There has been an increasing recognition that the tumor microenvironment contains host non-cancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with non-tumor cells, and the cancer cells may compete and/or cooperate with each other. It has been demonstrated that these interactions can alter the genotype and phenotype of the host cells as well as the cancer cells. The interaction of these cancer and host cells to remodel the normal host organ microenvironment may best be conceptualized as an evolving ecosystem. Describing tumors as ecological systems defines new opportunities for novel cancer therapies (“ecological therapy”). The ecology literature is filled with stories of how changing the ecosystem resulted in the death of a species. A key method, therefore, to kill cancer cells in the tumor ecosystem may be to inhbit other cell species within the environment that are supporting the growth and survival of cancer cells.

Chemokines are a family of small and secreted proteins that play pleiotropic roles in inflammation-related diseases, including cancer. Among the identified 50 human chemokines, chemokine (C-C motif) ligand 2 (CCL2) is of particular importance in cancer development since it serves as one of the key mediators of interactions between tumor and host cells. CCL2 is produced by cancer cells and multiple different host cells within the tumor microenvironment. In the bone marrow microenvironment, for example, it is produced by osteoblasts, osteoclasts, and endothelial cells. CCL2 mediates tumorigenesis in many different cancer types and has been reported to promote cancer cell proliferation, migration, invasion, and survival, via binding to its functional receptor CCR2. Most importantly, however, CCL2 induces the recruitment of monocytes to the tumor and their subsequent differentiation into tumor associated macrophages (TAMS). Upon CCL2 stimulation, CD11b(+) cells demonstrated a significant increase in the mannose receptor (CD206) and the CD14(+)/CD206(+) double-positive cells, suggesting a polarization of macrophages toward the CD206(+) M2-type phenotype. TAMs subsequently are major mediators of angiogenesis and matrix remodeling. CCL2 protects macrophages from autophagic death by activating survivin through a PI3K/AKT (phosphatidylinositol 3-kinase/protein kinase B)-dependent mechanism, increasing their ability to survive in the hypoxic tumor microenvironment. CCL2 induces up-regulation of the antiapoptotic proteins cFLIP(L) (cellular caspase-8 (FLICE)-like inhibitory protein), Bcl-2, and Bcl-X(L) and inhibits the cleavage of caspase-8 and subsequent activation of the caspase-cascade, thus protecting cells from apoptosis under serum deprivation stress.

Multiple studies have revealed that inhibition of CCL2 substantially decreases macrophage infiltration, decreases osteoclast function, and inhibits prostate cancer growth in bone in preclinical animal models. In one study, for example, utilizing neutralizing antibodies to human CCL2 (CNTO888) and the mouse homologue CCL2/JE (C1142), treatment with anti-CCL2/JE antibody (2 mg/kg, twice weekly i.p.) attenuated prostate cancer cell PC-3Luc-mediated overall tumor burden in an in vivo model of prostate cancer metastasis by 96% at 5 weeks post intracardiac injection.

These preclinical data have been successfully translated to the clinic. SWOG study S0916, for example, was a phase II, window trial of an anti-CCR2 antibody in patients with bone metastases. This biomarker driven study was designed to test the hypothesis that inhibiting the CCL-2-CCR2 axis in patients with cancer metastatic to bone osteoclast function would be inhibited as measured by a decrease in urinary NTX by 25% or more from baseline. Patients were given three doses of antibody two weeks apart and urinary NTX was measured at baseline, two weeks, 4 weeks, and 6 weeks. Preliminary results suggest that administration of anti-CCR2 antibody resulted in decreases in urinary NTX in a significant number of patients. These data suggest that altering the tumor microenvironment through inhibition of CCL2 may be a viable strategy for interfering with cancer cell activity and growth. This example of translation from bench to bedside demonstrating how an understanding chemokine effects on the tumor ecosystem can serve as a paradigm for other cytokines, chemokines, and cell interactions within the tumor microenvironment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PL06-04.