Organ selectivity in metastasis: regulation by chemokines and their receptors

Abstract

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.

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

“…By using a mouse metastatic model we were also able to establish that CXCR4 or CCR7 activity is required by breast cancer cells to survive in vivo within the lungs. Interestingly, adhesion to endothelium and extravasation of cancer cells were the two major steps in a metastatic cascade that were previously suggested to be affected by chemokine receptor activation 22 with the evidence mainly derived from in vitro cellular assays. In contrast with these reports our in vivo experiments show that the silencing of either CXCR4 or CCR7 did not change the rate of the initial arrest of cancer cells but critically reduced the number of metastatic breast cancer cells persisting in the lung 2 days after intravenous injection.…”

CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model

“…There are 18 to 22 chemokine receptors that bind more than 40 ligands (2). In the adult organism, the physiologic role of these receptor/chemokine pairs is to direct migration, chiefly of inflammatory and immune cells, to sites of tissue injury or inflammation.…”

“…injection into syngeneic BALB/c mice. Cells are grown in DMEM, supplemented with 10% fetal bovine serum (Gemini Bioproducts), 1.5 mg/mL sodium bicarbonate, 2 mmol/L L-glutamine, 100 Amol/L nonessential amino acids, 100 units/mL penicillin, and 100 units/mL streptomycin in a 10% CO 2 atmosphere.…”

“…Since the first description of chemokine receptors on malignant cells (1), an extensive literature has developed describing the expression and function of chemokine receptors in many malignancies. CXCR4 and CCR7 expression, in particular, is associated with more aggressive disease in many malignancies (1,2). Considerably less is known about the role of the related chemokine receptor, CXCR3, which binds the ligands CXCL9, CXCL10, and CXCL11.…”

Changes in gene expression of CXCR4, CCR7 and BCL2 after treatment of breast cancer cells with saponin extract from Tribulus terrestris

“…The high level of CXCR4 mRNA in tumor cells is believed to be involved in their survival under hypoxia [28]. Further, overexpression of CXCR4 has been associated with metastases formation and poor prognosis of patients with breast and other types of cancer [29][30][31], which explains the significant interest towards CXCR4 inhibitors [32,33].…”