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Review
. 2020 Dec 10:10:592733.
doi: 10.3389/fonc.2020.592733. eCollection 2020.

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

Hye Na Kim  1 , Yongsheng Ruan  1   2 , Heather Ogana  1 , Yong-Mi Kim  1
Affiliations
Review

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

Hye Na Kim et al. Front Oncol. .

Abstract

The interaction between leukemia cells and the bone microenvironment is known to provide drug resistance in leukemia cells. This phenomenon, called cell adhesion-mediated drug resistance (CAM-DR), has been demonstrated in many subsets of leukemia including B- and T-acute lymphoblastic leukemia (B- and T-ALL) and acute myeloid leukemia (AML). Cell adhesion molecules (CAMs) are surface molecules that allow cell-cell or cell-extracellular matrix (ECM) adhesion. CAMs not only recognize ligands for binding but also initiate the intracellular signaling pathways that are associated with cell proliferation, survival, and drug resistance upon binding to their ligands. Cadherins, selectins, and integrins are well-known cell adhesion molecules that allow binding to neighboring cells, ECM proteins, and soluble factors. The expression of cadherin, selectin, and integrin correlates with the increased drug resistance of leukemia cells. This paper will review the role of cadherins, selectins, and integrins in CAM-DR and the results of clinical trials targeting these molecules.

Keywords: bone marrow microenvironment; cell adhesion molecules; cell adhesion-mediated drug resistance; chemoresistance; leukemia.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
BM microenvironment. BM includes many types of cellular and non-cellular components. Cellular components express ligands or counter receptors, such as VCAM-1 or ICAM, that will bind to CAMs. Cells can also secret extracellular matrix (ECM) proteins that will bind to CAMs.
Figure 2
Figure 2
Cadherin and adherens junction. Upon engagement in homotropic manner, cytoplasmic tail of cadherins will bind to actin through p120, β-catenin, and α-catenin protein complex. Cadherin mediated protein complex formation is observed at adherens junction where adjacent cells are connected to each other.
Figure 3
Figure 3
Dimerization of integrins in leukemia. Dimerization of α and β integrins forms a functional heterodimer unit. This figure does not represent a comprehensive list of integrin heterodimers but rather includes integrins described by currently available publications in the field of leukemia, which are reviewed in this review.
Figure 4
Figure 4
Integrin signaling in leukemia. Talin binding to cytoplasmic tail of β-subunit activates integrin heterodimer and increases affinity of the complex towards ligands. Activation of integrin is followed by conformational change of the heterodimer and separation of cytoplasmic tails of each subunit, allowing recruitment of proteins. Recruited proteins, such as kindlin, paxillin, FAK and Src forms a protein complex that initiates integrin mediated intracellular signaling that results in cell adhesion, migration, survival and mechanotransduction of leukemia cells.
Figure 5
Figure 5
Overview of CAM-DR in leukemia. Cadherin, selectin, and integrin contribute to drug-resistance and metastasis upon engagement with their ligands in the BM. Homotropic engagment of cadherins can protect leukemia cells from chemotherapy (reference 92, 95) by modulating Wnt signaling and promote self-renewal of LSCs (reference 96, 97, 99). Leukemia cells can also bind to E-selectin expressed on endothelial cells through expressed selectin ligands on their surface (ref 132, 133). Interruption of E-selectin mediated interaction between leukemia and endothelial cells is actively being investigated in many clinical trials (ref 20). Integrin binding to BM stromal cells, ECM or counter receptors activates pro-survival signaling pathways such as PI3K/AKT and Ras/ERK pathway (ref 164, 221, 223, 229).
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