Obesity and cancer (Are they related)

1. OBESITY AND CANCER
Tom Peter

2. OBESITY AND CANCER
Introduction
What is obesity?
• Obesity is defined as an increase in fat mass
that is sufficient to adversely affect health.
• Obesity is defined by an excess of adipose
tissue, which consists of adipocytes or fat
cells, as well as immune cells, stromal cells,
blood vessels, and neurons.

3. Measurement of Obesity
How is Obesity measured?
• Although weight is the simplest anthropometric index of
excess body fat, it does not distinguish between lean
body mass (comprised primarily of muscle, bone, and
extracellular water) and adipose tissue (Willett, 1998).
• Several measures are used to assess obesity.
• Body mass index (BMI), an individual’s body weight (in
kg) divided by the square of their height (in m), is an
easily available measure often used for obesity
assessment.
• Other anthropometric measurements of obesity include
waist circumference and waist: hip ratio, which better
reflect the differential distribution of body fat than BMI
alone.

4. Measurement of Obesity
• Use of radiologic techniques such as computerized
tomography (CT) also allows the level of intraabdominal
fat to be assessed. Sophisticated technologies like dual
energy X-ray absorptiometry can provide an overall and
regional assessment of body composition.

5. Localization of Adipose tissue

6. Types of Adipose Tissue
• Three distinct types of adipocytes have been described
in mammals:
• white, brown, and beige.
• White adipose tissue (WAT) functions mainly to store
nutrients as lipid.
• Brown adipose tissue (BAT) has high levels of
uncoupling protein 1 (UCP1), which uncouples
oxidative phosphorylation from ATP synthesis, thereby
dissipating energy as heat.
• Beige adipose comes from a distinct lineage to BAT,
but can be activated to acquire a more brown-like
phenotype.

8. Causes of Obesity
• Environmental
Factors
• Genetic factors
Contribution of Genes and Environmental Factors to Weight Gain(obesity):Human adiposity is influenced by complex interactions
between genetic and environmental influences. The current environment potently facilitates the development of obesity.
Abundance of highly processed food has a major impact on energy intake, whereas numerous other environmental factors, such
as television watching, leisure activities, and transport, negatively affect energy expenditure. In any environment, there is a
variation in body fat and BMI in large part influenced by genetic variation disrupting energy homeostasis by either decreasing
energy expenditure or increasing energy intake

9. Adipogenesis
How Adipocytes are formed?
• Adipogenesis is a molecularly regulated process in which
adipose stem cells are converted into mature adipocytes
through commitment and differentiation.
• In commitment, the first stage, stem cells are converted
into preadipocytes.
• In differentiation, preadipocytes are converted into mature
adipocytes that are capable of secreting adipokines and
transporting, synthesizing, and releasing lipids.

10. Commitment
• Commitment is the process in which pluripotent stem cells
(PSCs) located in the vascular stroma of adipose tissue
respond to signal(s) telling them convert into preadipocytes.
• Adipose lineage cells originate from PSCs of mesodermal
origin.
• In the vascular stroma of fat tissue in mammals, two types of
adipocyte precursors are found:
• Pluripotent fibroblasts (stem cells) and Unipotent
preadipocytes.
• Once pluripotent fibroblasts commit to the adipose lineage,
they can be induced only to form adipocytes and no other cell
type. Bone morphogenic proteins (BMPs) play an important
role in the commitment of PSCs into preadipocytes.

11. • Both BMP2 and BMP4 were shown to induce
commitment of C3H10T1/2 pluripotent stem cells into
adipocytes. Treatment with these BMPs followed by
exposure to differentiation inducers allows nearly all cells
to enter the adipose development pathway, express
specific adipocyte markers, and acquire the adipocyte
phenotype.
• Other factors that may play a role in stem cell
commitment to the adipose lineage are cell shape and
density

12. Differentiation
• Differentiation is the process by which preadipocytes
(less specialized cells) turn into mature adipocytes
(more specialized cells).
• In cell culture models, in order to start differentiation
preadipocytes must reach confluence (cell‒cell contact)
and become growth-arrested (i.e., the cell cycle stops at
the G0–G1 boundary), which is due to cell density
inhibition. However, it is not the confluence but the
growth arrest itself that is necessary for preadipocyte
differentiation.
• After confluence (cell–cell contact), when they receive
adequate stimuli (via mitogenic and adipogenic
inducers), preadipocytes synchronously restart the cell
cycle and undergo mitotic clonal expansion.

