International Journal of Medical Physics, Clinical Engineering and Radiation Oncology, 2013, 2, 1-6
doi:10.4236/ijmpcero.2013.23B001 Published Online August 2013 (http://www.scirp.org/journal/ijmpcero)
Candidate Molecules and ki-67/MIB1 as Novel Diagnostic
Biomarker for Human Uterine Mesenchymal Tumors
Takuma Hayashi1,2, Akiko Horiuchi3, Nobuo Yaegashi4, Susumu Tonegawa5, Ikuo Konishi2
1Department of Immunology and Infectious Disease, Shinshu University School of Medicine,
Matsumoto, Nagano, Japan
2Department of Obstetrics and Gynecology, Kyoto University Graduate School of Medicine,
Kyoto-city, Kyoto, Japan
2Promoting Business using Advanced Technology, Japan Science and Technology Agency (JST),
Chiyoda-ku, Tokyo, Japan
3Horiuchi Ladies Clinic, Matsumoto, Nagano 390-0821, Japan
4Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Miyagi Japan
5Picower Institution and Department of Biology, Massachusetts Institute of Technology,
Cambridge, MA 02139-4307 USA
Received April, 2013
ABSTRACT
Human uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the
uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the
development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet
known. Importantly, a diagnostic-biomarker, which distinguishes malignant uterine LMS from benign tumor leio-
myoma (LMA), is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS,
to establish a clinical treatment method. Protea some β-ring subunit LMP2/β1i-deficient mice spontaneously develop
uterine LMS, with a disease prevalence of ~40% by 14 months of age. We found LMP2/β1i expression to be absent in
human uterine LMS, but present in human LMA. Therefore, defective-LMP2/β1i expression may be one of the risk
factors for human uterine LMS. LMP2/β1i is a potential diagnostic-biomarker under the combination of candidate mo-
lecules, for instance cyclin B1, cyclin E and calponin h1 and ki-67/MIB1 counts for uterine mesenchymal tumors, espe-
cially human uterine LMS, and may be a targeted-molecule for a new therapeutic approach.
Keywords: LMP2/β1i; Uterine Leiomyosarcoma; Uterine Leiomyoma; Biomarker
1. Introduction
The uterus, the organ in which the embryo grows, is
composed of three layers, the uterine endometrium which
serves as a bed for the embryo; the myometrium of the
wall which protects the embryo; and a serous membrane
enveloping the uterus. In general, the term uterine tumor
refers to an epithelial malignant tumor of the uterus,
which is roughly classified as a tumor of the uterine cer-
vix or the uterine body. Because of the prevalence of
screening, uterine cervix cancer is decreasing in inci-
dence, and usually detected at a very early stage. In con-
trast, cancer of the uterine body is increasing in incidence,
and rarely detected at the initial stages. While most tu-
mors of the uterine body are adenocarcinomas (derived
from the subintimal gland), tumors of the uterine cervix
are classified into squamous cancer and adenocarcinoma.
Smooth muscle tumors (SMTs) which develop in the
myometrium have been traditionally divided into benign
uterine leiomyoma (LMA) and malignant uterine leio-
myosarcoma (LMS) based on cytological atypia, mitotic
activity and other criteria. Uterine LMS is relatively rare,
having an estimated annual incidence of 0.64 per
100,000 women [1]. Uterine LMS accounts for 2% to 5%
of tumors of the uterine body and develops more often in
the muscle layer of the uterine body than in the uterine
cervix. As uterine LMS is resistant to chemotherapy and
radiotherapy, surgical intervention is virtually the only
means of clinical treatment [2-4]. The prognosis for
uterine LMS is not good, and the five-year survival rate
is approximately 35% [5]. However, developing an effi-
cient adjuvant therapy is expected to improve survival
rate. Uterine LMA may occur in as many as 70% ~ 80%
of women by the age of 50 years [6]. Distinguishing
uterine LMA from uterine LMS is very difficult, and a
diagnosis generally requires surgery and cytoscopy [7].

T. HAYASHI ET AL. 2
Diagnostic categories for uterine SMTs and morphologi-
cal criteria are used to assign cases [8,9] (Attention 1).
The non-standard subtypes of uterine SMTs such as the
epithelioid and myxoid types are classified in a different
way using these features, so the establishment of a dia-
gnostic method for the identification of non-standard
smooth muscle differentiation is important [8,9].
High estrogen levels are considered to significantly in-
fluence the development of tumors in the uterine body
[10-12]. The mechanisms by which uterine LMA and
uterine LMS develop are not yet known, though tumors
that have developed in the myometrium for some reason
gradually become larger due to the influence of the fe-
male hormone and generate tumors. However, no corre-
lation between the development of uterine LMS and
hormonal conditions, and no obvious risk factors has
been found. Although cases accompanied by hypocal-
caemia or eosinophilia have been reported, neither cli-
nical abnormality is an initial risk factor for uterine LMS.
The identification of a risk factor associated with the
development of uterine LMS would significantly contri-
bute to the development of preventive and therapeutic
treatments.
