Role of eotaxin-1 signaling in ovarian cancer.
OBJECTIVE
Tumor cell growth and migration can be directly regulated by chemokines. In the present study, the association of CCL11 with ovarian cancer has been investigated.


RESULTS
Circulating levels of CCL11 in sera of patients with ovarian cancer were significantly lower than those in healthy women or women with breast, lung, liver, pancreatic, or colon cancer. Cultured ovarian carcinoma cells absorbed soluble CCL11, indicating that absorption by tumor cells could be responsible for the observed reduction of serum level of CCL11 in ovarian cancer. Postoperative CCL11 levels in women with ovarian cancer negatively correlated with relapse-free survival. Ovarian tumors overexpressed three known cognate receptors of CCL11, CC chemokine receptors (CCR) 2, 3, and 5. Strong positive correlation was observed between expression of individual receptors and tumor grade. CCL11 potently stimulated proliferation and migration/invasion of ovarian carcinoma cell lines, and these effects were inhibited by neutralizing antibodies against CCR2, CCR3, and CCR5. The growth-stimulatory effects of CCL11 were likely associated with activation of extracellular signal-regulated kinase 1/2, MEK1, and STAT3 phosphoproteins and with increased production of multiple cytokines, growth factors, and angiogenic factors. Inhibition of CCL11 signaling by the combination of neutralizing antibodies against the ligand and its receptors significantly increased sensitivity to cisplatin in ovarian carcinoma cells.


CONCLUSIONS
We conclude that CCL11 signaling plays an important role in proliferation and invasion of ovarian carcinoma cells and CCL11 pathway could be targeted for therapy in ovarian cancer. Furthermore, CCL11 could be used as a biomarker and a prognostic factor of relapse-free survival in ovarian cancer.
University of Pittsburgh Cancer Institute, Department of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Vera
V
Levina
Brian M
BM
Nolen
Adele M
AM
Marrangoni
Peng
P
Cheng
Jeffrey R
JR
Marks
Miroslaw J
MJ
Szczepanski
Marta E
ME
Szajnik
Elieser
E
Gorelik
Anna E
AE
Lokshin
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054413:Chemokine CCL11 / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D016207:Cytokines / Q000032:analysis; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000032:analysis; D054390:Receptors, CCR2 / Q000378:metabolism; D054397:Receptors, CCR3 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000032:analysis
C515334:CCR2 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D016207:Cytokines; D010750:Phosphoproteins; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D014157:Transcription Factors