CXCL12 chemokine genotypes as predictive biomarkers of ovarian cancer outcome

Abstract

Abstract. Ovarian cancer is an aggressive disease with high mortality. The CXCL12 chemokine has been associated with the development of this neoplasia. The aim of this study was to evaluate the genetic influence of the CXCL12-3'A polymorphism as a prognostic/predictive factor in ovarian cancer patients treated with platinum/paclitaxel chemotherapy. The mean survival rates for early stages (I/II) of the disease were statistically different according to patient genotype (96 months for GG and 57 months for A carrier genotypes; p=0.017). The mean progression-free interval was statistically lower in patients with early stages (I/II) of the tumour carrying the A allele (55 months) than in those carrying the GG genotype (91 months; P=0.009). The CXCL12-3'A polymorphism leads to a poorer response to chemotherapy with cisplatin/paclitaxel, and diminishes the mean survival rate and the progression-free interval in patients with ovarian cancer. CXCL12-3'A may therefore serve as an important predictive biomarker for the determination of outcome in ovarian cancer. IntroductionOvarian cancer is the sixth most common type of cancer and ranks seventh as the most frequent cause of cancer-related death in women (4.0% of cases and 4.2% deaths) (1). At diagnosis, the majority of ovarian cancers have already progressed to stage III or IV, which results in poor long-term patient survival and quality of life (2). Standard treatment involves cytoreductive surgery followed by systemic platinumbased chemotherapy (3). Paclitaxel combinations with either cisplatin or carboplatin are first-line chemotherapy regimens, each combination producing similar responses (4). This therapy results in variable efficacy rates, with frequent recurrences at even early stages of the disease, and with most tumours eventually becoming resistant to chemotherapy (5).The biological mechanisms responsible for chemotherapy resistance remain unclear, but it is now widely accepted that the apoptotic capacity of cancer cells is pivotal in determining response to chemotherapeutic targets (6). Phosphatidylinositol 3-kinase (PI3K)/Akt (serine/threonine kinase subfamily) is a major cell survival pathway, and several targets of Akt, such as proapoptotic protein BAD and caspase-9, have roles in the regulation of apoptosis; phosphorylation by Akt inhibits their function (7).Akt overexpression or activation is correlated with poor prognosis in several tumour types, including gastric and hepatocellular carcinoma, breast and pancreatic cancer and melanoma (8). Previous studies have proposed that PI3K/Akt activation in ovarian cancer cells promotes resistance to cisplatin-induced apoptosis, serving as a mediator in chemoresistance (6,7). This activation may occur due to a variety of stimuli in different types of tumours. It has been suggested that one such stimulus is the chemokine CXCL12 (9-12).The chemokine receptor CXCR4 and its sole ligand, SDF-1/CXCL12 (stromal cell-derived factor-1), play important roles in inflammation and hematopoiesis by acting as chemoattractants for...