ARTICLE
Auteur(s) : Enrico
Crivellato1, Beatrice Nico2, Domenico
Ribatti2
1Department of Medical and Morphological
Research, Anatomy Section, University of Udine Medical School,
Udine, Italy
2Department of Human Anatomy and Histology,
University of Bari Medical School, Bari, Italy
accepté le 12 Juin 2009
Mast cells (MCs) were first described in 1878 by Paul
Ehrlich as metachromatically-staining basophilic cells found in
connective tissues [1]. He speculated on the function of these
cells and, remarkably, he interpreted MCs as fixed elements
implicated in “tissue trophism”, a concept that has recently been
rediscovered, MCs being currently regarded as key effector cells in
tissue vascularization, remodeling and homeostasis.
MCs may be defined as multi-functional secretory cells that
contain numerous toluidine blue- or alcian blue-staining granules
in their cytoplasm, expressing high levels of c-kit, the receptor
for stem cell factor (SCF), and FcεRI, the high affinity plasma
membrane receptor binding IgE antibodies and IgE-antigen complexes.
MC secretory granules store a complex mixture of preformed effector
molecules – such as biogenic amines, proteoglycans, cytokines and
neutral serine proteases – which are released upon appropriate cell
stimulation. Accordingly, MCs may be activated through either
IgE-dependent or IgE-independent pathways.
MCs have long been implicated in classic IgE-associated allergic
disorders such as urticaria, seasonal conjunctivitis, allergic
rhinitis and asthma. However, they are now considered to be crucial
protagonists in host defence, being first-line responders to
different chemical and biological insults in the context of either
acquired or innate immune responses. In addition, growing evidence
indicates that MCs may have distinct involvement in
non-immunological functions, such as angiogenesis, wound healing,
tissue remodeling and fibrosis, thus playing a role in tissue
homeostasis.
MCs are also involved in cancer. Indeed, they can be found in
many different tumor types, where they represent part of the
infiltrating elements that localize to the tumor stroma. It was
Paul Ehrlich who, besides discovering MCs, first observed that MCs
often crowded around tumor masses [1]. Interestingly, MCs have
apparently been associated with either resistance or susceptibility
to tumor growth. MCs indeed accumulate in the stroma surrounding
certain tumors and the molecules they secrete can benefit the
tumor. By contrast, MC numbers can also increase at the site of
tumor growth and participate in tumor rejection. A major point
linking MCs to cancer is their well-recognized capacity to
synthesize and release potent angiogenic cytokines. Formation of
new blood vessels around and inside the tumor mass represents, in
turn, a crucial step in the natural history of tumor growth.
This review article will first consider the angiogenic potential
of MCs, taking into account the complex array of MC products that
exert important stimulating effects on blood vessel proliferation.
Secondly, it will focus on the complex biology of tumor
vasculature. Thirdly, the angiogenic contribution of MCs, in the
context of the inflammatory infiltrate that surrounds neoplastic
cells and the different clinical outcome that results from the
participation of MC in tumor infiltration, will be discussed.
Biology of mast cells
MCs are long-lived, ubiquitous cells that are dispersed throughout
almost all of the major organs of the body. They can be found
particularly in association with connective tissue structures such
as blood vessels, lymphatic vessels and nerves, and in proximity to
surfaces that interface the external environment such as those of
the respiratory, genitourinary and gastrointestinal system and the
skin. MCs are bone marrow-derived elements that originate from
hematopoietic stem cells [2]. Committed progenitors, circulating as
mononuclear agranular cells, traverse the vascular space and
complete their maturation after moving into the different
peripheral tissues. Here, they acquire their final phenotypic
differentiation under the influence of local tissue
microenvironmental factors, which exert critical effects, in
particular on the MC protease profile [3]. One of these crucial
factors is the c-kit ligand (SCF) secreted by fibroblasts, stromal
cells and endothelial cells. A bipotent MC and basophil
progenitor has been found in the mouse spleen, although this has
not yet been traced back to the bone marrow [4].
