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ABSTRACT
Introduction: Chemokines control homing and trafficking of leukocytes in bone marrow and lymphoid organs. In particular, CXCL12 and its receptors CXCR4/CXCR7 control the homeostasis of multiple organs and systems. Their overexpression is linked to tumor development, both through a direct modulation of neoplastic cell proliferation, survival, and migration, and, indirectly, acting on the tumor microenvironment which sustains drug resistant tumor stem-like cells. Leukemia and lymphomas frequently display upregulation of CXCL12/CXCR4 in bone marrow that nurtures tumor cells, and confers resistance to conventional chemotherapy, increasing disease relapse.
Areas covered: The authors review the molecular and cellular mechanisms by which the CXCL12/CXCR4-7 system supports leukemic bone marrow and how it contributes to leukemia development, and their potential pharmacological targeting. Besides receptor antagonists that directly inhibit leukemic cell proliferation, preclinical and clinical studies demonstrate that CXCR4 inhibition mobilizes leukemic-lymphoma cells from their niches, improving conventional chemotherapy efficacy. Clinically available and experimental pharmacological tools targeting CXCR4/CXCR7 are also described.
Expert opinion: Studies have revealed the therapeutic efficacy of combining CXCR4 inhibitors and cytotoxic agents to sensitize leukemic cells, and overcome natural or acquired resistance. However, several issues are still to be unveiled (for example the role of CXCR7) to maximize therapeutic response and reduce potential toxicities.
Article highlights
CXCL12/CXCR4-7 network is relevant for the physiology of the immune system as well as for various pathological processes, particularly hematologic malignancies.
CXCR4 is the chemokine receptor most abundantly expressed in a variety of cancer types, involved in tumor cell proliferation and migration trough CXCL12 gradient: in leukemia, CXCL12/CXCR4 interaction regulates cell homing to the bone marrow and trafficking into the bloodstream.
Blood malignancies maintain their roots in the leukemic stem cell niche, whose cellular and secreted components, including CXCL12, modulate survival, proliferation and anchoring of leukemia stem cells, responsible for drug resistance and disease recurrence.
Several class of small molecules antagonizing CXCR4, able to disrupt tumor protective niche have been developed and are currently under investigation.
Currently, the only CXCR4 antagonist approved by FDA is plerixaflor, routinely used in combination with G-CSF for mobilization of normal hematopoietic stem cell in patients that undergo autologous and allogenic transplantation.
Pre-clinical and clinical studies are ongoing to explore the safety and benefits of plerixaflor and other compounds targeting the CXCL12/CXCR4-7 system, alone or in combination with conventional or targeted anticancer drugs in primary and relapsed hematologic tumors.
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Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.