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Page 10 of 22 García-Pardo et al. J Cancer Metastasis Treat 2021;7:62 https://dx.doi.org/10.20517/2394-4722.2021.103

Functional effects of CLL cell-derived exosomes
Exosomes are small extracellular vesicles secreted by normal and malignant cells via exocytosis in response
[118]
to multiple physiological and pathological conditions . Exosomes contain proteins, DNA, mRNAs and
non-coding RNAs (such as miRNAs) that play fundamental roles in cell-cell interactions and tumor-
[119]
induced microenvironment modifications . Exosomes released by CLL cells were shown to induce the
transition of mesenchymal stromal cells to cancer-associated fibroblasts, which support the growth and
survival of malignant cells . These exosomes also impacted on endothelial cells increasing angiogenesis in
[120]
[120]
CLL tissues and modulated intracellular signaling pathways on stromal cells, all favoring disease
progression [121,122] .

Analysis of the proteomic and miRNA profiles from exosomes produced by CLL cells revealed the presence
of several cell surface proteins (CD9, CD37, CD53, CD63, and CD82) and miRNAs, including miR-21,
miR-146a, miR-29 family, miR-150, miR-155, and miR-223 [120,123] [Table 1]. The expression of some of these
[123]
miRNAs increases upon BCR activation and has been associated with CLL pathogenesis . Moreover, the
expression levels of miR-155 in plasma exosomes were proposed to be a biomarker for the risk of
progression from monoclonal B-cell lymphocytosis to CLL, as well as for the identification of CLL patients
who may show resistance to therapy . In another study, Farahani et al. showed that exosomes released
[125]
[124]
by CLL cells altered the transcriptome of the stromal cell line HS-5, a fact that may influence the pro-
survival signals induced by these cells which favor CLL progression .
[86]
CLL cell-derived exosomes also contain proteins that affect the molecular pathways of recipient cells,
including those involved in angiogenesis. For instance, they contain the small calcium-binding protein
S100-A9, which regulates the PI3-K/Akt/NF-κB signaling pathway, VEGF production, and inflammatory
processes . Another protein present in CLL exosomes is Axl, a receptor tyrosine kinase, which induces
[126]
stromal cell activation, VEGF production, and CLL progression . Moreover, the chloride intracellular
[121]
channel 1 protein, also found in CLL exosomes, was recently shown to induce endothelial cell proliferation
and angiogenesis through upregulation of β1 integrin and the MAPK/ERK signaling pathway . It has also
[127]
been reported that extracellular vesicles from bone marrow stromal cells modify the gene expression pattern
in CLL cells, affecting BCR activation and other processes . Uptake of these vesicles also rescued CLL cells
[128]
from apoptosis and enhanced their migratory capacity in response to the CXCL12 chemokine .
[128]
Altogether, extracellular vesicles produced by CLL or stromal cells constitute another important way of
tumor-microenvironment communication in tissues, with consequences on many processes including
angiogenesis in CLL niches. These vesicles thus represent potential therapeutic targets, and several clinical
trials are currently addressing this possibility .
[30]

OTHER FUNCTIONS OF ANGIOGENIC FACTORS IN CLL
Besides contributing to the observed increased angiogenesis in CLL niches, several angiogenic factors
produced by CLL cells are also able to perform other functions that directly affect disease progression. The
best studied functions are the role of these factors in CLL cell migration and survival.

Function of angiogenic factors in CLL cell migration
VEGF
A role of VEGF in CLL cell migration was first inferred by the fact that blocking autocrine VEGF or the
VEGFR2 kinase activity reduced the chemokine-induced CLL cell migration through endothelium . This
[129]
study also showed that chemokine activation of αLβ2 integrin and subsequent transendothelial migration
was defective in CLL cells and that stimulation with autocrine VEGF and α4β1 integrin overcame this defect
and restored cell motility. Regulation of cell motility by these two proteins appears to be particularly