O Papel do Lactobacillus no Câncer Cervical

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Cancer Management and Research 2018:10 1219–1229
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Open Access Full Text Article
http://dx.doi.org/10.2147/CMAR.S165228
Role of Lactobacillus in cervical cancer
Xi Yang1 
Miao Da2 
Wenyuan Zhang3 
Quan Qi4 
Chun Zhang5 
Shuwen Han4
1Department of Intervention and 
Radiotherapy, Huzhou Central 
Hospital, 2Medical College of Nursing, 
Huzhou University, 3Department of 
Gynaecology, 4Department of Medical 
Oncology, 5Department of Infectious 
Diseases, Huzhou Central Hospital, 
Huzhou, Zhejiang Province, People’s 
Republic of China
Abstract: Cervical cancer is a common malignant cancer among women worldwide. Changes 
in the vaginal microecological environment lead to multiple gynecological diseases, including 
cervical cancer. Recent research has shown that Lactobacillus may play an important role in the 
occurrence and development of cervical cancer. This review explores the role of Lactobacillus 
in cervical cancer. A total of 29 articles were included after identification and screening. The 
pertinent literature on Lactobacillus in cervical cancer from two perspectives, including clinical 
studies and experimental studies, was analyzed. An association network for the mechanism by 
which Lactobacillus induces cervical cancer was constructed. In addition, we provide direction 
and insight for further research on the role of Lactobacillus in cervical cancer.
Keywords: CIN, cervical cancer, Lactobacillus, microorganism
Introduction
Cervical cancer is the third most commonly diagnosed cancer and the fourth leading 
cause of cancer-related deaths among women worldwide.1,2 Epidemiological investiga-
tions have shown that the number of new cases of cervical cancer per year is ~485,000, 
with 236,000 deaths occurring per year globally.3 Patients with cervical cancer often 
exhibit no obvious symptoms and signs at early stages; thus, the disease tends to be 
ignored and is easily misdiagnosed. Cervical cytologic screening has generally been 
used to detect cervical cancer and premalignant lesions over the past decade, and early 
diagnosis and appropriate treatment reduce the risk of cancer-related death.4
Current research has shown that microorganisms may play an important role in the 
occurrence and development of cervical cancer.5 Persistent infection with high-risk 
human papillomavirus (HR-HPV) is now believed to be a major causal factor in the 
development of the disease.6 The bacteria in the vagina maintain a dynamic balance 
under physiological conditions, but the imbalance of vaginal flora leads to multiple 
gynecological diseases, such as coleitis, high-grade cervical intraepithelial neoplasia 
(CIN), and cervical cancer.7 It has been confirmed that Gardnerella and Monilia are the 
main bacteria that induce coleitis.8,9 Previous research has shown that the abundance 
of vaginal flora such as Mycoplasma genitalium,10 aerobic lactobacilli, Staphylococcus 
epidermidis, Enterococci, Escherichia coli, and Bacteriodes species11 in patients with 
cervical cancer is different from that in healthy controls. However, the relationship 
between vaginal flora and cervical cancer has not yet been elucidated.
Lactobacillus is a group of bacteria that can act as a catalyst to produce lactic 
acid during the process of glycolysis.12 This group is the predominant bacteria in the 
healthy vagina and plays an important role in the protection of the female reproduction 
Correspondence: Shuwen Han 
Department of Medical Oncology, 
Huzhou Central Hospital, No 198 Hongqi 
Road, Huzhou, Zhejiang Province 313000, 
People’s Republic of China 
Tel +86 572 202 3301 
Email shuwenhan985@163.com
Journal name: Cancer Management and Research
Article Designation: REVIEW
Year: 2018
Volume: 10
Running head verso: Yang et al
Running head recto: Role of Lactobacillus in cervical cancer
DOI: http://dx.doi.org/10.2147/CMAR.S165228
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Yang et al
system.13 Summarizing previous studies, Lactobacillus in 
the vagina exerts its protective functions mainly through 
the following four potential mechanisms: 1) By preventing 
pathogenic bacteria from adhering to the epithelial tissue: 
vaginal epithelial cells (VECs) of fertile woman encounter 
periodic changes including hyperplasia, peeling, and repair 
under the effect of estrogen and progestin. Free glycogen that 
is produced during this process supplies matter and energy 
for the growth of Lactobacillus. Lactobacillus is adsorbed 
and occupies the VECs, and these bacteria can prevent the 
conglutination of invasive pathogenic bacteria that induce 
malignant tumors.14–16 2) By secreting organic acid: Lacto-
bacillus produces organic acid by decomposing glucogen to 
maintain the vaginal acidic environment,17 which can inhibit 
the growth and resist the invasion of pathogenic bacteria. 
In addition, the vaginal acidic environment is beneficial 
to maintain the activity of bacteriocins and H
2
O
2
.18 3) By 
secreting various metabolites: exopolysaccharides (EPSs), 
phosphorylated polysaccharides, and peptidoglycans, which 
are secreted by Lactobacillus, can inhibit the proliferation of 
malignant tumors.19,20 Bacteriocin and surface-active compo-
nents can inhibit the production of tumorigenic substances 
and the growth of harmful microorganisms.21 H
2
O
2
, which 
is also secreted by Lactobacillus, can directly kill harmful 
microorganisms or act in a bactericidal manner though the 
peroxidase-hydrogen peroxide-halide bactericidal system.18 
4) By activating the immune system: Lactobacillus affects 
cellular and humoral immunity. On one hand, these bacteria 
can increase the proliferation and differentiation of thymus-
derived cells (T cells).22 On the other hand, Lactobacillus, as 
an immune sensitizer, can increase immunological recogni-
tion and proliferation of bone marrow-derived cell (B cells).23 
Lactobacillus also produces nitric oxide (NO) by stimulating 
macrophages and disrupting the energy metabolism of cancer 
cells.24 Considering the importance of lactobacilli in cervi-
cal cancer, in this review, we comprehensively analyzed and 
classified the pertinent literature on lactobacilli in cervical 
cancer from two perspectives, clinical case investigations, 
and studies of molecular mechanisms. We also provide 
direction and insight for further research on intestinal flora 
in cervical cancer.
Methods
The databases PubMed, Embase, and Cochrane were searched 
for literature published up to January 10, 2018. To achieve 
maximum sensitivity of the search strategy and identify all 
studies, the following terms were combined: (“cervix uterus” 