13. • Mitotic clonal expansion consists of at least one round of cell replication
and is a required step in the differentiation of preadipocytes into
adipocytes in 3T3- L1 cells.
• It has been suggested that mitotic clonal expansion is needed to unwind
the DNA, thus allowing transcription factor binding to genes involved in
adipocyte differentiation.
• The extensive change in cell shape from fibroblastic to spherical is
considered as the first hallmark of adipogenesis.
• These changes happen simultaneously with changes in components
and levels of extracellular matrix and cytoskeletal components.
• The modifications that the cells undergo are critical for adipogenesis
regulation because they may promote the gene expression of C/EBPα
(CCAAT/enhancer-binding protein α) and/or PPARγ.
• These are fundamental adipogenic transcription factors.
• PPARγ and C/EBPα play an essential role in the progress of adipocyte
differentiation because both act synergistically to activate the
transcription of severalgenes that promote the adipocyte phenotype.

15. Leptin and Adiponectin
• Leptin was first discovered in 1994, named after the Greek
word “leptos”, meaning thin.
• It is a 167-amino acid peptide hormone encoded by the
obesity gene ( ob or lep ) localized on human chromosome
7 that, on reaching the brain, acts on receptors in the
hypothalamus to curtail appetite.
Production and Regulation
• Leptin is primarily synthesized and secreted by the white
adipose tissue (WAT).
• Serum leptin levels are positively correlated with the
amount of body fat, as obese subjects display higher leptin
levels compared with the lean subjects.

16. Factors that regulate leptin secretion
Factor promoting leptin
secretion
Factor inhibiting leptin
secretion
Overfeeding Fasting
Insulin Thyroid hormones
Glucocorticoids Catecholamines
Estrogen Testosterone
Acute infection Cold exposure
Pro-inflammatory cytokines - - - - - -

18. • Hypothalamic regulation of food intake and energy
expenditure.
• (a) Role of the hypothalamus in its interaction with
adipose tissue. The hypothalamus receives input (leptin)
from adipose tissue and responds with neuronal signals to
adipocytes.
• (b) This signal (norepinephrine) activates protein kinase A,
which triggers mobilization of fatty acids from TAG and
their uncoupled oxidation in mitochondria, generating heat
but not ATP. DAG, diacylglycerol; MAG, monoacylglycerol.

19. Adiponectin
• Adiponectin is an approximately 30-kDa polypeptide
containing an N terminal signal sequence, a variable
domain, a collagen like domain, and a C-terminal globular
domain.
• In addition, adiponectin increases nitric oxide production
in endothelial cells and stimulate angiogenesis. These
effects are mediated via increased phosphorylation of the
insulin receptor, activation of AMP activated protein
kinase, and modulation of the nuclear factor B pathway .
• adiponectin is a unique adipocyte derived hormone with
antidiabetic, anti-inflammatory, and anti- atherogenic
effects

20. Esophageal Cancer
• Esophageal cancer represents the eighth most common
cancer worldwide and the sixth most common cause of
cancer death.
• The case fatality ratio is as high as 83%, much higher
than that of other common malignancies like breast
cancer (36%) or colorectal cancer (52%).

21. Differences Esophageal squamous
cell carcinoma
Esophageal Adeno
carcinoma
Main risk factors Tobacco smoking, alcohol
use, thermal injury and
regional micronutrient
deficiency
Acid or bile reflux, Barrett
esophagus,
and central or visceral
obesity
Tumor location Throughout the esophagus,
more common in the upper
and middle third
More common in the distal
esophagus
Frequent comorbidity Liver cirrhosis, chronic
obstructive pulmonary
disease, synchronous and
metachronous cancer of the
aero-digestive tract, and
atherosclerosis
Obesity and atherosclerosis
Diagnosis and symptoms Similar Similar
Curative treatment Definitive
chemoradiotherapy, or
chemoradiotherapy followed
by surgery
Neoadjuvant or
perioperative chemotherapy
followed by surgery, or
neoadjuvant
chemoradiotherapy followed
by surgery

22. The pathogenesis of ESCC and EAC: The Esophageal mucosa is exposed to repeated insults, which
result in changes to the squamous esophageal mucosa. Molecular changes also accumulate, and this
ultimately leads to a malignant phenotype. In Esophageal squamous cell carcinoma (ESCC), squamous
hyperplasia precedes low-grade and high-grade squamous dysplasia, which then develops into invasive
cancer. In Esophageal adenocarcinoma (EAC), a metaplastic epithelium (Barrett esophagus) is
transformed through low-grade and high-grade dysplasia to invasive cancer. CDKN2A, cyclin-dependent
kinase inhibitor 2A; RB, retinoblastoma-associated protein

23. Increase in abdominal adiposity
Increase in intra-abdominal pressure
GERD
Barrett Esophagus
Esophageal adenocarcinoma
Potential pathway by which obesity leads to the development of esophageal adenocarcinoma

25. Underlying mechanisms of GERD in obese
individuals
• Defective lower esophageal sphincter (LES)
• Increased transient LES relaxations
• Abnormal esophageal clearance
• Increased intra-abdominal pressure
• Altered transdiaphragmatic pressure gradient
• Hiatal hernia
• Dietary habits (i.e. high-fat and low-fiber diet)

26. Increased gastro- esophageal reflux produces inflammation and tumorigenesis
in obesity.
COX-2: Cyclo-oxygenase-2; IL: Interleukin; LES: Lower esophageal
sphincter; TGF-b: Transforming growth factor b.

