.edu/group/nusselab/cgi-bin/wnt/sites/default/files/reviews/Cell%202012%20Clevers.pdf

Wnt/β-catenin signaling and disease.

Oxidative Stress, Inflammation, and Cancer: How Are They Linked?

// Bregje van Oorschot 1 , Giovanna Granata 1 , Simone Di Franco 2 , Rosemarie ten Cate 1 , Hans M. Rodermond 1 , Matilde Todaro 3 , Jan Paul Medema 1 , Nicolaas A.P. Franken 1 1 Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine, Department of Radiation Oncology, Academic Medical Center, Cancer Genomics Center, Amsterdam, The Netherlands 2 Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy 3 Biomedical Department of Internal and Specialistic Medicine (DIBIMIS), University of Palermo, Palermo, Italy Correspondence to: Nicolaas A.P. Franken, email: n.a.franken@amc.uva.nl Keywords: radiation oncology, DNA repair, hyperthermia, double-strand breaks Received: May 10, 2016      Accepted: August 24, 2016      Published: September 01, 2016 ABSTRACT Radiotherapy is based on the induction of lethal DNA damage, primarily DNA double-strand breaks (DSB). Efficient DSB repair via Non-Homologous End Joining or Homologous Recombination can therefore undermine the efficacy of radiotherapy. By suppressing DNA-DSB repair with hyperthermia (HT) and DNA-PKcs inhibitor NU7441 (DNA-PKcs i ), we aim to enhance the effect of radiation. The sensitizing effect of HT for 1 hour at 42°C and DNA-PKcs i [1 μM] to radiation treatment was investigated in cervical and breast cancer cells, primary breast cancer sphere cells (BCSCs) enriched for cancer stem cells, and in an in vivo human tumor model. A significant radio-enhancement effect was observed for all cell types when DNA-PKcs i and HT were applied separately, and when both were combined, HT and DNA-PKcs i enhanced radio-sensitivity to an even greater extent. Strikingly, combined treatment resulted in significantly lower survival rates, 2 to 2.5 fold increase in apoptosis, more residual DNA-DSB 6 h post treatment and a G2-phase arrest. In addition, tumor growth analysis in vivo showed significant reduction in tumor growth and elevated caspase-3 activity when radiation was combined with HT and DNA-PKcs i compared to radiation alone. Importantly, no toxic side effects of HT or DNA-PKcs i were found. In conclusion, inhibiting DNA-DSB repair using HT and DNA-PKcs i before radiotherapy leads to enhanced cytotoxicity in cancer cells. This effect was even noticed in the more radio-resistant BCSCs, which are clearly sensitized by combined treatment. Therefore, the addition of HT and DNA-PKcs i to conventional radiotherapy is promising and might contribute to more efficient tumor control and patient outcome.

/pdf/targeting-dna-double-strand-break-repair-with-hyperthermia-24zpqti3fc.pdf

Targeting DNA double strand break repair with hyperthermia and DNA-PKcs inhibition to enhance the effect of radiation treatment.

By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy

We previously showed that cancer cells from papillary, follicular, and anaplastic thyroid carcinomas produce interleukin-4 and interleukin-10, which counteract the cytotoxic activity of conventional chemotherapy through the up-regulation of antiapoptotic molecules. Here, we identify Janus kinase/signal transducers and activators of transcription (STAT) and phosphatidyl inositol 3-kinase (PI3K)/AKT as the down-stream pathways through which these cytokines confer resistance to cell death in thyroid cancer. We found that the absence of suppressors of cytokine signaling (SOCS) molecules allows the propagation of the survival signaling. Exogenous expression of SOCS1, SOCS3, and SOCS5 in the highly aggressive anaplastic thyroid cancer cells reduces or abolishes STAT3 and 6 phosphorylation and PI3K/Akt pathway activation resulting in alteration in the balance of proapoptotic and antiapoptotic molecules and sensitization to chemotherapeutic drugs in vitro. Likewise, exogenous expression of SOCS3 significantly reduces tumor growth and potently enhances the efficacy of chemotherapy in vivo. Our results indicate that SOCS3 regulation of cytokines-prosurvival programs might represent a new strategy to overcome the resistance to chemotherapy-induced cell death of thyroid cancer.

https://cancerres.aacrjournals.org/content/canres/69/15/6141.full.pdf

Suppressor of cytokine signaling 3 sensitizes anaplastic thyroid cancer to standard chemotherapy

T-cell activation in HLA-B8, DR3-positive individuals. Early antigen expression defect in vitro.

Hashimoto's thyroiditis is a common chronic autoimmune disease characterized by the loss of thyroid follicular cells (thyrocytes) that are gradually replaced by lymphocytic infiltration and diffuse fibrosis. These morphological findings suggested that autoreactive T-cell clones were responsible for thyrocyte destruction and hypothyroidism through effector-target cytotoxic recognition. Later, autonomous interaction between thyrocyte Fas and FasL has been proposed as a major mechanism of thyrocyte depletion in Hashimoto's thyroiditis. Here, we analyze the possible role of Fas and FasL in the pathogenesis of Hashimoto's thyroiditis. We suggest that the Fas-FasL system dictates the outcome of the autoimmune response by acting on both immune and target cells.

Matilde Todaro

Papers

Targeting DNA double strand break repair with hyperthermia and DNA-PKcs inhibition to enhance the effect of radiation treatment.

By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy

Suppressor of cytokine signaling 3 sensitizes anaplastic thyroid cancer to standard chemotherapy

T-cell activation in HLA-B8, DR3-positive individuals. Early antigen expression defect in vitro.

Fas-FasL in Hashimoto's thyroiditis.