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independent of caspase activation and was not overcome by survival factors such as IL-4 or γ-interferon. It
was later demonstrated that induction of apoptosis by TSP-1-CD47 interaction was mediated by
cytoskeleton reorganization, mainly involving the small GTP binding protein Cdc42 and the Wiskott-
[74]
Aldrich Syndrome protein signaling pathway . Another study has shown that peptides derived from the C-
terminal domain of TSP-1 targeted CD47 and efficiently induced apoptosis of CLL cells . This apoptotic
[142]
effect involved activation of phospholipase C γ-1 and was also observed in vivo when injecting these
peptides in a CLL xenograft murine model .
[142]

MMP-9
A role for MMP-9 in CLL cell survival was first demonstrated in co-cultures of CLL and bone marrow
[143]
stromal cells . These authors showed that blocking the constitutive MMP-9 activity with neutralizing
antibodies suppressed the anti-apoptotic effect of stromal cells. We reported that culturing CLL cells on
immobilized or soluble MMP-9 prevented their spontaneous apoptosis . The MMP-9 effect was dose-
[81]
dependent and persisted for the seven days of the assay. Importantly, induction of cell survival did not
involve the proteolytic activity of MMP-9 but was mediated by MMP-9 binding to α4β1 integrin and CD44v
at the CLL cell surface. Indeed, a catalytically inactive MMP-9 mutant or the isolated hemopexin domain of
MMP-9 fully reproduced the survival-supporting function of the molecule. This study further showed that
MMP-9 (or its hemopexin domain) binding to these receptors induces an intracellular signaling pathway
consisting in Lyn activation, STAT3 phosphorylation, and Mcl-1 upregulation. This pathway was observed
[81]
in all CLL cases studied and was active in CLL lymphoid tissues .

Besides preventing spontaneous apoptosis, MMP-9 also protected CLL cells from the apoptotic effect of
cytotoxic drugs, such as fludarabine or arsenic trioxide . This study showed that both of these compounds
[76]
transcriptionally upregulated MMP-9, which mainly localized at the CLL cell surface. Blocking MMP-9 with
antibodies reduced the protective effect of stromal cells to the apoptotic function of arsenic trioxide or
fludarabine.

Additionally, MMP-9 induced CLL cell drug resistance by modulating the balance of anti- and pro-
apoptotic proteins of the Bcl-2 family towards an anti-apoptotic pattern . Induction of cell survival
[76]
therefore represents another contribution of MMP-9 to CLL progression.

Other possible roles of angiogenic factors in CLL
During the course of CLL, approximately 2%-10% of patients develop an aggressive lymphoma, known as
Richter’s transformation or Richter’s syndrome . In the CLL phase, risk factors for Richter’s
[144]
transformation include an advanced clinical stage, presence of poor prognostic markers (unmutated IGVH,
CD38, and CD49d), and genetic aberrations/mutations of specific genes (TP53, NOTCH1, and MYC) .
[144]
Other factors, however, may certainly contribute to the CLL-lymphoma transformation. A recent study
used patient-derived samples and murine animal models and elegantly demonstrated that activation of Akt
[145]
triggers Richter transformation via induction of Notch1 signaling . Although the possible involvement of
angiogenic factors in Richter’s transformation has not been directly addressed, it is well known that
activation of the PI3-K/Akt pathway is a major signaling event upon binding of several angiogenic factors
(VEGF, bFGF, PDGF, and Ang-2) to their respective receptors [48,49,52,70] . It is therefore possible that these
factors, which, as explained above, are present at elevated levels in advanced CLL, contribute to Richter’s
transformation by activating Akt.