2. Spontaneous Development of Uterine
Leiomyosarcoma in LMP2/β1i-Deficient
Mice
Cytoplasmic proteins are mostly degraded by a protease
complex, which has many substrates consisting of twen-
ty-eight 20 to 30-kDa subunits, referred to as the 20S
proteasome [13,14]. The proteasomal degradation is
essential for many cellular processes, including the cell
cycle, the gene expression and immunological function
[15]. Interferon (IFN)- induces the expression of large
numbers of responsive genes, proteasome subunits, i.e.,
low-molecular mass polypeptide (LMP)2/β1i, LMP7/β5i,
and LMP10/β2i [16] (Figure 1).
The individual expression of LMP2/β1i, LMP7/β5i
and LMP10/β2i subunits in various cell types or tissues is
believed to contribute to the initiation and development
of disorders. A recent study revealed a unique role for
LMP7/β5i in controlling pathogenic immune responses
and provided a therapeutic rationale for targeting
LMP7/β5i in autoimmune disorders, especially rheuma-
toid arthritis [17].
Homozygous mice deficient in LMP2/β1i show tissue-
and substrate-dependent abnormalities in the biological
functions of the proteasome [18]. Here we identify
LMP2/β1i, as obligatory for tumor surveillance and
demonstrate a tissue-specific role for LMP2/β1i in pro-
tection from spontaneous uterus neoplasms. In short,
uterine LMS reportedly occurred in female LMP2/β1i-
deficient mice at age 6 months or older, and the inci-
dence at 14 months of age was about 40% [19,20] (Fig-
Figure 1. The immuno-proteasomal degradation pathway is
essential for antigen presentation by MHC class I.
ure 2). The curve indicating the incidence in mice is
similar to that indicating the incidence of human uterine
LMS, which occurs after menopause. Histological stud-
ies of LMP2/β1i-lacking uterine tumors have revealed
characteristic abnormalities of uterine LMS, and the tu-
mors lacked lymphoid infiltrates, a sign of immune rec-
ognition, and consisted of uniform elongated myo- me-
trium cells arranged into bundles [19] (Figure 2).
The nuclei of the tumor cells varied in size and shape,
furthermore, mitosis was frequent. In contrast, the myo-
metrium cells of its parental mice, C57BL/6 mice were
normal in appearance. Whereas relatively few ki-67/
MIB1-positive cells, the proliferating cells of solid tu-
mors, were observed in the basal cell layer of the normal
myometrium, most of the basal cells vividly expressed
ki-67/MIB1 in LMP2/β1i-deficient mice [19] (Figure 2).
Immunohistochemistry (IHC) study indicates abnormal
proliferation of the LMP2/β1i-lacking cells in the basal
layer. LMP2/β1i-deficient mice that have developed ute-
rine LMS undergo considerable weight loss, and then die
by 14 months of age [19,20]. The LMP2/β1i-deficient
mice also exhibit skeletal muscle metastasis from uterine
LMS. Therefore it is likely that LMP2/β1i-deficient mice
with uterine LMS die as a result of the tumor mass and
metastasis [19,20]. In general, it is not easy to distinguish
uterine LMA from uterine LMS, however, in mice, be-
cause of such characteristic pathological findings, sig-
nificant weight loss, and skeletal muscle metastasis, a
tumor that develops in the uterus of an LMP2/β1i-defi-
cient mouse can be considered malignant, i.e., uterine
LMS [19,20].
3. Defective LMP2/β1i Expression in Human
Leiomyosarcoma
IHC studies were performed to demonstrate the validity
and reliability of LMP2/β1i as a diagnostic biomarker

T. HAYASHI ET AL. 3
Figure 2. Homozygous mice deficient in LMP2/β1ian
nder the combination of other candidate molecules, for
Human Uterine Mesenchymal Tumors
an-
cector
,
IFN-γinducible factor, show tissue- and substrate-depend-
ent abnormalities in the biological functions of the protea-
some. uterine LMS reportedly occurred in female LMP2/
β1i deficient mice at age 6 months or older, and the inci-
dence at 14 months of age was about 40%.
u
instance cyclin B1, cyclin E and calponin h1, which re-
portedly function as anti-tumorigenic factor in human
uterine LMS [21-25]. IHC experiments revealed a seri-
ous loss in the ability to induce LMP2/β1i and calponin
h1 expression in human uterine LMS tissue in compari-
son with uterine LMA or normal myometrium located in
the same section [21-25]. Of the 54 cases we examined
with uterine LMS, 46 were negative for LMP2/β1i ex-
pression, 4 were focally positive, and 2 were partially
positive [21,22,24]. Two uterine LMS cases were stained
for LMP2/β1i. LMP2/β1i levels were also evaluated in
skeletal muscle and rectum metastases from individual
uterine LMS patients. Pathological examination of sur-
gical samples showed the presence of a mass measuring
3 cm in its largest diameter in the lumbar quadrate mus-
cle without a fibrous capsule. All lymph nodes were neg-
ative for uterine LMS metastases, and IHC analyses
showed positivity for ki-67/MIB1 and negativity for
LMP2/β1i. Histological findings were consistent with
metastatic LMS for the skeletal muscle and rectum le-
sions. In western blotting and RT-PCR experiments,
LMP2/β1i was expressed in normal myometrium, but not
in human uterine LMS, both strongly supportive of the
IHC findings [21,22]. Although we has previously dem-
onstrated that the abnormal expression of the ovarian
steroid receptors, TP53 and ki-67/MIB1 and mutations of
TP53 were frequently associated with uterine LMS, de-
fective LMP2/β1i expression appears to be more charac-
teristic of uterine LMS than these factors [21-25].
