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?

Role of Th cytokines in thyroid autoimmunity

Chimeric antigen receptor (CAR)-T cell therapy represents one of the most innovative immunotherapy approaches. The encouraging results achieved by CAR-T cell therapy in hematological disorders paved the way for the employment of CAR engineered T cells in different types of solid tumors. This adoptive cell therapy represents a selective and efficacious approach to eradicate tumors through the recognition of tumor-associated antigens (TAAs). Binding of engineered CAR-T cells to TAAs provokes the release of several cytokines, granzyme, and perforin that ultimately lead to cancer cells elimination and patient’s immune system boosting. Within the tumor mass a subpopulation of cancer cells, known as cancer stem cells (CSCs), plays a crucial role in drug resistance, tumor progression, and metastasis. CAR-T cell therapy has indeed been exploited to target CSCs specific antigens as an effective strategy for tumor heterogeneity disruption. Nevertheless, a barrier to the efficacy of CAR-T cell-based therapy is represented by the poor persistence of CAR-T cells into the hostile milieu of the CSCs niche, the development of resistance to single targeting antigen, changes in tumor and T cell metabolism, and the onset of severe adverse effects. CSCs resistance is corroborated by the presence of an immunosuppressive tumor microenvironment (TME), which includes stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and immune cells. The relationship between TME components and CSCs dampens the efficacy of CAR-T cell therapy. To overcome this challenge, the double strategy based on the use of CAR-T cell therapy in combination with chemotherapy could be crucial to evade immunosuppressive TME. Here, we summarize challenges and limitations of CAR-T cell therapy targeting CSCs, with particular emphasis on the role of TME and T cell metabolic demands.

Cancer cell targeting by CAR-T cells: A matter of stemness

Osmocellular Fas and Fas ligand interactions mediate thyrocyte destruction in Hashimoto's thyroiditis

Compelling evidence indicates that the survival and behavior of cancer stem cells (CSCs) are positively regulated by specific stimuli received from the tumor microenvironment, which dictates the maintenance of stemness, invasiveness, and protection against drug-induced apoptotic signals. CSCs are per se endowed with multiple treatment resistance capabilities, thus the eradication of CSC pools offers a precious strategy in achieving a long-term cancer remission. Numerous therapies, aimed at eradicating CSCs, have been elaborated such as: (i) selective targeting of CSCs, (ii) modulating their stemness and (iii) influencing the microenvironment. In this context, markers commonly exploited to isolate and identify CSCs are optimal targets for monoclonal antibody-based drugs. Furthermore, the molecules that inhibit detoxifying enzymes and drug-efflux pumps, are able to selectively suppress CSCs. Auspicious outcomes have also been reported either by targeting pathways selectively operating in CSCs (e.g. Hedgehog, Wnt, Notch and FAK) or by using specific CSC cytotoxic agents. Other compounds are able to attenuate the unique stemness properties of CSCs by forcing cell differentiation, and this being the case in ATRA, HDACi, BMPs and Cyclopamine, among others. Targeting the interplay between paracrine signals arising in the tumor stroma and the nearby cancerous cells via the inhibition of VEGF, HIF, CD44v and CXCR4, is increasingly recognized as a significant factor in cancer treatment response and holds alluring prospects for a successful elimination of CSCs. In the present chapter, we discuss the latest findings in the optimization and tailoring of novel strategies that target both CSCs and tumor bulk for the eradication of malignancies.

Targeting cancer stem cells and the tumor microenvironment

Despite an increasing gain of knowledge regarding small extracellular vesicle (sEV) composition and functions in cell-cell communication, the mechanism behind their biogenesis remains unclear. Here, we revealed for the first time that the sEV biogenesis and release into the microenvironment are tightly connected with another important organelle: Lipid Droplets (LD). We have observed this correlation using different human cancer cell lines as well as patient-derived colorectal cancer stem cells (CR-CSCs). Our results showed that the use of external stimuli such as radiation, pH, hypoxia, or lipid interfering drugs, known to affect the LD content, had a similar effect in terms of sEV secretion. Additional validations were brought using multiple omics data, at the mRNA and protein levels. Altogether, the possibility to fine-tune sEV biogenesis by targeting LDs, could have a massive impact on the amount, the cargos and the properties of those sEVs, paving the way for new clinical perspectives. Significance Statement

/pdf/lipid-droplets-fuel-small-extracellular-vesicle-biogenesis-2ghjzgy7.pdf

Matilde Todaro

Papers

Role of Th cytokines in thyroid autoimmunity

Cancer cell targeting by CAR-T cells: A matter of stemness

Osmocellular Fas and Fas ligand interactions mediate thyrocyte destruction in Hashimoto's thyroiditis

Targeting cancer stem cells and the tumor microenvironment

Lipid Droplets Fuel Small Extracellular Vesicle Biogenesis