27. Molecular mechanisms linking adiposity with increased EAC risk.
FFA: Free fatty acids; IGFBP: Insulin-like growth factor binding protein; IGF-1: Insulin-
like growth factor 1; IL: Interleukin; ROS: Reactive oxygen species; TNF-a: Tumour
necrosis factor a; VEGF: Vascular endothelial growth factor

28. Gut Microbiota
Gut microbiota in Esophageal Cancer
• In populations where the incidence of esophageal
adenocarcinoma has increased, the prevalence of
Helicobacter pylori infection has decreased, suggesting a
potential inverse relationship. In the latest meta-analysis of
13 studies involving 1145 patients with esophageal
adenocarcinoma (372 positive for H. pylori) and 3453
controls (1380 positive for H. pylori), the risk of esophageal
adenocarcinoma decreased by 43% (OR=0.57, 95%
CI=0.44, 0.73)(OR-odds ratio, CI-confidence interval)among
persons with H. pylori infection. A similar inverse
association has been reported for H. pylori infection and risk
of developing Barrett’s esophagus.

29. Inflammation
• The cytokines leptin and adiponectin secreted by adipocytes are other
factors that might contribute to the link between obesity and esophageal
adenocarcinoma. Serum leptin levels rise with an increase in BMI.
• It has been shown that leptin stimulates proliferation and inhibits
apoptosis in esophageal adenocarcinoma cells.
• In addition, this hormone can activate the epidermal growth factor
receptor, an important signaling mechanism for activation of G protein
coupled receptors, and promote cell proliferation.
• The serum concentrations of adiponectin, unlike most of the other
adipokines, are inversely correlated with BMI and most importantly, with
visceral fat accumulation.
• Obese individuals have altered plasmatic levels of pro-inflammatory
cytokines such as tumor necrosis factor-α (TNF- α), IL-6, and adipokines
(adiponectin and leptin) released from visceral fat which may contribute
to carcinogenesis.

30. • Soluble tumor necrosis factor receptor 2 (sTNFR2), resistin,
plasminogen activator inhibitor 1, C reactive protein, and serum amyloid
A have been identified as potential mediators of obesity- esophageal
adenocarcinoma associations, providing robust evidence of a link
between obesity, systemic inflammation, and EAC risk.
• Leptin regulates appetite and immunity and has also been shown to
stimulate cell proliferation and inhibit apoptosis in EAC cell lines In
addition, leptin receptors (ObR) have sequence homology to some
cytokines receptors expressed in immune cells. Activation of these
receptors leads to the production of cytokines such as TNF-α, IL-2, and
IL-6 which contributes to the obesity-related inflammatory state
• The inflammatory response mediated by leptin may contribute to EAC
development through several mechanisms. For example, TNF-α and IL-
6 have shown to induce c-myc oncogene expression and STAT3 anti-
apoptotic pathway, respectively, which may underlie the development of
dysplastic BE and tumor progression.

31. Drugs for controlling obesity
• The drugs commercially available are Orlistat, Lorcaserin,
Sibutramine, Rimonabant, Metformin, Exenatide and
Pramlintide.
• Antiobesity drugs can be broadly divided into two categories.
The first category acts centrally by repression of appetite.
The second category acts peripherally through suppression
of fat absorption.
• Surgical methods are even adopted in controlling obesity
• Bariatric surgery
• Adverse effects of bariatric surgery, including acute
pancreatitis, deep vein thrombosis, hernia and infections

33. Phytochemicals in treating obesity
• Considering the side-effects of the antiobesity drugs, a holistic approach
can be of much help in obesity control.
Phytochemicals have a number of health promoting activities.
• They are anticarcinogenic, antimutagenic, antioxidant and anti-
inflammatory
• They suppress appetite, mainly by targeting gut-derived hormones, also
called GLP-1 or ghrelin.
• Phytochemicals may act on different stages of the life cycle of adipocytes.
function via inhibition of cell proliferation and enhancement of
programmed cell death of fat cells.
• inhibit the absorption of triglyceride, hinder the absorption of lipid, reduce
the intake of energy and they help to expend more energy. Another
beneficial effect is the inhibition of lipogenesis.
• Phytochemical index is a good measure to assess the role of a particular
compound in obesity control. The ratio of the energy obtained from diet
and the energy expended per day is called the phytochemical index,
which maintains an inverse relation with adiposity and oxidative stress.