4. LMP2/β1i Differential Expressions in
In the case of gynecological cancers, such as breast c
r, a female hormonal imbalance is often a risk fa
for developing tumors [10-12]. As in the case of uterine
LMA, however, a correlation between the development
of uterine LMS, the female hormone, and hormone re-
ceptors has yet to be elucidated. A recent report showed
the expression of Lmp2 mRNA and protein in luminal
and glandular epitheliua, placenta villi, trophoblastic
shells, and arterial endothelial cells [26-27]. These results
implicate LMP2/β1i in the invasion of placental villi,
degradation of the extracellular matrix, immune tolerance,
glandular secretion, and angiogenesis [26,27]. The pre-
sent study should help to elucidate the regulatory role of
LMP2/β1i in the implantation of embryos [26-29]. Un-
fortunately, it is unclear whether defective LMP2/β1i
expression is involved in the onset of uterine LMS. Risk
factors for its development however, have not been iden-
tified because of the absence of a suitable animal model.
The LMP2/β1i-deficient mouse was the first animal
model of spontaneous uterine LMS to be established
[19,20]. Defective LMP2/β1i expression may be one of
the causes of uterine LMS. To demonstrate whether
LMP2/β1i is a potential biomarker for distinguishing
uterine LMS from uterine LMA, we are investigating the
reliability and characteristics of LMP2/β1i as a diagnos-
tic indicator with several clinical research facilities. To
demonstrate whether LMP2/β1i is a potential biomarker
for distinguishing human uterine LMS from uterine LMA
under the combination with other candidate molecules,
especially cyclin B1, cyclin E calponin h1, which are
identified as potential diagnostic candidates, and ki-67/
MIB1 counts [21,22,24,25,30-37], we are investigating
the reliability and characteristics of LMP2/β1i as a diag-
nostic indicator with several clinical research facilities
[22-25,30-32]. The clinical research is yet to be con-
cluded, and large-scale clinical studies need to be per-
formed with additional clinical research facilities. His-
tologic and IHC characteristics of uterine mesenchymal
tumors including mitotically active leiomyoma, bizarre
leiomyoma, lipoleiomyoma, uterine smooth muscle tu-
mors of uncertain malignant potential (STUMP), leio-
myomatoid angiomatous neuroendocrin tumor (LANT)
are summarized [32-37]. Clarification of the correlation
between these factors and the development of human
uterine LMS and the identification of specific risk factors
may lead to the development of new treatments for the
disease. Uterine LMS is refractory to chemotherapy and
has a poor prognosis. The molecular biological and cy-
tological information obtained from LMP2/β1i-deficient
mice will contribute remarkably to the development of
preventive methods, a potential diagnostic-biomarker,
and new therapeutic approaches against human uterine

T. HAYASHI ET AL. 4
LMS.
5. Final Considerations
tory to chemotherapy and
e LMP2/β1i expression is
nowledgements
r Luc Van Kaer (Vanderbilt
This study was suppor
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T. HAYASHI ET AL. 6
Attention 1
The typical gross appearance is a large (>10 cm), poorly
circumscribed mass with a soft, fleshy consistency and a
variegated cut surface that is grey-yellow to pink, with
foci of hemorrhage and necrosis [8,9]. The histologic
classification of uterine sarcomas is based upon homol-
ogy to normal cell types and include uterine LMS (analo-
gous to myometrium), stromal sarcoma (analogous to
endometrial stroma), and other heterologous cell types
(i.e., osteosarcoma, liposarcoma). Microscopically, most
human uterine LMS are overtly malignant, with hyper-
cellularity, coagulative tumor cell necrosis, abundant
mitoses [>10 to 20 mitotic figures (mf) per 10 high
power fields (hpf)], atypical mitoses, cytologic atypia,
and infiltrative borders. Mitotic rate is the most important
determinant of malignancy, but is modified by the pres-
ence of necrosis and cytologic atypia. The diagnosis of
human uterine LMS may be made in the presence of tu-
mor necrosis and any mitoses. In the absence of tumor
necrosis, the diagnosis can be made with moderate to
severe cytologic atypia and a mitotic index greater than
10mf/10hpf. Without tumor necrosis and significant
atypia, a high mitotic index is compatible with a benign
clinical course; however, data is limited [8,9].