or “neck of uterus” or “uterine neck” or “cervical” or “cervix” 
or “uterine cervical” or “uterine cervix”) and (“neoplasms” 
or “tumor” or “carcinoma” or “cancer” or “intraepithelial 
neoplasia” or “intraepithelialneoplasms”) and (“lactic acid 
bacteria” or “lactobacillus” or “lactobacilli” or “vagina/
vaginal flora” or “vagina/vaginal microflora” or “vagina/
vaginal microorganism” or “vagina/vaginal microbiome” or 
“vagina/vaginal microbiota” or “vagina/vaginal microbe” or 
“vagina/vaginal microbiology” or “vagina/vaginal bacteria” 
or “vagina/vaginal bacterium”). All relevant abstracts were 
independently retrieved by two authors, and the articles with 
available information for the present systematic review were 
fully reviewed. A total of 29 articles were included after 
identification and screening. The detailed search strategy is 
presented in Figure 1.
Study selection
Studies adhering to the following criteria were considered 
for inclusion: 1) those published in English and 2) those 
involving Lactobacillus in CIN or cervical cancer in vivo 
or in vitro. The exclusion criteria were as follows: 1) letters, 
case reports, reviews, or conference reports; 2) the main 
studies not focused on the topic of vaginal Lactobacillus in 
CIN or cervical cancer; and 3) correlation clinical studies 
with a low quality score according to the Grading of Rec-
ommendations, Assessment, Development and Evaluation 
(GRADE) method.25
Results
CIN, which is considered to be a precancerous lesion of the 
cervix,26 was included in the present study. After identifica-
tion, screening, and validation, we identified a total of 29 
pertinent studies related to Lactobacillus and several of its 
subgenera in cervical cancer and precancerous lesions of 
the cervix published in recent years. The 29 pertinent stud-
ies were divided into two groups that comprised 14 clinical 
studies in one group and 15 experimental studies in the 
other group. The clinical studies and experimental studies 
are shown in Tables 1 and 2, respectively.
As shown in Table 1, 16S rRNA gene sequencing was the 
main method used to detect microbial community structure 
and relative abundance. The presence of cervical cancer and 
precancerous lesions in women was associated with a high 
relative abundance of Lactobacillus iners and Lactobacillus 
sp and low relative abundance of Lactobacillus jensenii and 
Lactobacillus crispatus. Two investigations revealed that the 
abundance of Lactobacillus in women with human papil-
lomavirus (HPV) infection was lower (panel numbers 6 and 
10). A randomized, double-blind, placebo-controlled study 
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Role of Lactobacillus in cervical cancer
showed that an oral lactobacilli (panel number 11) and an 
HR-HPV E7-expressing Lactobacillus-based vaccine (panel 
number 8) were able to decrease the risk of CIN. Moreover, 
two randomized controlled trial studies (panel numbers 12 
and 13) supported the hypothesis that LC9018 (a biological 
response modifier prepared from heat-killed Lactobacillus 
casei YTT9018) was able to protect patients from radiation-
induced leukopenia with few side effects.
As shown in Table 2, cancer cell and animal models were 
used along with molecular biology techniques such as the cell 
counting kit-8 assay, Western blots, immunohistochemistry, 
polymerase chain reaction, and enzyme-linked immunosorbent 
assays to study the role of Lactobacillus and several subgenera 
in cervical cancer. The results showed that Lactobacillus, its 
subgenera, and their supernatants exhibited antimetastatic 
and antiproliferative activities in cervical cancer cell lines by 
regulating cancer-related genes and eliciting an immunological 
response. Lactobacillus inhibited the viability of cervical can-
cer cells through regulating HPV oncogenes (panel numbers 1 
and 6), and HPV-type 16 E7 protein displayed on lactobacillus 
could protect against HPV-induced tumors through regulating 
cellular immunity (panel numbers 10–14). In particular, a nega-
tive result showed that L. casei extract was not able to inhibit 
the viability of cervical cancer cells in vitro (panel number 7). 
As shown in Figure 2, a network of the mechanisms of Lacto-
bacillus in cervical cancer was constructed to better visualize 
the theory behind the experimental studies.
Discussion
The vaginal microecological balance is dynamic and relative, 
and patients are able to recover from slight vaginal dysbac-
teriosis. The persistence of vaginal dysbacteriosis is thought 
to promote gynecological cancer.7,27 A decline in the quan-
tity and activity of Lactobacillus leads to an overgrowth of 
anaerobic bacteria.28 Deleterious metabolites such as nitrous 
acid can be produced by these organisms, and the risk of HPV 
infection also increases.29 Persistent infection of oncogenic 
HPV is a cause of cervical cancer.6 The abundance of Lac-
tobacillus in HPV infection is lower, and HPV oncogenes 
may be involved in regulation of the viability of cervical 
cancer cells inhibited by Lactobacillus. CIN, precancerous 
lesions of the cervix, is much more likely to occur with dys-
bacteriosis. Thus, the regulation and control of Lactobacillus 
may block the progression of cervical cancer.
The present study attempts to clarify the cross-talk 
between Lactobacillus and cervical cancer using both clinical 
and experimental studies by reviewing the pertinent litera-
ture. Experimental study can lay an important foundation for 
Figure 1 Literature search strategy.
Notes: Databases including PubMed, Embase, and Cochrane were searched for literature published up to January 10, 2018. A total of 29 studies including 17 clinical studies 
and 14 experimental studies were included after identification and screening.
Abbreviation: CIN, cervical intraepithelial neoplasia.
PubMed (n=130)
Id
en
tif
ic
at
io
n
S
cr
ee
ni
ng
E
lig
ib
ili
ty
In
cl
ud
ed
Embase (n=89) Cochrane (n=10)
Records excluded (n=21):
1. Reviews, case reports:
(n=16)
2. Low quality score: (n=5)
66 Articles excluded, with
reasons:
1. Not involving CIN or
cervical cancer (n=21)
2. Not involving vaginal
lactobacillus (n=39)
3. Paper without using
English (n=6)
Records after duplicates removed (n=118)
Records screened (n=97)
Full-text articles assessed for eligibility (n=31)
Studies included (n=31)
Experimental studies (n=14) Clinical studies (n=17)
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Yang et al
T
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Role of Lactobacillus in cervical cancer
9
20
13
R
oc
ha
 e
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al
Pa
tie
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ut
er
in
e 
le
si
on
s
La
ct
ob
ac
illu
s 
sp
 w
as
 t
he
 m
os
t 
fr
eq
ue
nt
 