Human MCs, as well as mouse MCs, may be classified into one of
two types depending on the expression of different proteases in
their granules [5]. MCt cells, also regarded as “immune
cell-associated”, contain tryptase and are predominantly located in
the respiratory and intestinal mucosa, where they co-localize
around T lymphocytes. MCtc cells contain both tryptase and chymase,
along with other proteases such as carboxypeptidase A and
cathepsin G. They are predominantly found in connective tissue
areas, such as skin, submucosa of stomach and intestine, breast
parenchyma, myocardium, lymph nodes, conjunctiva and synovium.
A third type of MC, the MCc cell has also been identified:
this MC expresses chymase without tryptase and resides mainly in
the submucosa and mucosa of the stomach, small intestinal submucosa
and colonic mucosa [6].
MCs have the potential to secrete a wide variety of biologically
active products upon exposure to many different immunological and
non-immunological stimuli. These mediators are classified as: 1)
preformed mediators that are store in the cytoplasmic granules; 2)
de novo synthesized lipid mediators, e.g., metabolites of
arachidonic acid via either cyclooxygenase (e.g., PGD2)
or lipoxygenase (e.g., LTC4) pathways; 3) a large number
of cytokines, chemokines and growth factors [7]. Preformed
mediators stored in the secretory granules can be released by two,
morphologically distinct secretory pathways, referred to as
exocytosis (also called “anaphylactic degranulation”), and
piecemeal degranulation.
Role of mast cells in inflammatory conditions
Not only do MCs display critical effector functions in type I,
IgE-associated allergic disorders, but they also participate in
host defence against parasites, bacteria, viruses and fungi.
Indeed, MCs release a multitude of biologically potent mediators,
which exert proinflammatory or immunoregulatory functions, and
express a wide spectrum of surface receptors for cytokines,
chemokines, immunoglobulins, complement and bacterial products [8].
This enables MCs to exert crucial functions in the context of
either acquired or innate immune responses. It is now clear that
MCs are involved in a variety of pathological contexts, including
autoimmunity [9]. Interestingly, MCs have been shown to express
either beneficial or detrimental effects in a number of essential
biological functions [10]. MCs, for instance, have a crucial,
life-saving role in experimental bacterial infections. Using
genetically MC-deficient W/WV mice, it has been shown
that MCs exert a fundamental protective role in a model of acute
septic peritonitis following caecum ligation and puncture, and in a
model of enterobacteria inocula [11, 12]. This protective effect is
mainly due to the release of tumor necrosis factor (TNF)-α, but
other MC-derived products, such as cathelicidins, chymase and
leukotrienes, may exert direct bactericidal activity or degrade
toxic peptides [13]. Thus, MCs may behave as vital sentinels that
orchestrate potent inflammatory reactions against different
microorganisms, linking the innate immunity with the adaptive
immune system. On the other hand, they play a critical role in
initiating or worsening diseases such as rheumatoid arthritis,
multiple sclerosis, bullous pemphigoid and atherosclerosis [14]. In
addition, growing evidence suggests that MCs exert distinct,
non-immunological functions, playing a relevant role in tissue
homeostasis, remodeling and fibrosis, as well as in the processes
of tissue angiogenesis.
Mast cell-derived secretory products
The function of MCs is related to their capacity to release huge
amounts of biologically active products upon appropriate
stimulation. MCs release low molecular weight substances, such as
histamine, as well as cytokines and chemokines that exert profound
effects on inflammation and cancer [7]. Electron microscopy has
provided ultrastructural evidence that preformed mediators stored
in MC secretory granules can be released by two distinct secretory
pathways, referred to as exocytosis (also called “anaphylactic
degranulation”) and piecemeal degranulation [15, 16]. Exocytosis is
an “all-or-nothing” event, which consists of a rapid and massive
secretory process that occurs during IgE-dependent hypersensitivity
reactions. In exocytosis, the membranes of cytoplasmic granule fuse
with each other and with the plasma membrane, causing the formation
of open secretory channels that allow the discharge of granule
constituents into the local extracellular environment. Piecemeal
degranulation, conversely, represents a particulate mode of MC
secretion, which is characterized by a mechanism of a slow and
“little by little” release of granule contents that occurs without
membrane fusion or granule opening to the cell exterior.
