The role of adhesion molecules in acute myeloid leukemia and (hemato)oncology: A systematic review

Abstract

Background. The treatment of malignancies like acute myeloid leukemia (AML) is often complicated by the heterogeneity of the disease and the mechanisms of the disease progression. This heterogeneity is often not reflected in standard treatment approaches which provide predictable outcomes in the majority of patients but fail in individual cases even with high-dose multi-agent chemotherapy regimens and allogeneic stem cell transplantation. Further, the unselective effect of chemotherapy causes high treatment-related toxicity and accelerates the risk of infection during prolonged pancytopenia, preventing further dose escalation. Despite rapid progress in therapeutic strategies, the fatality of high-grade malignancies remains enormous. Objectives. Adhesive interactions trigger signal transduction pathway activation and this prevents the apoptosis of both normal and malignant cells. A correlation between expression of defined adhesion molecules and patient outcome has been found for several malignant diseases including AML. We aim to describe how disruption of these signalling pathways can overcome the high resistance to treatment and increase the selectivity of targeting malignant cells. This could effectively reduce the overall treatment-related toxicity and improve the general outcome. Conclusions. Adhesion molecules facilitate growth of malignant diseases. This review provides a deeper insight into these processes. Modulation of adhesion molecules-mediated interactions is an innovative and feasible approach in treatment of AML and many other malignancies. Due to expected low toxicity it is an acceptable addition to standard chemotherapeutical regimens for all age groups of patients. This approach could improve the overall treatment outcome in the future.

Adhesion Deregulation in Acute Myeloid Leukaemia

“…Chemotherapy induces expression of CXCR4 in AML cells, leading to therapy resistance and AML blast survival. Indeed, an interaction between CXCR4 on leukaemic cells and niche-derived SDF-1, together with the VLA-4/VCAM-1 interaction, is necessary for proper homing and growth of malignant CD34+ cells [3,47,48,49]. Instead, the CCL2/CCR2 axis is expressed in the majority of monocytoid AML blasts and is involved in cell trafficking and proliferation [50].…”

“…Integrins are heterodimeric trans-membrane glycoproteins consisting of an α and a β subunit, assembled in different ways to generate a wide range of dimers (reviewed in [1]). Each type of integrin has a unique repertoire of ligands that can be either ECM molecules or trans-membrane cell AMs [2,3,4]. Unlike other cell adhesion receptors, integrins require prior conformational activation by extracellular soluble mediators to bind their ligands [1].…”

“…Unlike other cell adhesion receptors, integrins require prior conformational activation by extracellular soluble mediators to bind their ligands [1]. Selectins are a family of three trans-membrane calcium-dependent lectins (L-, E-, and P-selectin) mediating cell-to-cell adhesion [2,3,4]. While L-selectin is expressed by most leukocytes, P-selectin is displayed by megakaryocytes, platelets, inflamed endothelial cells, and a subset of bone marrow (BM) endothelial cells, whereas E-selectin is expressed by endothelial cells during inflammation, as well as in specialized domains of the BM endothelium [5].…”

“…While L-selectin is expressed by most leukocytes, P-selectin is displayed by megakaryocytes, platelets, inflamed endothelial cells, and a subset of bone marrow (BM) endothelial cells, whereas E-selectin is expressed by endothelial cells during inflammation, as well as in specialized domains of the BM endothelium [5]. Cadherins, e.g., E-, VE- and N-cadherin, are glycoproteins that take part in cell-to-cell adhesion through the generation of intercellular junctions, providing isolation of different compartments [2,3]. Cadherins also participate in signal transduction pathways, due to their cytoskeleton anchorage [2,3].…”

“…Cadherins, e.g., E-, VE- and N-cadherin, are glycoproteins that take part in cell-to-cell adhesion through the generation of intercellular junctions, providing isolation of different compartments [2,3]. Cadherins also participate in signal transduction pathways, due to their cytoskeleton anchorage [2,3]. IgSF proteins are characterized by the presence of one or more immunoglobulin-like domain(s) [2].…”