m
ic
ro
or
ga
ni
sm
 (
65
%
) 
in
 t
he
 p
at
ie
nt
s 
w
ith
 
pr
en
eo
pl
as
tic
 a
nd
 n
eo
pl
as
tic
 c
er
vi
ca
l 
ut
er
in
e 
le
si
on
s
53
10
20
13
D
ar
en
g 
et
 a
l
W
om
en
 (
n=
27
8)
N
ig
er
ia
n;
 A
bu
ja
, 
N
ig
er
ia
La
ct
ob
ac
illu
s
16
S 
rD
N
A
 g
en
e 
se
qu
en
ci
ng
, R
oc
he
 
Li
ne
ar
 A
rr
ay
(R
) 
H
PV
 
ge
no
ty
pi
ng
 t
es
t 
an
d 
lo
gi
st
ic
 r
eg
re
ss
io
n 
m
od
el
s
W
om
en
 w
ith
 o
r 
w
ith
ou
t 
H
R
-H
PV
 
in
fe
ct
io
n
Lo
w
 r
el
at
iv
e 
ab
un
da
nc
e 
of
 L
ac
to
ba
cil
lu
s 
sp
p 
is
 in
 5
0%
 o
f H
PV
 in
fe
ct
io
n
54
11
20
12
O
u 
et
 a
l
W
om
en
 w
er
e 
ra
nd
om
iz
ed
 t
o 
or
al
 
la
ct
ob
ac
ill
i (
n=
40
) 
an
d 
or
al
 p
la
ce
bo
 
(n
=4
0)
C
hi
ne
se
; T
ai
w
an
, 
C
hi
na
La
ct
ob
ac
ill
i
H
PV
 t
es
t, 
pa
p 
sm
ea
r,
 
