Role of Adipose Cells in Tumor Microenvironment - The Mechanobiology of Obesity and Related Diseases - page 273

Fibronectin secreted by obesity-associated ASC, increasing matrix rigidity, could
be one of the key tumor matrix molecules promoting vascularization and growth.
Another ECM molecule abundant in WAT is collagen VI, which is secreted by
adipocytes and undergoes obesity-associated processing [ 96 , 113 ]. A cleavage
product of the COL6a3 chain, endotrophin (ETP), promotes malignant tumor
progression partly as a leukocyte chemoattractant [ 114 ]. As many tumor-
promoting signaling events are cell contact-dependent, ECM molecules also
mediate adipose stroma interaction with malignant cells.
Apart for the secretion of ECM molecules, WAT cells contribute to tumor
stromatogenesis through secretion of enzymes. WAT produces many proteinases
responsible for angiogenic ECM remodeling. Matrix metalloproteinases (MMPs)
are among key enzymes implicated in cancer-cell invasion and metastasis. For
example, MMP-2 and MMP-9 produced in WAT, play a role in several steps in the
angiogenic process [ 115 ]. In addition, ASC within tumor microenvironment are
likely to be a substantial source of MMP-11 (stromelysin-3), which facilitates
cancer angiogenesis [ 116 ]. Increased levels of several MMPs in obesity, as well as
their role in adipocyte differentiation, might represent a potential molecular link
between obesity and cancer [ 117 ]. In addition to indirect pro-angiongenic effect on
tumors, WAT cell-derived factors appear to directly stimulate tumor progression
to advance stages through the EMT [ 13 ]. In vicinity of CAFs, epithelial cells lose
the epithelial morphology, expression of the intercellular adhesion molecule
(E-cadherin and keratin), the epithelial marker (cytokeratins) and acquire the
mesenchymal markers (fibronectin, N-cadherin, and vimentin), spindle-like mor-
phology and increased motility, invasiveness and metastatic ability. In a set of
studies, EMT and tumor metastasis have been linked to excessive adipose stroma
in various cancer types [ 31 , 118 - 120 ].
2.5 Adipose Cell Role in Tumor Metabolism
Tumor cells utilize special metabolic pathways to support their proliferation and
survival [ 121 ]. Aerobic glycolysis is the main pathway providing cancer cells with
energy as well as the building blocks, such as carbohydrates, proteins, lipids and
nucleic acids, for macromolecule synthesis [ 122 ]. According to the ''Warburg
effect'' paradigm, that has evolved mainly based on cancer cell culture models,
glucose is a predominant fuel source for tumors [ 123 ]. However, recent studies
have revealed the ''reverse Warburg effect'' corresponding to the complex inter-
play between cancer cells and the surrounding stroma [ 124 ]. Moreover, there is
increasing evidence indicating a crosstalk between WAT and cancer metabolism.
It has become clear that fatty acids can serve as an important alternative energy
source for a number for cancer types [ 125 ]. Alterations of phospholipid metabo-
lism have been reported in many obesity-related (e.g. ovarian and breast) cancers
[ 126 - 128 ]. Latest metabolic profiling and isotopic fatty acid tracing showed that
lipid metabolism underlies cancer progression [ 129 ]. Specifically, aggressive