Etiology of tumors: Environmental Carcinogenesis Bianchi

Question 1

Epidemiology of Cancer:

Answer 1

Epidemiology of Cancer:
Epidemiologic studies have established the causative link between environmental (tobacco smoke, composition of diet, pollutants…), racial (possibly hereditary), and cultural influences and specific neoplasms. Several studies have proved that environmental influences are the dominant risk factors for most
cancers (80%), especially due to chemicals and pollutants found in the environment.

Question 2

Example of how an initiator like polycyclic aromatic hydrocarbon (PAH) is able to produce a genetic disorder. It is an indirect carcinogen; it is metabolized by the CYP enzyme and after being metabolized, it can cause genetic mutations.
How is the mechanism?

Answer 2

1. The first step is the upregulation of the CYP450 able to metabolize it.
   The gene transcription is mediated by the interaction of the hydrocarbon with the specific cytoplasmic receptor that allows the expression of the CYP450 enzyme, mainly the CYP1A1.
2. The cell has acquired a greater biocatalytic potential and is
   able to metabolize a higher amount of PAH, which then can be transformed into the final carcinogen.
3. After this transformation the PAH is able to create DNA adducts that may cause a genetic disorder. In this genetic
   the disorder also participates in the repair systems which are activated where there is big DNA damage, even if in this
   case it won’t be able to repair the damage since it is too big

Question 2

The role of environmental factors on the pathogenesis of cancer has been consolidated.
Among the best-established environmental factors affecting cancer risk:

Answer 2

● Chemical carcinogens: chemical carcinogens are everywhere, they lurk in the ambient environment, in the workplace, in food, and personal practices. Individuals may be exposed to carcinogenic molecules when they go outside (e.g. smog), drink well water (e.g., arsenic, particularly in underdeveloped countries), take certain medications (e.g., methotrexate), go to work (e.g., asbestos), or lounge at home (e.g., grilled meat, high-fat diet)
● Alcohol consumption: alcohol abuse increases the risk of carcinoma of the
oropharynx (excluding lip), larynx, and esophagus, and, by the development of alcoholic cirrhosis, hepatocellular carcinoma. Moreover, the risk of cancers in the upper airways and digestive tract imposed by alcohol is increased synergistically when combined with tobacco use.
● Smoking: cigarette smoking is the single most important environmental factor
contributing to premature death in the United States. Smoking, particularly cigarettes, is implicated in cancer of the mouth, pharynx, larynx, esophagus, pancreas, and
bladder and, most significantly, in about 90% of lung cancers.
● Obesity: The most overweight individuals in the U.S. population have 52% (men) to
62% (women) have higher death rates from cancer than do their slimmer counterparts; it follows that approximately 14% of cancer deaths in men and 20% in women are
associated with obesity. Diets are characterized by a higher intake of carbohydrates
and fats

Question 3

Chemical carcinogenesis:
They are classified according to:

Answer 3

● The metabolic activation in the body:
1. direct-acting carcinogens: not requiring metabolic activation in the body for their
carcinogenicity (activation independent); they are weak carcinogens; and include many
therapeutic alkylating agents used as anticancer drugs.
2. indirect carcinogens (procarcinogens): require metabolic conversion in the liver to
produce carcinogenesis in the cells; include most of the known potent carcinogens
activated by cytochrome P450 oxidase. Some examples: are benzo(a)pyrene, vinyl-chloride, and nitrosamine (that is converted into epoxide by our metabolic system, which is able to damage the DNA). The ultimate carcinogenic effect of the chemical will depend on the balance between 3 activities: activation, detoxication, and repair of DNA damage. Cancer will only develop as a result of sublethal DNA damage which is not repaired while the cell is viable enough to undergo mitosis. If the damage is lethal, the cell dies and so no cancer occurs.
So, to be considered a potent carcinogen, the effect on the genome must be high enough to be fixed in the population without being repaired.
● The Organ specificity: every chemical can have a neoplastic effect on a specific organ,
depending on the tropism of the chemical, carcinogen is largely determined by the sites of their activation or excretion. Chemicals can determine cancer in the activation site or in the
excretion site. Accordingly, they are grouped into two main categories:
1. Single organ affection → Aflatoxin, butter yellow, vinyl chloride can lead to liver cancer (activation site), and to bladder cancer (excretion site). The enzymes present in these organs are themselves the cause of cancer when they come in contact with these chemicals.
2. Multiple organ affection → nitrosamine and polycyclic aromatic hydrocarbons can cause cancers or neoplastic transformation in different organs, depending on the route of administration.
● the degree of evidence of carcinogenesis: The International Agency for Cancer Research (IARC) categorizes human carcinogens into:
1. Sufficient evidence of carcinogenicity
2. Limited evidence of carcinogenicity
3. Inadequate evidence of carcinogenicity
The classification is based on epidemiological studies in the population or in animals. It is
difficult to have a definition performed only in vitro, it needs to be confirmed in vivo in the population

