Role of Eotaxin-1Signaling in Ovarian Cancer

Purpose: Tumor cell growth and migration can be directly regulated by chemokines. In the present study, the association of CCL11with ovarian cancer has been investigated. Experimental Design and Results: Circulating levels of CCL11in 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 CCL11in ovarian cancer. Postoperative CCL11levels 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. CCL11potently 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. Conclusion: 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, CCL11could be used as a biomarker and a prognostic factor of relapse-free survival in ovarian cancer. In western and northern Europe as well as in the United States, ovarian cancer represents the third most frequent cancer of the female genital tract. Worldwide, there are an estimated 191,000 women newly diagnosed each year (1 - 3). The majority of early- stage cancers are asymptomatic, and over three-quarters of the diagnoses are made at a time when the disease has already established regional or distant metastases. With presently available platinum-based chemotherapy, the 5-year survival for patients with clinically advanced ovarian cancer is only 15% to 20%, although the cure rate for stage I disease is usually >90% (1 - 3). Therefore, identification of factors and pathways respon- sible for the accelerated cancer growth is of critical importance