The role of colony-stimulating factor 1 and its receptor in the etiopathogenesis of endometrial adenocarcinoma.
Colony-stimulating factor 1 (CSF-1) is a homodimeric growth factor that humorally regulates the growth and differentiation of mononuclear phagocytes, and locally regulates maternal-fetal interactions during pregnancy. It exerts these actions through a transmembrane tyrosine kinase receptor, colony-stimulating factor 1 receptor (CSF-1R), the product of the c-fms proto-oncogene. Recent studies have demonstrated overexpression of CSF-1 and its receptor in breast, ovarian, and endometrial adenocarcinomas. To further investigate the possible role of CSF-1 and its receptor in the pathogenesis of endometrial adenocarcinoma, a prospective study was undertaken to study CSF-1 expression in benign and neoplastic endometrial epithelium and to compare serum CSF-1 levels in endometrial adenocarcinoma patients with healthy perimenopausal women. The mean serum levels of CSF-1 in 71 patients with endometrial cancer (4.9 +/- 1.8 microgram/liter) were significantly elevated compared with levels found in the 32 controls (3.5 +/- 1.1 microgram/liter). Within the endometrial adenocarcinoma group, circulating CSF-1 levels were significantly elevated in patients with large tumor volume, high grade, myometrial invasion, residual disease, and circulating CA-125 levels. High serum levels of serum CSF-1 were associated with elevated serum CA19-9 and CA-125 levels. Immunohistochemistry results revealed in tumor epithelium intense staining for CSF-1R (27 of 54 cases, 50%) and elevated staining for CSF-1 (41 of 54 cases, 75.9%), with intense staining of CSF-1 in 16 of 54 cases (29.6%). Staining was significantly greater in intensity and number of cells involved in malignant compared with benign epithelium for CSF-1R and CSF-1 (P = 0.05 and <0.0001, respectively). A positive correlation between amount and intensity of CSF-1 and CSF-1R staining in endometrial adenocarcinoma tissue was also demonstrated (P = 0.007). CSF-1 and CSF-1R mRNA was also detected in the tumor samples, confirming the expression of the protein in these tissues. Reverse transcription-PCR demonstrated the presence of mRNA for both the transmembrane and secreted forms of CSF-1 in all tumors analyzed. These results therefore support the hypotheses that CSF-1 and CSF-1R are overexpressed in endometrial adenocarcinoma, that levels of expression significantly correlate with clinicopathological risk factors for poor outcome, and that CSF-1 in association with its receptor via autocrine, juxtacrine, and/or paracrine interactions has a causal role in endometrial adenocarcinoma development and proliferation.
Smith
H O
HO
Department of Obstetrics and Gynecology, Department of Developmental and Molecular Biology, and Department of Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461, USA.
Anderson
P S
PS
Kuo
D Y
DY
Goldberg
G L
GL
DeVictoria
C L
CL
Boocock
C A
CA
Jones
J G
JG
Runowicz
C D
CD
Stanley
E R
ER
Pollard
J W
JW
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D014408:Biomarkers, Tumor / Q000097:blood; D018394:CA-125 Antigen / Q000097:blood; D018395:CA-19-9 Antigen / Q000097:blood; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D005260:Female; D006801:Humans; D007044:Hysterectomy; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008593:Menopause; D008875:Middle Aged; D009367:Neoplasm Staging; D011247:Pregnancy; D000090063:Proto-Oncogene Mas; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis
D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D018395:CA-19-9 Antigen; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor