CCL2/CCR2 signaling in cancer pathogenesis

Abstract

Chemokines are a family of small cytokines, which guide a variety of immune/inflammatory cells to the site of tumor in tumorigenesis. A dysregulated expression of chemokines is implicated in different types of cancer including prostate cancer. The progression and metastasis of prostate cancer involve a complex network of chemokines that regulate the recruitment and trafficking of immune cells. The chemokine CCL2 and its main receptor CCR2 have been receiving particular interest on their roles in cancer pathogenesis. The up-regulation of CCL2/CCR2 and varied immune conditions in prostate cancer, are associated with cancer advancement, metastasis, and relapse. Here we reviewed recent findings, which link CCL2/CCR2 to the inflammation and cancer pathogenesis, and discussed the therapeutic potential of CCL2/CCR2 axis in cancer treatment based on results from our group and other investigators, with a major focus on prostate cancer. Video Abstract.

Fig. 1

Crosstalk between tumor cells and pro-inflammatory factors in the tumor microenvironment further amplifies the extravasation of tumor cells. Tumor cells produce chemokines, such as CCL2, CCL7, CCL8 and CCL13 that drive the generation of multiple types of regulatory immune cells, including T cells, B cells and myeloid-derived suppressor cells (MDSCs), and promote further TAM development by enhancing the recruitment of macrophages to the tumor site. Immune Cells in the modified tumor microenvironment subsequently produce cytokines, chemokines and other molecules that promote immune escape of tumor cells

Fig. 2

A CCR2 inhibitor RS 504393 inhibited xenograft prostate tumor growth in SCID mice fed high fat diet. Tumors were measured weekly with caliper from the initiation of treatment. Tumor volumes were calculated and data were plotted using the geometric mean for each group vs. time. Each point represents the mean tumor volume (± SD) of measurements from the 10 mice in each group

Fig. 3

Treatment with RS 504393 reduced blood levels of free fatty acids in high-fat diet-fed SCID mice bearing LAPC-4 xenograft prostate tumor. LF Con, regular diet-fed control mice; HF Con, high-fat diet-fed control mice; HF RS, high-fat diet-fed mice treated with RS 504393. Columns with different letters indicate significant difference between groups, P < 0.05

Fig. 4

A. Schematic of LNCaP cells chemotactic assay In vitro. A. LNCaP cells migration through 8 μm pore size transwell inserts toward differentiated 3 T3-L1 cells in the bottom wells. B. Migrated LNCaP cells under a light microscope at the undersurface of the inserts were stained with crystal violet (scale bar: 20 μm). C. Cell number assessment of LNCaP cells co-cultured with differentiated 3 T3-L1 cells. **p < 0.01 versus undifferentiated 3 T3-L1 cells; ##p < 0.01 versus differentiated 3 T3-L1 cells

Fig. 5

Interaction between obesity and tumor in promotion of tumor growth. During obesity, White Adipose Tissue WAT releases a plethora of molecules with autocrine, paracrine and endocrine functions including growth factors, adipokines, proinflammatory molecules, fatty acids (FA) and lipid metabolites and many others, which create a favorable condition for prostate cancer to develop