The CXL12/CXCR4/CXCR7 axis in female reproductive tract disease: Review

Abstract

Initial studies on the chemokine stromal derived factor 1 (now referred to as CXCL12) were proposed to be enhanced in several diseases including those which affect the female reproductive tract. These include endometriosis, Asherman's syndrome, endometrial cancers, and ovarian cancers. Additionally, recent studies from our laboratory suggest that CXCL12 signaling is involved in leiomyomas (fibroids). These diseases present an inflammatory/hypoxic environment which further promotes pathology. At first, studies focused on signaling by CXCL12 via its well-known receptor, CXCR4. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in endometrial disease and cancer progression has questioned the potential of "selective blockade"' of CXCR4 to treat these ailments. This review will focus on the signaling and effects of the potent chemokine CXCL12, and its long-known G protein-coupled receptor CXCR4, as well as the alternate receptor CXCR7 on the female reproductive tract and related diseases such as endometriosis, Asherman's syndrome, leiomyomas, endometrial cancer, and ovarian cancer. Although several other mechanisms are inherent to these diseases such as gene mutations, differential expression of miRNAs and epigenetics, for this review, we will focus on the CXCL12/CXCR4/CXCR7 axis as a novel target.

CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

“…Subsequently, it has actually been discovered that PBGF is constitutively expressed by bone marrow stromal cells, so it has been called factor 1 derived from stromal cells (SDF1) [27, 31]. This homeostatic chemokine plays a constitutive role in physiological processes such as embryogenesis, haematopoiesis, angiogenesis [31, 33, 34], development of cardiovascular and nervous systems [35], regulation of different cell functions like differentiation, distribution, activation, immune synapse formation, effector function, proliferation, and survival in the immune system [33]. In contrast to all these physiological functions, it also plays an inflammatory role in many diseases.…”

“…In contrast to all these physiological functions, it also plays an inflammatory role in many diseases. It is involved in different pathological processes, such as HIV infection, neovascularization, chronic inflammatory disorders, tumor growth, distant metastasis formation, and chemoresistance [28, 31, 33, 36–38]. In cancer, the binding between CXCL12 and its receptors causes different pathways activation, that, through cancer cells, migration, angiogenesis, and epithelial to mesenchymal transition (EMT) [39], are involved in tumor initiation and progression [36, 40].…”

“…CXCR4 and ACKR3 can form homo or heterodimers on the cell membrane. Depending on whether CXCL12 binds to its monomeric or dimeric (homo-ether dimer) receptors, different signaling pathways may be activated [33]. In particular, (i) the CXCR4 monomer signaling is preferably mediated by the G proteins which activate the MAPK/PI3K/Akt pathways; (ii) the CXCR4 homodimerization, induced by CXCL12, involves the activation of the JAK/STAT pathway, but it is not known if G proteins or β -arrestin are involved; (iii) the ACKR3 monomer acts as a CXCL12 scavenger and activates ERK 1/2 signaling via β -arrestin; (iv) the CXCR4/ACKR3 heterodimer formation shifts the signaling from G proteins to β -arrestin.…”

Effects of CXCL12/CXCR4/CXCR7 axis on human sperm motility and chemotaxis

“…In the other hand, specific blockade of CXCR7 had no significant effect on sperm motility or calcium concentration. Current studies suggested that although both CXCR4 and CXCR7 were CXCL12 receptors, they might have different biological characteristics in different cells, and be regulated by complex interactions (Krikun, 2018; Hattermann and Mentlein, 2013). In some cases, CXCR7 alone was enough to mediate the metastasis and infiltration of tumor cells after binding with CXCL12 through the activation of the downstream pathways (Sánchez-Martín et al, 2013; Qian et al, 2018).…”

Modulators of CXCR4 and CXCR7/ACKR3 Function

“…Modulation of CXCL12-scavenging activity of ACKR3 regulates CXCR4 function (Abe et al, 2014). Both receptors form heterodimers (Levoye et al, 2009;Fumagalli et al, 2019) and play an important role in CXCL12 biology (Hattermann and Mentlein, 2013;Krikun, 2018;Murphy and Heusinkveld, 2018). The CXCR4/ACKR3/CXCL12 system remains a contemporary target for therapeutic application, and the development of novel, potent, and selective modulators is of great interest to both academia and the pharmaceutical industry.…”