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[169]
that sorafenib was able to overcome the drug resistance effect of stromal cells on CLL cells . Another
report has shown that sorafenib blocked the survival signals induced by CXCL12 engagement to its receptor
CXCR4, particularly the activation of ERK and MEK kinases, and induced apoptosis in a caspase dependent
[170]
manner . In another study, sorafenib improved the response of CLL cells to the cytotoxic effect of
rituximab or ofatumumab, and this effect involved a decrease in the expression of complement regulatory
[171]
proteins . It was therefore suggested that sorafenib could constitute a potential second line therapy for
refractory CLL patients. Altogether these studies indicate that treatments addressing angiogenic factors and
their receptors may constitute a useful approach to treat CLL, particularly when used in combination
therapies.

CONCLUSION
Increased bone marrow angiogenesis is a common feature found in CLL, and it is widely accepted that it
contributes to the pathogenesis of the disease. CLL cells are active contributors to this aberrant
angiogenesis, as they produce and secrete many angiogenic factors and express angiogenic receptors. CLL
cells in niches establish functional bidirectional interactions with microenvironmental cells, which induce a
proangiogenic profile in CLL cells and enhanced the angiogenic capacity of stromal cells. Clinical trials
addressing angiogenic factors have proven to be insufficient as single treatments and indicate that these
therapies should rather be used in combined treatments. Moreover, CLL cells in tissues receive survival and
proliferation signals that contribute to disease progression. Consequently, the CLL microenvironment is
now considered a crucial target for treatment, and current therapies are aimed at the signaling pathways
induced by CLL cell-microenvironment interactions.

DECLARATIONS
Authors’ contributions
Contributed to the preparation of the manuscript: García-Pardo A, Redondo-Muñoz J

Availability of data and materials
Not applicable.

Financial support and sponsorship
Work for the author’s laboratory was supported by grants SAF2009-07035, SAF2012-31613, SAF2015-
69180-R, PI060400, RD06/0020/0011, RD12/0036/0061 (to García-Pardo A) and SAF2017-86327-R (to
Redondo-Muñoz J) from the Ministerio de Ciencia e Innovacion- Fondo Europeo de Desarrollo Regional
(FEDER), Madrid; P2010/BMD-2314 from the Comunidad de Madrid/European Union (to García-Pardo
A); the Fundación de Investigación Mutua Madrileña (to García-Pardo A); the 2020 Leonardo Grant for
Researchers and Cultural Creators (BBVA Foundation) (to Redondo-Muñoz J).

Conflicts of interest
Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.