Remarkably, piecemeal degranulation represents the most frequently
observed pattern of MC secretion [15]. It has been particularly
detected in MCs infiltrating areas of chronic inflammation or
tumors. During piecemeal degranulation, MCs are believed to
differently and selectively release distinct granule components
[17].
During the immediate hypersensitivity reaction, MCs undergo a
sequence of releasing events [14]. Exposure to specific multivalent
antigens results in the bridging of IgE molecules bound to FcεRI on
the MC surface. This event causes a rapid discharge of preformed,
vasoactive, proinflammatory and nociceptive mediators from
secretory granules, as well as the release of newly-formed
mediators. The cross-linking of surface-bound IgE by antigen leads
to the rapid release of histamine, specific proteases, vascular
endothelial growth factor (VEGF) and TNF-α from rich, intracellular
stores. On activation, MCs also rapidly synthesize bioactive
metabolites of arachidonic acid, prostaglandins and leukotrienes.
In addition, MC activation leads to the de novo synthesis of
several cytokines, such as interleukin (IL)-3, IL-4, IL-5, IL-6,
IL-10, IL-13, IL-14, nerve growth factor (NGF), and different
chemokines, such as macrophage inflammatory protein (MIP)-1α,
monocyte chemoattractant protein (MCP)-1 and lymphotactin.
Remarkably, the types of cytokines produced are not fixed but
depend upon the type of MC stimulation. Thus, the response of MCs
is flexible.
The process of angiogenesis
The term angiogenesis refers to the formation of new blood vessels
from pre-existing vascular structures, i.e. capillaries and
post-capillary venules [18]. Angiogenesis first occurs during
embryonic development and represents a key factor for tissue and
organ expansion. Particularly in the later stages of embryo
development, the vascularization of many tissues – such as the yolk
sac, kidney, thymus, brain, limb and choroid plexus - occurs by
angiogenesis. Angiogenesis is a complex process that involves a
highly orchestrated series of molecular and cell events, which are
under the control of different genetic and epigenetic mechanisms
[19]. Angiogenesis may be considered as at least two types
according to the different morphological pattern: (a) the so-called
“sprouting” angiogenesis, which is characterized by the
proliferation and migration of endothelial cells into avascular
sites; (b) “non-sprouting” angiogenesis or intussusceptive
microvascular growth, which occurs by splitting of the existing
vasculature by transluminal pillars or transendothelial bridges
[18, 20]. Angiogenesis also occurs during adult life. In such
instance, it accompanies the course of various important
physiological and pathophysiological conditions, such as ovulation,
endometrial vascularization in the menstrual cycle and pregnancy,
and wound healing.
There is general consensus that angiogenesis occurs during
inflammation and tumor progression. Increasing evidence indicates
that angiogenesis is a key accompanying event in the development of
inflammatory reactions and in the pathophysiology of tissue
remodeling during allergic disorders [21]. In tumor areas,
angiogenesis creates a new vascular supply that conveys oxygen and
nutrients to the rapidly proliferating tissue and removes the
by-products of cellular metabolism.
Numerous fixed and inflammatory cells can produce and release
angiogenic growth factors. Molecules that favour new vessel
formation can also be secreted by tumor cells [22]. The process of
angiogenesis depends on the balance of the positive and negative
angiogenic mediators within the vascular microenvironment and
requires the functional activities of a number of molecules,
including angiogenic factors, extracellular matrix proteins,
adhesion receptors, and proteolytic enzymes [18]. Thus, vascular
development in a given tissue is controlled in a remarkably complex
way by many microenvironmental factors. Among these, increasing
attention has recently been devoted to inflammatory cells.
Inflammatory cells indeed regulate endothelial cell functions
related to physiological angiogenesis as well as inflammatory and
tumor-associated angiogenesis.
