Common bone marrow homing pathways for HSC and SCLC stem cells

Type of Award: catalyst
Award Number:
Award Period: July 2012 - June 2014
Amount Awarded: $ 200,000.00
PI(s): Geoffrey Kansas, PhD, NU; Ravi Salgia, MD, PhD, UChicago;

Abstract: Small cell lung cancer (SCLC) is a nearly invariably fatal disease, with a 5 year survival rate of <10%. This extremely poor prognosis is due almost completely to the strong tendency of malignant cells to metastasize to distant organs, of which the bone marrow (BM) is a major site. However, molecular mechanisms which underlie metastasis of SCLC to BM remain largely unknown. Hematopoietic stem cells (HSC) home to BM via a multistep process entirely analogous to mature leukocyte recruitment to sites of inflammation or infection: selectins initiate recognition of the blood vessel wall by mediating tethering and rolling of leukocytes along the endothelium; chemokines on the lumenal surface activate integrins on the rolling cells; and these activated integrins mediate firm arrest and subsequent transmigration into the tissue. In the case of HSC, it is known that the endothelial selectins (E- and P-selectin) are constitutively expressed on BM sinusoidal endothelium and mediate the initial rolling step, that the chemokine CXCL12/SDF-1 binding to its monogamous receptor CXCR4 on HSC mediates the second step, and that the broadly expressed integrin VLA-4 on HSC mediates the third step via binding to its cellular ligand on BM endothelium VCAM-1. Each of these molecules may also comprise part of the HSC "niche", the specialized microenvironment in the BM responsible for HSC maintenance, regulation and survival. We have shown that 100% of SCLC cells also express CXCR4, and scattered reports suggest that at least some SCLC can express glycan ligands for the endothelial selectins. These findings suggest that SCLC, and by implication other BM-tropic metastatic cancers, "hijack" the normal homing pathway used by HSC. If true, this would represent a major advance in understanding the molecular basis of metastasis, and should provide an array of targets for preclinical and translational studies.