The countercurrent principle in invasion and metastasis of cancer cells. Recent insights on the roles of chemokines

Chemokine production by cancer cells constitutes a duality. Leukocyte recruitment under the pressure of chemokines may be beneficial for the host or for the tumor. Here, the emphasis will be on the detrimental effects of chemokines in tumor biology. A decade ago, the countercurrent principle of tumor-derived chemokine and peritumoral protease production was formulated to explain chemokine expression as a selective advantage for specific tumors and as a phenotype of invasive and metastasizing cancer cells. Chemoattracted leukocytes may provide trophic factors and produce invasion and metastasis-promoting proteinases. On the basis of the consensus sequence glutamic acid-leucine-arginine (ELR) preceding the canonical cysteine-any amino acid-cysteine (CXC), ELR-positive CXC chemokines, such as interleukin-8 and granulocyte chemotactic protein-2, are angiogenic and thus instruct the host to feed the tumor and bring the vessels into closer contact with the tumor cells. These mechanisms may enhance lymphogenic and hematogenic metastasis. Recent research and proofs of this countercurrent concept are here reviewed and compared. In addition, we discuss how alterations in chemokine ligand and receptor expression profiles may contribute to tumor growth, invasion, metastasis and immune evasion. These comparisons imply practical consequences for future cancer diagnosis and therapy. The implications include methods to diminish metastasis by inhibiting angiogenic CXC chemokine ligands and receptors, therapeutic combinations of chemokine overexpression with antigenic stimuli and co-treatment with angiostatic chemokines and tumor antigens.