|Year : 2019 | Volume
| Issue : 2 | Page : 172-175
Dichotomy of exosomes in oral squamous cell carcinoma: Prey or play!
HR Shwetha1, T Smitha2
1 Department of Oral Pathology, MMNGH Institute of Dental Science, Belgaum, Karnataka, India
2 Department of Oral Pathology, VSDC, Bengaluru, Karnataka, India
|Date of Submission||21-Jun-2019|
|Date of Acceptance||22-Jun-2019|
|Date of Web Publication||20-Aug-2019|
H R Shwetha
Ph.D Scholar, Department of Oral Pathology, MMNGH Institute of Dental Science, Belgaum, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Exosomes are nano-sized particles which belong to the family of extracellular vesicles (EVs) that are produced in the endosomal compartment of those cells which mediate intercellular communication. These particles can be found abundantly in the biological body fluids such as urine, blood, saliva, cerebrospinal fluid and breast milk. These vesicles can transfer genetic materials such as the microRNAs, noncoding RNAs, DNA and lipids by means of direct or indirect cell-to-cell interaction. Consequently, there has been lot of growing interest related to cancer exosomes as biomarkers and as potential therapeutics. There are studies done which demonstrate the exosomes in relation to cancer, by targeting specific cells and also promote the tumor progression. The other part of the spectrum has stressed the importance of exosomes stability and its potential role in targeting cancer cells through drug delivery system of anticancer molecules. The dichotomy allied with exosomes and their role in oral squamous cell carcinoma biomarkers or as therapy enhancement will be highlighted.
Keywords: Biomarkers, drug delivery, exosomes, oral squamous cell carcinoma
|How to cite this article:|
Shwetha H R, Smitha T. Dichotomy of exosomes in oral squamous cell carcinoma: Prey or play!. J Oral Maxillofac Pathol 2019;23:172-5
|How to cite this URL:|
Shwetha H R, Smitha T. Dichotomy of exosomes in oral squamous cell carcinoma: Prey or play!. J Oral Maxillofac Pathol [serial online] 2019 [cited 2019 Oct 20];23:172-5. Available from: http://www.jomfp.in/text.asp?2019/23/2/172/264810
| Introduction|| |
Oral squamous cell carcinoma (OSCC) is one of the most common cause for death and is the tenth most common cancer types occurring worldwide. Despite the progress happening in the field of diagnosis and treatment, the survival rate for OSCC is accounted to be only 50%. Surgical resection, radiotherapy and chemotherapy have been the common treatments for OSCC. However, not all tumors respond to these treatments due to their therapy resistance and recurrence which pose a challenge since their mechanism is not well known. Hence, a better knowledge on the initial genetic mutations occurring in OSCC is necessary for the primary detection and early intervention of the disease.
Genetic biomarkers-based diagnosis would be essential for the detection of early molecular changes and better prognosis. Apart from early detection of OSCC, the discovery of drug-related targeted therapies has been advanced in cancer treatment which has increased the overall patient survival rate., These therapies mainly focus on proliferation and survival of cancer cells, angiogenesis and metastasis. It is proven that cancer cells can communicate with cell-to-cell or within their microenvironment to proliferate and metastasize through cell junctions and cytokine interactions., Recently, focus has been shifted on extracellular vesicles (EVs) which act as important players for intercellular crosstalk with adjacent or distant cells and their microenvironment. Earlier, EVs were thought to be cellular junk and were later established that it had a pivot role in maintaining homeostasis, immunomodulation and physiological regulation of functions, blood coagulation and various stages of cancer progression.,, There are different variants of EVs described based on their origin including apoptotic bodies, microvesicles and exosomes, but exosomes are commonly studied subtype in cancer-related research. Clinically, exosomes are used as diagnostic biomarkers, therapeutic targets or as anticancer drug delivery vehicles, and have all been emphasized as a result of their unique biological and pathophysiological characteristics. Here, we provide a comprehensive overview of exosomes in cell biology and their role as cancer biomarkers. In addition, we summarize the role of exosomes in clinical applications in relation to their molecular and biological characteristics.
