Chemokine Receptor CXCR4 Expression in Patients With Melanoma and Colorectal Cancer Liver Metastases and the Association With Disease Outcome

The mechanisms of cancer metastasis are still debated more than 100 years after the “seed and soil” theory was hypothesized by Paget.1 Through his experience with breast cancer patients, Paget theorized that cancers metastasize preferentially to organs or sites that support and/or nurture the growth of cancer cells. Ewing later countered that patterns of blood flow from the primary tumor could entirely account for the patterns of metastasis.2 His “mechanical” hypothesis predicted that the circulation would deliver the greatest metastatic tumor burden to the first organ encountered.3 Neither model is absolute, as clinical examples of exceptions to both exist.4 In light of these deficiencies, new mechanisms have been sought and a recent addition to these theories is the signaling or “homing” hypothesis. This mechanism is based upon the complex signaling patterns that occur in organogenesis, development, hematopoeisis, and immune responses. As such, it incorporates principles from both seed-and-soil and mechanical hypotheses. In the signaling or homing mechanism for cancer metastasis, cancer cells are drawn to specific metastatic sites as a result of a complex interchange of signals.5 Key mediators in this mechanism are chemokines, which are chemoattractive signaling molecules that function in a myriad of cell trafficking events. Chemokines attained, perhaps, their greatest notoriety when the chemokine receptor CXCR4 was identified as a coreceptor for T-tropic HIV-1 and HIV-2.6–8 Since then, intense research with chemokines has led to the discovery that these chemoattractive molecules may play a significant role in cancer metastasis. Currently, chemokines and their respective receptors have been identified as contributing metastatic factors in numerous cancers.9–20 Muller et al9 and Zeelenberg et al10 have provided compelling in vivo data in murine models to implicate chemokine receptors in the metastatic progression of cancers to the liver. Such chemokines and receptors are typically quiescent in many normal tissues, with the notable exception of immune cells, and appear to be activated or up-regulated in cancer. Activation of chemokine receptors promotes the growth, adhesion, and most importantly directional migration of immune cells during antigen-specific inflammatory responses.21–23 Evidence now indicates that cancer cells exploit these innate signaling mechanisms to yield specific targeted metastasis. Recently, our group identified the significance of chemokine receptor CXCR4 expression in patients with colorectal cancer (CRC).24 We demonstrated a significant association between high CXCR4 gene expression of primary CRC tumors and poor clinical outcomes. This finding was concordant with reports in other cancers identifying a correlation of CXCR4 expression with disease outcome.19,20,25–27 Our report also noted an up-regulation of CXCR4 gene expression in liver metastases compared with primary tumors and identified a potential chemoattractive relation between CRC CXCR4 receptors and the liver, which is a rich source of CXCL12, the specific ligand for CXCR4.9 In the present study, we hypothesized that cancers that have metastasized to the liver may express the same or similar chemokine receptors (CR). We selected CRC based on our previous report24; we selected melanoma because of its propensity for hepatic metastasis demonstrated by postmortem examination.28,29 Our objective was to determine the role of CR in patients with liver metastases of these 2 different cancers and to evaluate the clinical relevance of CR expression in both groups of patients.