Medical

Communication

Biosci. Biotech. Res. Comm. 11(3): 347-355 (2018)

The central roles of exosomesin hematological

malignancies: A new frontier review

Bing Xia

*, Mengzhen Li

Ruifang Yang

, Xi Wang

, Chengtao Shun

and Yizhuo Zhang*

1,3

Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical

Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical

Research Center for Cancer; 300060, China

Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital,National

Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s

Clinical Research Center for Cancer; 300060,China

Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology

in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China

ABSTRACT

Exosomes, which are 30- to 120-nm vesicles, are released by most types of cells, including tumor cells. In hemato-

logical malignancies, exosome-mediated expulsion of a number of key proteins and micro RNAs, resulting in in u-

ence of major tumor-related pathways. Emerging evidence suggests that the component secreted by exosomescan

promote tumor survival,angiogenesis and metastasis, and also mediate tumor microenvironment induced drug resist-

ance and immune escape. Furthermore, exosomes contain a great variety of bioactive molecules andare emerging

as rich reservoirs of hematological tumor-speci c biomarkers for the detection and therapeutics.This comprehensive

review highlights the advancements in understanding of the pathogenesis of exosomes secretion and the consequence

onhematological malignancies development. Full knowledge of the contribution of exosomes to the potential medi-

cal application ofdiagnosis and treatment will depend on the ingenuity of future investigators and their insight into

biological processes.

KEY WORDS: HEMATOLOGICAL MALIGNANCIES; EXOSOMES; DISEASE DEVELOPMENT;DIAGNOSIS; TREATMENT

347

ARTICLE INFORMATION:

*Corresponding Authors: forxiabing@163.com, Bing Xia and

Yizhuo Zhang

Received 12

July, 2018

Accepted after revision 19

Sep, 2018

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007 CODEN: USA BBRCBA

Thomson Reuters ISI ESC / Clarivate Analytics USA and

Crossref Indexed Journal

NAAS Journal Score 2018: 4.31 SJIF 2017: 4.196

Online Contents Available at: http//www.bbrc.in/

DOI: 10.21786/bbrc/11.3/1

348 THE CENTRAL ROLES OF EXOSOMESIN HEMATOLOGICAL MALIGNANCIES BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Bing Xia etal.

INTRODUCTION

Hematological malignancies, which include lymphoid,

myeloid, histiocytic, and mast cell neoplasms, are a hetero-

geneous group of diseases of diverse incidence, pathogen-

esis and prognosis (Kornblau etal., 1998). The prognosis

of hematological malignancies patients diverges greatly,

largely depending on thepathological types of the patient

(Li et al., 2016). Nonetheless, enhancing understanding

of tumorigenesis mechanism is critical for development

of novel diagnosis and therapeutic strategy. Exosomes

are a kind of extracellular vesicles (EVs), which was  rst

reported by Pan and Johnstone in 1983 as unwanted cel-

lular components extruding from reticulocytes. EVs are

medium-sized vesicles, ranging from 30 to 120 nm and

are secreted by different cell types under both physi-

ological and pathological conditions. Exosomes are rich

in cholesterol, sphingomyelin, ceramide lipids, protein,

mRNA, miRNA, and various other signaling molecules

from donor cell. In addition, CD9, CD63, and CD81 are

most frequently detected and are considered asthe classic

markers of exosomes, (

Malla etal., 2018).

Then, the MVB’s can either fuse with lysosomes result-

ing in degradation of intra-luminal contents or they can

secrete their content as exosomes outside the donor cells.

Furthermore, there are several ways by which exosomes

are taken up by recipient cells: receptor- or lipiddraft-

mediated endocytosis, phagocytosis, macropinocytosis,

or fusion with the plasma membrane of a target cell, For

transportation, exosomes mainly originate from multi-

vesicular bodies (MVB’s) in the cells which are produced

by the invagination of endosomal limiting membrane

(Pfrieger etal., 2018).