Question 4

___________ used several years ago as buffer, now it is exploited as
chemotherapeutic agent to treat tumor cells.

Answer 4

nitrogen mustard
The use of these molecules in cancer treatment derives from the evidence that cancerogenic cells hyperproliferate and so are more sensitive to them. However, being direct carcinogens, they are genotoxic for normal cells as well, so may also represent a source of tumors too. The patients treated with these molecules are often affected by a second tumor during their life due to exposure to these potential cancerogenic drugs, it is a-specific treatment.

Question 4

Obesity:

Answer 4

The most overweight individuals in the U.S. population have 52% (men) to 62%
(women) higher death rates from cancer than do their slimmer counterparts; it follows
that approximately 14% of cancer deaths in men and 20% in women are associated with
obesity

Question 5

alcohol abuse increases the risk of

Answer 5

risk of carcinoma of the oropharynx
(excluding lip), larynx, and esophagus and, by the development of alcoholic cirrhosis,
hepatocellular carcinoma. Moreover, the risk of cancers in the upper airways and
digestive tract imposed by alcohol is increased synergistically when combined with
tobacco use

Question 6

_______________is the single most important environmental factor
contributing to premature death in the United States. Smoking, particularly of cigarettes,
is implicated in cancer of the mouth, pharynx, larynx, esophagus, pancreas, and bladder
and, most significantly, in about 90% of lung cancers.

Answer 6

cigarette smoking

Question 7

Chemical + Viral factors=

Answer 7

HCC and nasopharyngeal carcinoma

Question 7

Virus + smoking + Contraceptive pills(extrincis)=

Answer 7

Cervical carcinoma

Question 8

Genetics + Hormonal factors (intrinsic)=

Answer 8

Familial breast cancer ( mutation of BRCA1-2)

Question 9

Intrinsic and extrinsic factors
Genetics (DNA repair defect) + Physical factor (UV radiation)=

Answer 9

Cutaneous cancer in xeroderma pigmentosum

Question 10

extrinsic and intrinsic factors
Genetics + immune factor + Virus + UV radiation=

Answer 10

SCC in epidermodysplasia verruciformis

Question 11

Direct acting carcinogens:

Answer 11

do not require metabolic activation in the body for their carcinogenicity (activation independent)

weak carcinogens

include many therapeutic alkylating agents used as anticancer drugs (cyclophosphamide, chlorambucil, melphalan, busulfan, thiotepa and cisplatin)

Question 12

“Activation” of PAH by CYP enzymes:

Answer 12

1- AhR complex binds to B[a]P or any
other PAH in cell cytoplasm
2- activated transcription factor
increases mRNA levels of CYP1A1
3- the biocatalytic potential of the cells
rises because of the overexpression of
the CYP1A1 protein
4- CYP1A1-mediated biotrasformation of
B[a]P produce high amounts of
electrophil groups that form DNAadducts

Question 13

___________originally
produced as a chemical
warfare agent; it was one of
the first chemotherapeutic
agents for treatment of
cancer

Answer 13

Nitrogen mustard
They transfer alkyl groups to DNA: the damage destroys cancer cells, but also is
genotoxic for normal ones (“second cancer”). Mutagens = risk of transformation

Question 14

__________________ is a chemotherapy medication used to
treat a number of cancers. Common side effects
include bone marrow suppression, hearing
problems, including total irreversible hearing loss

Answer 14

Cisplatin

Question 14

“Alkylating-like” agents:

Answer 14

they do not have an alkyl group, but nevertheless damage DNA. They
permanently coordinate to DNA to interfere with DNA repair. Mutagens = risk of transformation.

Question 15

Any substance or condition that produces
cytotoxicity leads to cell death and, therefore, a
continuous compensatory proliferative stimulus=

Answer 15

increased incidence of tumours upon several chronic
inflammations

Question 15

Many factors in humans act by stimulating proliferation and thus can be thought of conceptually as
__________________

Answer 15

tumor promoters.
-Hormone stimulation (e.g., oestrogen stimulation of the endometrium and breast)
-Growth factors (IGF, PDGF, VEGF)
-Chronic inflammatory processes associated with tissue repair (e.g., inflammatory bowel disease,
chronic hepatitis, and Barrett esophagus)

Question 16

Women who are overweight are more likely to:

Answer 16

develop Breast cancer, be diagnosed at a late stage of cancer, have higher mortality rates

