Biomedical Engineering Reference
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peroxisomes. The ROS can be oncogenic, as oxidation of DNA is one of the main
causes of mutations produced by DNA damage, such as base modifications, pro-
tein-DNA adducts, cross-links, and single-strand breaks, The ROS are implicated
in cancer progression due to their lately appreciated function in cell signaling
through cascades such as mitogen-activated protein kinases (MAPK) pathway
[
138
]. Although white adipocytes are low in mitochondria, obesity increases ROS
generation in adipocytes, which is apparently mediated by peroxisomes. Therefore,
ROS-mediated signaling by intratumoral or peritumoral WAT-derived cells could
provide an additional mechanism through which they affect tumor metabolism.
The molecular mechanisms underlying the functional crosstalk between malignant
cells and WAT-derived cells remain to be further investigated [
139
].
3 Potential Mechanisms of Adipose Cell Trafficking
to Tumors
The dynamic constitution of tumor microenvironment relies on recruitment of
stromal cells locally from adjacent tissues and systemically from distant organs via
cell mobilization. Several circulating progenitor cell populations have been
identified: hematopoietic and endothelial progenitor cells, mature endothelial cells,
monocytic fibroblast progenitors and stromal cells [
140
]. Recently evidence
suggests that, in addition to the bone marrow, WAT serves as a resource of
mobilizable progenitor cells [
141
]. Consistent with this possibility, increased
circulation of hematopoietic progenitor cells has been detected in obesity [
142
].
It is now demonstrated by independent groups that mesenchymal cells from
WAT can also traffic to tumors and their paracrine contribution to the microen-
vironment appears to be important at multiple levels of cancer progression [
31
].
Analysis of peripheral blood in mouse WAT graft models demonstrates that ASC
and adipose endothelial cells can traffic through the systemic circulation to engraft
their respective perivascular and vascular niches in the tumor [
33
]. A possibility
that cells from WAT may undergo spontaneous mobilization was supported by a
recent study demonstrating that obesity results in detectable systemic circulation of
cells with the ASC immunophenotype in humans [
142
]. Unlike bone marrow-
derived MSC that are CD34-negative, ASC can be identified by flow cytometry as
cells bright for progenitor cell marker CD34 and lacking expression of endothelial
and hematopoietic markers (CD31 and CD45-). These CD34bCD45-CD31- cells
are absent (detected at a background frequency) in circulation of lean individuals.
Our group has recently shown that CD34bCD45-CD31- cells circulate in obese
donors, consistent with their WAT origin [
142
]. These cells express pericyte and
MSC markers as well as differentiate in culture into adipocytes, osteoblasts and
chondrocytes, which confirms them as ASC. Subsequently, we measured circu-
lating ASC in the peripheral blood of cancer patients [
143
]. After adjusting for age
and BMI, the mean frequency of ASC was significantly higher in the circulation of
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