Chemokines orchestrate tumor cells and the microenvironment to achieve metastatic heterogeneity.

Chemokines, a subfamily of the cell cytokines, are low molecular weight proteins known to induce chemotaxis in leukocytes in response to inflammatory and pathogenic signals. A plethora of literature demonstrates that chemokines and their receptors regulate tumor progression and metastasis. With these diverse functionalities, chemokines act as a fundamental link between the tumor cells and their microenvironment. Recent studies demonstrate that the biology of chemokines and their receptor in metastasis is complex as numerous chemokines are involved in regulating site-specific tumor growth and metastasis. Successful treatment of disseminated cancer is a significant challenge. The most crucial problem for treating metastatic cancer is developing therapy regimes capable of overcoming heterogeneity problems within primary tumors and among metastases and within metastases (intralesional). This heterogeneity of malignant tumor cells can be related to metastatic potential, response to chemotherapy or specific immunotherapy, and many other factors. In this review, we have emphasized the role of chemokines in the process of metastasis and metastatic heterogeneity. Individual chemokines may not express the full potential to address metastatic heterogeneity, but chemokine networks need exploration. Understanding the interplay between chemokine-chemokine receptor networks between the tumor cells and their microenvironment is a novel approach to overcome the problem of metastatic heterogeneity. Recent advances in the understanding of chemokine networks pave the way for developing a potential targeted therapeutic strategy to treat metastatic cancer.