| Exosomes|| |
Exosomes, nano-sized EVs, were discovered three decades ago measuring about 40–100 nm in size. They were initially noticed as Microvesicles (MVs) reticulocyte culture media containing proteins and later in the extracellular environment. They are secreted by all types of cells including epithelial, endothelial, neuronal, fibroblasts, immune cells and tumor cells. These are endosomal in origin and are released through the fusion of the plasma membrane with cytosolic multivesicular bodies. The composition varies according to the origin of site and the parent cell type reflecting their physiologic or pathologic conditions. The membranes of exosomes are composed of a cholesterol-enriched bilayer of lipids, sphingomyelin, gangliosides and ceramide, which provide them high stability. Exosomal genetic cargo is enriched with extensive range of proteins along with bioactive molecules of mRNAs, long noncoding RNAs and miRNAs. B lymphocyte-derived exosomes showed antigen-presenting properties, which suggested their role in immune response, aiding the initiation of T-cell and dendritic cell response.,
| Exosomes as Cancer Biomarkers|| |
Exosome-mediated cellular crosstalk is not limited to tumor cells, but inside the tumor microenvironment locally and distantly also. They have the ability to deliver specific bioactive molecules at different stages of cancer progression, which suggest their potential role as a diagnostic biomarker. Once the exosomes are being detached from its parental cells, the exosomal carriers resemble the intracellular structure of the original secreted cell. Thus, finding the changes within exosomal molecules might provide information for the fundamental requirement of accuracy medicine in terms of diagnosis, prognosis and disease monitoring. Currently, cancer diagnostics rely mostly based on tissue biopsies. The latent use of exosomes has the benefit of being a highly sensitive and noninvasive method. These cancer exosomes allow the early detection of cancer including oral, breast, prostate and ovarian cancer, melanoma and many more. These are noninvasive testing procedures causing less discomfort to the patient. Several functional studies have reported the increased level of exosomes in different types of cancer origins. These cancer exosomes provide an enhanced source of biomarkers since they contain bioactive molecules suggesting the pathological condition of host cells.
Tumor-specific markers such as proteins, mRNA and miRNAs and long-coding RNA have been found in circulating exosome and have gained attention as proficient biomarkers. Precise marker molecules were found on the surface of exosomes, such as CD9, CD81 and CD63. Recently, pilot studies have shown that miRNA, salivary exosome protein and amniotic fluids are useful markers for the detection of many diseases. miRNA content can be useful to detect more than one condition which provides a potential prenatal diagnostic tool.,, Zlotogorski-Hurvitz et al. in their study demonstrated that the molecular and morphological characteristics of exosomes vary between healthy and oral cancer patients, which could aid as an early diagnostic tool to detect any malignant changes in patients with high risks. Furthermore, Li et al. found that exosomes secreted by hypoxic OSCC cells enhanced the migration and invasion of OSCC cells.
| Exosomes as Therapeutic Targets|| |
Exosomes, being a nano-level intercellular carrier, are known as potential therapeutics since they can produce effective cellular responses in vitro/in vivo and improve the efficiency during chemotherapies., Currently, experimental trials are ongoing to validate this mode of therapeutic approach; but still, the production, isolation and packing them into nano-sized vesicles are challenging their use for drug delivery. The ability of exosomes to cross blood–brain barrier and cytoplasmic membranes makes it the most advantageous property as a therapeutic target molecules., They have a property of natural material carrier and transportation, long-term internal circulatory capability and excellent biocompatibility suitable for drug delivery including variety of chemicals, nucleic acids, genetic and protein therapeutic mediators. Experimental studies have found that the process of angiogenesis, cellular immunity and regenerative effects in cell-based therapy which is mediated through mesenchymal stem cells (MSCs) and other cells are executed by the exosomes released by these cells. Hence, exosomal-based cell therapy is proved to be a great potential in the field on oncology to regenerative medicine,, which provides the possibility of “cell-free cell therapy.”
Currently, the application of exosomes in clinical treatment can alienate into the subsequent areas. Direct aiming of exosomal therapy directly inhibits the synthesis and secretion of tumor-associated EVs by preventing absorption. EV-based immunization preparations, relating the separation and purification of autoimmune cell-derived EVs from patients with tumor and modification of antigen for delivering to the patient, can trigger the capability of the immune system to destroy tumor cells. Sometimes, patients may develop side effects with the use of aggressive measure, and thus, further clinical trials in larger number before exosomal cell-based therapy on patients in the future are required.
It is beneficial to use exosomes relating to cell-based procedures. This is because the exosomes are of nano size and can easily pass through capillaries when compared with MSCs which are large to pass through capillaries. The usage of exosomes evades complications associated with damaged or mutated DNA within the cells  Exosomes attain high dose than transplanted MSCs where their levels decrease after transplant. Exosomes may also be useful to confront toxicity and immunogenicity complications resulting from biomaterial therapies as nanoparticles. All these characteristics make them suitable for theranostic approach.
| Conclusion|| |
OSCC is the most prevalent oral cancer, which poses a challenge during diagnosis and treatment. Exosomes being a microvesicle, plays a significant role in cancer development, progression to different stages and as biomarkers in OSCC. Research related to these studies are going on. On the other hand, the ability of exosomes in drug delivery anticancer molecules for cancer treatment is also focused. This “all-in-one theranostic approach” has a huge potential in personalized medicine, as it permits the recognition and monitoring of a disease in early stages of individual patients, along with targeted drug delivery molecules at the site of the disease. Although the study of exosome application has made great advancement, many challenges still remain unanswered and need further investigation.
Pictures courtesy by Atlas of Science.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
Vigneswaran N, Williams MD. Epidemiologic trends in head and neck cancer and aids in diagnosis. Oral Maxillofac Surg Clin North Am 2014;26:123-41.
Adelstein DJ, Li Y, Adams GL, Wagner H Jr., Kish JA, Ensley JF, et al.