an
d 
va
gi
na
l g
ra
m
 
st
ai
n;
 r
an
do
m
iz
ed
, 
do
ub
le
-b
lin
d,
 p
la
ce
bo
-
co
nt
ro
lle
d 
st
ud
y
H
ig
h-
ri
sk
 H
PV
 
in
fe
ct
io
n;
 C
IN
C
om
pa
ri
ng
 w
ith
 w
om
en
 in
 o
ra
l l
ac
to
ba
ci
lli
 
gr
ou
p,
 w
om
en
 in
 t
he
 p
la
ce
bo
 g
ro
up
 h
ad
 a
 
si
gn
ifi
ca
nt
 h
ig
he
r 
pe
rc
en
ta
ge
 o
f s
ub
se
qu
en
t 
C
IN
 le
si
on
 d
ur
in
g 
fo
llo
w
-u
p
55
12
19
93
O
ka
w
a 
et
 a
l
Pa
tie
nt
s 
w
ith
 s
ta
ge
 
III
B 
ce
rv
ic
al
 c
an
ce
r 
(n
=2
28
) 
Sp
an
is
h;
 
50
 in
st
itu
tio
ns
, 
Sp
ai
n
La
ct
ob
ac
illu
s 
ca
se
i
R
an
do
m
iz
ed
 
co
nt
ro
lle
d 
tr
ia
l
C
er
vi
ca
l c
an
ce
r 
of
 
st
ag
e 
III
B
LC
90
18
 (
a 
bi
ol
og
ic
al
 r
es
po
ns
e 
m
od
ifi
er
 
pr
ep
ar
ed
 fr
om
 h
ea
t-
ki
lle
d 
La
ct
ob
ac
illu
s 
ca
se
i Y
T
T
90
18
) 
co
ul
d 
pr
ot
ec
t 
th
e 
pa
tie
nt
s 
fr
om
 r
ad
ia
tio
n-
in
du
ce
d 
le
uk
op
en
ia
 d
ur
in
g 
ra
di
ot
he
ra
py
 w
ith
 fe
w
 s
id
e 
ef
fe
ct
s
56
13
19
89
O
ka
w
a 
et
 a
l
Pa
tie
nt
s 
w
ith
 s
ta
ge
 
IIB
 o
r 
III
 c
er
vi
ca
l 
ca
nc
er
 (
n=
61
) 
Ja
pa
ne
se
; 
D
ep
ar
tm
en
t 
of
 
R
ad
io
lo
gy
, T
ok
yo
 
W
om
en
’s
 M
ed
ic
al
 
C
ol
le
ge
, T
ok
yo
, 
Ja
pa
n
La
ct
ob
ac
illu
s 
ca
se
i 
R
an
do
m
iz
ed
 
co
nt
ro
lle
d 
tr
ia
l
C
er
vi
ca
l c
an
ce
r 
of
 
st
ag
e 
IIB
 o
r 
III
LC
90
18
 e
nh
an
ce
d 
th
e 
th
er
ap
eu
tic
 e
ffe
ct
 
of
 t
he
 ir
ra
di
at
io
n.
 L
C
90
18
 c
ou
ld
 p
ro
te
ct
 
th
e 
pa
tie
nt
s 
fr
om
 le
uk
op
en
ia
 d
ur
in
g 
ra
di
ot
he
ra
py
57
14
19
78
M
ea
d
Pa
tie
nt
s 
w
ith
 
in
va
si
ve
 c
er
vi
ca
l 
ca
nc
er
 (
n=
21
)
A
m
er
ic
an
; 
D
ep
ar
tm
en
t 
of
 
O
bs
te
tr
ic
s 
an
d 
G
yn
ec
ol
og
y 
at
 
th
e 
U
ni
ve
rs
ity
 o
f 
V
er
m
on
t 
C
ol
le
ge
 
of
 M
ed
ic
in
e,
 
Bu
rl
in
gt
on
, 
V
T
, U
SA
A
er
ob
ic
 
la
ct
ob
ac
ill
i
Ba
ct
er
ia
 is
ol
at
io
n 
an
d 
pu
ri
fic
at
io
n
C
er
vi
ca
l c
an
ce
r
Pa
tie
nt
s 
w
ith
 c
er
vi
ca
l c
an
ce
r 
ha
ve
 a
 
