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CC Chemokines
CXC chemokines can exert direct effects on ECs, whereas CC chemokines contribute to neovascular- ization generally in indirect manners, although direct role of certain CC chemokines has also been reported.
Several CC chemokine members are thought to con- tribute to tumor angiogenic activities, including CCL2 (MCP-1), CCL5 (RANTES), CCL7 (MCP-3), CCL8
(MCP-2), CCL17 (TARC) CCL 20 (LARC/MIP-3α), CCL22 (MDC) and CCL23 (MPIF-1/MIP-3). These chemokines are produced mainly by tumor infiltrating lymphocytes, and some of them also by tumor cells.
They attract circulating mesenchymal cells and tumor cells that have the corresponding CC chemokine recep- tors, and accelerate tumor angiogenesis and distant metastasis. For example, in colon carcinoma model mice, BM-derived CCR1+ immature myeloid cells migrate into tumor invasion front and interact with CCL9+ (putative human homolog of CCL23) tumor cells (Kitamura et al., 2007). CCL2 and CCL5 highly produced by tumor-associated macrophages (TAMs) induce monocyte recruitment and activate progression cascades in human solid tumors.
In conclusion, recent topics of the complexities of tumor vessels and hematogenous metastasis are dis- cussed in this chapter from the viewpoint of TECs and BM-derived cells. Tumor angiogenesis and proin- flammatory microenvironment depend on tumor types, progression stages, host conditions, and so on. Tumors obtain resistance to chemotherapeutic agents dur- ing cyclic administration and tumor vessels poten- tially reconstruct alternative angiogenic pathways in response to VEGF-targeting therapies. Detailed stud- ies will provide us important information for better management of vascular-targeting therapies against highly malignant tumors including glioblastomas and metastatic brain tumors.

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