The CXCR4/CXCL12 axis in endometrial cancer

Abstract

Chemokines and their receptors seem to act as important regulators of the metastatic cascade. CXCL12 and its receptor CXCR4 were shown to be involved in human cancer progression. There is increasing evidences suggesting that the expression of CXCR4 in human cancers is correlated with poor patient prognosis and that CXCR4 neutralization can prevent metastases in vivo. Here we tested the role of the CXCR4/CXCL12 axis in a neoplasia with a reduced risk of metastatic progression, such as human endometrial cancer. CXCR4 and CXCL12 mRNA expression was measured in 41 endometrial cancers and in corresponding not affected tissues. The expression of CXCR4 was predominant in endometrial cancer (P = 0.035) whereas CXCL12 was overexpressed in normal mucosae (P = 0.002). CXCR4 expression (P = 0.035), but not CXCL12, was significantly related to cancer differentiation. Endometrial cancer cells (HEC1A) were able to generate diffuse metastases in peritoneum, lung and liver of CD-1 nude mice, but the simultaneous treatment with a neutralizing anti-CXCR4 monoclonal antibody dramatically reduced the number and the size of metastases in the animals. In conclusion, our data seem to indicate that the CXCR4-CXCL12 axis can play a role in the progression of endometrial carcinoma and that specific therapies with antagonists of chemokines receptors could be of help in the treatment of metastatic patients.

Chemokines and Cancer Progression: A Qualitative Review on the Role of Stromal Cell-derived Factor 1-alpha and CXCR4 in Endometrial Cancer

“…This relationship mirrors the paradigm of expression noted in other cancers; CXCR4-expressing cancer cells are able to migrate to non-cancerous tissues where SDF-1alpha is high in concentration, leading to invasion and metastasis in distant sites. Additionally, CXCR4 mRNA expression was significantly lower in grade 1 tumors compared to grades 2 and 3 tumors indicating that CXCR4 expression tends to increase in poorly differentiated cancers [15]. With regard to CXCR7, no significant difference in mRNA expression between the cancer and paired normal tissues was noted, suggesting that this receptor is not an important factor in endometrial cancer prognosis.…”

“…Muscular infiltration is an important prognostic factor in endometrial cancer. Regional node metastases and distant organ metastases are significantly more likely to occur as the depth of muscular invasion increases [15]. Five human endometrial cancer cell lines and endometrial cancer tissues resected from endometrial cancer patients (N=34) were examined.…”

“…Most recently, Gelmini et al [15] examined mRNA and protein expression of CXCR4, CXCR7, and SDF-1alpha in 41 patients who underwent hysterectomy for the treatment of endometrial cancer. CXCR7 was identified by Burns et al [17] as a novel receptor for SDF-1alpha; in vitro, the interaction of SDF-1alpha and CXCR7 enhanced growth and adhesion of cells from several different cell lines.…”

“…In addition to exploring this pathway in human endometrial cancer tissues, an in vivo mouse model was used to explore the invasive capacity of CXCR4 [15]. Following intraperitoneal injection of the HEC1A human endometrium adenocarcinoma cell line, experimental mice developed distant metastases in the lung, liver, and peritoneum.…”

“…In vitro studies report that SDF-1alpha is a potent stimulator of endometrial cancer cell proliferation [10,11], yet the association between expression of these markers and prognostic factors is inconsistent in the literature [12][13][14][15]. Understanding the association between these proteins and clinical factors may inform therapeutic protocols to better impact survival.…”