CXCL12-CXCR4/CXCR7 Axis in Colorectal Cancer: Therapeutic Target in Preclinical and Clinical Studies

Abstract

Chemokines are chemotactic cytokines that promote cancer growth, metastasis, and regulate resistance to chemotherapy. Stromal cell-derived factor 1 (SDF1) also known as C-X-C motif chemokine 12 (CXCL12), a prognostic factor, is an extracellular homeostatic chemokine that is the natural ligand for chemokine receptors C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or cluster of differentiation 184 (CD184) and chemokine receptor type 7 (CXCR7). CXCR4 is the most widely expressed rhodopsin-like G protein coupled chemokine receptor (GPCR). The CXCL12–CXCR4 axis is involved in tumor growth, invasion, angiogenesis, and metastasis in colorectal cancer (CRC). CXCR7, recently termed as atypical chemokine receptor 3 (ACKR3), is amongst the G protein coupled cell surface receptor family that is also commonly expressed in a large variety of cancer cells. CXCR7, like CXCR4, regulates immunity, angiogenesis, stem cell trafficking, cell growth and organ-specific metastases. CXCR4 and CXCR7 are expressed individually or together, depending on the tumor type. When expressed together, CXCR4 and CXCR7 can form homo- or hetero-dimers. Homo- and hetero-dimerization of CXCL12 and its receptors CXCR4 and CXCR7 alter their signaling activity. Only few drugs have been approved for clinical use targeting CXCL12-CXCR4/CXCR7 axis. Several CXCR4 inhibitors are in clinical trials for solid tumor treatment with limited success whereas CXCR7-specific inhibitors are still in preclinical studies for CRC. This review focuses on current knowledge of chemokine CXCL12 and its receptors CXCR4 and CXCR7, with emphasis on targeting the CXCL12–CXCR4/CXCR7 axis as a treatment strategy for CRC.

The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis

“…CAFs are the biggest source of CXCL12 release in the tumor microenvironment (TME), which is further stimulated by TGF-β1 [ 61 , 62 ]. This CXCR4/CXCL12 axis has been reported to play an important role in CRC invasion and metastasis, and is being assessed as a therapeutic CRC target [ 63 ].…”

Study On the Mechanism of LMP2A Maintaining Epstein-barr Virus Latency Infection Through Interaction With CXCR4

“…as its typical ligand [11]. CXCR4 is highly expressed in various types of tumor cells and tissues, and can be involved in tumor growth, invasion, angiogenesis and metastasis, such as breast cancer, colorectal cancer, pancreatic cancer, etc.…”

Cancer-Associated Fibroblasts and Tumor Cells in Pancreatic Cancer Microenvironment and Metastasis: Paracrine Regulators, Reciprocation and Exosomes

“…Further study is needed to answer why outcome between the study with CXCR4 inhibitor and with Cxcr4 loss are inconsistent. CXCL12 binds CXCR7 with higher affinity than CXCR4 [53]. High CXCR7 expression is associated with shorter overall survival of pancreatic cancer patients.…”

“…Lack of NF-κB subunit Nfkb1 in PSCs reduces CXC12 secretion, increases infiltration of CD8 + T cells, inhibits tumor growth, and improves host survival, evaluated by orthotopic co-injection experiments with primary tumor cells from KPC mice and PSCs [52]. CXCL12 is the ligand for the chemokine receptor CXCR4 (also known as Fusin or CD184) and CXCR7 (also known as atypical chemokine receptor 3, ACKR3) (Figure 3) [53]. Treatment with AMD3100 (plerixafor), a CXCR4 antagonist, attenuates tumor growth after co-injection of tumor cells from KPC mice and PSCs [52].…”