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

Hallmarks of cancer: the next generation.

http://aiocm.org/member/Immunity,%20Inflammation,%20and%20Cancer.pdf

Immunity, Inflammation, and Cancer

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

/pdf/the-basics-of-epithelial-mesenchymal-transition-xe9crzoewf.pdf

The basics of epithelial-mesenchymal transition

The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, here we use a combination of automated approaches and expert curation to develop a collection of “hallmark” gene sets as part of MSigDB. Each hallmark in this collection consists of a “refined” gene set, derived from multiple “founder” sets, that conveys a specific biological state or process and displays coherent expression. The hallmarks effectively summarize most of the relevant information of the original founder sets and, by reducing both variation and redundancy, provide more refined and concise inputs for gene set enrichment analysis.

https://www.cell.com/cell-systems/pdf/S2405-4712(15)00218-5.pdf

The Molecular Signatures Database Hallmark Gene Set Collection

Non-invasive early cancer diagnosis remains challenging due to the low sensitivity and specificity of current diagnostic approaches. Exosomes are membrane-bound nanovesicles secreted by all cells that contain DNA, RNA, and proteins that are representative of the parent cells. This property, along with the abundance of exosomes in biological fluids makes them compelling candidates as biomarkers. However, a rapid and flexible exosome-based diagnostic method to distinguish human cancers across cancer types in diverse biological fluids is yet to be defined. Here, we describe a novel machine learning-based computational method to distinguish cancers using a panel of proteins associated with exosomes. Employing datasets of exosome proteins from human cell lines, tissue, plasma, serum and urine samples from a variety of cancers, we identify Clathrin Heavy Chain (CLTC), Ezrin, (EZR), Talin-1 (TLN1), Adenylyl cyclase-associated protein 1 (CAP1) and Moesin (MSN) as highly abundant universal biomarkers for exosomes and define three panels of pan-cancer exosome proteins that distinguish cancer exosomes from other exosomes and aid in classifying cancer subtypes employing random forest models. All the models using proteins from plasma, serum, or urine-derived exosomes yield AUROC scores higher than 0.91 and demonstrate superior performance compared to Support Vector Machine, K Nearest Neighbor Classifier and Gaussian Naive Bayes. This study provides a reliable protein biomarker signature associated with cancer exosomes with scalable machine learning capability for a sensitive and specific non-invasive method of cancer diagnosis.

A novel machine learning algorithm picks proteome signature to specifically identify cancer exosomes

In most adult epithelia the process of replacing damaged or dead cells is maintained through the presence of stem/progenitor cells, which allow epithelial tissues to be repaired following injury. Existing evidence strongly supports the presence of stem cells in the adult kidney. Indeed, recent findings provide evidence in favour of a role for intrinsic renal cells and against a physiological role for bone marrow-derived stem cells in the regeneration of renal epithelial cells. In addition, recent studies have identified a subset of CD24+CD133+ renal progenitors within the Bowman's capsule of adult human kidney, which provides regenerative potential for injured renal epithelial cells. Intriguingly, CD24 + CD133 + renal progenitors also represent common progenitors of tubular cells and podocytes during renal development. Chronic injury causes dysfunction of the tubular epithelial cells, which triggers the release of fibrogenic cytokines and recruitment of inflammatory cells to injured kidneys. The rapid interposition of scar tissue probably confers a survival advantage by preventing infectious microorganisms from invading the wound, but prevents subsequent tissue regeneration. However, the existence of renal epithelial progenitors in the kidney suggests a possible explanation for the regression of renal lesions which has been observed in experimental animals and even in humans. Thus, manipulation of the wound repair process in order to shift it towards regeneration will probably require the ability to slow the rapid fibrotic response so that renal progenitor cells can allow tissue regeneration rather than scar formation.

/pdf/fibrogenesis-tissue-repair-373vtv9kvy.pdf

Fibrogenesis & Tissue Repair

Regardless of the underlying etiology, most forms of chronic kidney diseases are characterized by progressive fibrosis as a final common pathway that eventually affects all substructures of the kidney with the final consequence of end-stage renal disease. Although there has been a great deal of research, comprehensive understanding of the pathogenetic mechanisms of kidney fibrosis remains uncertain and that hampers the development of effective therapeutic strategies. Fibrosis is a process of normal wound healing and repair that is activated in response to injury to maintain the original tissue architecture and functional integrity. However, prolonged chronic injurious stimuli may cause deregulation of normal processes and result in an excess deposition of extracellular matrix and fibrosis. It involves a complex multistage inflammatory process with inflammatory cell infiltration, mesangial and fibroblast activation, tubular epithelial to mesenchymal transition, endothelial to mesenchymal transition, cell apoptosis, and extracellular matrix expansion that is orchestrated by a network of cytokines/ chemokines, growth factors, adhesion molecules, and signal

https://www.kidney-international.org/article/S0085-2538(15)54475-X/pdf

Mechanistic connection between inflammation and

Fibroblasts are spindle-shaped mesenchymal cells and an abundantly studied cell type that are easy to culture. Their adaptive response in culture conditions allows for use in many different cell biological experiments, including their utility in generating induced pluripotent stem cells. Despite extensive use of fibroblasts in cell and molecular biology and genetics experiments, fundamental evaluation of their resiliency and survival programs, in comparison with other cell types, is undetermined. Here, we demonstrate that fibroblasts exhibit remarkable survival capacity in post-mortem tissue decaying at room temperature and can be cultured from ear, tail, kidney, lung, fetal, and mammary tumor tissue after 12-hours of post-mortem tissue decay. Fibroblasts can be cultured from ear and lung tissue after 24-hours, and from ear after up to 120-hours of post-mortem tissue decay. Gene expression profiling of post-mortem lung tissue fibroblasts compared to fresh tissue cultured fibroblasts suggested a transition to a more quiescent phenotype with activation of nutrient scavenging pathways as evidenced by downregulation of genes associated with DNA replication, ribosomes, cell cycle, and spliceosomes as well as upregulation of genes associated metabolism, autophagy, and lysosomes. Measurement of light chain 3B (LC3B)-I/LC3B-II ratio and lysosomal-associated membrane protein (LAMP)-1 indicate that autophagy is increased in post-mortem fibroblasts, with evidence for potential increase in autolysosomes and senescence program. Our study provides evidence for the ability of normal fibroblasts to overcome extreme stress conditions and offers new insights into cell survival mechanisms and aging, with potential utility in tissue regeneration and repair.

/pdf/autophagy-is-associated-with-survival-and-resiliency-of-16mfft8o.pdf

Autophagy is associated with survival and resiliency of fibroblasts in long-term decaying post-mortem parenchymal tissue

Provided herein are compositions comprising exosomes comprising an immunomodulatory molecule, e.g ., ICOSL or OX40L, on their surface. Further provided are methods of using such exosomes for the treatment of diseases requiring immunomodulation, such as cancer, autoimmune disease, or infectious disease.

Raghu Kalluri

Papers

A novel machine learning algorithm picks proteome signature to specifically identify cancer exosomes

Fibrogenesis & Tissue Repair

Mechanistic connection between inflammation and

Autophagy is associated with survival and resiliency of fibroblasts in long-term decaying post-mortem parenchymal tissue

Immuno-exosomes and methods of use thereof