Neoplasia

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NEOPLASIA-VII

Q: WHO are the usual suspects?


 Inflammation?
 Teratogenesis?

 Immune
Suppression?
 Neoplasia?

 Mutations?
A: The SAME 3 that are
ALWAYS blamed!
1) Chemicals
2) Radiation

3) Infectious
Pathogens
Induction of cancer by application of coal tar to the skin of rabbits (Yamagiwa. 1915)
CHEMICALS
Direct-acting agents Indirect-acting agents

• Does not require metabolic • Require metabolic conversion to


conversion to become carcinogenic become active carcinogenic

• Weak
• E.g: polycyclic
carcinogens
hydrocarbons, aromatic
amines, azo dyes

• E.g: alkylating agents


Chemical carcinogens and the
tumours with which they are
associated:
Chemical Tumor Comments
Polycyclic hydrocarbon Lung cancer Present on fossil fuels
Aromatic amines Skin cancer Bladder Rubber and dye
cancer workers

Nitrosamines Gut cancer Proven in animals


Azo dyes Bladder n liver cancer Proven in animals
Alkylating agents Leukemia Small risk in human
e.g: cyclophosphamide
Other organic Liver angiosarcoma PVC manufactures
chemicals e.g: vinyl
chloride
Arsenic compounds Skin cancer No longer a common
event
Chemical Carcinogenesis:

 Initiation/Promotion concept:
 BOTH initiators AND promotors are needed
 NEITHER can cause cancer by itself

 INITIATORS (carcinogens) cause


MUTATIONS
 PROMOTORS are NOT carcinogenic by
themselves, and MUST take effect AFTER
initiation, NOT before
 PROMOTORS enhance the proliferation of
initiated cells
Steps Involved in Chemical Carcinogenesis

 carcinogenesis is a multistep process , in which the stages of


initiation and progression during cancer development have
been identified.

 Initiation results from exposure of cells to a sufficient dose of


a carcinogenic agent (initiator);
 an initiated cell is altered, making it potentially capable of
giving rise to a tumor.
 Initiation alone, however, is not sufficient for tumor formation
 Initiation causes permanent DNA damage (mutations). It is
therefore rapid and irreversible and has "memory."
Promoters
 Promoters can induce tumors in initiated cells, but
they are non tumorigenic by themselves.
 tumors do not result when the promoting agent is
applied before, rather than after, the initiating
agent.
 the cellular changes do not affect DNA directly
and are reversible.
 promoters enhance the proliferation of initiated
cells, an effect that may contribute to the
development of additional mutations in these cells.
Experiments demonstrating the
initiation and promotion
 phases of carcinogenesis in
mice.
 Group 2: application of
promoter repeated at twice-
weekly intervals for several
months.
 Group 3: application of
promoter delayed for several
months and then applied
twice weekly.
 Group 6: promoter applied
at monthly intervals.
CARCINOGENIC AGENTS
 hundreds of chemicals - transform cells in vitro and
to be carcinogenic.
 Some of them;
1. (e.g., the polycyclic aromatic hydrocarbons) have
been extracted from fossil fuels or
2. are products of incomplete combustions.
3. are synthetic products created by industry .
 naturally occurring components of plants and
microbial organisms.
 medical drugs have been strongly implicated in the
causation of cancers in humans.
CHEMICAL CARCINOGENS:
INITIATORS
 DIRECT  “PRO”CARCINOGENS

 β-Propiolactone  Polycyclic and Heterocyclic

 Dimeth. sulfate Aromatic Hydrocarbons


 Aromatic Amines, Amides,
 Diepoxybutane
Azo Dyes
 Anticancer drugs
 Natural Plant and Microbial
(cyclophosphamide,
chlorambucil, nitrosoureas, Products
 Aflatoxin B1 Hepatomas
and others)
 Griseofulvin Antifungal
 Acylating Agents
 Cycasin from cycads
 1-Acetyl-imidazole
 Safrole from sassafras
 Dimethylcarbamyl chloride
 Betel nuts Oral SCC
CHEMICAL CARCINOGENS:
INITIATORS

OTHERS
 Nitrosamine and amides (tar, nitrites)
 Vinyl chloride angiosarcoma
 Nickel
 Chromium
 Insecticides
 Fungicides
 PolyChlorinated Biphenyls (PCBs)
CHEMICAL CARCINOGENS:
PROMOTORS

 HORMONES
 PHORBOL ESTERS (TPA), activate kinase C
 PHENOLS
 DRUGS, many

“Initiated” cells respond and proliferate


FASTER to promotors than normal cells
RADIATION CARCINOGENS
 UV: BCC, SCC, MM (i.e., all 3)

 IONIZING: photons and particulate


 Hematopoetic and Thyroid (90%/15yrs) tumors
in fallout victims
 Solid tumors either less susceptible or require a
longer latency period than LEUK/LYMPH
 BCCs in Therapeutic Radiation
RADIATION CARCINOGENESIS

 Radiant energy, can transform virtually all cell types in vitro


and induce neoplasms in vivo.

 UV light -sun
 ionizing radiation
1. exposure from medical or occupational exposure,
2. nuclear plant accidents, and
3. atomic bomb detonations have produced a variety of forms of
malignant neoplasia.

