Elevated nm23 protein expression is correlated with diminished progression-free survival in patients with epithelial ovarian carcinoma.
OBJECTIVE
The role of the candidate metastasis-suppressor gene nm23-H1 first characterized in breast cancer remains controversial, with both metastasis suppression and disease progression being linked to elevated nm23-H1 gene expression in different human tumor types. We sought to characterize (1) the pattern and intensity of nm23-H1/nucleoside diphosphate (NDP) kinase expression in human epithelial ovarian carcinoma (EOC) and (2) the relationship between nm23-H1/NDP kinase expression and tumor extent at diagnosis (FIGO stage) and response to treatment as defined by progression-free survival and actuarial survival.


METHODS
Twenty-four patients with EOC aged 61.1 +/- 13.0 (mean +/- SD) years were followed for 614.0 +/- 289.7 days after a debulking procedure, cisplatin-based chemotherapy (19 of 24), and second-look laparotomy (9 of 24). After the primary debulking procedure, 63% of patients had no or microscopic residual disease. Overnight incubation of formalin-fixed tumor sections at 4 degree C with primary rabbit polyclonal IgG antibody to human nm23-H1/NDP kinase was followed by detection with standard ABC method. Nonimmune rabbit serum and normal breast tissue served as controls. Immunohistochemical staining was graded by a clinically blinded observer for intensity of staining (0, negative; 1, weak; 3, strong), pattern of staining (focal or diffuse), and histologic grade of tumor (1 through 4).


RESULTS
Of the EOCs, 54% were histologic grade 3 or 4 and 58% were FIGO stage III; 88% (21 of 24) stained positively, and 18 of 21 stained strongly and 14 of 21 stained diffusely. No correlation was found between either intensity or pattern of nm23-H1/NDP kinase immunostaining and histologic grade. No correlation was found between either staining pattern or intensity and FIGO stage. There was a trend toward decreased actuarial survival with both focal pattern (P = 0.12, log-rank test) and strong intensity (P = 0.15, log-rank test) of nm23-H1 staining. Decreased progression-free survival was likewise correlated with focal nm23-H1/NDP kinase immunostaining pattern (P = 0.02, log-rank test) and strong intensity of nm23-H1/NDP kinase staining (P = 0.08, log-rank test).


CONCLUSIONS
Expression of nm23-H1/NDP kinase is strongly upregulated in most EOCs. Redundant overexpression of nm23-H1/NDP kinase may contribute to deranged cell cycle progression and EOC proliferation. Pattern and intensity of nm23-H1/NDP kinase immunostaining of EOC tissue retrieved at primary operation may identify patients at risk for tumor progression and help guide treatment strategies. These findings suggest that nm23-H1 gene expression may have distinct if not opposite biologic functions in EOC and breast carcinoma.
Srivatsa
P J
PJ
Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Cliby
W A
WA
Keeney
G L
GL
Dodson
M K
MK
Suman
V J
VJ
Roche
P C
PC
Podratz
K C
KC
D000293:Adolescent; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; D009367:Neoplasm Staging; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*
D054778:NM23 Nucleoside Diphosphate Kinases; D014157:Transcription Factors; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D020559:Monomeric GTP-Binding Proteins