Biomedical Engineering Reference
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cancer patients compared to non-cancer controls. Moreover, the frequency of
circulating ASC was also found to be significantly higher in the circulation of
obese cancer patients compared to lean cancer patients. The significance of this
discovery is that the observed BMI-related increase in circulating ASC identifies
them as a diagnostic biomarker of cancer. A better scientific understanding of how
external factors such as cancer progression and weight control may impact the
presence and manifestation of mobilized ASC is needed [
73
]. Currently, it is not
clear if the systemic circulation is an actual mechanism of ASC migration to
tumors. Circulating ASC may be merely a byproduct of WAT remodeling, and
their migration through solid tissues from the surrounding WAT could be the main
route of their trafficking. In fact, this possibility is consistent with epidemiological
data indicating that obesity predominantly accelerates the progression of cancers
arising in sites surrounded by WAT [
7
].
While the significance of WAT-derived stromal cells in cancer progression has
been established, how they traffic to tumors is not well understood. Mobilization
and migration of cells in the body is directed by cell adhesion and signaling
molecules, such as integrins, in concert with chemokine gradients [
144
-
146
].
Under pathological conditions, homeostatic balance is disrupted and new che-
motactic gradients are created. Hypoxic environment within the tumor stimulates
expression of chemokines that recruit macrophages, mast cells, neutrophils, and
lymphocytes, as well as endothelial and mesenchymal cell populations. The che-
mokine gradient of stromal cell-derived factor (SDF1) and its receptor (CXCR4)
appears to be important in this process for many hematopoietic cell types [
147
].
Still, little is known about chemokine gradients recruiting cells from adipose
tissue. In response to hypoxia CXCR4 expression is augmented in ASC, which
may contribute to their migration [
148
], however high amounts of the ligand
(SDF1) secreted by ASC themselves make it difficult to reconcile how that
pathway could operate in this case. A number of chemokines and chemokine
receptors have been identified as potential critical players upregulated in MSC
activated to undergo migration [
149
]. For example, chemokine receptors CCR1,
CCR4, CCR7 and CXCR5 are found on ASC and bone marrow derived MSC, with
many induced by inflammation stimuli [
150
]. Our recent studies suggest that the
presence of CXCR1 or CXCR2 on omental ASC may explain their migration in
response to IL-8 and CXCL1 secreted by endometrial tumor cells [
47
]. Further
studies are required to decipher these complicated signaling networks involved in
regulating ASC migration into tumor microenvironment.
4 Modeling Adipose Cell Role in Tumor
Microenvironment
Development of ex vivo models adequately simulating intercellular communica-
tions between the cell populations and the ECM composing human tumors is
critical for improving the accuracy of preclinical drug efficacy screening and
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