Chemical carcinogenesis involves chemicals being metabolized in vivo into electrophilic reactants that can damage DNA. Carcinogenesis is a multi-stage process involving initiation, promotion, and progression. Initiation involves acquiring genetic changes that put a cell on a cancer path. Promotion provides a selective advantage allowing primed cells to survive locally. Progression accumulates further changes for malignancy. Chronic inflammation contributes at each stage by generating DNA-damaging species and altering cell-stroma relationships to facilitate invasion and spread. The most common chemical carcinogens metabolize into electrophilic reactants that can damage DNA.

1. Animal cell science and Technology
17. Chemical carcinogenesis
Shailendra Singh Shera, Ph.D

2. 17 Chemical Carcinogenesis
Content outline
1. Chemical carcinogenesis
2. Types of electrophilic reactant in vivo
3. Practice questions

3. Chemical carcinogenesis
•Chemicals appear to be of major importance in the induction of human cancers. The known
chemical carcinogens include a wide range of structures. Their common feature is that their
ultimate forms are electrophilic reactants; in most cases, these reactants arise through metabolism
in vivo.
•Carcinogenesis by chemicals is a multistage process.
Cancer arise in 3-steps
i. Initiation (the process of acquisition of genetic and epigenetic changes that sets the cell on
path to cancer),
ii. Promotion (a step during which the primed cells express altered responses that provide a
selective advantage allowing them to survive and develop locally),
iii. Progression (a series of steps during which the now established cancer cells accumulate
further changes on the path to malignancy

4. •Chronic inflammation contributes to each of these mechanisms. First, inflammation generates an overload in
reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage DNA and enhance several
mutagenic processes, thereby accelerating the acquisition of mutations that drive the cancer process. Second,
chronic inflammation involves the production of a complex combination of factors, some of which promote cell
proliferation and survival, while others induce cell death.
•Third, inflammation profoundly alters the relationships between cells and their stroma, and also enhances
angiogenesis, thus facilitating local invasion and distal dissemination of cancer cells.
•The role of inflammation in initiation, promotion, and progression stages of cancer development. The
sequence of development of an epithelial tumor is represented and divided in three steps: initiation,
promotion, and progression. The contribution of inflammatory mechanisms to each step is summarized.

5.  The main DNA-damaging reactive species produced during inflammation are hydrogen peroxide (H2O2), nitric
oxide (NO.), and reactive intermediates such as hydroxyl radicals (OH.), superoxide (O2
−⋅), and peroxynitrite
(ONOO−).
During inflammatory response, NO. is also produced inside cells through the activation of the transcription of
inducible nitric oxide synthase (NOS)-2 in response to cytokines. The promoter of NOS-2 contains binding sites
for nuclear factor kappa B (NFκB). Overproduction of NO. causes two main mechanisms of mutagenesis. One is
direct DNA damage through radical attack of DNA (generating DNA strand break, base damage, and
chromosome damage). The second is enhanced deamination of 5-methylcytosine (5mC), the most common
methylated form of cytosine representing about 3% of all cytosines in the genome. Deamination of 5mC into
thymine generates a DNA mismatch (G:T) whichif not repaired, may result in a mutation (from a G:C base pair to
an A:T base pair) Since 5mC preferentially occurs at CpG dinucleotides, this type of mutation is often found
within this particular sequence context.
Mutations at CpG dinucleotides are the most frequent form of single base substitutions in inflamed tissues and
in cancers arising in an inflammatory context. For example, about 50% of mutations in the TP53 tumor
suppressor gene occur at CpG dinucleotides in colon cancer and in adenocarcinoma of the esophagus – two
cancers with well-defined inflammatory precursors.
Types of electrophilic reactant in vivo

6. 1.Chemicals appear to be of major importance in the induction of human cancers. The known chemical
carcinogens include a wide range of structures. The most common feature of these chemicals are
A. Electrophilic reactant
B. Nucleophilic reactant
C. Acidic reactant
D. Basic reactant
2.With respect to chemical carcinogenesis, initiation refers to
A. The process of acquisition of genetic and epigenetic changes that sets the cell on path to cancer
B. The process in which the primed cells express altered responses that provide a selective advantage allowing
them to survive and develop locally.
C. A series of steps during which the now established cancer cells accumulate further changes on the path to
malignancy
D. None of these
3.With respect to chemical carcinogenesis, progression refers to
A. The process of acquisition of genetic and epigenetic changes that sets the cell on path to cancer
B. The process in which the primed cells express altered responses that provide a selective advantage allowing
them to survive and develop locally.
C. A series of steps during which the now established cancer cells accumulate further changes on the path to
malignancy
D. None of these
4. With respect to chemical carcinogenesis, Initiation of cancer is caused by
A. Irreversible changes to DNA
B. Irreversible changes to RNA
C. Irreversible changes to mRNA
D. Irreversible changes to protein
*Questions adapted from: Practice and Learn Animal cell Science and Technology: Multiple choice question for learning.
Author: Shailendra Singh Shera . Publisher: Amazon Kindle.
Practice questions*

7. References & Further reading
1. Watson, J.D., Gilman, M., Witowski J.and Zoller, M. Recombinant DNA, 2nd ed., Scientific American
Books, 1983
2. Glick, B.R. and Pasternack, J.J. Molecular Biotechnology, 3rd ed., ASM Press, 2003
3. Davis J.M. Basic Cell Culture: A Practical Approach, IRL Press, 1998
4. Freshney R.I. Animal Cell Culture a practical approach, 1987
MCQ Practice questions
1. Practice and Learn Animal cell Science and Technology: Multiple choice question for learning.
Author: Shailendra Singh Shera . Publisher: Amazon Kindle.
Available on: amazon.com