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Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy.

ABSTRACT: Exosomes are secreted extracellular vesicles (EVs) that carry micro RNAs and other factors to reprogram cancer cells and tissues affected by cancer. Exosomes are exchanged between cancer cells and other tissues, often to prepare a premetastatic niche, escape immune surveillance, or spread multidrug resistance. Only a few studies investigated the function of lipids in exosomes although their lipid composition is different from that of the secreting cells. Ceramide is one of the lipids critical for exosome formation, and it is also enriched in these EVs. New research suggests that lipids in the exosomal membrane may organize and transmit "mobile rafts" that turn exosomes into extracellular signalosomes spreading activation of cell signaling pathways in oncogenesis and metastasis. Ceramide may modulate the function of mobile rafts and their effect on these cell signaling pathways. The critical role of lipids and, in particular, ceramide for formation, secretion, and function of exosomes may lead to a radically new understanding of cancer biology and therapy.

SUBMITTER: Elsherbini A

PROVIDER: S-EPMC6109973 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy.

Elsherbini Ahmed A Bieberich Erhard E

Advances in cancer research 20180609

Exosomes are secreted extracellular vesicles (EVs) that carry micro RNAs and other factors to reprogram cancer cells and tissues affected by cancer. Exosomes are exchanged between cancer cells and other tissues, often to prepare a premetastatic niche, escape immune surveillance, or spread multidrug resistance. Only a few studies investigated the function of lipids in exosomes although their lipid composition is different from that of the secreting cells. Ceramide is one of the lipids critical fo ...[more]

PMID: 30060807

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Project description:Tumor-related activities that seem to be operationally induced by the division of function, such as inflammation, neoangiogenesis, Warburg effect, immune response, extracellular matrix remodeling, cell proliferation rate, apoptosis, coagulation effects, present itself from a systems perspective as an enhancement of complexity. We hypothesized, that tumor systems-directed therapies might have the capability to use aggregated action effects, as adjustable sizes to therapeutically modulate the tumor systems' stability, homeostasis, and robustness. We performed a retrospective analysis of recently published data on 224 patients with advanced and heavily pre-treated (10% to 63%) vascular sarcoma, melanoma, renal clear cell, cholangiocellular, carcinoma, hormone-refractory prostate cancer, and multivisceral Langerhans' cell histiocytosis enrolled in nine multi-center phase II trials (11 centers). Each patient received a multi-targeted systems-directed therapy that consisted of metronomic low-dose chemotherapy, a COX-2 inhibitor, combined with one or two transcription modulators, pioglitazone +/- dexamethasone or IFN-alpha. These treatment schedules may attenuate the metastatic potential, tumor-associated inflammation, may exert site-specific activities, and induce long-term disease stabilization followed by prolonged objective response (3% to 48%) despite poor monoactivity of the respective drugs. Progression-free survival data are comparable with those of reductionist-designed standard first-line therapies. The differential response patterns indicate the therapies' systems biological activity. Understanding systems biology as adjustable size may break through the barrier of complex tumor-stroma-interactions in a therapeutically relevant way: Comparatively high efficacy at moderate toxicity. Structured systems-directed therapies in metastatic cancer may get a source for detecting the topology of tumor-associated complex aggregated action effects as adjustable sizes available for targeted biomodulatory therapies.

Project description:Exosomes are a subset of tiny extracellular vesicles manufactured by all cells and are present in all body fluids. They are produced actively in tumor cells, which are released and utilized to facilitate tumor growth. Their characteristics enable them to assist major cancer hallmarks, leveraged by cancer cells in fostering cancer growth and spread while implementing ways to escape elimination from the host environment. This review updates on the latest progress on the roles of cancer-derived exosomes, of 30-100 nm in size, in deregulating paracrine trafficking in the tumor microenvironment and circulation. Thus, exosomes are being exploited in diagnostic biomarker development, with its potential in clinical applications as therapeutic targets utilized in exosome-based nanoparticle drug delivery strategies for cancer therapy. Ongoing studies were retrieved from PubMed® and Scopus database and ClinicalTrials.gov registry for review, highlighting how cancer cells from entirely different cell lines rely on genetic information carried by their exosomes for homotypic and heterotypic intercellular communications in the microenvironment to favor proliferation and invasion, while establishing a pre-metastatic niche in welcoming cancer cells' arrival. We will elaborate on the trafficking of tumor-derived exosomes in fostering cancer proliferation, invasion, and metastasis in hematopoietic (leukemia and myeloma), epithelial (breast cancer), and mesenchymal (soft tissue sarcoma and osteosarcoma) cancers. Cancer-derived exosomal trafficking is observed in several types of liquid or solid tumors, confirming their role as cancer hallmark enabler. Their enriched genetic signals arising from their characteristic DNA, RNA, microRNA, and lncRNA, along with specific gene expression profiles, protein, or lipid composition carried by the exosomal cargo shed into blood, saliva, urine, ascites, and cervicovaginal lavage, are being studied as a diagnostic, prognostic, or predictive cancer biomarker. We reveal the latest research efforts in exploiting the use of nanoparticles to improve the overall cancer diagnostic capability in the clinic.

Dataset Information

Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy.

Publications

Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy.

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