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[Cancer Research 60, 3662-3665, July 1, 2000]
© 2000 American Association for Cancer Research

Tumor Biology

The Value of Platelet-derived Endothelial Cell Growth Factor as a Novel Predictor of Advancement of Uterine Cervical Cancers

Jiro Fujimoto1, Hideki Sakaguchi, Ikumi Aoki and Teruhiko Tamaya

Department of Obstetrics and Gynecology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu City 500-8705, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Serum platelet-derived endothelial cell growth factor (PD-ECGF) in patients with uterine cervical cancers revealed a significantly positive correlation with clinical stage and tumor size and with the advancement indicators lymph node metastasis, parametrial involvement, and vessel permeation in both squamous cell carcinomas and adenocarcinomas. The prognosis of the patients with high serum PD-ECGF was extremely poor, whereas the 36-month survival rate of the other patients with low serum PD-ECGF was 81.3% in squamous cell carcinomas and 80.0% in adenocarcinomas. Our data indicate that serum PD-ECGF levels reflect the status of advancement of uterine cervical cancers and thus may be recognized as a novel tumor marker for both squamous cell carcinomas and adenocarcinomas of the uterine cervix.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PD-ECGF2 was cloned as a novel angiogenic factor (Mr 45,000 polypeptide) from human platelets (1) . Thereafter, PD-ECGF was completely identified with TP (2 , 3) . PD-ECGF/TP does not stimulate the growth of endothelial cells but chemotaxis of them and induces angiogenesis in vivo with the activation of TP as an enzyme (4 , 5) . PD-ECGF is expressed in lymph nodes, peripheral lymphocytes, spleen, lung, liver, and placenta among normal tissues. Among solid tumors, PD-ECGF is expressed in malignant gliomas, thyroid tumors, cancers of the breast, esophagus, stomach, colon, pancreas, gallbladder, kidney, bladder, ovary, uterine cervix, and lung (6) .

PD-ECGF action on the advancement of female genital tract diseases can be gleaned from the following. PD-ECGF was up-regulated in normal uterine endometrium after ovulation (7) , whereas steroidal regulation of PD-ECGF was deficient in ovarian endometriosis during the menstrual cycle (8) . In uterine endometrial cancers, PD-ECGF was dominantly expressed in interstitial cells and contributed to myometrial invasion of the cancer cells and tumor growth in the early stage (9) . In ovarian cancers, PD-ECGF was remarkably highly expressed in some ovarian cancers; however, its levels did not correlate with patient prognosis (10) . In uterine cervical cancers, PD-ECGF was dominantly expressed in interstitial cells, and its levels correlated with microvessel density and patient prognosis (11) .

Among female genital tract cancers, PD-ECGF in the primary tumor of uterine cervical cancers is recognized as a prognostic indicator. On the other hand, the presence of lymph node metastasis, recognized as the most common metastatic lesion, is critical to patients’ prognosis (12, 13, 14, 15) . The prognosis of patients with a high level of PD-ECGF in metastatic lymph node lesions was extremely poor, which indicates that PD-ECGF might contribute to the advancement of metastatic lesions and that the PD-ECGF level in metastatic lesions might be a prognostic indicator (16) . If serum PD-ECGF can be used as a tumor marker, the level of PD-ECGF in serum may become more convenient and popular for clinical usage than PD-ECGF in tumor tissues and metastatic lymph nodes.

SCC antigen, one of 14 subfractions of tumor antigen TA-4 (17, 18, 19, 20, 21, 22, 23) , has been reported to be a reliable tumor marker for SCCs of the uterine cervix (24 , 25) . Its levels correlate well with clinical stage and tumor advancement, including nodal metastasis, and are useful for patient management, especially the monitoring of tumor recurrence and therapeutic response (17, 18, 19, 20, 21, 22, 23, 24, 25) . The aim of this study was to investigate whether serum PD-ECGF in comparison with serum SCC can be used as a tumor marker of uterine cervical cancers.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Specimens.
Consent for the following studies was obtained from all patients and the Research Committee for Human Subjects, Gifu University School of Medicine. One hundred twenty patients ranging from 31 to 74 years of age and 20 volunteers ranging from 31 to 74 years of age provided peripheral blood at the Department of Obstetrics and Gynecology, Gifu University School of Medicine, between January 1992 and July 1996. None of the patients had received any preoperative therapy. The clinical stage of uterine cervical cancers was determined by International Federation of Obstetrics and Gynecology classification (26) .

