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Colon Cancer and Obesity A Na
Colon Cancer and Obesity A Na
Colon Cancer and Obesity A Na
Abstract
Obesity has played a crucial role in the pathogenesis of various cancers, including colorectal cancer (CRC).
Obesity has shown to increase the blood levels of insulin, insulin-like growth factor-1 (IGF-1), leptin,
resistin, inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α),
monocyte chemoattractant protein-1 (MCP-1) which in turn acts via various signaling pathways to induce
colonic cell proliferation and in turn CRC development. It has been shown that estrogen can prevent and
cause CRC based on which receptor it acts. Obese patients have relatively low levels of ghrelin and
adiponectin that inhibit cell proliferation which further adds to their risk of developing CRC. Obesity can
alter the microbial flora of the gut in such a way as to favor carcinogenesis. Weight loss and good physical
activity have been related to a reduced incidence of CRC; obese individuals should be screened for CRC and
counseled about the importance of weight reduction, diet, and exercise. The best way of screening is using
BMI and waist circumference (WC) to calculate the CRC risk in obese people. This study has reviewed the
association between obesity and its pathophysiological association with CRC development.
Review
Obesity has been linked to CRC in several studies. Obesity can be assessed using the body mass index (BMI),
and the relative risk of obese patients getting CRC is higher in males when compared to females [9,10]. About
11 years-
Li et al. Central obesity and general obesity correlated
female 5.5 China Cohort 124,225 935
[13] to colon cancer in males.
years -male
Maclnnis
- - - 16,556 153 Obesity led to colon cancer in male patients.
et al. [15]
TABLE 1: Population table explaining the association between obesity and CRC
CRC: colorectal cancer; BMI: body mass index; WC: waist circumference
TLR-4: Toll-like receptor-4; VEGFR: vascular endothelial growth factor receptors; MMP-1: matrix
metalloproteinases-1; MMP-2: matrix metalloproteinases-2
IL-6 is mainly produced by the fibroblast cells, and it stimulates the fibroblasts to make vascular endothelial
growth factor (VEGF) which mediates neovascularization and thus favors carcinogenesis in CRC [49]. Studies
show that IL-6 and C-reactive protein can be used as diagnostic tools to determine the further progression
and evaluate the CRC’s prognosis [50]. It is seen that transforming growth factor-beta (TGF-β) acts via IL-6
to activate the signal transducer and activator of transcription-3 (STAT-3) in the tumor cells, which requires
the soluble IL-6 receptor present in the tumor cells [51]. IL-6 activates glycoprotein-130 (gp-130) and also
has a positive effect on a few signaling pathways like STAT-3 and Janus kinases (JAKs) [52]. TNF-α plays a
role in CRC pathogenesis via the Wnt/β-catenin pathway and PI3K/AKT pathway [52]. The Wnt signaling
pathway includes various proteins like cyclin-D1, c-Myc, and epithelial-mesenchymal transition-related
proteins, which are involved in the formation of cancers [53,54]. TNF-α can exhibit varying effects on the
tumor microenvironment (TME) and hence be responsible for tumor progression and suppression [55]. The
tumor microenvironment (TME) is the support system for the cancer cells that favors cancer cells in
metastasis and growth [56]. TME includes various immune cells infiltrating cancer like lymphocytes,
fibroblasts, neovascularization, lymphatics, fat cells, and extracellular matrix [56]. It can exhibit antitumor
effects by acting at the TNF receptor 1 and 2 (TNFR1 and TNFR2), which work through various signaling
pathways [57]. The permeability of the blood vessels increases, resulting in the migration of the immune
cells into the tumor location and destruction of the tumor’s blood vessels, making it an effective mode of
treatment in cancer patients [57].
The adipocytes secrete the pro-inflammatory cytokine monocyte chemoattractant protein-1 (MCP-1) [58,59].
Macrophages are the predominant immune cells that can enter cancer cells [60,61]. The cancer cells are the
primary cells that release MCP-1, which plays a vital role in the inflammatory response at CRC by bringing
the monocytes into the tumor location, enhancing the process of carcinogenesis [60,61].
Oxidative stress
Obesity promotes the development of CRC and the formation of reactive oxygen species (ROS) [75,76]. ROS
is necessary to maintain good cell function, but if present in abundance, it can lead to detrimental effects
since it favors CRC; ROS can cause DNA breaks at locations such as the tumor suppressor gene or oncogenes,
which destroys the proteins responsible for regulating cell growth and proliferation, thus leading to the
development of various cancers [75,76]. Obesity can cause chronic inflammation and increase the level of
leptin, activation of protein kinases, activation of polyol pathways, and other mechanisms that can elevate
the oxidative stress inside the cell [77].
Prevention
In obese people, diet is critical in avoiding the development of CRC. Cabbage, broccoli, onions, ginger,
wheat, honey, turmeric, a few herbs, carrots, and berries are among the foods that can help prevent CRC [4].
Most food substances raise the antioxidant level and help reduce obesity-associated CRC [4]. Studies show
Limitations
This study explains various mechanisms that cause CRC in obese people, few of which will require further
studies to be proven. Diet and physical activity modification play a vital role in the development of CRC;
hence can be used as a target for treatment and prevention. But the part of medical management is not
discussed in this study.
Conclusions
One of the main determinants for developing CRC is having a BMI corresponding to overweight or obesity.
This review article elaborates on the association between obesity and CRC and explains the risk factors and
common mechanisms involved in CRC pathogenesis. Its pathogenesis is mainly mediated by obesity-
associated hyperinsulinemia, increased circulating levels of leptin, resistin, and various cytokines by
altering the gut microbial flora and oxidative stress. Thus, physicians should regularly screen obese
individuals to pick up early cases of changes in colonic mucosa to prevent CRC development in the future.
We should formulate new guidelines based on the BMI, WC, body fat distribution (central or general obesity),
and total body fat to aid in the early and easy screening of CRC risk in obese people. Patients should be
encouraged to reduce weight through a healthy diet and regular physical activity since weight loss can
prevent CRC development. It can also reduce mortality in obese people who have already developed CRC.
Thus, weight loss is the primary modality for avoiding and reducing mortality of obesity-associated CRC. In
the future, we need more in-depth research about this topic to understand the association between obesity
and CRC, screening, and treatment.
Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
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