 . An increased incidence of breast cancer has become apparent


decades later among women exposed during childhood to the
atomic bomb.
 The effects of UV light on DNA differ from those of ionizing
radiation.
Mechanism of action-Radiations

 U-V rays- damage to DNA by formation of


pyrimidine dimers

 Ionizing radiations-can directly cause mutation


or indirectly by generation of free radicals from
water and oxygen
MICROBIAL AGENTS

Oncogenic Viruses DNA/RNA


Bacterial agent H.pylori

Mechanism of Action Oncogenic viruses


 Genome of oncogenic DNA viruses integrate into and form stable
association with host cell genome, cell transformation by DNA viruses

 Virus unable to complete its replicative cycle , viral genes essential for
completion of replication are interrupted during integration of viral DNA.
Thus, virus can remain in a latent state for years.

 Viral genes transcribed early in the viral life cycle (early genes) are
important for cellular transformation, and are expressed in transformed
cells.
So what is an oncovirus?
 Virus that causes cancer
 Known oncoviruses are:
 Hepatitis C
 Hepatitis B
 HTLV-1
 HPV
 HHV-8 (KSHV)
 Merkel Cell Polyomavirus
 EBV
VIRAL CARCINOGENESIS
 HPV SCC
 EBV Burkitt Lymphoma
 HBV HepatoCellular Carcinoma (Hepatoma)
 HTLV1 T-Cell Malignancies
 KSHV Kaposi Sarcoma
 Areas of the world with high mortality rates for HCC also
have high HBV infection rates
 Cirrhosis is closely related with chronic HBV infection, at
least 80% of liver cancers occur in cirrhotic livers
 Case control studies in all regions of the world have shown
that chronic HBV infection is much more common in HCC
cases than controls
› OR ranged from 5:1 to 65:1
 Prospective studies of chronic HBV carriers have shown
very high relative risks for HCC
› 400 and 500 /100,000 compared with 5/100,000
› Prevention of HBV reduces risk of subsequent HCC
Effect of HPV proteins E6 and E7 on the cell cycle.

 E6 and E7 enhance p53


degradation, causing a block
in apoptosis and decreased
activity of the p21 cell cycle
inhibitor.
 E7 associates with p21 and
prevents its inhibition of the
Cyclin/CDK4 complex;
 E7 can bind to RB,
removing cell cycle
restriction.
 The net effect of HPV E6
and E7 proteins is to block
apoptosis and remove the
restrains to cell proliferation
Kaposi’s sarcoma-associated
herpesvirus (HHV-8)
 -Kaposi’s sarcoma
 -Rarely, primary effusion lymphoma

 -Causes disease in
immunosuppressed patients;
asymptomatic in healthy people
 -HIV/AIDS patients, transplant
patients, the elderly, chemo patients
 -While this virus is typically
associated with AIDS patients in the
U.S., infection is widespread in sub-
Saharan Africa and there are more
cases of KS there
 Sexually transmitted
 -Infects lymphocytes, establishes latency
 -Inflammation or some other stimulus ignites
the lytic cycle
 -Inhibits p53 tumor suppressor protein
 -Cell lysis allows virus to escape and infect
surrounding cells
Epstein-Barr Virus (EBV)

 -90-95% of people are


infected in childhood, with
no symptoms
 -Causes infectious
mononucleosis in
adolescents
 -Causes cancer in certain
geographical locations, and
in immunocompromised
patients
 Which cancer?

 -Hodgkin’s lymphoma, Burkitt’s lymphoma,


nasopharyngeal carcinoma

 -In HIV patients, infection associated with CNS


lymphomas and hairy leukoplakia
Schema depicting the possible evolution of Epstein-
Barr virus (EBV)-induced Burkitt lymphoma
H. pylori CARCINOGENESIS

 100% of gastric lymphomas (i.e., M.A.L.T.-omas)

 Gastric CARCINOMAS also!


Science 347: 78-81, 2015

Variation in cancer risk among


tissues can be explained by the
number of stem cell divisions

Cristian Tomasetti and Bert Vogelstein

Some tissue types give rise to human cancers millions of times more often than other
tissue types. Although this has been recognized for more than a century, it has never been
explained. Here, we show that the lifetime risk of cancers of many different types is strongly
correlated (0.81) with the total number of divisions of the normal self-renewing cells
maintaining that tissue’s homeostasis. These results suggest that only a third of the
variation in cancer risk among tissues is attributable to environmental factors or inherited
predispositions. The majority is due to “bad luck,” that is, random mutations arising
during DNA replication in normal, noncancerous stem cells. This is important not only for
understanding the disease but also for designing strategies to limit the mortality it causes.

This paper is a subject of active debate.


Estimated percentage of cancer deaths attributed to
different factors in the United States and the United
Kingdom

 Diet 41%
 Tobacco 24%
 Infection 10%
 Ultraviolet light 10%
 Sexual factors 7%
 Occupation 5%
 Alcohol 3%
 Pollution 1%
 Medical procedures 1%
 Ionizing radiation 1%

 The data are taken from a review by Roush et al. And represent the
approximate midpoint of ranges derived from the data of Doll and Peto,
Higginson and Muir, and Wynder and Gori.
Thank you

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