Biomedical Engineering Reference
In-Depth Information
common progenitor [
88
], suggesting that plastic WAT-derived ASC could directly
contribute to the tumor endothelium. According to the evolving paradigm, WAT-
derived cells potentiate the supportive properties of the tumor microenvironment,
resulting in increased survival and proliferation of neighboring malignant cells.
Many adipokines secreted by cells of adipose tissue promote angiogenesis as
paracrine factors. Leptin is an adipokine that stimulates key steps of angiogenesis
[
89
]. Adipocytes produce [
28
] leptin, VEGF, FGF-2, HGF, IGF, TNF-a, TGF-b,
placental growth factor (PlGF), VEGF-C, resistin, and tissue factor (TF) that all
play roles in vascularization [
90
-
100
]. Preadipocytes and adipocytes also secrete
basic fibroblast growth factor (bFGF) that stimulates vascular endothelial cell
proliferation and migration, as well as HGF, which has been shown to promote
angiogenesis [
101
]. The adipose progenitor cells are also a source of several
angiogenic factors including VEGF, HGF, GM-CSF, FGF-2, and TGF-b [
23
-
25
].
Recruitment of inflammatory cells also significantly contributes to adipose neo-
vascularization [
102
]. For example, activated macrophages produce potent
angiogenic factors such as TNF-a, VEGF, FGF-2, IL-1b, IL-6, and IL-8 [
103
]. As
adiponectin produced by mature adipocytes exerts antiangiogenic activity [
60
,
61
],
its reduced levels in obesity and cancer [
53
] could contribute to tumor angio-
genesis. It is likely that many of these bioactive molecules, produced by tumor-
infiltrating WAT-derived cells, are responsible for enhanced vascularization and
tumor growth in obese patients.
2.4 Adipose Cell Role in Tumor Matrix Remodeling
In addition to neovascularization and infiltration of inflammatory cells, cancer
progression is accompanied by fibrosis, which involves recruitment, activation,
and proliferation of stromal cells, leading to their differentiation into myofibro-
blasts, deposition of collagen and of other fibrillar molecules remodeling the
matrix [
39
]. This altered desmoplastic response leads to tumor stroma stiffness and
relies on mechanisms governing tissue injury and repair, which are chronically
activated in cancer [
104
,
105
]. ECM remodeling is an integral component of the
angiogenic process underlying cancer progression. Cell signaling and fate is reg-
ulated by surface interaction of integrins with collagens, laminins, fibronectin,
elastins are other fibrous proteins [
106
]. Proteolytic activity within the ECM
facilitates degradation of the basement membrane, matrix remodeling, and cell
migration and invasion, all of which are integral components of angiogenesis, as
well as metastasis [
107
]. Matricellular proteins abundantly secreted by cells of
WAT, such as SPARC [
108
] and decorin [
109
,
110
], also play important in des-
moplasia. Like bone marrow MSC, ASC are potent ECM sources [
111
]. Recent
reports demonstrate that in animal models ASC support the formation of the
fibrous tumor capsule and contribute to intratumoral ECM deposition [
47
,
104
].
ASC are capable of secreting large amounts of many extracellular matrix proteins,
such as most collagens and fibronectin, the major ECM protein in WAT [
112
].
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