34. Bioavailability of Phytochemicals
• A compound might have better bioavailability when it contains
maximum 5 hydrogen-bond donors, and 10 hydrogen-bond
acceptors, in association with having a molecular mass not
more than 500 daltons; a partition coefficient log 𝑃 value
should not be more than 5 and contains less than 10 rotatable
bonds.
• solubility of the compounds, stability due to gastric and colonic
pH, metabolism by gut microflora, absorption across the
intestinal wall, active efflux mechanism, and first-pass
metabolic effects may also play crucial role in limiting the
bioavailability of phytochemical.
• rapid conjugation of a phytochemicals, especially by
glucuronidation in the intestine and liver, in association with
reaction of cytochrome P450 (C-P450) enzymes, which are
recognized as important clearance mechanisms, is primarily
responsible for their poor bioavailability

35. • Phytochemicals with an agent that can modulate the
activity of glucuronidation or inhibit CP450 mediated
clearance mechanism is possible to increase the
bioavailability of active compound of interest at the target
site.
• Piperine, a component of black pepper, inhibits
glucuronidation and is able to enhance the bioavailability
of several bioactive compounds by altering the C-p450
mediated enzymatic biotransformation.
• Rapid mobilization in the intestine is largely responsible for
low bioavailability of curcumin at target site; however
consumption of curcumin along with piperine, a known
inhibitor of intestinal and hepatic 𝛽-glucuronidation of
curcumin, may induce the bioavailability of curcumin about
20-fold.

36. Classification of Phytochemicals

37. Phytochemicals in obesity related cancers
• Phenolic phytochemicals have strong antioxidant activities
due to the phenolic hydroxyl groups providing hydrogen
atoms for capturing reactive oxygen species (ROS).
• Excessive oxidative stress is mainly due to H2O2 and OH and
these agents are responsible for cancer cell proliferation.
Phenolic phytochemicals can inhibit the effects of H2O2 by
intervening in several pathways including NF-kB and MAPK.
• Epigallocatechin gallate (EGCG) is a phenolic phytochemical
present in green tea and has very effective antioxidant effects.
The effect of EGCG on human epidermal keratinocytes has
been observed by inducing oxidative stress through ultraviolet
radiation, as UV radiation increases the concentration of
H2O2.This in turn increases the phosphorylation of JNK and
MAPK. It was observed that EGCG could inhibit MAPK
activation by scavenging of H2O2.

38. • Resveratrol, the phenolic phytochemical found in grapes,
prevented NF-kB activation in several cell lines, including
Jurkat, HeLa and U-937.
• Lycopene, a carotenoid is found in fruits and vegetables having
red color, particularly tomatoes.
• Phloretin,a flavonoid is found in apples.
• kaempferol, found in kale, beans, spinach and broccoli etc. All
these three contribute as anticancer,anti-obesogenic agents.
• Quercetin, a flavonoid is found in onions, green tea, apples,
berries, St. John’s wort, buckwheat tea etc. Some other
antioxidant phytochemicals that contribute in this regard are
• Naringenin, a flavonoid, flavones like luteolin, daidzein,
genestein etc.
• Allicin, an organosulfur compound, phenolic acids like caffeic
acid, chlorogenic acid, ferulic acid, tannins are good anti-
obesogenic and anti-cancer agents.

39. • ROS impacts activation of transcription factors like Activator
Protein-1 (AP-1) or NF-κB. These in turn can modulate
proinflammatory cytokines such as Tumor Necrosis Factor
α (TNF-α), Interleukins like IL-6, IL-8, and IL-1.
• Glycosides of apigenin, leuteolin are anti-inflammatory and
can work in this regard.
• Apigenin is capable of suppressing nitric oxide (NO) via
inhibition of inducible nitric oxide synthase (iNOS) and
COX-2.
• Luteolin is capable of inhibiting inflammation of adipocytes.
• Inflammation in macrophages and phosphorylation of JNK
in macrophages can be inhibited by luteolin.
• Anthocyanins are good anti-inflammatory molecules that
works through mitogen activated protein kinase (MAPK)
pathway.

40. • Licorice roots contain triterpenes like glycyrrhizin and
glycyrrhetinic acid, which are also promising anti-
inflammatory agents. They act through P13K/Akt/GSK3-β
pathway to reduce cytokine production.
• Polyphenols like curcumin, genistein and epigallocatechin
are particularly effective in this respect for mitigating the
effects of obesity related tumor onset and progression.
• Curcumin is a lipophylic polyphenol and a popular Indian
spice. Curcumin has been found to inhibit TNF-α, IL-1β
and suppress NF-κB.

41. THANK YOU