Abstract
A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival.
Highlights
Compelling evidence supports that CLL cell survival within the tumor microenvironment is highly dependent on extrinsic signals provided by non-leukemic cell types [1, 2]
CLL cells, but not normal B cells, can suffer apoptosis through physical contact with TNF-α activated endothelium resulting in impaired survival after transendothelial migration (TEM)
The viability of CLL cells in the TEM assays was even more decreased in the two TEM fractions and, especially, in the TM cells compared to basal levels in the control suspension cultures in bottom chambers (Figure 1A-i) indicating that direct contact with endothelium was involved in these effects
Summary
Compelling evidence supports that CLL cell survival within the tumor microenvironment is highly dependent on extrinsic signals provided by non-leukemic cell types [1, 2]. Endothelial cells can protect CLL cells from spontaneous apoptosis in vitro through soluble factors and/ or direct physical contacts [1,2,3,4,5,6,7] Both findings suggest that endothelial cells could play a similar role during extravasation an issue that, to our knowledge, has not been previously addressed. CD49d can mediate contact dependent survival of CLL cells within tumor microenvironment [6, 15] associating with inferior prognosis groups including unmutated (UM) IgHV or CD38 expressing cases Together these lines of evidence strongly suggest that integrin dependent extravasation may be further linked to a survival advantage that needs, a definitive demonstration
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