Recently, it has been reported by many workers that

the potential functions of exosomes contributed to vari-

ous aspects of hematological tumorigenesis, particularly

with a focus on the exosome-mediated tumor progression,

metastasis, drug resistance and immune escape by alter-

ing the function of receiver cells via diverse exosomal car-

goes including proteins, DNA, messenger RNAs (mRNAs),

and microRNAs ) (Whiteside and Boyiadzis, (2017). Fur-

thermore, exosomes are found in most biological ﬂuids

including urine, blood, ascites, saliva and cerebrospinal

ﬂuid, which can be made for very attractive targets for

diagnostic application.Although the known information is

limited, exosomes have been reported to play an emerging

role in various aspects of the tumor survival, metastasis,

drug resistance, and immune escape of hematologic tumor.

In this review, we will focus speci cally on the effects of

exosomes on tumorigenesis, diagnosis and treatment of

hematological malignanciesand the relevantnew prospects.

THE ROLE OF EXOSOMES IN DEVELOPMENT

OF HEMATOLOGICAL MALIGNANCIES

Recently, considerable amount of studies have revealed

that exosomes were secreted by tumor cells or tumor micro-

environment cells and cross-talk in uence tumor prolifera-

tion, angiogenesis, drug resistance and immune escape of

several hematological cell types ( gure1) (Sun, etal., 2018).

FIGURE 1. Biogenesis, transportation and composition of exosome, and the possible communication

mechanism between donor cells and targetcells. Diagram depicting the well-accepted model for exo-

some biogenesis. Exosomes secreted by donor cells included release, shedding, transporter-mediated

release and apoptotic body formation. Receptor cells receive exosomes including endocytosis, phago-

cytosis, fusion and receptor-mediated uptake.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS THE CENTRAL ROLES OF EXOSOMESIN HEMATOLOGICAL MALIGNANCIES 349

Bing Xia etal.

Survival and proliferation

One study demonstrated that the level of sera-derived

exosomes in acute myeloid leukemia (AML) patients

are higher than sera-derived exosomes from healthy

controls

[Hong etal., 2014] and the exosomes secreted

by AML cells express higher level of mRNA, such as

GATA1, FOX3, SHIP1, ID1, E2F1, CEBP-, CEBP-, Myc

and MEF2C, which are the group of transcripts of genes

to the development of AML

[Huan J. etal., 2013]. Fur-

thermore, another study showed that levels of active

TGF-1 carried by exosomes obtained at AML diag-

nosis were high and then decreased following induc-

tion chemotherapy. In addition, in long-term remis-

sion of AML patients, TGF-1 levels in plasma-derived

exosomes approach the same levels seen in exosomes

of normal controls. The results indicate that exosomal

protein and TGF-1 levels in AML plasma could serve

as biomarkers of response to chemotherapy.These data

showed that both AML cell lines and primary AML blasts

released exosomes relevant to AML pathogenesis (Huan

etal., 2013 and Long etal., 2017).

For chronic myelocytic leukemia ( CML), CML cell

line LAMA84-derived exosomes increase levels of IL-8

mRNA and protein in HS-5 (bone marrow stromal

cell line), and further promote HS-5 induced CML cell

proliferation , (Zhou et al., 2012) . In another way, the

exosomes also reduce expression of the proapoptotic

genes BAD, BAX and PUMA and increase expression of

anti-apoptotic genes BCL-xL, BCL-w, and BIRC5.Moreo-

ver, exosomes also activate the PI3/AKT and MAPK/ERK

signaling pathways. Collectively, the exosomes secreted

by CML cells both educate the tumor microenvironment

cells and directly affected the proliferation and apopto-

sis of LAMA84 cells and  nally promote the CML cells

survival. Human T-lymphotropic virus type 1 ( HTLV1)

infected T cells release exosomes that contain viral Tax

protein and Tax, HBV, and EBV mRNA, which increase

levels of phosphorylated AKT and active NF-kB path-

way, and further facilitate T-cell tumor cells survival.

These results suggest that the exosomes released from

HTLV-1-infected cells play key role in the pathogene-

sis of T-cell leukemia (Jaworski etal., 2014, Raimondo

etal., 2015).