The process of tumor angiogenesis
Angiogenesis is a critical process in tumor progression because the
vascular network produced by the host is essential to allow
neoplastic cell populations to form a clinically observable tumor
[23, 24]. In addition, new blood vessels provide the neoplastic
cells with a gateway through which they may enter the circulation
and metastasize to distant sites. Indeed, the special structure of
tumor blood vessels, with their often incomplete endothelial
envelope and their increased permeability, favours escape of
neoplastic cells and generation of metastases. Both solid and
hematological tumors are endowed with angiogenic capability and
their growth, invasion and metastasis are angiogenesis-dependent
[23, 25]. Thus the “angiogenic switch” – the passage from the
preangiogenic phenotype to the angiogenic phenotype – is
indispensable for tumor growth and metastatic dissemination because
it allows the formation of a tumor neovasculature [26, 27]. The
different components of the tumor “microenvironment” play a crucial
role in regulating tumor growth. The extracellular matrix, the
stromal cells localized in the tumor domain, the microvessels and
angiogenic factors released by a cohort of cell types, and the
inflammatory cells surrounding and infiltrating the tumor mass, all
participate in the tumor evolution. Such a microenvironment is a
complex system influenced by many cell types, including endothelial
cells and their precursors, pericytes, smooth-muscle cells,
fibroblasts, neutrophils, eosinophils, basophils, MCs, T, B and
natural killer lymphocytes, and antigen-presenting cells, such as
macrophages and dendritic cells, which communicate through a
complex network of intercellular signaling pathways that are
mediated by surface adhesion molecules, cytokines and their
receptors. In particular, tumor angiogenesis results not only from
the interaction of cancer cells with endothelial cells. Surrounding
inflammatory cells also have a crucial role in directing the
neoformation of blood vessels.
Remarkably, tumor blood vessels display many structural defects
that explain the functional abnormality of this kind of blood
vasculature. They are irregular in size, shape and branching
pattern, they lack the normal vessel hierarchy and do not display
the recognizable features of arterioles, capillaries and venules
[28]. Tumor-associated endothelial cells form a structurally
defective endothelium, which shows discontinuities or gaps that
allow hemorrhage, and facilitate permeability of macromolecules and
the traffic of tumor cells into the bloodstream. They are
disorganized, irregularly shaped, overlap one another, have luminal
projections and give rise to abluminal sprouts. The basement
membrane that envelops endothelial cells and pericytes of tumor
vessels may have extra layers that have no apparent association
with the cells. Pericytes of tumor vessels are loosely associated
with endothelial cells, have abnormal shape, paradoxically extend
cytoplasmic processes away from the vessel wall, and have extra
layers of loosely fitting basement membrane. Thus, tumor
vasculature is typically aberrant and disordered. For this reason
tumor vasculature does not form an effective barrier, allowing for
microvascular leakiness and tumor cell escape.
Mast cells and angiogenesis
MCs are an abundant source of angiogenic factors [29]. Under
physiological conditions, MCs are particularly prominent in the
close vicinity of capillaries and lymphatic channels. In many
inflammatory disorders characterized by a profound vascular
remodeling, the flogistic infiltrate exhibits numerous MCs that
show the structural features of degranulating elements. In various
tumor models, MCs appear at the edges of invasive tumors, where
they facilitate angiogenesis by releasing preformed mediators or by
triggering proteolytic release of extracellular matrix-bound
angiogenic compounds. Human, rat and mouse MCs release preformed
fibroblast growth factor (FGF)-2 from their secretory granules
[30, 31]. Human cord blood-derived MCs release VEGF upon
stimulation through FcεRI and c-kit. Both FGF-2 and VEGF have
also been identified by immunohistochemistry in mature MCs in human
tissues [30, 32, 33]. It has recently been shown that human MCs are
a potent source of VEGF in the absence of degranulation, through
activation of the EP(2) receptor by prostaglandin E2 [34].
