Ablation of intestinal epithelial sialylation predisposes to acute and chronic intestinal inflammation in mice.

BACKGROUND & AIMS: Addition of sialic acids (sialylation) to glycoconjugates is a common capping step of glycosylation. Our study aims to determine the roles of the overall sialylation in intestinal mucosal homeostasis. METHODS: Mice with constitutive deletion of intestinal epithelial sialylation (IEC Slc35a1-/- mice) and mice with inducible deletion of sialylation in intestinal epithelium (TM-IEC Slc35a1-/- mice) were generated, which were used to determine the roles of overall sialylation in intestinal mucosal homeostasis by ex vivo and muti-omics studies. RESULTS: IEC Slc35a1-/- mice developed mild spontaneous microbiota-dependent colitis. Additionally, 30% of IEC Slc35a1-/- mice had spontaneous tumors in the rectum over the age of 12 months. TM-IEC Slc35a1-/- mice were highly susceptible to acute inflammation induced by 1% DSS vs controls. Loss of total sialylation was associated with reduced mucus thickness on fecal sections and within colon tissues. TM-IEC Slc35a1-/- mice showed altered microbiota with an increase in Clostridia disporicum, which is associated a global reduction in the abundance of at least 20 unique taxa; however, metabolomic analysis did not show any significant differences in short-chain fatty acid levels. Treatment with 5-fluorouracil (5-FU) led to more severe small intestine mucositis in the IEC Slc35a1-/- mice vs. WT littermates, which was associated with reduced Lgr5+ cell representation in small intestinal crypts in IEC Slc35a1-/-;Lgr5-GFP mice. CONCLUSIONS: Loss of overall sialylation impairs mucus stability and the stem cell niche leading to microbiota-dependent spontaneous colitis and tumorigenesis.

Organically derived exosomes as carriers of anticancer drugs and imaging agents for cancer treatment.

Extracellular vesicles (EVs), is the umbrella term used for different types of vesicles produced by the cells, among which exosomes form the largest group. Exosomes perform intercellular communication by carrying several biologics from donor or parental cells and delivering them to recipient cells. Their unique cargo-carrying capacity has recently been explored for use as delivery vehicles of anticancer drugs and imaging agents. Being naturally produced, exosomes have many advantages over synthetic lipid-based nanoparticles currently being used clinically to treat cancer and other diseases. The finding of the role of exosomes in human diseases has led to numerous preclinical and clinical studies exploring their use as an amenable drug delivery vehicle and a theranostic in cancer diagnosis and treatment. However, there are certain limitations associated with exosomes, with the most important being the selection of the biological source for producing highly biocompatible exosomes on a large scale. This review article explores the various sources from which therapeutically viable exosomes can be isolated for use as drug carriers for cancer treatment. The methods of exosome isolation and the process of loading them with cancer therapeutics and imaging agents are also discussed in the follow-up sections. Finally, the article concludes with future directions for exosome-based applications in cancer diagnosis and treatment.

Extracellular Vesicles in Oncology: from Immune Suppression to Immunotherapy.

Exosomes are involved in cell-to-cell communication and play a crucial role in cellular physiology. The role of exosomes in cancer has been widely explored. Tumor cells have evolved and adapted to evade the immune response. The study of the immune system's modulations in favor of rogue tumor cells led to the development of a novel immunotherapeutic strategy targeting the immune checkpoint proteins (ICPs). In clinical settings, the response to ICP therapy has been inconsistent and is difficult to predict. Quantitating the targeted ICPs through immunohistochemistry is one approach, but is not pragmatic in a clinical setting and is often not sensitive. Examining the molecules present in bodily fluids to determine ICP treatment response, "liquid biopsy" is a convenient alternative. The term "liquid biopsy" refers to circulating tumor cells (CTCs), extracellular vesicles (EVs), non-coding (nc) RNA, circulating tumor DNA (ctDNA), circulating free DNA (cfDNA), etc. EVs includes exosomes, microvesicles, and oncosomes. Herein, we focus on exosomes isolated from bodily fluids and their use in liquid biopsy. Due to their unique ability to transfer bioactive molecules and perturb the physiology of recipient cells, exosomes have garnered attention for their immune modulation role and as a resource to identify molecules associated with liquid biopsy-based diagnostic methods. In this review, we examine the putative role of exosomes and their cargo in influencing the immune system. We discuss the immune and tumor cells present in the tumor microenvironment (TME), and the exosomes derived from these cells to understand how they participate in creating the immune-suppressive TME. Additionally, use of exosomes in liquid biopsy-based methods to measure the treatment response elicited by immunotherapy is discussed. Finally, we describe how exosomes have been used to develop immune therapies, especially cell-free vaccines, for cancer treatment.