The study by Raphael Koch shows that diffuse large

B-cell lymphoma (DLBCL) possess a self-organized infra-

structure comprising side population (SP) and non-SP

cells, where transitions between clonogenic states are-

modulated by exosomes mediated Wnt signaling. Lym-

phoma SP cells exhibit autonomous clonogenicity and

export Wnt3a via exosomes to neighboring cells, thus

modulating population equilibrium in the tumor (Koch

etal., 2014). The study about the role in MCL observes

that MCL exosomes are taken up rapidly and preferen-

tially by MCL cells. Only a minor fraction of exosomes

was internalized into T-cell leukemia and bone mar-

row stroma cell lines, when these cells werecocultured

with MCL cells. Moreover, MCL patients’ exosomes were

taken up by both healthy and patients’ B-lymphocytes

with no apparent internalization to T lymphocytes and

NK cells. Exosome internalization was not inhibited by

speci c siRNA against caveolin1 and clathrin but was

found to be mediated by a cholesterol-dependent path-

way. These  ndings demonstrate natural speci city of

exosomes to B-lymphocytes and ultimately might be

used for therapeutic intervention in B cells malignan-

cies, (Hazan etal., 2015).

EBV infection of B cells in vitro induces the release

of exosomes that harbor the viral latent membrane pro-

tein 1 (LMP1). LMP1 via exosomes actives CD40 sign-

aling and induces proliferation of B lymphocytes and

T cell independent class-switch recombination.Finally,

LMP1 drove B cell differentiation toward a plasmab-

last-like phenotype. In conclusion, the results suggest

that exosomes released by EBV-infected lymphoma

cells include the production of the activation-induced

cytidine deaminase (AID), and further promote tumor

cells aggressive and progression, ( Nanbo etal., 2013).

In addition, Chugh etal. (2013) reported that exosomes

derived from patients with KSHV-associated malignan-

cies and KSHV mouse modelscontained KSHV encoded

microRNAs such as miR-17-92 cluster, which are affect

the targets of KSHV signaling pathways that may there-

fore be part of the paracrine signaling mechanism that

mediates KSHV pathogenesis.

A research about relationship between MSC and

plasma cells demonstrated that the tumor-supportiverole

of BMSC-derived exosomes: Compared with normal mes-

enchymal stem cells, BMSC-derived exosomes in MMex-

presslower level of microRNA15a and microRNA15a

isa tumor-suppress factor thatcontributeto MM disease

progression. In addition, BMSC-derived exosomes in

MM expresshigher content levels  bronectin, indicat-

ing that BM-MSC-derived exosomes may differentially

impact MM cell adhesion , (Roccaro etal., 2013). Kim De

Veirman etal. (2016) showed that miRNA-146a in MM-

derived exosomes can be transmitted into mesenchymal

stem cells, resulting in induction of expression for some

cytokines and chemokines including CXCL1, IL6, IL-8,

IP10, MCP-1, and CCL-5, thus lead to increasing vitality

and progression of MM cells.

Angiogenesis and metastasis:Exosomes have been

increasingly recognized as a new mediator for angio-

genesis and metastasis of hematological malignancies.

For example, Umezu etal.(2013) showed that leukemia

cells K562 released the exosomal miRNAs, such as miR-

17-92 cluster, especially miR-92a, into human umbili-

cal vein endothelial cells (HUVECs) ,and target reduced

the expression of integrin 5 in HUVECs by exosomal

Bing Xia etal.

350 THE CENTRAL ROLES OF EXOSOMESIN HEMATOLOGICAL MALIGNANCIES BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

miR-92a, indicating that exogenous miRNA via exo-

somal transport can function like endogenous miRNA

in HUVECs, which enhance endothelial cell migration

and tube formation. In the study, which investigated

the angiogenic role of exosomes produced by acute

promyelocytic leukemia cells NB4.PML-R ARA tran-

script has been detected in NB4 exosomes and taken

up by endothelial cells, resulting in decreasing the lev-

els of VEGF and tissue factor (TF) through increasing

IL-8 mRNA and protein content in their EVs, renders

the HUVECs more TF-positive and procoagulant, (Fang

etal., 2016).