Selective release of VEGF by human MCs is regulated by
corticotrophin-releasing hormone [35]. It has also been
demonstrated that rat peritoneal MCs contain angiogenic factors
stored in their secretory granules [36]. Granulated MCs and their
granules, but not degranulated mast cells, are able indeed, to
stimulate an intense angiogenic reaction in the chick embryo
chorioallantoic membrane (CAM) assay. This angiogenic activity is
partly inhibited by anti-FGF-2 and -VEGF antibodies,
suggesting that these cytokines are involved in the angiogenic
reaction. Similarly, it has been demonstrated, using the rat
mesenteric-window angiogenic assay, that intraperitoneal injection
of compound 48/80 – a potent MC secretagogue – causes a
vigorous angiogenic response [37]. The same treatment in mice also
causes angiogenesis [38].
MCs store large amounts of preformed, active serine proteases,
such as tryptase and chymase, in their secretory granules [39].
A role in angiogenesis for the proteolytic enzymes tryptase
and chymase has been established. Tryptase, in particular,
stimulates the proliferation of human vascular endothelial cells,
promotes vascular tube formation in culture and also degrades
connective tissue matrix to provide space for neovascular growth.
Tryptase also acts indirectly by activating latent matrix
metalloproteinases (MMPs) and plasminogen activator (PA), which, in
turn, degrade the extracellular connective tissue with consequent
release of VEGF or FGF-2 from their matrix-bound state [40].
MC-derived chymase degrades extracellular matrix components and
therefore matrix-bound VEGF could be potentially released. In a
hamster sponge implant model, chymase promotes angiogenesis through
generating angiotensin II from angiotensin I [41]. Chymase also
activates ProMMP-9 to generate MMP-9, also known as gelatinase
B, which is a matrix metalloproteinase involved in angiogenesis,
stromal remodeling and tumor cell invasion. MCs also have the
potential to synthesize and release MMP-9 [42].
Other MC-specific mediators with angiogenic properties include
histamine and heparin. Both molecules have been shown to stimulate
proliferation of endothelial cells and to induce the formation of
new blood vessels in the CAM-assay [43, 44]. Histamine, the major
preformed mediator, stimulates new vessel formation by acting
through both H1 and H2 receptors [44]. Heparin, the main
glycosaminoglycan constituent of MC granules, may act directly on
blood vessels or indirectly by inducing release of FGF-2 from
the extracellular storage site. In addition, other cytokines
produced by MCs, such as TNF-α TGF-β, NGF [45] and IL-8, have been
implicated in normal and tumor-associated angiogenesis [40].
Recently, MCs from human uterine leiomyomas have been found to
contain leptin, a 167-amino-acid residue peptide mainly secreted by
adipocytes which, in addition to its involvement in obesity
development, has also been found to express angiogenic activity
[46, 47]. Endothelial cells might exert maintenance functions on
MCs since it is known that human dermal endothelial cells express
the MC growth and chemotactic factor SCF [48]. Furthermore, SCF may
induce urokinase-type plasminogen-activator-receptor
(uPAR)-expression in MCs, and cells stimulated in this way could
also respond chemotactically to uPA released by endothelial cells
[49]. Several factors released by tumor cells, such as SCF and
adrenomedullin, are thought to be responsible for the recruitment
of MCs into tumors [50, 51]. MCs also express a number of
chemochine receptors, including CXCR4, CCR3 and CCR5, the
ligands that are upregulated by various cell types in most forms of
tumors [52]. An inventory of MC-derived angiogenic mediators is
depicted in figure
1.
Mast cells and angiogenesis in human pathology
Solid tumors
Extensive clinical investigations suggest that MCs are key host
cells in the tumor infiltrate, with important consequence for tumor
cell fate. In general terms, MC density correlates with
angiogenesis and poor tumor outcome. In some studies however,
increased MC numbers have been found either to correlate with
improved clinical survival or not to correlate with survival at
all. We have already seen that MCs synthesize and release a vast
array of proinflammatory and angiogenic molecules that favour new
vessel formation, either directly or via local recruitment of
activated inflammatory cells. Accordingly, early laboratory
investigations have documented a decreased rate of tumor
angiogenesis in MC-deficient W/Wv mice [53]. As to human
pathology, an increased number of MCs has been reported in
angiogenesis associated with a number of vascular, solid and
hematological neoplasms. At present, it is not known if
tumor-associated MCs are involved in “sprouting” angiogenesis or in
“non-sprouting” angiogenesis, or in both.