Tumor size was determined by measurement of the maximum longitudinal diameter of the extirpated tumors. Several microscopic sections from each extirpated tumor with the approximate maximum longitudinal diameter were stained with H&E. All extirpated specimens were histologically examined to demonstrate pelvic lymph node metastasis, PI, and VP as advancement indicators. Intravessel tumor cells in these specimens demonstrated vessel permeation. The histological classification of the tumors was based on WHO criteria.

Enzyme Immunoassay for Determination of Serum PD-ECGF and SCC Antigen Levels.
Serum PD-ECGF and SCC antigen levels were determined by the sandwich enzyme immunoassay of the modified Nishida’s method (27) and by enzyme immunoassay using an IMX SCC kit (Dinabot, Tokyo, Japan), respectively, in triplicate.

Statistics.
Survival curves were calculated using the Kaplan-Meier method and analyzed by the log-rank test. Statistical analysis was performed with Student’s t test. Differences were considered significant when P < 0.05.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Serum SCC levels were significantly (P < 0.05) higher in 72 SCCs (3.37 ± 2.97 ng/ml) compared with 48 adenocarcinomas of the uterine cervix (0.69 ± 0.15 ng/ml) and increased with increasing disease stage in SCCs but not in adenocarcinomas (Fig. 1)Citation . There was no significant difference in serum PD-ECGF levels between SCCs and adenocarcinomas of the uterine cervix and levels increased with increasing disease stage, regardless of histopathological type (Fig. 1)Citation .



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  		Fig. 1. Serum PD-ECGF and SCC levels related to clinical stages in uterine cervical cancers. The clinical stage of SCCs (Sq) and adenocarcinomas (Ad) of the uterine cervix was determined by International Federation of Obstetrics and Gynecology classification (26) .

 
To analyze the correlation between tumor size and serum SCC or PD-ECGF level, the patients with stage Ib and II uterine cervical cancers were selected. There was a significant positive correlation between tumor size and serum SCC level in SCCs (SCC = 0.0540 x tumor size + 0.480; r = 0.839; P < 0.01), but not in adenocarcinomas, as shown in Fig. 2Citation . There was a significant positive correlation between tumor size and serum PD-ECGF level, regardless of histopathological type (SCCs: PD-ECGF = 1.33 x tumor size - 1.50; r = 0.818; P < 0.01; adenocarcinomas: PD-ECGF = 1.32 x tumor size - 4.30; r = 0.842; P < 0.01), as shown in Fig. 2Citation .



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  		Fig. 2. Serum PD-ECGF and SCC levels related to tumor diameter in uterine cervical cancers. Tumor diameter was measured as the maximum longitudinal diameter of the extirpated tumors of stage Ib and II SCCs (Sq) and adenocarcinomas (Ad) of the uterine cervix.

 
In SCC patients, serum SCC levels were significantly (P < 0.05) higher in 36 patients with positive pelvic LN meta compared with 36 patients with negative LN meta (Fig. 3a)Citation , in 44 patients with positive PI compared with 28 patients with negative PI (Fig. 3b)Citation , and in 41 patients with positive VP compared with 31 patients with negative VP (Fig. 3c)Citation . There were no such differences in adenocarcinoma patients (Fig. 3)Citation . Regardless of histopathological type, serum PD-ECGF levels were significantly (P < 0.05) higher in 63 patients with positive LN meta compared with 57 patients with negative LN meta (Fig. 3a)Citation , in 74 patients with positive PI compared with 46 patients with negative PI (Fig. 3b)Citation , and in 69 patients with positive VP compared with 51 patients with negative VP (Fig. 3c)Citation .