An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8.
Teh MT, Hutchison IL, Costea DE, Neppelberg E, Liavaag PG, Purdie K, et al.
Exploiting FOXM1-orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis. Int J Cancer 2013;132:2095-106.
Afghahi A, Sledge GW Jr. Targeted therapy for cancer in the genomic era. Cancer J 2015;21:294-8.
Mendes D, Alves C, Afonso N, Cardoso F, Passos-Coelho JL, Costa L, et al.
The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer – A systematic review. Breast Cancer Res 2015;17:140.
Hughes PE, Caenepeel S, Wu LC. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol 2016;37:462-76.
Hale JS, Li M, Lathia JD. The malignant social network: Cell-cell adhesion and communication in cancer stem cells. Cell Adh Migr 2012;6:346-55.
Brücher BL, Jamall IS. Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment. Cell Physiol Biochem 2014;34:213-43.
Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM. Exosome mediated communication within the tumor microenvironment. J Control Release 2015;219:278-94.
Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borrà s FE, Buzas EI, et al.
Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015;4:27066.
Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, et al.
Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 2011;71:5346-56.
Jia S, Zocco D, Samuels ML, Chou MF, Chammas R, Skog J, et al.
Emerging technologies in extracellular vesicle-based molecular diagnostics. Expert Rev Mol Diagn 2014;14:307-21.
Trams EG, Lauter CJ, Salem N
Jr. Heine U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta 1981;645:63-70.
Johnstone RM, Bianchini A, Teng K. Reticulocyte maturation and exosome release: Transferrin receptor containing exosomes shows multiple plasma membrane functions. Blood 1989;74:1844-51.
Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol 2014;29:116-25.
Sreekumar PG, Kannan R, Kitamura M, Spee C, Barron E, Ryan SJ, et al.
AB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells. PLoS One 2010;5:e12578.
Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014;30:255-89.
Mutschelknaus L, Peters C, Winkler K, Yentrapalli R, Heider T, Atkinson MJ, et al.
Exosomes derived from squamous head and neck cancer promote cell survival after ionizing radiation. PLoS One 2016;11:e0152213.
Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al.
B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183:1161-72.
Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al.
Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes. Nat Med 1998;4:594-600.
Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol 2018;6:18.
Tai YL, Chen KC, Hsieh JT, Shen TL. Exosomes in cancer development and clinical applications. Cancer Sci 2018;109:2364-74.
De Toro J, Herschlik L, Waldner C, Mongini C. Emerging roles of exosomes in normal and pathological conditions: New insights for diagnosis and therapeutic applications. Front Immunol 2015;6:203.
Brinton LT, Sloane HS, Kester M, Kelly KA. Formation and role of exosomes in cancer. Cell Mol Life Sci 2015;72:659-71.
Tkach M, Théry C. Communication by extracellular vesicles: Where we are and where we need to go. Cell 2016;164:1226-32.
Michael A, Bajracharya SD, Yuen PS, Zhou H, Star RA, Illei GG, et al.
Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis 2010;16:34-8.
Palanisamy V, Sharma S, Deshpande A, Zhou H, Gimzewski J, Wong DT. Nanostructural and transcriptomic analyses of human saliva derived exosomes. PLoS One 2010;5:e8577.
Keller S, Rupp C, Stoeck A, Runz S, Fogel M, Lugert S, et al.
CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int 2007;72:1095-102.
Zlotogorski-Hurvitz A, Dayan D, Chaushu G, Salo T, Vered M. Morphological and molecular features of oral fluid-derived exosomes: Oral cancer patients versus healthy individuals. J Cancer Res Clin Oncol 2016;142:101-10.
Li L, Li C, Wang S, Wang Z, Jiang J, Wang W, et al.
Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res 2016;76:1770-80.
EL Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: Biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013;12:347-57.
Hood JL, Wickline SA. A systematic approach to exosome-based translational nanomedicine. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2012;4:458-67.
Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 2012;1820:940-8.
Liu C, Su C. Design strategies and application progress of therapeutic exosomes. Theranostics 2019;9:1015-28.
Baglio SR, Pegtel DM, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol 2012;3:359.
Barile L, Lionetti V, Cervio E, Matteucci M, Gherghiceanu M, Popescu LM, et al.
Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res 2014;103:530-41.
Campos JH, Soares RP, Ribeiro K, Andrade AC, Batista WL, Torrecilhas AC. Extracellular vesicles: Role in inflammatory responses and potential uses in vaccination in cancer and infectious diseases. J Immunol Res 2015;2015:832057.
Marote A, Teixeira FG, Mendes-Pinheiro B, Salgado AJ. MSCs-derived exosomes: Cell-secreted nanovesicles with regenerative potential. Front Pharmacol 2016;7:231.
Teixeira FG, Carvalho MM, Sousa N, Salgado AJ. Mesenchymal stem cells secretome: A new paradigm for central nervous system regeneration? Cell Mol Life Sci 2013;70:3871-82.
Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells 2017;35:851-8.