de
cr
ea
se
d 
fr
eq
ue
nc
y 
of
 is
ol
at
io
n 
of
 a
er
ob
ic
 
la
ct
ob
ac
ill
i
11
N
ot
es
: C
er
vi
ca
l c
an
ce
r 
an
d 
pr
ec
an
ce
ro
us
 le
si
on
s 
in
 w
om
en
 w
er
e 
as
so
ci
at
ed
 w
ith
 h
ig
h 
re
la
tiv
e 
ab
un
da
nc
e 
of
 L
ac
to
ba
cil
lu
s 
an
d 
se
ve
ra
l o
f i
ts
 s
ub
ge
ne
ra
. O
ra
l l
ac
to
ba
ci
lli
 (
pa
ne
l n
um
be
r 
11
) 
an
d 
an
 E
7-
ex
pr
es
si
ng
 L
ac
to
ba
cil
lu
s-
ba
se
d 
va
cc
in
e 
(p
an
el
 n
um
be
r 
8)
 w
er
e 
ab
le
 t
o 
de
cr
ea
se
 t
he
 r
is
k 
of
 C
IN
. L
C
90
18
 p
ro
te
ct
ed
 p
at
ie
nt
s 
fr
om
 r
ad
ia
tio
n-
in
du
ce
d 
le
uk
op
en
ia
 w
ith
 fe
w
 s
id
e 
ef
fe
ct
s.
A
bb
re
vi
at
io
ns
: C
C
K
-8
, c
el
l c
ou
nt
in
g 
ki
t-
8;
 C
IN
, c
er
vi
ca
l i
nt
ra
ep
ith
el
ia
l n
eo
pl
as
ia
; C
T
, c
om
m
un
ity
 ty
pe
; H
PV
, h
um
an
 p
ap
ill
om
av
ir
us
; H
R
-H
PV
, h
ig
h-
ri
sk
 H
PV
; H
SI
L,
 h
ig
h-
gr
ad
e 
sq
ua
m
ou
s 
in
tr
ae
pi
th
el
ia
l l
es
io
n;IC
C
, i
nv
as
iv
e 
ce
rv
ic
al
 c
an
ce
r;
 
L.
 c
ris
pa
tu
s, 
La
ct
ob
ac
illu
s 
cr
isp
at
us
; L
. i
ne
rs
, L
ac
to
ba
cil
lu
s 
in
er
s; 
L.
 je
ns
en
ii, 
La
ct
ob
ac
illu
s 
je
ns
en
ii;
 L
SI
L,
 lo
w
-g
ra
de
 s
qu
am
ou
s 
in
tr
ae
pi
th
el
ia
l l
es
io
n;
 P
C
R
, p
ol
ym
er
as
e 
ch
ai
n 
re
ac
tio
n.
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Yang et al
T
ab
le
 2
 E
xp
er
im
en
ta
l s
tu
di
es
 o
f L
ac
to
ba
cil
lu
s 
in
 c
er
vi
ca
l c
an
ce
r
N
um
be
r
Y
ea
r
A
ut
ho
rs
E
xp
er
im
en
ta
l a
ni
m
al
 
an
d 
ce
ll 
m
od
el
Su
bg
en
er
a 
of
 
La
ct
ob
ac
ill
us
M
et
ho
ds
D
is
ea
se
s
Fi
nd
in
gs
R
ef
er
en
ce
1
20
17
W
an
g 
et
 a
l
C
aS
ki
 c
el
ls
L.
 c
ris
pa
tu
s, 
L.
 je
ns
en
ii, 
an
d 
L.
 g
as
se
ri
M
T
T
 a
ss
ay
, fl
ow
 c
yt
om
et
ry
, 
an
d 
PC
R
C
er
vi
ca
l 
ca
nc
er
Su
pe
rn
at
an
ts
 o
f L
. c
ris
pa
tu
s, 
L.
 je
ns
en
ii, 
an
d 
L.
 g
as
se
ri 
ha
ve
 in
hi
bi
to
ry
 e
ffe
ct
s 
on
 t
he
 v
ia
bi
lit
y 
of
 c
er
vi
ca
l 
ca
nc
er
 c
el
ls
 v
ia
 r
eg
ul
at
io
n 
of
 H
PV
 o
nc
og
en
es
 a
nd
 
ce
ll 
cy
cl
e-
re
la
te
d 
ge
ne
s
43
2
20
17
Li
 e
t 
al
H
eL
a 
an
d 
U
14
 c
el
l l
in
es
 
