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Role of Exosomes in cancerby

LARAIB ARIF (11011560-055)UNIVERSITY OF GUJRAT

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Contents:

• What are exosomes?• Exosomal composition and functions• Exosomal synthesis and secretion• Uptake of Exosomes by recipient cells• Exosomes as mediator of intracellular communication• Exosomes and Canceri. Role in metastasisii. Role in angiogenesisiii. Role in diagnosisiv. Role in cancer therapy and drug resistance

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Introduction to exosomes:• Exosomes are cell-derived vesicles present in almost all body

fluids including: Blood and serum Urine Breast milk and amniotic fluid Nasal secretions and CSF Cultured mediums of cell cultures• Diameter is 30-100 nm.• Encapsulated by a lipid bilayer.• High concentration in circulation during pregnancy and cancer.

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Electron microscope image of exosomes derived from bladder cancer cells100nm

Composition:Exosomes are composed of a wide range of contents including:

• Proteins ( integrins, selectins, Rab proteins, SNAREs, tetraspanins like CD9, CD81, CD63 etc)

• Lipids (e.g, steroids, sphingolipids, glycerophospholipids)• Nucleic acids (mRNA, miRNA, sRNA, DNA)• Growth receptors • Soluble factors

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Functions:• Different biological functions both in normal and pathophysiological

conditions.• Elimination of un-necessary proteins & molecules from cell and blood

coagulation.• Exchange of materials between cells, intercellular communication.• Propagation of pathogens, immune responses (inhibitory and regulatory),

Antigen presentation and many more….!!!

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Synthesis and Secretion:

The process of exosome biogenesis is divided into four stages• Initiation• Endocytosis• Multivesicular bodies (MVBs) formation and • Exosome secretion

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Uptake by recipient cell:Recipient cells uptake exosomes by 3 mechanisms:Through receptors:

• No specified receptors. Some molecules act like EUR including Tim1, Tim4, ICAM-1.

Direct fusion with plasma membrane:• Smallest amount studied mode of uptake.• Malignant melanoma cells take up exosome by fusion with low H-ion

concentration which facilitate this process.Phagocytosis:

• Most effective approach of exosomal uptake.• For example, exosomes from PC12 cells (rat pheochromocytoma) were internalized through endocytosis.

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Intracellular communication:

• Exosomes play a vital role in cell to cell communication. • They transfer proteins, ribonucleic acid and miRNA into

recipient cells.

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Exosomes and cancer:

Cancer cells secrete exosomes, that act in several ways:

Paracrine mode: release their miRNAs on recipient neighboring cells, that induce post-transcriptional repression or activate membrane surface receptors to favor growth and invasiveness. Endocrine mode: come into circulation, approach tissues at distant organs, wherever they're pre-occupied by recipient cells and stimulates pathologic process.

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Role in metastasis:• Pre-metastatic niche: Primary tumor cells release a variety of cytokines

and growth factors that firstly mobilizeand recruit bone-marrow- derived cells (BMDCs) to the site of future metastasis, creating the permissive environment for incoming tumor cells, that is called the pre-metastatic niche.

• In addition to endothelial cells, exosomes also affect other cells viz, fibroblasts, immune cells etc.

• Fibroblasts activated to myofibroblasts stimulates tumor growth, vascularization and metastasis.

• Deregulation of extracellular matrix through glycoproteins and metalloproteinases of cancer exosomes.

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Role in Angiogenesis: • Angiogenesis is the formation of new blood vessels and it

is important in growth into distant site. • Vescular endothelial growth factor (VEGF): secretion of VEGF causes

enhanced growth.• Tetraspanins: that are enriched in exosomes, are found to contribute to

exosome-mediated angiogenesis.• Epidermal growth factor receptor (EGFR):

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Fusion between epithelial membrane and exosome via PS mediated process.

Growth cells over-express molecules like CD147 which activate MMPs.

Degradation of basement membrane, liberation of

angiogenic factors, cappillaries formed.

Exosomes as biomarkers??• Exosomes may provide an excellent biomarker to monitor the emergence,

progression, and prognosis of cancer, as well as the efficacy of treatment regimes.

• Exosomes can be readily detected in tumor tissue, and can be found in higher concentrations, both in tumor tissue, and the serum and plasma of cancer patients.

Examples:• The presence of nucleic acid in exosomes has been described as a

biomarker in glioblastoma patients via the identification of the disease-specific EGF receptor transcript.

• In melanoma patients exosomes contain high levels of the proteins Caveolin-1 and CD63.

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Cancer therapy:• Exosomes regulate immune responses both in a negative as well as positive

way, i.e, to promote and to treat cancer.• For example, in case of ovarian tumor if tumor-derived exosomes are removed

from circulation , immune responses generated which start degrading cancer cells.

• Moreover, exosomes can also be used in selected combination with cancer therapeutics and targeted to recipient cancer cells.

Drug resistance:• The blood-brain barrier (BBB) essentially restricts therapeutic drugs from

entering into the brain. Brain endothelial cell derived exosomes can deliver anticancer drug across the BBB for the treatment of cancer.

• In case of ovarian cancer, malignant neoplastic disease cells develop resistance against drug cisplatin.

• Exosomes can also function to neutralize antibody-based drugs and help to reduce the anti-body dependent cytotoxicity. 15