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Page 8 of 12 Conti et al. J Cancer Metastasis Treat 2019;5:64 I http://dx.doi.org/10.20517/2394-4722.2019.015

Although the influence of BMI on the FA changes in CRC-affected subjects was not considered in the above
studies, its relevance emerged in our subsequent studies in which the VAT FA composition was analyzed
in newly diagnosed CRC patients, sub-grouped in lean and obese according to BMI [26,27,29] . A reduced
ω3/ω6 PUFA ratio as well as an increased content of dihomo-γ-linolenic and docosatetraenoic acids,
coupled with STAT3 activation characterize CRC subjects, irrespective of BMI [26,27] . However, compared
to healthy individuals, obese CRC patients show a selective accumulation of arachidonic acid in VAT,
whereas a lower SFA content is specific of lean CRC subjects despite a higher dietary intake [27,29] . The lack of
correspondence between SFA intake and storage in the latter subjects could in part rely on an accelerated
[29]
SFA to MUFA conversion as suggested by the increased estimated activity of SCD1 Δ9-18 . Interestingly,
the increased content of pro-inflammatory FA in AT from CRC-affected individuals is associated to an
enhanced adipocyte release of inflammatory cytokines and chemokines (IL-6, CCL2, CXCL8) and with the
[27]
establishment of an immunosuppressive VAT microenvironment .
[76]
AT and its FA content have also been related to tumor progression by Mosconi et al. , who analyzed
VAT peri-tumoral fat composition in CRC patients at different tumor stages. The total content of MUFA
in close proximity of, but not far from the tumor lesion, was found significantly increased in patients at
higher tumor stage, especially stage IV. Comparable levels of SFA and PUFA were instead found in the
same patients, irrespective of the tumor stage, suggesting a selective involvement of MUFA in cancer
[76]
progression . Some food processing techniques (industrial hydrogenation of fats) and cooking methods
(heating and frying at temperatures > 220 °C) convert FA, naturally present in food in the cis form,
into their trans form, and the latter configuration has been associated with increased risk of cancer and
[77]
cardiovascular diseases . In the EURAMIC epidemiological study the FA composition of SAT samples was
[78]
used as a measure of FA intake and associated with CC risk . Statistically significant inverse correlations
were found between cis-MUFA concentration and the incidence of CC. Conversely, CC incidence
[78]
positively correlates with the content of trans-MUFA . As it stems from these results, the same category of
FA (e.g., MUFA) can exert a protective or promoting effect on CRC onset/progression, depending on their
configuration, the fat depot in which they are enriched, and the tumor stage [76,78] .

As stated above, AT FA profiles are influenced also by the activity of enzymes driving FA synthesis and/
or conversion. The expression/activity of these enzymes have been found dysregulated in tumor and AT
from cancer patients. In particular, FA synthase (FASN), a key anabolic enzyme, increases in the intestinal
mucosa of subjects with CRC or with pre-cancerous lesions according to the increased metabolic demand
[79]
of cancer cells . In contrast, FASN expression and activity are significantly reduced in VAT adjacent
[80]
to the tumor lesion, resulting in impairment of FA synthesis and AT storage . The inflammatory VAT
microenvironment might account for this reduction as a comparable FASN downregulation was described
in obese and CRC-affected individuals [27,45,81] .

Altogether, the alterations of FA metabolism and profiles in different fat depots, in proximity or far from
the tumor lesions, contribute to maintain a pro-inflammatory microenvironment in CRC patients, and
strongly support a role for both unbalanced dietary intake and changes in FA metabolism and storage in
colon and rectal carcinogenesis.

CONCLUSION
The type of daily consumed dietary fat together with metabolic activities influence the FA profile in AT
and can alter its functionality thus contributing to the onset of meta-inflammation that characterizes
obesity and metabolic diseases [Figure 1]. The promotion of inflammatory processes within AT determines
an inflamed microenvironment that can represent a trigger for the development of a number of obesity-
related pathologies including CRC. All together these findings highlight the relevance of maintaining
healthy dietary habits and the central role of AT in preserving health and well-being. However, the studies,