Role of Adipose Cells in Tumor Microenvironment - The Mechanobiology of Obesity and Related Diseases - page 269

Transducer and Activator of Transcription (JAK-STAT) pathway and nuclear
factor kappa-light-chain-enhancer of activated B cells (NF-jB). This leads to the
expression of various genes involved in cell survival, proliferation, angiogenesis,
differentiation and regulation of immune response [ 64 ]. Activation of signal
transducer and activator of transcription 3 (Stat3) has been observed in many
human cancers [ 65 ] and correlates with malignancy [ 66 , 67 ]. Tumor necrosis
factor alpha (TNF-a) is another inflammatory adipokine that may not only account
for chronic low-grade inflammatory state setting in obesity but also contribute to
tumor cell proliferation, survival and invasion [ 68 , 69 ].
Other adipokines are mainly secreted by mesenchymal cells of adipose stroma.
One pathway widely implicated in obesity-fueled development of malignancies
depends on insulin-like growth factor 1 (IGF-1) axis. IGF-1 is an anabolic growth
factor/hormone that primarily acts by binding to the IGF-1 receptor (IGF-1R).
Signaling downstream of IGF-1R activation involves phosphorylation of insulin
receptor substrate 1 (IRS1). Upon engagement of phosphatidylinositol-3 kinase
(PI3K), the signal culminates in activation of Akt (Protein Kinase B) and a major
downstream effector, the mammalian target of rapamycin (mTOR). mTORC1
(mTOR Complex 1) regulates cell growth, cell proliferation, cell motility, cell
survival, protein synthesis, and transcription. In addition to IGFs, epidermal
growth factor (EGF), transforming growth factor-beta (TGF-b) and plasminogen
activator inhibitor-1 (PAI-1) secreted by the SVF may function as tropic factors,
for instance by supporting malignant cell proliferation and survival [ 70 ]. In
addition, SVF cells may support tumor vasculature through activating pro-
angiogenic signaling mediated by vascular endothelial growth factor (VEGF) [ 62 ],
hepatocyte growth factor (HGF) [ 62 ], and fibroblast growth factors (FGF-1 and
FGF-2) [ 71 ].
In obesity, WAT overgrowth leads to tissue remodeling involving hypoxia,
fibrosis, and inflammation [ 2 ]. This triggers abnormal adipokine signaling cas-
cades that feed back upon the cellular components within WAT to further promote
adipogenesis, as well as the accompanying stromatogenesis and vascularization
[ 13 ]. Progressive accumulation of WAT leads to escalating secretion of various
adipokines, whose endocrine activity could stimulate cancer [ 18 ]. However,
experimental data suggest that systemic circulation of such key adipokines as IGF1
is not detrimental in controlling cancer progression [ 72 ]. Hence, the function of
paracrine adipokines produced by adipose cells at the tumor site has been
hypothesized as an additional mechanism linking increased adiposity and tumor
growth (Fig. 3 ). The stroma/vasculature of WAT is in the state of constant
remodeling and it could be expected that cells may egress from WAT in patho-
logical conditions. Indeed, this is observed both in the mouse models and clinically
[ 17 ]. Our studies have established the concept that trafficking of adipose cells
toward tumor hypoxia/inflammation signals result in their engraftment in tumor
microenvironment where secreted adipokines are more concentrated and, there-
fore, more potent [ 18 , 73 ].