Biomedical Engineering Reference
In-Depth Information
Obesity is a state of low-grade systemic inflammation. Serum levels of C-reactive
protein (CRP), an inflammatory marker, are increased in individuals with higher
BMI, and, which correlates with poor prognosis [
76
]. Systemic and WAT-proximal
levels of proinflammatory cytokines, such as TNF-a and IL-6 secreted by dys-
functional adipose tissue, are also elevated in obesity [
77
]. It is possible that the
production of these and other cytokines by tumor-infiltrating WAT-derived cells is
more pathologically relevant than their systemic circulation. The role of various
myeloid populations migrating to tumors and affecting cancer course has been
demonstrated by numerous groups [
36
,
78
]. Alternatively activated (M2) macro-
phages and regulatory T cells (T-regs) are the most well characterized populations
of cells that promote cancer progression by helping tumor evade the immune
response [
79
]. Because these and other immunomodulatory leukocyte populations
are known to accumulate in WAT [
24
], it is possible that their trafficking from
WAT to tumors in cancer patients facilitates disease [
80
]. In addition, it has been
shown that bone marrow-derived MSC have their capacity to mute T-cells [
81
]. It is
likely that ASC recruited from WAT also have immunomodulatory properties and
provide immune protection for cancer cells.
2.3 Adipose Cell Role in Tumor Vascularization
It is well known that the vascular system is crucial for tumor progression and
metastasis [
12
]. In tumors, the aggressive growth of the neoplastic cell population
and the associated hypoxia induce angiogenesis [
82
]. This process involves
recruitment of vasculogenic precursors and their differentiation, followed by
vascular cell proliferation and migration, ECM remodeling, and tube formation.
While angiogenic proliferation of endothelial cells at the tip of the sprouting
vasculature is clearly important, recruitment of vasculogenic endothelial precursor
cells from the bone marrow definitely contributes to tumor vascularization. MSC
are a key population responsible for chemotactic attraction of endothelial pro-
genitors to the tumor [
34
]. Recent evidence shows that WAT, vasculature and
stroma of which is activated and expands in obesity [
83
-
86
], serves as a source of
precursor cells for vascular remodeling alternative to the bone marrow. In an
experimental model based on transplantation of WAT, it has been shown that
WAT grafts release both endothelial and perivascular cells that become hijacked
by tumors and engraft their respective niches within the tumor [
32
]. Importantly,
tumors grow significantly faster in mice carrying WAT implants indicating that
excess WAT is sufficient to promote cancer. In recent studies based on bone
marrow transplantation, we confirmed that endogenous WAT promotes cancer
progression by serving as a source of stromal progenitor cells [
33
]. We showed
that ASC recruited into tumors incorporate into blood vessels as pericytes in an
obesity-dependent manner [
33
,
47
]. Observations of increased tumor vasculari-
zation and growth promoted by ASC have been made by other groups [
30
,
31
,
87
].
Interestingly, a recent study suggests that adipocytes and endothelial cells share a
Search WWH ::
Custom Search