A recent study by Hiroko Tadokoro etal. has clearly

demonstrated that hypoxia promotes the release of

exosomes in K562 cells,the amount of exosomal miR-

210, which down-regulated EFNA3, an inhibitor of

angiogenesis , (Tadokoro etal., 2013). The results suggest

that exosomal miRNA derived from cancer cells under

hypoxic conditions may partly affect angiogenic activ-

ity in endothelial cells. Paggetti etal. found that CLL-

derived exosomes are actively incorporated by endothe-

lial and mesenchymal stem cells ex vivo and in vivo

and that the transfer of exosomal protein and microRNA

induces an in ammatory phenotype in the target cells,

which resembles the phenotype of cancer-associated

 broblasts (CAFs), (Paggetti etal., 2015).

Exosomeswere uptakenby endothelial cells increased

angiogenesis ex vivo and in vivo, and coinjection of

CLL-derived exosomes and CLL cells promoted tumor

growth in immunode cient mice. These  ndings dem-

onstrate that CLL-derived exosomes actively promote

disease progression by modulating several functions

of surrounding stromal cells that acquire features of

cancer-associated  broblasts, (Paggetti et al., 2015).

Another similar study found that EBV-positive Burkitt’s

lymphoma cells Raji released exosomes with miR-155

inducing angiogenesis in remote recipient cells, whereas

no major difference was found in co-culture with EBV-

negative Burkitt’s lymphoma cells, (Yoon etal., 2016).

Thus, it would be reasonable to believe that speci c

viral exosomal microRNAs contribute to angiogenesis

of vascular endothelial cells, subsequently leading to

pathophysiologic angiogenesis. In accord with a study

by Umezu etal. (2014), miRNA-135b from MM-derived

exosomes accelerated HIF-1 transcriptional activity via

inhibition of FIH-1, which is called the HIF-FIH signal-

ing pathway, exertinganangiogenesis in uence . Collec-

tively, these results suggest that hematological malig-

nancy cells release exosomes that could promote tumor

metastasis and the formation of pre-metastatic niches

to create a microenvironment favorable to survival and

proliferation of tumor cells themselves.

Drug resistance: Like many other tumors, increasing

evidences also revealed that the tumor microenvironment

( TME) has crucial impact on hematological malignancies

initiation and progression (Rizzo etal., 2011). Given the

central role of exosomes in cellular communication, it

is undoubtable that exosomes also contribute to micro-

environment-induced drug resistance. One intuitive

mechanism involving exosomes would be the sequestra-

tion of cytotoxic drugs in the intracellular vesicles and

subsequent expulsion, to negate drug effect within the

cells. Notably, emerging evidence suggests that both the

exosomes released from TME cells and the tumor cells

themselves help the hematological malignancy cells to

resist chemotherapy, (Isidori etal., 2014). One prominent

example, exosomes from both AML-BMSC and healthy

controls protect MOLM-14 FLT3 internal tandem dupli-

cation (FLT3-ITD+) AML cells from cytarabine and stro-

mal exosomes alter chemo-resistance in AML cells. Fur-

ther, only AML-BMSC exosomes signi cantly protected

AML cells from the FLT3 inhibitor AC220 after exposure.

The protection might be associated with elevated level

of miRNA-155, miRNA-375, cytokine epidermal growth

factor (EGF) and TGF-1 (Viola etal., 2016).

Finally, these data imply a few novel approaches to

overcome drug resistance on AML blasts by either block-

ing exosome-leukemia cell communication, or inhibiting

tumor microenvironment exosome production. Moreo-

ver, several studies unveiled that galectin-3 was upregu-

lated and stabilized anti-apoptotic Bcl-2 family proteins

in survival leukemia cells, which facilitates escape from

apoptotic stimuli through activation of Wnt/-Catenin

signaling pathway and the PI3K/Akt pathway, (Cheng

etal., 2011, Hu K. etal., 2015).

In another study about lymphoma, the results revealed

that high levels of adenosine triphosphate (ATP)-binding

cassette (ABC) transporter A3 (ABCA3) were related to

drug resistance, especially by drug expulsion which

might be modulated by microparticles (Chapuy et al.,

2008, Steinbach, et al., 2006). Oksvold et al. (2014)

showed a similar observation that exosomes secreted

by B-cell lymphoma reduced rituximab-induced cyto-

toxicity. These studies indicated a novel mechanism

of drug resistance in lymphoma, which is linked to an

ABCA3-dependent pathway of exosome secretion, (Oks-

vold et al., 2014). In particular, it was suggested that

increased expression of cellular galectin-3 and elevated

concentration of galectin-3 in circulating system may

contribute to tumor progression and drug resistance.

