Role of Adipose Cells in Tumor Microenvironment - The Mechanobiology of Obesity and Related Diseases - page 278

with murine endothelial bEND.3 cells led to vascular-like network assembly
concomitantly with lipid droplet formation in perivascular cells. Adipocyte-
depleted SVF of mouse WAT cultured in 3D, but not in 2D, underwent assembly
into organoids with vascular-like structures containing luminal endothelial and
perivascular stromal cells layers. Adipospheres made from primary WAT cells
displayed robust proliferation and complex hierarchical organization reflected by a
matricellular gradient incorporating ASC, endothelial cells, and leukocytes, while
ASC quickly outgrew other cell types in adherent 2D culture. Upon adipogenesis
induction, adipospheres derived from the SVF displayed more efficient lipid
droplet accumulation than 2D cultures, indicating that levitation culture recapit-
ulates WAT organogenesis [ 159 ]. Such culture systems of new generation provide
a new platform for modeling tumor cell/matrix interaction and mechanobiology.
5 Summary and Conclusions
Cancer progression is accelerated in obese patients due to mechanisms that are not
well understood. Accumulating evidence indicates that WAT overgrown in obese
patients promotes cancer progression partly as a source of cells contributing to
tumor microenvironment. This shifts the paradigm of cancer-obesity relationship,
currently centered on the roles of diet and endocrine adipokines. At this point it is
unclear what functions of WAT-derived cells primarily contribute to tumor growth
and progression observed in obesity. While some adipokines are secreted exclu-
sively by differentiated adipocytes, many are products of ASC and infiltrating
leukocytes [ 23 - 25 ]. Clearly, there are multiple molecular mechanisms underlying
the link of WAT overgrowth with cancer, and their relative significance is yet to be
determined. It is likely that they act synergistically to promote a multifactorial
tumor-promoting environment. The interplay of these mechanisms likely differs by
cancer type, and future research will need to address patient-specific variation in
clinical settings. Importantly, recent studies suggest the role of ASC in promoting
cancer metastasis in mouse models [ 30 ]. Due to their high multipotency and
proliferation/migration capacity, ASC may promote not only cancer but possibly
other diseases accompanied by fibrosis [ 13 ]. Recent studies reveal that adipocytes
in WAT can become replaced with 'beige' ('brite') adipocytes [ 160 , 161 ] that
simulate cells of brown adipose tissue (BAT) responsible for adaptive thermo-
genesis [ 162 ]. BAT is now known to exist in adult humans, and emerging imaging
technologies will help to monitor how this tissue changes in disease [ 163 ]. A
growing body of evidence indicates that white and brown-like adipocytes arise
from distinct ASC populations [ 164 - 166 ]. It will be important to investigate how
these different ASC types engage in cancer and other fibrotic pathologies.
Despite the availability of numerous drugs aimed at neoplastic and vascular
tumor cells, resistance of cancer to treatment remains a challenge. Mounting
evidence points to the role of stromal cells not only in cancer progression but also
in therapy resistance. Indeed, MSC have chemoprotective effects on tumor cells