an
d 
X
en
og
ra
ft 
m
ou
se
La
ct
ob
ac
ill
i
C
C
K
-8
, W
es
te
rn
 b
lo
t, 
an
d 
im
m
un
oh
is
to
ch
em
is
tr
y
C
er
vi
ca
l 
ca
nc
er
La
ct
ob
ac
ill
i i
nh
ib
it 
th
e 
m
ig
ra
to
ry
 a
bi
lit
y 
of
 c
er
vi
ca
l 
ca
nc
er
 c
el
l l
in
es
 a
nd
 t
he
 u
pr
eg
ul
at
io
n 
of
 E
-c
ad
he
ri
n 
m
ay
 b
e 
in
vo
lv
ed
 in
 t
he
 m
ol
ec
ul
e 
m
ec
ha
ni
sm
58
3
20
17
Su
ng
ur
 e
t 
al
W
om
en
, c
er
vi
ca
l c
an
ce
r 
ce
ll 
an
d 
C
ac
o-
2 
ce
ll 
lin
es
L.
 g
as
se
ri 
st
ra
in
s 
H
PL
C
, W
ST
-1
 c
el
l 
pr
ol
ife
ra
tio
n 
as
sa
y,
 E
LI
SA
, 
an
d 
PC
R
C
er
vi
ca
l 
ca
nc
er
EP
Ss
 o
f L
. g
as
se
ri 
st
ra
in
s 
is
ol
at
ed
 fr
om
 h
um
an
 v
ag
in
a 
in
du
ce
 a
po
pt
os
is
 in
 H
eL
a 
ce
lls
 b
y 
as
so
ci
at
in
g 
w
ith
 a
n 
up
re
gu
la
tio
n 
of
 B
ax
 a
nd
 C
as
pa
se
 3
44
4
20
17
Ja
ng
 e
t 
al
T
h1
7 
ce
lls
 a
nd
 H
eL
a 
ce
ll 
lin
es
La
ct
ob
ac
illu
s 
rh
am
no
su
s 
H
N
00
1 
(L
1)
 a
nd
 
La
ct
ob
ac
illu
s 
ac
id
op
hi
lu
s 
La
-1
4 
(L
2)
En
zy
m
e-
lin
ke
d 
im
m
un
os
po
t 
as
sa
y,
 im
m
un
ob
lo
tt
in
g,
 P
C
R
, 
an
d 
flo
w
 c
yt
om
et
ry
C
er
vi
ca
l 
ca
nc
er
La
ct
ob
ac
illu
s 
rh
am
no
su
s 
H
N
00
1 
(L
1)
 a
nd
 L
ac
to
ba
cil
lu
s 
ac
id
op
hi
lu
s 
La
-1
4 
(L
2)
 in
hi
bi
te
d 
th
e 
ad
he
re
nc
e 
of
 
G
ar
dn
er
el
la
 v
ag
in
al
is 
to
 c
er
vi
ca
l c
an
ce
r 
ce
lls
59
5
20
16
N
ou
ri
 e
t 
al
H
eL
a 
ce
ll 
lin
es
 
LR
S 
an
d 
LC
S
M
T
T
 a
ss
ay
 a
nd
 P
C
R
C
er
vi
ca
l 
ca
nc
er
LR
S 
an
d 
LC
S 
ha
ve
 a
nt
im
et
as
ta
tic
 a
nd
 
an
tip
ro
lif
er
at
iv
e 
ac
tiv
iti
es
 o
n 
H
eL
a 
ce
ll 
lin
es
60
6
20
16
M
ot
ev
as
el
i 
et
 a
l
H
eL
a 
ce
lls
L.
 c
ris
pa
tu
s 
an
d 
La
ct
ob
ac
illu
s 
rh
am
no
su
s
PC
R
C
er
vi
ca
l 
ca
nc
er
L.
 c
ris
pa
tu
s 
an
d 
La
ct
ob
ac
illu
s 
rh
am
no
su
s 
cu
ltu
re
 
su
pe
rn
at
an
ts
 c
an
 d
ec
re
as
e 
th
e 
ex
pr
es
si
on
 o
f A
T
G
14
 
an
d 
BE
C
N
1 
as
 w
el
l a
s 
th
e 
H
PV
 E
6 
on
co
ge
ne
 in
 
H
eL
a 
ce
lls
61
7
20
15
K
im
 e
t 
al
C
aS
ki
 a
nd
 H
eL
a 
ce
ll 
lin
es
La
ct
ob
ac
illu
s 
ca
se
i
Fl
ow
 c
yt
om
et
ry
C
er
vi
ca
l 
ca
nc
er
La
ct
ob
ac
illu
s 
ca
se
i e
xt
ra
ct
 c
an
no
t 
in
hi
bi
t 
th
e 
vi
ab
ili
ty
 
of
 c
er
vi
ca
l c
an
ce
r 
ce
lls
 o
r 
th
e 
gr
ow
th
 o
f c
an
ce
r 
ce
lls
 
in
 t
he
 p
re
se
nc
e 
of
 a
nt
ic
an
ce
r 
dr
ug
s 
in
 v
itr
o
62
8
20
14
N
am
i e
t 
al
W
om
en
; H
eL
a 
ce
ll 
lin
es
 
an
d 
H
U
V
EC
 n
or
m
al
 c
el
ls
La
ct
ob
ac
illu
s 
pl
an
ta
ru
m
16
S 
rD
N
A
 g
en
e 
se
qu
en
ci
ng
, 
di
sk
 d
iff
us
io
n 
an
tib
io
tic
 