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  		Fig. 3. Serum PD-ECGF and SCC levels related to advancement indicators pelvic lymph node metastasis, PI, and VP in uterine cervical cancers. All extirpated specimens were examined histologically. a, pelvic lymph node metastasis; b, PI; c, VP. Sq, SCC; Ad, adenocarcinoma.

 
To analyze patient prognosis related to serum SCC and PD-ECGF levels, the patients with stage II uterine cervical cancer after curative resection were selected. The prognosis of SCC patients with high serum SCC was very poor, whereas the 36-month survival rate of the other SCC patients with low serum SCC was 81.3%. There was no significant difference in the prognosis of adenocarcinoma patients according to serum SCC levels (Fig. 4)Citation . The prognosis of both SCC and adenocarcinoma patients with high serum PD-ECGF was extremely poor, whereas the 36-month survival rate of the other patients with low serum PD-ECGF was 81.3% in SCCs and 80.0% in adenocarcinomas (Fig. 4)Citation .



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  		Fig. 4. Survival rate after curative resection for uterine cervical cancers. All cases of stage II SCCs (Sq) and adenocarcinomas (Ad) of the cervix were divided into two groups with the same number of cases of high and low PD-ECGF or high and low SCC. The prognosis of the patients was analyzed with a 36-months survival rate as follows: a, high (n = 16; >= 34 ng/ml) and low PD-ECGF (n = 16; <34 ng/ml) in Sq; b, high (n = 10; >=34 ng/ml) and low PD-ECGF (n = 10; <34 ng/ml) in Ad; c, high (n = 16; >=1.9 ng/ml) and low SCC (n = 16; < 1.9 ng/ml) in Sq; d, high (n = 10; >=0.7 ng/ml) and low SCC (n = 10; <0.7 ng/ml) in Ad.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
SCC has been recognized as a very reliable marker for tumor advancement including nodal metastasis of SCCs of the uterine cervix (24 , 25) . In the present study, serum SCC levels in patients with SCC of the cervix revealed a significantly positive correlation with clinical stage and tumor size and with the advancement indicators lymph node metastasis, PI, and VP. The prognosis of the patients with high serum SCC was very poor in SCCs. On the other hand, serum SCC in adenocarcinomas was always low, and the levels revealed no positive correlation with clinical stage or tumor size, nor with the advancement indicators lymph node metastasis, PI, and VP. Additionally SCC levels had no correlation with adenocarcinoma patients’ prognoses. Our findings reconfirm that SCC is an excellent tumor marker for SCC of the cervix.

Researchers have attempted to use CA125 as a tumor marker for adenocarcinoma of the cervix. Expression of CA125 was diffusely positive in normal endocervical glands, whereas the expression was significantly decreased in minimal deviation adenocarcinoma of the uterine cervix (28) . Conversely, elevated serum CA125 was detected with large variation of positive ratio in adenocarcinomas of the cervix (29 , 30) . Therefore, CA125 seems not to be a reliable tumor marker for the advancement of uterine cervical cancers.

In the present study, the levels of serum PD-ECGF revealed a significantly positive correlation with clinical stage and tumor size, and with the advancement indicators lymph node metastasis, PI, and VP in both SCCs and adenocarcinomas of the uterine cervix. Furthermore, the prognosis of the patients with high serum PD-ECGF was extremely poor, regardless of histopathological type. Our data indicate that serum PD-ECGF levels reflect the status of advancement of uterine cervical cancers and thus may be recognized as a novel tumor marker for both SCCs and adenocarcinomas of the uterine cervix. Additionally, the levels of PD-ECGF in the serum are only 1,000- to 10,000-fold lower than those in uterine cervical cancer tissues we determined previously (11 , 16) .


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Obstetrics and Gynecology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu City 500-8705, Japan. Phone: 81-58-267-2631; Fax: 81-58-265-9006. Back

2 The abbreviations used are: PD-ECGF, platelet-derived endothelial cell growth factor; TP, thymidine phosphorylase; SCC, squamous cell carcinoma; LN meta, lymph node metastases; PI, parametrial involvement; VP, vessel permeation. Back

Received 12/20/99. Accepted 5/18/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
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