Site-specific metastasis formation: chemokines as regulators of tumor cell adhesion, motility and invasion

Abstract

The metastatic spread of tumors is a well-coordinated process in which different types of cancers tend to form metastases in defined organs. The formation of site-specific metastases requires full compatibility between the intrinsic properties of the tumor cells and the tumor microenvironment. It was recently found that chemokines which are expressed in specific loci promote the adhesion, migration and invasion of tumor cells that express the corresponding receptor(s). Of the different members of the family, the CXCL12 chemokine and its cognate CXCR4 receptor are the prototypes of this process, although other members of the family (e.g. CCR7 and CCR10) also play a role in determination of the metastatic spread. This commentary addresses the fundamental roles of chemokines and their receptors in site-specific metastasis, with emphasis on CXCL12-CXCR4. The article also describes some of the efforts that were performed thus far in order to identify the intracellular components involved in this process. The focus is put on the roles played by proteins that regulate adhesion and migration of tumor cells in response to CXCL12, including mainly focal adhesion kinase (FAK), Pyk2/RAFTK and members of the Rho family of GTPases (RhoA, Rac, Cdc42). This is followed by discussion of open questions that need to be addressed in future research, and of the potential therapeutic implications of the findings that are available to date in this field.

Figure 1

Chemokines and additional microenvironmental factors in site-specific metastasis. Chemokines are important contributors to site-specific metastasis formation and they constitute a part of a very complex microenvironment that interacts with tumor cells that have reached the potential metastatic sites. In this respect, only a full compatibility between the chemokine/additional microenvironmental factor (one or more) and the corresponding properties of the tumor cells would support a successful and full-blown metastatic process. (A) The microenvironment counterpart of the process: successful establishment of metastasis is dictated by factors that are expressed at the microenvironment of the potential metastatic site(s), chemokines and others. (#1) Full compatibility between the factors that are found at the potential metastatic site (chemokines such as CXCL12 and others) and receptors that are expressed by the tumor cells supports the successful establishment of metastases. (#2, #3) The lack of essential chemokine/s, or of other tumor-supporting factor(s) reduces the efficacy of metastasis formation, or leads to failure of this process, despite the fact that receptors for both are expressed by the tumor cells. (B) The tumor counterpart of the process: successful establishment of metastasis is dictated by the array of receptors that are expressed by the tumor cells. Although the potential metastatic site is enriched with the essential tumor-promoting chemokines/additional microenvironmental factors, the metastatic process can not reach its maximal potential or fails, because the tumor cells lack the expression of the required receptor(s) for these factors (or express non-functional receptors). (C) The microenvironment at the potential metastatic site is diverse and complex, including a large array of pro-malignancy factors [chemokine(s) and other(s)] whose activities complement each other, therefore together amplifying the metastatic process. (#1) A microenvironment enriched with all the potential tumor-supporting factors can interact with tumor cells that express functional receptors for all these factors, together leading to the most intensified levels of metastasis. (#2, #3, #4) A microenvironment that lacks one or more of the essential factors would not enable the formation of full-blown metastatic process, although the tumor cells express the required receptors.