su
sc
ep
tib
ili
ty
 t
es
t, 
M
T
T
 
as
sa
y,
 D
A
PI
 s
ta
in
in
g 
m
et
ho
d,
 
an
d 
flo
w
 c
yt
om
et
ry
C
er
vi
ca
l 
ca
nc
er
La
ct
ob
ac
illu
s 
pl
an
ta
ru
m
 5
BL
, w
hi
ch
 is
 is
ol
at
ed
 fr
om
 
va
gi
na
l s
ec
re
tio
ns
 o
f a
do
le
sc
en
t 
an
d 
yo
un
g 
ad
ul
t 
w
om
en
, e
xh
ib
its
 d
es
ir
ab
le
 p
ro
bi
ot
ic
 p
ro
pe
rt
ie
s 
an
d 
re
m
ar
ka
bl
e 
an
tic
an
ce
r 
ac
tiv
ity
 a
ga
in
st
 t
he
 H
eL
a 
ce
ll 
lin
es
 w
ith
 n
o 
si
gn
ifi
ca
nt
 c
yt
ot
ox
ic
 e
ffe
ct
s 
on
 H
U
V
EC
 
no
rm
al
 c
el
ls
63
9
20
13
M
ot
ev
as
el
i 
et
 a
l
H
um
an
 n
or
m
al
 fi
br
ob
la
st
-
lik
e 
ce
rv
ic
al
 (
no
rm
al
 