Regarding ALL, the levels of exosomal Gal-3 mRNA and

protein, which originated from stromal cells in B-ALL

were in relation with the appearance of drug-resistance

through activated MEK/ERK pathway, (Fortuna et al.,

2014). Galectin-3 is enriched in OP9 exosomes, and exo-

somal galectin-3 can be internalized by ALL cells, and

activates NFB signaling pathway, whichisoften linked

to anti-apoptosis and drug resistance (Hu etal., 2015).

Bing Xia etal.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS THE CENTRAL ROLES OF EXOSOMESIN HEMATOLOGICAL MALIGNANCIES 351

Another study showed that exosomal evasion of

humoral immunotherapy in aggressive B-cell lymphoma

wasmodulated by ATP-binding cassette transporter

A3. B-cell lymphoma cells released exosomes that car-

ried CD20, bound therapeutic anti-CD20 antibodies,

consumed complement, thereby impairing antibody-

dependent cell mediated cytotoxicity (ADCC) and pro-

tected target cells from antibody attack through linked

in an ABCA3-dependent pathway of exosome secretion.

Additionally, removing exosomes from plasma samples

of B-NHL resulted in considerable improvements in

the effect of rituximab against lymphoma cell in vitro,

(Aung etal., 2011). In multiple myeloma, the integrin-

mediated interaction of cancer cells with MSC, upregu-

lates the secretion of soluble factors such as IGF-1, FGF,

IL-6 and others that provide growth advantage and drug

resistance to multiple myeloma cells (Isidori etal., 2014,

Greco etal., 2009).

Another study by Wang etal. (2014) indicated that

bone marrow stromal cell–derived exosomes in MM can

promote proliferation, migration, and survival of MM

cells, andcan also induce chemotherapy drug resistance

to bortezomib, in uencing several pathways including

c-Jun N-terminal kinase, p38, p53, and Akt which are

relevant to survival of MM cells.All these studies suggest

that exosome mediate drug resistance through both the

direct shuttling of drugs out of the cells and the horizon-

tal transfer of molecules/molecular signals that bestow

drug resistance to the otherwise sensitive cells.

Immune escape: Hematological malignancy cells can

evade host immune surveillance, a well-known phenom-

enon called as immune evasion or immune escape, which

is also a hallmark of tumor. Many research groups have

demonstrated abundant quantity of exosomes released

by tumor cells exerting an immunosuppressive effect

that helps them evade immune response. Dysfunctions

of natural killer (NK) cells, which are a major component

of the anti-tumor immune response, have been reported

in various hematologic malignancies, including chronic

lymphocytic leukemia (CLL). BAG6, which issecreted by

tumor cell, activate receptor NKp30 on the surface of NK

cells, further increase NK cell cytotoxicity and promote

NK cells to kill cancer cells , and is suggested that down-

regulated or absent of exosomal BAG6 in CLL patients

evasion of CLL cells from NK cell anti-tumor activity,

(Reiners etal., 2013).

TGF-1 is a potent immunosuppressive molecule that

inhibits NK cell cytotoxicity. The serum concentration

of exsomal TGF-1 in the newly diagnosed AMLwas-

signi cantly higher than that of the normal control.

Furthermore, NK cell differentiation is IL-15 dependent,

and IL-15 plays a major role in NK-cell expansion and

promotes NK-cell survival, IL-15 is also able to counter-

act immunosuppressive effects mediated by TGF- car-

ried on exosomes from AML patients. Taken together,

these evidence suggest IL-15 can enhance anti-tumor

effects of NK cells in AML patient s, (Greco etal., 2009,

Hong et al., 2014). In virus-related lymphomas, EBV+

lymphoma cells are embedded in non-neoplastic by

standers: B and T cells, macrophages. There is increasing

evidence that the indirect actions (i.e. immunosuppres-

sion and TME components) of different viruses also play

signi cant roles in lymphomagenesis, (Esau, 2017).