An association between MCs and new vessel formation has been
reported in breast cancer [54, 55]. In malignant breast lesions,
the number of MCs with tryptase activity has been found to be
significantly higher than in benign lesions. MCs are concentrated
at the tumor edge, the so-called “invasion zone” [56]. Breast
cancer patients with metastasis in the axillary nodes reveal
greater numbers of MCs in all nodes examined compared with patients
without metastases [57]. In a study on the sentinel lymphnodes in
breast cancer patients, angiogenesis has been shown to increase
with the number of tryptase-positive MCs, and their values were
significantly higher in lymph nodes with micrometastasis compared
with those without [58]. By contrast, other authors have maintained
that the presence of MCs in the peritumoral stroma of breast
carcinoma is associated with a favourable prognosis [54, 59,
60].
An association between MCs and angiogenesis has also been
reported in colorectal carcinoma. Increased accumulation of
toluidine blue- or tryptase-positive MCs infiltrating colorectal
carcinoma has been shown to correlate with increased microvessel
density and a less favorable prognosis [61, 62]. Patients with low
MC density and hypovascular tumor tissues had significantly longer
survival than those with high MC density and hypervascular tumor
biopsies.
Again, an association between MCs and new vessel formation has
been documented in cervical carcinoma. Indeed, tryptase-positive
MCs increase in number, and vascularization increases in a linear
fashion, from dysplasia to invasive cancer of the uterine cervix
[63]. In another study, the total number of MCs has been shown to
remain constant through the different stages of malignant
transformation (cervical intraepithelial neoplasia grade 1-3), but
a significant increase in the invasive carcinoma group was
observed, this increase being mainly due to the MCt phenotype [64].
Recently, angiogenesis has been shown to correlate with the
tryptase-positive MC count in human endometrial cancer. Both
parameters were found to increase in agreement with tumor
progression [65]. In this type of tumor, the extent of angiogenesis
has been shown to correlate with expression of MMP-2 and
MMP-9, both metalloproteinases being potentially secreted my
infiltrating MCs [66]. In uterine leiomyomas, the number of
tryptase- and leptin-positive MCs was also seen to correlate with
vascular density [67]. In this type of uterine tumor, the
predominant subset of infiltrating MCs was the MCtc type, possibly
recruited by the CCL5 and CCL11 chemokines secreted by
the smooth muscle tumor cells [68]. Angiomyofibroblastoma in the
vaginal wall is a rare, highly vascularized tumor.
Immunohistochemical analysis of VEGF-positive cells in a case of
this tumor indicated that MCs and not tumor cells express this
angiogenic cytokine, implying that MCs may play a crucial role in
angiogenesis in angiomyofibroblastoma [69]. An association between
VEGF and MCs with angiogenesis has been demonstrated in laryngeal
carcinoma [70] and in small lung carcinoma [71, 72]. In lung
adenocarcinoma, chymase-positive MCs accumulate in the neoplastic
lesion. A significant correlation has been found between
chymase-positive MC counts and microvessel counts in Noguchi type-C
tumors (localized bronchioloalveolar carcinoma with active
fibroblastic proliferation) [73]. In a similar way, significant
correlations were observed not only between Mtc and microvessel
count, but also between MCtc and microvessel count in the border
region of stage I non-small cell lung cancer [74]. In the central
region, a significant correlation between MCtc and the number of
microvessels was observed, but there was no significant correlation
between MCt and the microvessel count. This study demonstrates that
MCs tend to aggregate with higher density in the border region of
non-small cell lung carcinomas where microvessel density is also
much higher than in the central region. Conversely, according to
another study, the number of MCs (along with macrophages and
eosinophil leukocytes) did not correlate with angiogenesis and
tumor stage in non-small cell lung carcinomas [75]. The number of
total MCs and chymase-positive MCs also correlates with microvessel
counts in gastric carcinoma, and both parameters are associated
with a poorer clinical prognosis, suggesting that MCs may
contribute to tumor growth and progression [76, 77].
