CXCR4/CXCL12 axis in non small cell lung cancer (NSCLC) pathologic roles and therapeutic potential

Abstract

Lung cancer is the second most common malignancy and the leading cause of cancer-related death in the western world. Moreover, despite advances in surgery, chemotherapy and radiotherapy, the death rate from lung cancer remains high and the reported overall five-year survival rate is only 15%. Thus, novel treatments for this devastating disease are urgently needed. Chemokines, a family of 48 chemotactic cytokines interacts with their 7 transmembrane G-protein-coupled receptors, to guide immune cell trafficking in the body under both physiologic and pathologic conditions. Tumor cells, which express a relatively restricted repertoire of chemokine and chemokine receptors, utilize and manipulate the chemokine system in a manner that benefits both local tumor growth and distant dissemination. Among the 19 chemokine receptors, CXCR4 is the receptor most widely expressed by malignant tumors and whose role in tumor biology is most thoroughly studied. The chemokine CXCL12, which is the sole ligand of CXCR4, is highly expressed in primary lung cancer as well as in the bone marrow, liver, adrenal glands and brain, which are all sites for lung cancer metastasis. This review focuses on the pathologic role of the CXCR4/CXCL12 axis in NSCLC and on the potential therapeutic implication of targeting this axis for the treatment of NSCLC.

Keywords: Chemokines.; Human; Lung; NSCLC.

Figure 1

Potential roles for CXCR4/CXCL12 in NSCLC. NSCLC tumor cells express CXCR4 and produce CXCL12. Tumor expressed CXCR4 guides metastatic spread to sights such as the brain, bone marrow and liver that express high levels of CXCL12. In addition, CXCR4/CXCL12 interactions act locally in autocrine and paracrine manners to enhance primary tumor growth and to alter its inflammatory milieu. Tumor and tumor microenvironment secreted CXCL12 enhance tumor cell survival and growth and may also guide trafficking of immune and bone marrow derived cells into the tumor microenvironment. Furthermore, alternations in the tumor microenvironment result from the stimulation of tumor cells with CXCL12 that in turn enhance the production of additional chemokines such as the pro-inflammatory and pro-proliferative chemokine CCL20) pro-angiogenic and pro-proliferative chemokine (CXCL1 - IL-8).