Vol.:(0123456789) 1 3 Int J Clin Oncol (2017) 22:991–1000 DOI 10.1007/s10147-017-1187-x REVIEW ARTICLE Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer Alireza Nazari 1,2  · Hossein Khorramdelazad 2  · Gholamhossein Hassanshahi 2,3   Received: 26 April 2017 / Accepted: 21 August 2017 / Published online: 11 October 2017 © Japan Society of Clinical Oncology 2017 their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Furthermore, CXCL12 itself has the capability to stimulate survival and growth of neoplastic cells in a paracrine fashion. CXCL12 is a sup- portive chemokine for tumor neovascularization via attract- ing endothelial cells to the tumor microenvironment. It has been suggested that elevated protein and mRNA levels of CXCL12/CXCR4/CXCR7 are associated with human blad- der cancer (BC). Taken together, mounting evidence sug- gests a role for CXCR4, CXCR7, and their ligand CXCL12 during the genesis of BC and its further development. How- ever, a better understanding is still required before exploring CXCL12/CXCR4/CXCR7 targeting in the clinic. Keywords Bladder cancer · CXCL12 · CXCR4 · CXCR7 · Angiogenesis Introduction Chemokines are a subfamily that fit within the larger family of cytokines and serve as recruitment/migratory factors for a wide spectrum of cell types. After ligation to appropriate seven-transmembrane receptors on cell surfaces, target cells are recruited to the foci of infam- mation, infection, and insult injury [1–3]. According to the latest classifcation, depending on the position of con- served cysteine motifs in their biochemical structure, these pro-migratory proteins are divided into C, CC, CX3C and CXC subdivisions [4]. The CXC chemokine ligand CXCL12 [which is also known as stromal cell0derived factor SDF-1α and pre-B cell-growth-stimulating factor (PBSF)] was previously introduced as the frst member of the CXC chemokine subdivision and was further shown to play pivotal parts in multiple developmental processes, Abstract CXC chemokine ligand 12 (CXCL12) is an important member of the CXC subfamily of chemokines, and has been extensively studied in various human body organs and systems, both in physiological and clinical states. Ligation of CXCL12 to CXCR4 and CXCR7 as its receptors on peripheral immune cells gives rise to pleiotropic activi- ties. CXCL12 itself is a highly efective chemoattractant which conservatively attracts lymphocytes and monocytes, whereas there exists no evidence to show attraction for neu- trophils. CXCL12 regulates infammation, neo-vasculariza- tion, metastasis, and tumor growth, phenomena which are all pivotally involved in cancer development and further metas- tasis. Generation and secretion of CXCL12 by stromal cells facilitate attraction of cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoi- etic and non-hematopoietic tumor cells. CXCR4 stimulates tumor progression by diferent mechanisms and is required for metastatic spread to organs where CXCL12 is expressed, thereby allowing tumor cells to access cellular niches, such as the marrow, which favor tumor cell survival and prolif- eration. It has also been demonstrated that CXCL12 binds to another seven-transmembrane G-protein receptor or G-protein-coupled receptor, namely CXCR7. These studies indicated critical roles for CXCR4 and CXCR7 mediation of tumor metastasis in several types of cancers, suggesting * Gholamhossein Hassanshahi ghassanshahi@gmail.com 1 Department of Surgery, School of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran 2 Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran 3 Department of Immunology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran