Lysophosphatidic acid uses cyclin D1 to stimulate ovarian cancer growth

US-based cancer researchers have discovered that lysophosphatidic acid (LPA), a normal constituent of blood, can directly promote the growth of ovarian tumors by upregulating cyclin D1.

“This [finding] should facilitate developing strategies to treat ovarian cancer by inhibition of LPA, its receptors, and the LPA signaling pathways,” Dr. Robert B. Jaffe of the University of California in San Francisco told Reuters Health.Cyclin D1, a key regulator of cyclin-dependent kinase activity, is believed to play an important role in oncogenesis, Dr. Jaffe and colleagues explain in the May 21st issue of the Journal of the National Cancer Institute. Overexpression of the gene has been observed in many types of cancer including ovarian cancer.In their study, Dr. Jaffe and colleagues found that four of six ovarian cancer cell lines overexpressed cyclin D1 relative to levels in normal ovarian epithelial cells. They also found that LPA treatment led to a roughly 3-fold increase in cyclin D1 promoter activity in cultured ovarian cancer cells but not in normal ovarian cells. LPA appears to act mainly through the EDG4-mediated pathways.Previously in JNCI, Dr. Jaffe and colleagues reported that LPA, at concentrations present in ascitic fluid, indirectly stimulates the growth of malignant ovarian tumors by stimulating vascular endothelial growth factor (VEGF), a key angiogenic factor.”This lends additional support for the treatment of ovarian cancer and ascites by blocking the action VEGF, which we have shown is very effective in a nude mouse model of ovarian cancer with ascites, particularly when combined with a chemotherapeutic agent,” Dr. Jaffe told Reuters Health.Taken together, these studies suggest to the team that “dual mechanisms are probably involved in LPA stimulation of ovarian tumor growth in vivo – an indirect endothelial cell-dependent mechanism that involves increasing angiogenesis via VEGF and a direct endothelial cell-independent mechanism that involves increasing cell proliferation via cyclin D1.”Finding ways to block these two distinct pathways may lead to new therapies for ovarian cancer, the researchers say.(Source: J Natl Cancer Inst 2003;95:733-740: Reuters Health: May 22, 2003: Oncolink)