Organ selectivity in metastasis: regulation by chemokines and their receptors

Cancer metastasis results from a non-random process, in which organ selectivity by the tumor cells is largely determined by factors that are expressed at the remote organs that eventually turn into preferred sites of metastasis formation. These factors support the consecutive steps required for metastasis formation, including tumor cell adhesion to microvessel walls, extravasation into target tissue and migration. Of the different components that regulate organ selectivity, instrumental roles were recently attributed to chemokines and their receptors. The present review presents the rationale standing behind the first studies looking at the potential involvement of chemokine-related components in organ selectivity. Based on these studies and many others that followed, the current paradigm is that chemokines that are expressed at specific organs determine to large extent organ specificity by promoting tumor cell adhesion to microvessel walls, by facilitating processes of extravasation into the target tissue and by inducing tumor cell migration. Moreover, chemokines can possibly support additional steps that are required for "successful" establishment of metastases, such as tumor cell proliferation and survival. The review focuses on the CXCL12-CXCR4 pair as the role model in our current understanding of chemokine involvement in organ selectivity. This review also describes the prominent roles played by CCR7 and its corresponding chemokine ligands (CCL21, CCL19) in lymph node metastasis, and of the CCR10-CCL27 axis in melanoma skin survival and metastasis. Overall, the present discussion describes chemokines as important constituents of the tumor microenvironment at metastatic sites, dictating directionality of chemokine receptor-expressing tumor cells, facilitating their adhesion and extravasation, and eventually contributing to organ selectivity.