Role of chemokine network in the development and progression of ovarian cancer: a potential novel pharmacological target

Abstract

Ovarian cancer is the most common type of gynecologic malignancy. Despite advances in surgery and chemotherapy, the survival rate is still low since most ovarian cancers relapse and become drug-resistant. Chemokines are small chemoattractant peptides mainly involved in the immune responses. More recently, chemokines were also demonstrated to regulate extra-immunological functions. It was shown that the chemokine network plays crucial functions in the tumorigenesis in several tissues. In particular the imbalanced or aberrant expression of CXCL12 and its receptor CXCR4 strongly affects cancer cell proliferation, recruitment of immunosuppressive cells, neovascularization, and metastasization. In the last years, several molecules able to target CXCR4 or CXCL12 have been developed to interfere with tumor growth, including pharmacological inhibitors, antagonists, and specific antibodies. This chemokine ligand/receptor pair was also proposed to represent an innovative therapeutic target for the treatment of ovarian cancer. Thus, a thorough understanding of ovarian cancer biology, and how chemokines may control these different biological activities might lead to the development of more effective therapies. This paper will focus on the current biology of CXCL12/CXCR4 axis in the context of understanding their potential role in ovarian cancer development.

Figure 1

Chemokine subfamilies classification. The first cysteine (C) in the sequence forms a covalent bond with the third, the second and the fourth cysteines also form a disulfide bond to create the tertiary structure characteristic of chemokines. In the CC subfamily the first two cysteines are adjacent to each other, in the CXC group there is one amino acid between the first two cysteines, and in the CX3C group there are three amino acids between cysteines.

Figure 2

Signaling pathways downstream CXCR4 receptor activation. Upon CXCL12 binding the G protein complex dissociates into α and βγ subunits that trigger parallel signal transduction cascades culminating in tumor cell proliferation, migration, or survival. AC: adenylyl cyclase; ER: endoplasmic reticulum; PLC: phospholipase C; PI3K: phosphoinositide 3-kinase; PKB/Akt: protein kinase B; PKC: protein kinase C; PYK2: proline-rich tyrosine kinase 2; ERK1/2: extracellular regulated kinase.

Figure 3

Role of chemokines in the tumor-specific immune response. The type and the amount of the chemokines secreted by tumor and inflammatory cells determine the extent and the effect of immune response leading to antitumor cytotoxic response, limited inflammatory, and vascular activation or potentiating tumor cell proliferation and neoangiogenesis.