For example, EBV and HIV-1 are proved capable

of inducing the overexpression of PD-L1 on antigen-

presenting cells, thus resulting in immunosuppression

by the increased apoptosis of T cells . Furthermore, the

EBV-miRNAs in the exosome secreted from EBV posi-

tive lymphoma cells were transferred to macrophage and

promote the development of lymphoproliferative disease

(LPD) in vivo mouse model, (Lichterfeld et al., 2008).

Another study showed that the exosomes present in the

serum of CHB patients contain both HBV nucleic acids

and HBV proteins, HBV might in uence NK-cell func-

tion via exosomes through upregulating immunosup-

pressive factors, such as TGF-, in HBV-infected CHB

patients. These observations suggest that exosomes may

serve as important regulators of HBV transmission and

may be involved in escaping innate immunity.

THE ROLE OF EXOSOMES IN DIAGNOSIS

AND PROGNOSIS OF HEMATOLOGICAL

MALIGNANCIES

Early cancer detection and disease strati cation or clas-

si cation are critical to successful treatment. Accessible,

reliable, and informative hematological malignancies

biomarkers can be medically valuable and can provide

some relevant insights into cancer biology [Elsherbini

and Bieberich., 2018]. Early detection of cancer could

be easily performed using exosomes isolated from body

 uids such as blood plasma, serum, and urine, which

is allowing for a non-invasive method of detection of

hematological malignancies, (Kang etal., 2018).

Microvesicles are found in higher concentrations in

the sera of different types of hematological malignan-

cies, such as AML, AL L, CML, CLL, diffuse large B‐cell

lymphoma ( DLBCL), Hodgkin’s lymphoma (HL) and MM

patients and abundantly express surface proteins unique

to their cell of origin, which is rarely observed from serum

microvesicles of normal controls [Kang etal., 2018]. AML

biomarkers NPM1, FLT3, CXCR4, MMP9 and IGF-IR are

also present in AML cell derived exosomes, along with

mRNAs involved in leukemia development(Boyiadzis,

2016). Hong. etal (2014). indicated that exosomal TGF-

1 levels and relative levels of the three TGF-1 forms

(TGF-1 pro-peptide, latency-associated peptide (LAP),

and mature TGF-1 were distinct in AML patients in

Bing Xia etal.

352 THE CENTRAL ROLES OF EXOSOMESIN HEMATOLOGICAL MALIGNANCIES BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Table 1. The role of exosome in the development of hematologic tumor.

Targets Type Disease Function Reference

TGF-1 MICA,

MICB,ULBP1,ULBP2,

BAG6

protein AML Reduce the ability of

natural killer (NK)

cells to kill leukemic

cells.

Cheng etal., 2011

Jaworski etal., 2014

GATA1, FOX3, SHIP1,

ID1, E2F1, CEBP-,

CEBP-, Myc, MEF2C

protein AML Induce development

of leukemia.

Malla etal., 2018.

PI3/AKT,MAPK/ERK,

NF-kB,TGF-1

protein CML Enhance cell survival

of LAMA84 cell

Sun etal., 2017

Tax, AKT, Rb, cFLIP,

NF-kB

ATL Enhance cell survival

in murine and human

T-cell cell lines.

Hong etal., 2014

Galectin-3, NF-kB protein ALL Promote ALL drug

resistance.

Hong etal., 2014

SRC, TSP-1, IL-8 protein CML Promotes endothelial

cell angiogenesis.

Nanbo etal., 2013

MiR-210 microRNA CML Promote the vascular

activity of CML.

Nanbo etal., 2013

Wnt3a protein DLBCL Promote the growth of

DLBCL cells.

Huan etal., 2014

IL-6, CCL2,

 bronectin

protein MM Promote the growth of

MM cells.

Raimondo etal., 2015

miR-135b microRNA MM Promoteendothelial

vessel formation.

De etal., 2016

miR-34a, miR-125b- 5p,

miR-146a, miR-15a, miR

-137/197, miR- 21

microRNA MM Facilitate multiple

myeloma growth and

progression

Nanbo etal., 2013

Jaworski etal., 2014

AML: acute myeloid leukemia; CML: chronic myelocytic leukemia; ATL: T-cell acute lymphoblastic leukemia; ALL:

acute lymphoblastic leukemia; DLBCL: diffuse large B-cell lymphoma; MM: multiple myeloma

Table 2. Circulating vesicles as a general hematological malignancies biomarker.

