Upregulation of bikunin in tumor-infiltrating macrophages as a factor of favorable prognosis in ovarian cancer.
OBJECTIVE
This study was carried out to clarify the localization of bikunin, a Kunitz-type protease inhibitor, and relation between expression of individual bikunin protein and ovarian cancer progression.


METHODS
We performed a retrospective study on the immunohistochemical expression of bikunin, urokinase-type plasminogen activator (uPA) and macrophages (CD68) in surgical specimens derived from 89 ovarian cancer patients to investigate correlations between the expression of bikunin and the clinicopathologic features and the prognosis. Furthermore, bikunin and uPA levels were measured by immunoblot analysis.


RESULTS
Immunohistochemical staining revealed that the localization of bikunin was similar to that of CD68 for macrophages. We identified high expression of bikunin in 40 (45%) of 89 ovarian cancers. The results of Western blot analysis showed a significant correlation with immunohistochemical data. There was a significant inverse correlation between bikunin levels and uPA levels in ovarian cancer tissues. High bikunin expression was an independent predictor for disease-free survival (P = 0.040) and overall survival (P = 0.042). The 5-year survival rate of the 49 patients with low bikunin expression in ovarian cancers was 39%, whereas that of the other 40 patients with high bikunin expression was 63%. In addition, macrophage-derived bikunin protein was induced by exogenous IL-6.


CONCLUSIONS
Bikunin derived from tumor-infiltrating macrophages might be a prognostic indicator as an antiinvasive factor supplied from macrophages within and around the tumor possibly through down-regulation of tumor-associated uPA expression.
Tanaka
Yoshiko
Y
Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
Kobayashi
Hiroshi
H
Suzuki
Mika
M
Kanayama
Naohiro
N
Suzuki
Mitsuaki
M
Terao
Toshihiko
T
D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D015153:Blotting, Western; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome; D014360:Trypsin Inhibitor, Kunitz Soybean / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D006133:Growth Substances; D008562:Membrane Glycoproteins; D014360:Trypsin Inhibitor, Kunitz Soybean; D014568:Urokinase-Type Plasminogen Activator; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C109148:SPINT2 protein, human