OVEREXPRESSION OF EPITHELIAL MACROPHAGE-COLONY-STIMULATING FACTOR (CSF-1) AND CSF-1 RECEPTOR - A POOR PROGNOSTIC FACTOR IN EPITHELIAL OVARIAN-CANCER, CONTRASTED WITH A PROTECTIVE EFFECT OF STROMAL CSF-1

Markedly elevated levels of macrophage colony-stimulating factor (CSF- 1) in the serum and ascites of epithelial ovarian cancer patients have been previously associated with a poor prognosis, However, measuremen ts of circulating CSF-1 cannot separate CSF-1 originating in the cance r cell from that originating in stromal macrophage or fibroblast, To s tudy the prognosis related to expression of CSF-1 and its receptor in primary and metastatic ovarian cancers and to compare the significance of epithelial versus stromal CSF-1 expression, an immunohistochemical study of 130 ovarian carcinomas was performed. Twenty-two stage I and II and 108 stage III and IV primary tumors were studied, Metastatic l esions were also studied in 96 of these 130 cases, 90 of which came fr om those cases with advanced-stage disease, The intensity and extent o f staining for CSF-1 in epithelium and stroma and for epithelial CSF-1 receptor was scored, Kaplan-Meier curves of survival were compared wi th the log-rank test, The Cox regression model was used for multivaria te analysis. In the primary tumors, there was strong expression of CSF -1 receptor in 65%, epithelial CSF-1 in 36%, and stromal CSF-1 in 22%. In the metastases, there was strong staining for CSF-1 receptor in 65 %, epithelial CSF-1 in 41%, and stromal CSF-1 in 15%; strong staining for both CSF-1 receptor and epithelial CSF-1 was noted in 26% of the c ases, When the metastases expressed both CSF-1 receptor and epithelial CSF-1 strongly, a significant decrease in disease-free survival in st age III invasive ovarian cancers was observed (P = 0.043), which was f ound to be an independent prognostic factor (P = 0.007), with an incre ased relative risk of recurrence of 2.3-fold, Although strong staining for stromal CSF-1 in the primary tumor was not found to have prognost ic value, for all stages and for the subsets of stages In and IV and f or stage III alone, the finding of any degree of stromal CSF-1 express ion in the ovary was a favorable prognostic factor for disease-free (P = 0.046) and overall (P = 0.015) survival, This finding was associate d with younger patients (P = 0.007) and low-grade tumors (P = 0.033) a nd was not an independent prognostic factor on multivariate analysis, Among the primary tumors, there was a significant association (P = 0.0 22) between stromal CSF-1 staining and lack of strong coexpression of CSF-1 receptor and epithelial CSF-1; 67 of 94 cases shared these featu res in the primary tumors, In the metastases of invasive stage III cas es, strong staining for stromal CSF-1 was a favorable prognostic facto r for overall survival in the absence of strong CSF-1 receptor stainin g (P = 0.033) and was associated with low-grade tumors (P = 0.0002). W e report that strong expression of epithelial CSF-1 along with its rec eptor in the metastases of ovarian cancer patients appears to be a str ong independent poor prognostic factor for outcome, We find that expre ssion of the same cytokine (CSF-1) in the stroma of the primary tumors is associated with low-grade tumors and lack of strong coexpression o f CSF-1 receptor and epithelial CSF-1, leading to an improved long-ter m outcome, This study may help explain the previous observations that elevated levels of CSF-1 in serum and ascites are associated with a wo rse prognosis in advanced ovarian cancer patients; the results suggest that the source of secreted CSF-1 may largely be the epithelium. The results of this study suggest that paracrine effects of stromal CSF-1 on tumor behavior contrast with those demonstrated when the tumor cell is capable of autocrine intracellular or extracellular interactions b etween CSF-1 and its receptor.