A significantly increased number of MCs (and macrophages) has
been found in pancreatic ductal adenocarcinoma in comparison with
normal pancreas, the number of MCs directly correlating with the
presence of lymph node metastases [78]. MCs were found to express
VEGF-A, VEGF-C and FGF-2. Tumors with higher microvessel density
had higher number of infiltrating MCs (and macrophages), suggesting
that MCs may influence the metastatic capacity of the cancer cells
and may contribute to the development of tumors with high
angiogenic activity. In a similar way, the number of MCs was found
to be significantly increased in hepatocellular carcinoma, with
higher values in poorly differentiated versus well differentiated
specimens [79]. MC count correlated with the number of
microvessels.
In renal cell carcinomas, MCs were found to be significantly
increased both in the tumor mass and surrounding areas. Increased
MC density significantly correlated with microvessel density,
suggesting that MC infiltration may contribute to tumor
angiogenesis and acceleration of tumor growth possibly through
secretion of VEGF and MMP-9 [80]. In one study however, higher
numbers of MCs in tumors of the kidney correlated positively with
increased microvessel density, but this correlation did not
translate to patient survival [81].
An association between MCs and angiogenesis has also been
reported in skin and oral tumors [82]. MC accumulation has been
noted repeatedly around melanomas, especially invasive melanoma
[83-85]. MC accumulation was correlated with increased
neovascularization, MC expression of VEGF [86] and FGF-2 [87],
tumor aggressiveness and poor prognosis. Indeed, a prognostic
significance has been attributed to MCs and microvascular density
not only in melanoma [88], but also in squamous cell cancer of the
oesophagus [89]. In oral squamous cell carcinoma, the density of
MCs and microvessels appears to increase with disease progression
[90]. Indeed, MC and microvessel counts are significantly higher in
oral squamous cell carcinoma than in hyperkeratosis and normal oral
mucosa.
In human pterygium, a benign and highly vascularized tumor of
the conjunctiva soft tissue, the number of tryptase-positive
infiltrating MCs was found to be significantly increased in
comparison to MC values in normal conjunctiva, and to correlate
with microvessel count [91]. This suggests that the characteristic
neovascularization observed in pterygium may be sustained, at least
in part, by MC angiogenic mediators, in particular tryptase.
Hematological malignancies
The role of angiogenesis in the growth and progression of cancers
of hematopoietic lineage is also well established [92]. Indeed,
tumors such as B-cell non-Hodgkin’s lymphomas (B-NHL),
lymphoblastic leukaemia, B-cell chronic lymphocytic leukaemia,
acute myeloid leukaemia and multiple myeloma are clearly related in
their progression to the degree of angiogenesis [93]. In general
terms, MC density, bone marrow microvessel count and clinical
prognosis have been found to correlate in hematological
malignancies. Bone marrow angiogenesis, evaluated as microvessel
area, and MC counts are highly correlated in patients with
non-active and active multiple myeloma and in those with monoclonal
gammopathies of undetermined significance (MGUS). In addition, both
parameters increase simultaneously in active multiple myeloma
[94-97]. These data tentatively suggest that an increasing number
of MCs may be recruited and activated by more malignant plasma
cells in active multiple myeloma, and that angiogenesis in this
disease phase may be mediated, at least in part, by angiogenic
factors contained in their secretory granules [24, 98].
Angiogenesis is involved in the pathogenesis of B-cell chronic
lymphocytic leukaemia (CLL). Indeed, low cellular levels and high
serum concentrations of VEGF, as well as the extent of bone marrow
angiogenesis, correlate closely with the outcome of the disease
[99]. Remarkably, tryptase-positive MCs are increased in the bone
marrow of patients with B-cell CLL and their density reflects bone
marrow angiogenesis [100]. In addition, there is also a correlation
with disease progression, thus tryptase-positive MCs predict
clinical outcome in patients with early B-cell chronic lymphocytic
leukaemia [101].
