Oncotarget

Research Papers:

Hedgehog inhibitors selectively target cell migration and adhesion of mantle cell lymphoma in bone marrow microenvironment

Han Zhang _, Zheng Chen, Sattva S. Neelapu, Jorge Romaguera and Nami McCarty

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Oncotarget. 2016; 7:14350-14365. https://doi.org/10.18632/oncotarget.7320

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Abstract

Han Zhang1, Zheng Chen1, Sattva S. Neelapu2, Jorge Romaguera2, Nami McCarty1

1Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, Texas, USA

2Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence to:

Nami McCarty, e-mail: [email protected]

Keywords: mantle cell lymphoma, adhesion, migration, bone marrow microenvironment, hedgehog

Received: November 02, 2015    Accepted: January 29, 2016    Published: February 11, 2016

ABSTRACT

The clinical benefits of a Hedgehog (Hh) inhibitor, LDE225 (NPV-LDE-225, Erismodegib), have been unclear in hematological cancers. Here, we report that LDE225 selectively inhibited migration and adhesion of mantle cell lymphoma (MCL) to bone marrows via very late antigen-4 (VLA-4) mediated inactivation of focal adhesion kinase (FAK) signaling. LDE225 treatment not only affected MCL cells, but also modulated stromal cells within the bone marrow microenvironment by decreasing their production of SDF-1, IL-6 and VCAM-1, the ligand for VLA-4. Surprisingly, LDE225 treatment alone did not suppress cell proliferation due to increased CXCR4 expression mediated by reactive oxygen species (ROS). The increased ROS/CXCR4 further stimulated autophagy formation. The combination of LDE225 with the autophagy inhibitors further enhanced MCL cell death. Our data, for the first time, revealed LDE225 selectively targets MCL cells migration and adhesion to bone marrows. The ineffectiveness of LDE225 in MCL is due to autophagy formation, which in turn increases cell viability. Inhibiting autophagy will be an effective adjuvant therapy for LDE225 in MCL, especially for advanced MCL patients with bone marrow involvement.


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