Question 16

Chemical carcinogenesis
another possible mechanism:

Answer 16

Substance → metabolism via cytochromes P450 → ROS production → genotoxic damage from
oxidative stress.
It is also possible that the substance leads to
chronic inflammation with local production of
ROS by inflammatory cells (e.g. asbestosis)

Question 17

________ reduces the risk of breast, prostate and colorectal cancers

Answer 17

low-fat diet

Question 18

food additives, pesticides represent less than 1% of ________________

Answer 18

carcinogens found in food

Question 19

aflatoxins in badly stored grains lead to

Answer 19

HCC( hepatocellular carcinoma )

Question 20

Smoked fish (NOSs) lead to

Answer 20

nasopharyngeal cancer

Question 20

HAA (frying or grilling high protein food) or PAHs (broiling and smoking food) NOSs (Salting and picking food cured with nitrite and nitrate) leads to?

Answer 20

DNA adducts and breast cancer and colorectal cancer

Question 21

Aflatoxins form one of the main groups of _______________

Answer 21

mycotoxins
They are mutagenic and carcinogenic
compounds (among the most powerful ever known) produced by the fungi Aspergillus flavus and
Aspergillus parasiticus.

Question 22

The _________ grow in the soil, in forages and plant foods and are present in various improperly stored
foods such as manioca, various cereals, peanuts, sesame or sunflower seeds, various spices.

Answer 22

Fungi

Question 23

Animals fed contaminated vegetables can pass __________ into products such as eggs, meat and dairy products.

Answer 23

aflatoxin
Exposure to aflatoxins usually occurs by ingestion, but the most toxic form (aflatoxin B1)
can pass through the skin.

Question 23

A GROUP OF INDIRECT CARCINOGENS OF NUTRITIONAL IMPORTANCE: _____________

Answer 23

THE AFLATOXINS

Question 24

Metabolism of ________can lead to epoxide (direct carcinogen) or to the less toxic aflatoxins M1 and
M2. The conditions that favour the growth of A. flavus and parasitises are high temperature and
humidity.

Answer 24

AFB1
The mutagenic action of aflatoxin
B1 derives from the ability of the
epoxide (obtained through
metabolism) to alkylate the DNA
(hence the urine alkyl-guanine test
to evaluate exposure) in strategic
sites, among which the codon 249
of TP53 gene where it causes a
transversion point mutation G > T

Question 25

Adults are relatively resistant to__________________

Answer 25

acute toxicity (although episodes of mortality clusters from acute
toxicity have been described)
On the other hand, children are relatively sensitive to aflatoxicosis,
showing growth retardation, as well as yellow-acute liver atrophy. Chronic exposure does not initially
cause striking symptoms but increases the risk of hepatocellular carcinoma and gallbladder
carcinoma. In addition to being mutagenic, AB1 is capable of causing immunosuppression.

Question 26

sugar-sweetened beverage consumption, mainly fructose is linked to ?

Answer 26

insulin resistance, obesity, and NAFLD which then lead to the establishment of HCC.

Question 26

a diet rich in ___________________________ seems to reduce the risk of carcinogenicity.

Answer 26

Apiaceae (Umbelliferae: carrots, celery, parsley, parsnips,
coriander, cumin….)

All animals are sensitive to toxicity
from a. In particular, turkeys are very sensitive and dogs have a susceptibility of the same order of
magnitude as that for humans, hence the need for controls not only on products for human
consumption but also on animal feed

Question 27

The three BCAA (leucine, isoleucine and valine)
are among the nine essential amino acids for humans
They have been shown to affect __________________________

Answer 27

gene expression, protein metabolism, apoptosis, and regeneration of hepatocytes
and insulin resistance.

They have also been shown to inhibit the proliferation of liver cancer cells in vitro. In
addition, all three BCAA were found to accelerate insulin-induced vascular endothelial growth factor mRNA
degradation at the post-transcriptional level, down-regulating vascular endothelial growth factor expression
during the development of HCC. BCAA were also shown to induce apoptosis of liver cancer cell lines by inhibiting
insulin-induced PI3K/Akt and NFκB pathways through mTORC1- and mTORC2-dependent mechanisms. Moreover,
BCAA may inhibit obesity-related hepatocarcinogenesis by suppressing the stimulatory effect of visfatin, an
adipokine with a critical role in HCC proliferation.

Question 28

clinical studies showed that BCAA supplementation can help in the management
of?

Answer 28

HCC, including reducing early recurrence of HCC, improving quality of life and liver functions among patients
undergoing liver resection for HCC, and increasing serum albumin levels during radiotherapy. Interestingly, a
recent meta-analysis of seven cohort and ten case–control studies indicated a potential protective association
between BCAA and HCC risk. However, to date, there has been no epidemiological research to directly investigate
the putative association between dietary BCAA intake and liver cancer risk to our knowledge.”