A similar pattern of correlation between bone marrow microvessel
count, total and tryptase-positive MC density, and tumor worsening
has been found in patients with myelodysplastic syndromes [102].
Data suggest that angiogenesis in myelodysplastic syndromes
increases with their progression and that MCs may intervene in the
angiogenic response in these syndromes through tryptase contained
in their secretory granules.
A striking association between MCs and microvessel counts has
been found also in benign lymphadenopathies and B-NHL, and both
parameters have been shown to increase as a function of tumor
progression, as defined by its increasing malignancies grades [103,
104]. In B-NHL and multiple myeloma, MCs rest near or around blood
or lymphatic capillaries. Interestingly, electron microscopic
examination of lymph node and bone marrow MCs in B-NHL and multiple
myeloma patients show ultrastructural features of slow and
particulate secretion as it occurs in piecemeal degranulation [16,
94, 104, 105]. This ultrastructural appearance may reflect slow and
progressive release of angiogenic factors by infiltrating MCs,
favouring chronic and progressive stimulation of MC degranulation
[106].
Besides stimulating angiogenesis in the bone marrow of multiple
myeloma patients, MCs have the property of contributing to
vasculogenic mimicry [107]. Indeed, electron and confocal
microscopy studies have demonstrated that in the bone marrow of
patients with multiple myeloma, typical tryptase-positive MCs
interact physically with the endothelial cells lining the vascular
lumina, perhaps as a result of dysregulated vasculogenic
development. This evidence highlights the importance of the stromal
microenvironment during angiogenesis in the pathophysiology of
multiple myeloma, and provides a novel perspective into the complex
interplay between stromal and vascular components in the bone
marrow microenvironment involved in the induction of
hypervascularization in multiple myeloma.
Conclusion
Despite numerous studies suggest a correlation between MC density,
angiogenesis and tumor progression, there is still controversy over
the role of MCs and MC-dependent angiogenesis in the development of
tumors. The divergence of opinion on the functional role of MCs as
effector cells in tumor angiogenesis is not surprising given MC
versatility and the plentiful mediators these cells release in the
tumor microenvironment. As MCs have the potency to express either
favourable or detrimental effects on tumor cell growth, the
hypothesis has been proposed that this dual role may depend on the
way MCs release their bioactive molecules from secretory granules
[106]. Frank exocytosis would export secretory cytokines mainly
involved in promoting tumor cell apoptosis, whilst piecemeal
degranulation, a particulate and possibly selective way of MC
secretion, would allow for release of mediators and growth factors
principally responsible of angiogenesis, immuno-suppression and
extracellular matrix disruption [106].
MCs per se may exert inhibiting effects on tumor cell growth
through secretion of cytotoxic/apoptotic mediators contained in
their cytoplasmic granules, such as IL-4, TNF-α and chymase. The
matter is even more complicated because MCs, despite their ability
to release so many angiogenic factors, are also known to secrete
antiangiogenic modulators, such as IFN-α, IFN-β, IFN-γ and TGF-β.
This puzzling scenario is properly exemplified by the role played
by MCs in hemangioma. MCs have been shown to be abundant within
hemangioma tissues [108]. However, the number of MCs is highest
during the involuting phase, lower in the involuted phase and
lowest in the proliferating phase [109]. It has been suggested that
one of the functions of MCs in hemangioma is to release factors
leading to regression of neovessels. The observation of a
significant increase in MC numbers after steroid treatment supports
this hypothesis, and indicates that MCs may play antiangiogenic
roles and accelerate the involution of hemangioma. Another
apparently paradoxical aspect of MC-related angiogenesis in tumors
is to be found in advanced ovarian cancer. Surprisingly, patients
with high peritumoral MC infiltration and higher microvascular
density have a better prognosis than those with low MC or low
microvascular densities [110].
In conclusion, the great majority of clinical studies to date
support an accessory role for MCs in the development and
progression of solid and hematological tumors through their strong
angiogenic potential. Further studies are needed to dissect the
complex cell and mediator signaling network operating in the tumor
microenvironment in order to elucidate the specific contribution of
MCs to tumor growth and tumor-related angiogenesis.
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