Biomarker Type Source

Hematological

Malignancies

Reference

NPM1, FLT3, CXCR4, MMP9

and IGF-IR

protein serum

AML

Wang etal., 2014

MiR-92a MicroRNA serum ALL Hong etal., 2014

TGF-1 protein serum AML Reiners etal., 2014

miR155 MicroRNA serum

AML, CLL, WM,

MDS, MM

Elsherbini &

Bieberich 2018

Src protein serum CML Hong etal., 2014

MiR-155, MiR-210, MiR-21 MicroRNA serum DLBCL Rekker etal., 2014

MiR-22 MicroRNA plasma HL Caviano etal., 2014

MiR-15a, let-7b miR-18a,

MicroRNA plasma MM Caviano etal., 2014

AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; CLL: chronic lymphocytic leukemia; WM:

macroglobulinemia of Waldenstrom; MDS: myelodysplastic syndrome; MM: multiple myeloma; CML: chronic

myelocytic leukemia; DLBCL: diffuse large B-cell lymphoma; HL: Hodgkin’s lymphoma.

different stages of chemotherapy[Hong C.S. etal., 2014].

This stability makes exosomes as suitable mines for

hunting reproducible and consistent biomarkers. ALL-

associated expression of miRNA92a can be detected in

the circulating vesicles of a majority of ALL patients

(Rekker K. etal., 2014)

In CML, Mineo etal. (2012), showed that a co-evolu-

tion between endothelial cells and CML cells are essential

Bing Xia etal.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS THE CENTRAL ROLES OF EXOSOMESIN HEMATOLOGICAL MALIGNANCIES 353

for leukemia progression and resistance to therapy. This

is possible because of the fact that K562 malignant cells

secret growth factors and various miRNAs and transport

these ‘endothelial inducing factors’ via exosomes. As a

result, tube formation is stimulated, even when treating

with imatinib, a tyrosine kinase inhibitor that targets the

Philadelphia chromosome-positive (Ph+) myeloid leuke-

mia cells. In this case, the development of angiogenesis

was reported to regulate the progression and dissemina-

tion of this hematological malignancy, (Wojtuszkiewicz

etal., 2016 Caivano etal., 2017).

Parikh etal. (2016) found the EV miR155 level may

serve as a promising prognostic/predictive biomarker in

CLL, independent of clinical stage . In conjunction with

the previously reported data, Caivano etal. (2017) found

that the EV miR155 levels were signi cantly higher in

CLL, AML and Waldenström’smacroglobulinemia (WM)

cases compared to controls (Parikh et al., 2016, Zhu

et al., 2018). Conversely, they also found that the EV

miR155 levels were signi cantly lower in myelodys-

plastic syndrome (MDS) and MM cases, (Caivano etal.,

2017). In addition, they found that high EV miR155 lev-

els correlated with high white blood cell counts in AML

patients. In conclusion, this study indicated that EV

miR155 may serve as an attractive new, non-invasive

diagnostic biomarker in human hematologic malignan-

cies. Levels of exosomal miR-155, miR-210 and miR-21

in serum from DLBCL patients (n=60) were higher than

control sera (n=43)(P=0.009), (Mineo etal. 2012).

Monique et al. found that EV-associated miR21-5p,

miR127-3p, let7a-5p, miR24-3p, and miR155-5p signals

were higher in primary and relapsed classic Hodgkin’s

lymphoma (cHL) patients compared with healthy indi-

viduals [van Eijndhoven M.A. etal., 2016]. However, they

also detected that miR21-5p and miR155-5p is small,

but signifcant, decreases (2-fold, P = 0.016) in plasma

after therapy. Nevertheless, the decrease in miR155-5p

was more pronounced in the EV fraction, (4-fold, P =

0.016). They detected high levels of miR127-3p in EVs

produced by HRS cells in plasma EVs of cHL patients but

less abundant levels in healthy control EVs, which sug-

gests that the pool of miR127-3p detected in the protein

fraction is unrelated to cHL tumor tissue and is derived

from other sources [van Eijndhoven M.A., etal., 2016].

miR-15a is lower in mesenchymal stromal cells derived

vesicles of MM patients compared with healthy subject,

and miRNA-rich exosomes secreted from MM-mesen-

chymal stromal cells facilitate MM progression , (Manier

etal., 2017).

