CCR9 homes metastatic melanoma cells to the small bowel.

The question of why certain types of tumors often metastasize to the same organs has intrigued scientists for over a century. In 1889, Paget put forth the ‘‘seed and soil’’ concept that cancer cells (seed) spread in a nonrandom fashion to distant target organs where they are drawn based on a conducive microenvironmental milieu (soil; ref. 1). A second concept that has been around for sometime is that tumor cells express ‘‘homing signals’’ to direct their movement to appropriate microenvironments for growth of metastatic lesions. A homing signal acts like a lighthouse to allow the ship to move toward the land. We have recently come to understand that chemokine receptors displayed on tumor cells allow the tumor cell (seed) to follow a gradient of chemokine to its target organ milieu (soil) that expresses the ligand for this chemokine receptor. The chemokine receptors are seven-transmembrane, G protein–coupled receptors that respond to ligand binding to activate a series of downstream signals that result in a polarized distribution of the actin cytoskeleton to form a leading pseudopod, followed by organization of the uropod cytoskeleton to allow a myosinmediated contraction. This process repeats as the cell senses higher and higher concentrations of the ligand gradient and, as a result, the cell moves up the chemokine gradient and stops when the concentration of the ligand saturates receptors. Chemokine receptors are divided into four classes, based on whether they bind CXC, C, CC, or CX3C chemokines. The CXC chemokine binding receptors (CXCR1-7) bind largely CXC chemokines (CXCL1-16); the C chemokine binding receptor (CR) binds CL1; the CC chemokine receptors (CCR1-10) bind CC chemokines CCL1-27; and the CX3C chemokine receptor binds CX3CL1 (2). Most of these chemokine/chemokine receptor interactions are quite promiscuous such that receptors bindmultiple chemokine ligands and, likewise, the ligands bind a number of receptors. These receptors are abundantly expressed by leukocytes, which, in turn, usually display a number of chemokine receptors, establishing the necessary redundancy to ensure appropriate recruitment of leukocytes to sites of wounding, repair, infection, or inflammation. The expression of chemokines and their receptors is not limited to leukocytes. In fact, most cell and tissue types express chemokines or chemokine receptors at specific stages of differentiation. Chemokine/chemokine receptor engagement results in activation of downstream signals, including phosphatidylinositol 3-kinase; ras/raf/mitogen-activated protein kinase; small GTPases such as Rac, Rho,Cdc42, and others; pAKT; src kinases; DOCK/ELMO; p130Cas; FAK; machinery involved in the organization of the actin cytoskeleton; and PKC-mediated signals that lead to mobilization of intracellular free calcium (3). These events occur in a cyclic fashion that involves local excitation followed by global inhibition, allowing for modulation of the actin cytoskeleton to facilitate extension of pseudopods and retraction of uropods in a continuously cycling manner such that the end result is directed migration up the chemokine gradient. Activation of integrins is an important component of the events required for directed migration. This directed migration is highly important during development, in the immune response, in the inflammatory response, in angiogenesis, and in tumor cell extravasation and intravasation as is essential for metastasis. In addition, a number of transcriptional enhancers are activated by chemokine receptors that allow transcription of factors that modulate apoptosis and cell growth (4). Some of the CXC chemokines stimulate angiogenesis (CXCR1, CXCR2, and several CC chemokine receptors), whereas CXCR3 regulates angiostasis. CXCR4 has been described as angiogenic in some studies (5, for review), but not in others (6). CXCR7 is involved in tumor cell proliferation (7, 8). CXCL12 binds both CXCR4 and CXCR7 (7, 8). Our knowledge of the role of chemokine/chemokine receptor interactions has been developing for >27 years. However, only in the last 6 to 7 years have we come to understand that chemokine receptor display on tumor cells can have a major effect on directed metastasis of tumor cells to organs that strongly express the chemokine ligand for the specific chemokine receptor the tumor cell expresses. Initial documentation of chemokine receptors serving as ‘‘homing signals’’ came from the landmark paper of Muller et al. (9), where CXCR4 chemokine receptor expression in breast cancer tumor cell lines and human ductal breast carcinoma biopsy tissue samples was enhanced, compared with cell lines established from normal mammary gland or the normal mammary gland tissue itself. Muller et al. also correlated expression of CXCR4 with metastasis to distant organs expressing CXCL12, the chemokine ligand for CXCR4 (bone, liver, lung, and lymph node). These early studies have been verified by a host of other studies showing CXCR4 expression in melanoma and a number of other metastatic tumor types (5, 10). Several antagonist for CXCR4/CXCL12 interactions (CXCR4 blocking antibody, CXCR4 small-molecule antagonists, peptide antagonist for CXCR4, small interfering RNA for CXCR4) have been tested in animal models and were shown to inhibit the number or size of tumor metastasis in breast cancer, non–small cell lung cancer, melanoma, renal cancer, osteosarcoma, colorectal cancer, The Biology Behind