Question 29

Previous studies suggested that high dairy product intake may increase the levels of?

Answer 29

plasma IGF-1.
The increased concentration of IGF-1, an important factor in the regulation of cell proliferation, differentiation,
apoptosis and carcinogenesis might contribute to the development of several cancers including HCC in experimental
studies. In line with the evidence, two cohort studies but not all showed that higher total dairy product intake (three
serving per d or more) was associated with a statistically significant higher risk of HCC, while yogurt consumption
was suggestively associated with lower HCC risk, and these associations remained within participants who were free
of HBV and HCV infections……

Question 30

we found that a vegetable-based dietary pattern was associated with a lower risk of

Answer 30

cancer. Consistently, total fibre and vegetable fibre, especially cereal fibre, were possibly associated with lower HCC
risk, while fibre from fruit did not seem to be associated with lower HCC risk. ……. The exact reasons for such a difference
remain unknown.
A potential explanation is that fruits, particularly fruit juice, contain sugar or added sugar (e.g., fructose and sucrose), which may cause hepatic damage and NAFLD, thereby masking the possible benefit of fibre intake. Nuts are rich in unsaturated fatty acids, vegetable protein, vitamins, folate, fibre, minerals and other bioactive compounds. Nut consumption was associated with a reduced risk of NAFLD. We did not find any protective association between total nut or walnut consumption and HCC risk in the two USA cohorts, although increasing intake of tree
nuts was found to possibly reduce the HCC risk. These findings need to be validated due to limited HCC cases and
relatively low intake levels of tree nuts in the stud

Question 31

The features of cancer include metabolic alterations
These are tumor-dependent and they may concern:

Answer 31

• acceleration of glycolysis: even in aerobic conditions, with an increased consumption of glucose (exploited in PET with 18F-deoxyglucose)
• increased dependence on certain amino acids: (AA addiction, different from tumor to tumor) to maintain
  accelerated protein synthesis or correct particular enzymatic defects: e.g. glutamine, serine, arginine,
  asparagine, aspartate, proline
• increased synthesis of fatty acids: (necessary for cell proliferation)

Question 32

Influence of Dietary Carbohydrates on Tumor Metabolism:

Answer 32

• Increased glucose uptake and glycolysis
  (biomass generation, energy production, and
  antioxidant defense)
• Fructose can promote glycolysis and exacerbate
  cancer development

Question 32

Restricting cancer cell growth by limiting the glucose supply:

Answer 32

1) -Limiting glucose supply and restraining glycolysis
(fasting, ketogenic diet, or mannose)
2) ↓ availability of insulin and IGF-1 to the tumor.
3) ↓ activation of the PI3K pathway
(hyperactivated in many cancers)
4) ↑ therapeutic response to PI3K inhibitors.

Question 33

Many diet-based therapeutic approaches are under active clinical trials:

Answer 33

The most common protocols consist of calorie restriction through periods of fasting or very low-calorie diets (fasting-mimicking diets, FMDs), based either on chronic calorie restriction or intermittent fasting.

The mechanisms that would justify the efficiency of these approaches consist of:
- plasma levels reduction of glycemia, insulinemia, and IGF-1
- induced proliferative arrest and activation of AMPK (the AMP-dependent kinase, activated by metformin),
- increase in antioxidants and the activation of autophagy
In addition to these “generalist” approaches, other protocols suggest a limitation of the intake of individual nutrients, taking into account the metabolic characteristics of specific tumors

Question 34

Diet and cancer therapy
“Generalist” approaches:

Answer 34

Calorie Restriction (CR):
A dietary regimen that decreases calorie intake relative to the subject’s habits or the
average without causing dietary deficiencies.
Fasting-mimicking diet (FMD), intermittent fasting:
It is the name of at least 3 different types of diet regimens: alternate-day fasting (ADF),
periodic fasting, time-restricted eating (e.g. 8:16)

Question 35

Targeted approaches (“precision nutrition”):

Answer 35

-Ketogenic diet (KD): normocaloric diet with high fat content, normal/high protein
content, reduced (i.e. < 20%) carbohydrate intake.
-reduction in fructose intake (reduction in the prevalence of obesity)
-protein restriction (activation of ER stress and autophagy, inhibition of mTOR), exploiting
the “weak points” of neoplastic metabolism
-targeted reduction of essential amino acids: methionine, BCAA
-targeted reduction of non-essential amino acids: glutamine, asparagine, arginine,
cysteine, serine
-reduced intake/increased need for vitamins