ce
rv
ic
al
) 
an
d 
H
eL
a 
(c
er
vi
ca
l t
um
or
) 
ce
lls
L.
 g
as
se
ri 
an
d 
L.
 c
ris
pa
tu
s
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Role of Lactobacillus in cervical cancer
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 further clinical study, and clinical study can be the reliable 
test of experimental study. Lactobacillus as a probiotic is 
characterized by fewer side effects and can be used as oral 
preparation. The signal peptide of S-layer on monolayer 
cell membrane of Lactobacillus is easy to combine with the 
exogenous target protein. These characteristics determine 
the Lactobacillus as a desired vector for recombinant pro-
tein vaccine and, moreover, Lactobacillus in vaginal flora 
as protection against HPV-related disease. Thus, the use 
of Lactobacillus as a vector to construct the HPV-related 
protein vaccine can achieve admirable antitumor effects in 
clinical practice.
Many clinical studies found that a decline in the quantity 
and activity of Lactobacillus was involved in the initiation 
and progression of cervical cancer, which provides a novel 
insight into the use of probiotics to prevent cervical can-
cer.47,54,58 Some experimental studies found that Lactobacil-
lus and its metabolites inhibit the proliferation of cervical 
cancer cells by regulating cancer-related genes or through 
an immunological mechanism. These studies provide a theo-
retical basis for further clinical application of Lactobacillus 
in cervical cancer.
Lactobacillus and its metabolites, which are used as treat-
ments as well as prophylactic agents, have unique advantages. 
Lactobacillus as a vaginal parasitical bacterium has a lower 
toxicity and fewer side effects compared to other bacteria. 
It acts mainly by regulating the microecological environ-
ment and, compared to other bacteria, is less susceptible to 
resistance.30 Lactobacillus and its metabolites are efficacious 
and superior in clinical applications for the prevention of 
cervical cancer.31
In addition to cervical cancer, Lactobacillus is associated 
with the proliferation and regulation of cells of other cancer 
types, such as breast cancer,32 colorectal cancer,33 gastric 
cancer,34 and oral cancer.35,36 Observations in these other 
cancers may offer insights into the study of Lactobacillus in 
cervical cancer. The main observations regarding Lactobacil-
lus in cancers are as follows: 1) Lactobacillus can activate 
and strengthen the antitumor effects of immunocytes such 
as thymus-derived cells (T cells), natural killer (NK) cells, 
dendritic cells (DCs), and macrophages and immunological 
factors produced by immunocytes;37–39 2) a large amount 
of unmethylated dinucleotide repeat sequences present in 
the nuclei of Lactobacillus can activate the innate immune 
response by binding to a specific receptor that exists on the 
surface of human cells;40 3) Lactobacillus that is suitable for 
reproduction and growth in an anaerobic environment can 
selectively accumulate in the hypoxic zones of solid cancers;41 
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Yang et al
and 4) Lactobacillus can selectively locate to solid cancers 
and can be used as a vector for gene therapy and targeted 
therapies.35
The diagnosis and treatment of cervical cancer have been 
advanced considerably in recent years, but there is still a long 
way to go in regard to cancer prevention. This review cannot 
include some unpublished research or ongoing studies. There 
is also a lack of large-scale multicenter clinical trials and 
clinical prospective cohort studies in the literature. A perfect 
theory cannot be constructed for the mechanism of action of 
Lactobacillus in cervical cancer. Vaginal Lactobacillus and its 
metabolites may provide a novel insight into the prevention 
of cervical cancer. Thus, we put forth some future directions 
for further study.
Figure 2 Network illustrating the effects of Lactobacillus in cervical cancer.
Note: An association network for Lactobacillus in cervical cancer was constructed based on the analysis of experimental studies and allows improved visualization of these 
studies.
Abbreviations: HPV, human papillomavirus; L. acidophilus, Lactobacillus acidophilus; L. casei, Lactobacillus casei; L. crispatus, Lactobacillus crispatus; L. gasseri, Lactobacillus gasseri; 
L. jensenii, Lactobacillus jensenii; L. lactis, Lactobacillus lactis; L. plantarum, Lactobacillus plantarum; L. rhamnosus, Lactobacillus rhamnosus.
Lactobacillus L. gasseri
HPV-16 L1
capsid protein
HPV-16 E6
oncoprotein
HP
V-1
6 E
7
onc
opr
ote
in
L. l
act
is a
nd 
L. c
ase
i
L. gasseriand L. crispatus
Vagina
8
Se
cr
et
e
Secrete
Inhibit proliferation
65
65
63
62
61
61
45
60
60
70
L. casei
Vaccine
U
pregulate
E-cadherin
Inhibit m
igration
In
du
ce
s
ap
op
to
si
s
44, 62, 63
Supernatant
Inhibit migration and proliferation
Inhibit cell adherence
Att
en
ua
te
L. crispatus, L. jensenii,
and L.gasseri
L. rhamnosus and L. acidophilus
Induce autophagy U
pre
gu
lat
e
63
Vagina
L. plan
tarum
 5BL
67,
 68
, 69
Va
cci
ne
L. casei
23 23
66
In
du
ce
s 
ap
op
to
si
s
Exopolysaccharides
Se
cr
et
e
45
45
Ga
rdn
ere
lla 
va
gin
alis
Bax 
and c
aspa
se 3U
pr
eg
ul
at
e
Vaccine
CD4(+) or CD8(+) T cells
ATG14 and BECN1
Future directions
Elucidate the role of vaginal Lactobacillus 
in cervical cancer
Lactobacillus is the dominant bacteria in the vagina and 
affects the growth of other bacteria.42 There appears to be a 
complex relationship between cervical cancer and vaginal 
Lactobacillus. However, many problems deserve further con-
sideration. How do the community structure and diversity of 
Lactobacillus vary with differences in race, region, lifestyle, 
and diet? How does Lactobacillus drive the occurrence and 
development of cervical cancer? What is the role of Lacto-
bacillus metabolites in balancing vaginal microecology and 
the development of cervical cancer?
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Role of Lactobacillus in cervical cancer
Elucidate the immunological functions 
mediated by vaginal Lactobacillus in 
cervical cancer
Immunotherapy provides a broad perspective for the treat-
ment of cancers. Vaginal Lactobacillus and its metabolites 
do affect theimmune system in cervical cancer.22 Though 
much effort has been made into understanding the mecha-
nisms of this effect, many bottlenecks must be addressed 
before stepping from the imbalanced vaginal microecological 
system to the immune system to cervical cancer genesis and 
development. Lactobacillus is an easily available probiotic 
that is safe and has no side effects or toxicity. The envelope 
of Lactobacillus is often used as a carrier to express an 
alternative antigen for vaccines, which may provide a novel 
idea for the primary prevention of cervical cancer. A cervical 
cancer vaccine based on Lactobacillus with an HPV vaccine 
promises to be a new method for the prevention of cervical 
cancer. Prospective studies on cervical cancer incidence 
after intervention with the Lactobacillus vaccine should be 
performed.
Elucidate the molecular mechanism by 
which Lactobacillus inhibits cervical 
cancer
Lactobacillus inhibits the proliferation of cells from multiple 
cancer types. Most studies have focused on the relationship 
between Lactobacillus and cancer, but the mechanisms 
underlying this relationship have yet to be clarified. Many 
enzymes and peptides and the lactic acid secreted by Lacto-
bacillus are involved in activating and regulating important 
signaling molecules and pathways in cervical cancer.43,44 It is 
necessary to elucidate the specific molecular mechanism or 
construct the molecular regulatory network in future research. 
Lactobacillus acts as a valuable cloning vector and is cur-
rently mainly used as a plasmid vector for the experimental 
research of cancer in vitro. This use may suggest additional 
therapeutic use as a carrier to express antioncogenes or 
encapsulated anticarcinogens in the future.
In light of the importance of Lactobacillus in cervical 
cancer, much attention has been paid to the study of vagi-
nal microecology in recent years. Lactobacillus has shown 
tremendous promise for the prevention and treatment of 
cervical cancer. However, knowledge of vaginal microecol-
ogy and Lactobacillus is far from complete. More research 
will be required before clinical application of Lactobacillus 
in cervical cancer is achieved.
Acknowledgment
This work was supported by the Huzhou Public Welfare 
Technology Application Research Program (2016GYB14).
Disclosure
The authors report no conflicts of interest in this work.
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