Lower expression of let-7b or miR-18a was signi -

cantly associated with a high ISS stage. However, both

let-7b and miR-18a were independent predictors after

adjusting for the ISS and speci c cytogenetic abnormal-

ities. The effect of the two miRNAs on PFS and OS was

illustrated by Kaplan-Meier curves with dichotomized

miRNAs at the median [Manier S. etal., 2017]. These data

indicate that speci c miRNAs can be critical in de n-

ing worse prognosis in patients with newly diagnosed

MM. Nevertheless, to establish circulating exosomes as

biomarkers, well-designed clinical trials are required. So

far, there is no trial registered that is relevant to hema-

tology and investigates circulating exosomes as a pre-

dictive marker in hematological malignancies. Exosomes

are currently viewed as tumor cell surrogates or ‘liquid

biopsies’ and as a promising non-invasive metrics of

cancer. Exosomes might emerge as the most informative

non-invasive predictors of cancer outcome orresponse

to therapy.

EXOSOME-BASED HEMATOLOGIC

MALIGNANCIESTHERAPEUTICS

Exosome-based therapies serve as attractive strategy

against hematologic malignancies and solid tumors.

Exosome-based delivery methods have been tested in

the clinic successfully and were found to be well toler-

ated in patients. Being autologously generated within

the host, they can be engineered to carry drugs or tar-

get proteins without invoking immunogenic response.

A number of different strategies have been applied to

harness the potential of these exosomes. Nano injections

of RNAi in dendritic-derived exosomes allowed delivery

to the brain without invoking immune response. These

 ndings were con rmed when Gurwitz et al. showed

that siRNAs can be delivered across the blood brain

barrier in a mouse model using systemic injections of

exosomes , (Gurwitz, 2016).

In another study, tumor-derived exosome-pulsed DCs,

tumor-derived exosomes, and exosomes isolated from

malignant ascites all have been investigated for their

ability to elicit antitumor immune response in patients,

(Liu et al., 2018). Likewise, their ef cacy on exosome

release or against exosomes has also been tested in dif-

ferent laboratories independently. These are some of the

studies highlighting the bene t of applying nanobased

assays in the design of exosomes drug therapies for

cancer. However, its clinical utility needs to be tested

in future studies. At present, there are several clini-

cal studies that utilize an exosome-based regimen for

solid tumors, (Que etal., 2016), but there is no clinical

trial about exosome-based agents against hematologic

malignancies ( ClinicalTrials.gov Website keyword search

exosome). These studies clearly point to an unexplored

area of research where researchers can  nd answers to

some of the unexplained mechanisms attributed to the

multifaceted natural agents against hematologic malig-

nancies. Altogether, exosomes have multiple potential

clinical uses including the development of vaccines for

Bing Xia etal.

354 THE CENTRAL ROLES OF EXOSOMESIN HEMATOLOGICAL MALIGNANCIES BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

targeting tumors; also, tumor-derived exosomes may be

useful as surrogate endpoints in evaluating therapeutic

and preventive approaches to hematological tumors.

CONCLUSIONS

Success in diagnosis and treatment of complex hema-

tological malignancies is dependent on our full under-

standing of the intricacies of interactions between dif-

ferent components within tumors. On the one hand, a

number of studies showed exosomes are emerging as

major players in inter- and intracellular communica-

tions. Exosomes have been shown to secrete diverse

biological molecules, which are in the context of tumor

cells survival, metastasis, drug resistance and immune

evasion. On the other hand, tumor relevant exosomes

play the important role in the areas of diagnostics and

drug therapy, regenerative medicine, and vaccines.

Taken together, technology and biology will inevitably

pave the way for the future use of exosomes analysis in

many preclinical research and clinical applications.

FUNDING

This work was supported by grants 81600163 and

81570201 from the National Natural Science Foundation

of China (NSFC) and Shandong Provincial Natural Sci-

ence Foundation (ZR2017PH057).

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