Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response

Abstract

The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8(+) and CD4(+) T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples.

Figure 1

Schematic illustrate of this review. (a) Chemokine receptors expressed on cancer cells in cancer metastasis. (b) Chemokines derived from cancer cells in cancer progression.

Figure 2

Marked inhibitory effect of the CXC chemokine receptor 4 (CXCR4) antagonist AMD3100 on experimental peritoneal carcinomatosis in gastric cancer. Photographs show representative results of phosphate‐buffered saline (PBS)‐treated mice and AMD3100‐treated mice 40 days after intraperitoneal inoculation of CXCR4‐expressing NUGC4 cells. Treatment with PBS or AMD3100 was carried out daily starting from the day of tumor inoculation. Ascites fluids and omental tumors in the abdominal cavity are shown.

Figure 3

The CXCL12–CXC chemokine receptor 4 (CXCR4) axis plays a pivotal role in peritoneal carcinomatosis of gastric cancer and novel therapeutic strategies targeting CXCR4 for peritoneal carcinomatosis of gastric cancer. The molecular mechanisms that promote the development of peritoneal carcinomatosis. CXCR4‐expressing gastric carcinoma cells are preferentially attracted to the peritoneum cavity where their ligand CXCL12 is produced abundantly. CXCL12 produced by peritoneal mesothelial cells acts on proliferation and survival of CXCR4‐expressing gastric carcinoma in the peritoneal cavity in a paracrine manner. CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma and especially beneficial for patients with i.p.‐free cancer cells without macroscopic peritoneal metastasis.

Figure 4

High‐level expression of cancer cell‐derived CXCL16 correlates with increased tumor‐infiltrating lymphocytes and a good prognosis in colorectal cancer. (a) Tumor‐infiltrating lymphocyte (TIL) counts. CD8⁺ and CD4⁺ cells were counted in five randomly selected areas at the tumor border for each case. The average TIL counts were plotted and compared between weak and strong CXCL16 expression groups. The number of CD8⁺ and CD4⁺ cells was significantly increased in the strong group compared with the weak group. (b) Kaplan–Meier survival curves of 58 colorectal cancer patients. The strong CXCL16 expression group had significantly longer survival than the weak CXCL16 expression group (Log‐rank, P = 0.041).

Figure 5

Cancer cell‐derived chemokines: friends or enemies? Cancer cell‐derived chemokines have conflicting aspects: positive or negative regulation of cancer progression. Immature myeloid cells (iMC) are recruited by cancer cell‐derived CCL9, and tumor‐associated macrophages (TAM) by CCL2, CCL3, and CCL5. Consequently, CCL9, CCL2, CCL3, and CCL5 induce the invasion of cancer cell via abundant matrix metalloproteinases produced by infiltrating iMC and TAM in cancer tissue. In contrast, CXCL16 and CX3CL1 inhibit cancer progression. CXCL16 and CX3CL1 guide tumor‐infiltrating lymphocytes (TIL), especially, CD8⁺ and CD4⁺ T cells, into cancer tissue. A fraction of TIL attracted by CXCL16 may be directed to cancer cells, leading to a certain degree of anticancer immunity.