Cancer

Biochemistry of Cancer
A quick revision and a quiz
Namrata Chhabra
MHPE, MD, MBBS, FAIMER FELLOW

Cancer
“International Union Against cancer” has defined
Cancer as:
• a disturbance of growth, characterized by
• excessive proliferation of cells
• without apparent relation to physiological demands
of the organ involved.
24/12/2020 OurBiochemistry 2

Properties of cancer cells

Properties of cancer cells
Three important properties-
1) Diminished or unrestricted control of growth
2) Capability of invasion of local tissues
3) Capable of spreading to distant parts of body by metastasis

Characteristics of cancer cells
1) Morphological changes
• Round shape, larger than normal
• Altered nuclear: cytoplasmic ratio
• Transformed cells grow over another and form multilayers.
• Can grow without attaching to the surface (in vitro), diminished
adhesion

2) Biochemical Changes
• Increased synthesis of DNA and RNA
• Increased rate of glycolysis- both aerobic and anaerobic
• Show alteration of permeability and surface charges
• Alteration of oligosaccharide chains
• Increased activity of Ribonucleotide reductase and decreased
catabolism of pyrimidines

2) Biochemical Changes
• Alteration of isoenzyme pattern to fetal proteins
• Appearance of new antigens and loss of certain antigens
• Changes of glycolipid and glycoprotein constituents on cell
surface
• Alteration of the activities of certain enzymes such as proteases
• Alteration in transport properties
• Inappropriate synthesis of certain hormones and growth factors.

Etiology of cancer

Etiology of cancer
Agents causing cancer fall in to three broad groups-
a) Radiant energy
b) Chemical compounds
c) Viruses
There may also be familial causes due to mutation in specific genes
(e.g. tumor suppressor genes)

a) Radiant energy
• UV Rays cause the formation of pyrimidine dimers, apurinic or apyrimidinic
sites, single or double strand breaks or by causing cross linking of strands.
•X-rays and Y-Rays, apart from causing direct damage to DNA, cause
generation of free radicals also.
The resultant free radicals interact with DNA and other macromolecules,
leading to molecular damage contributing to carcinogenic effect of radiant
energy.

b) Chemical Compounds
S.No. Class Compound
1. Polycyclic aromatic
hydrocarbons
Benzo(α) pyrene, Dimethyl benzanthracene
2. Aromatic amines 2-Acetyl amino fluorine,N-Methyl-4 amino azo
benzene
3. Nitrosamines Dimethylnitrosamine, Diethyl nitrosamine
4. Drugs Alkylating agents, diethyl stilbestrol
5. Naturally occurring compounds Dactinomycin, Aflatoxin B
6. Inorganic compounds Arsenic, asbestos, beryllium, cadmium,
chromium, nickel, vinyl chloride, β-
propiolactone etc.24/12/2020 OurBiochemistry 11

Mechanism of action of chemical carcinogens
• Direct acting- β- propiolactone, methyl cholanthrene; these agents
interact directly with the target molecule.
• Requiring metabolic activation- Aromatic hydrocarbons, aromatic
amines etc.
Metabolic activation- The process whereby one or more enzyme
catalyzed reactions convert procarcinogens to active carcinogens is
called metabolic activation.
Procarcinogen-----> Proximate Carcinogen----->Ultimate carcinogen

Metabolic activation
The metabolism of procarcinogens involves action by mono-oxygenases
(cytochrome P450) and transferases.
The activities of these enzymes are affected by several factors- such as
species, age, gender and genetic variations.
The variations in activities of these enzymes help explain the often-
appreciable differences in carcinogenicity of chemicals among different
species and different individuals of the same species.

Damage to DNA by chemical carcinogens
Covalent binding
• The carcinogens and their derivatives bind covalently to cellular
molecules such as DNA, RNA and proteins.
• These agents interact with the purines, pyrimidines or Phospho
diester groups of DNA.
• Most common site of attack is guanine.
• The covalent interactions of direct or ultimate carcinogens with DNA
can result in several types of DNA damage.
• This damage can be repaired by the repair system.
• The unrepaired damage leads to mutations.

c) Viral Oncogenesis
The Oncogenic viruses contain DNA or RNA as a genome.
i) DNA Viruses
Many DNA viruses cause tumor in animals. The DNA viruses causing
cancers in human are-
• Epstein- Barr virus-causes Burkitt’s lymphoma and nasopharyngeal
carcinoma.
• Hepatitis B Virus- is probably the major etiological agent for many
primary liver cancers.
• Human Papilloma virus (HPV)- Multiple warts and cervical cancer.

Mechanism of action of DNA viruses
• DNA viruses bind tightly to the DNA and alter the gene expression.
• The viral proteins show co-operative effect suggesting that alteration
of more than one reaction takes place for malignant transformation.

ii) RNA Viruses (retro viruses)
• These viruses convert their RNA genome into DNA with the help of
reverse transcriptase enzyme,
• The resultant DNA is integrated into the DNA of normal cells causing
malignant transformation by various mechanisms

Oncogenes

Oncogenes in Human Cancer
Oncogenes are cancer susceptibility genes.
• Proto-oncogenes are normal genes that are present in normal cells
and are involved in normal growth and development.
•Under certain circumstances because of certain processes proto-
oncogenes are converted to Oncogenes.

Significance of Proto-oncogenes
• The normal growth and differentiation of cells is controlled by growth
factors that bind to receptors on the surface of the cell.
• The signals generated by the membrane receptors are transmitted
inside the cells through signaling cascades involving kinases, G
proteins, and other regulatory proteins.
• These signals affect the activity of transcription factors in the nucleus,
which regulate the expression of genes crucial in cell proliferation, cell
differentiation, and cell death.
• Proto-oncogene products have been found to function at critical steps
in these pathways and inappropriate activation of these pathways can
lead to tumorigenesis

Significance of Proto-oncogenes

Mechanisms of Oncogene Activation
Mechanisms that up regulate (or activate) cellular oncogenes (Proto-
oncogenes) fall into four broad categories:
• Point mutation,
• Gene amplification,
• Chromosomal rearrangement and
• Insertional mutagenesis

1) Point Mutation
• Point mutation is a common
mechanism of oncogene
activation.
• Mutations in one of the RAS
genes (HRAS, KRAS, or NRAS)
are present in up to 85% of
pancreatic cancers and 50%
of colon cancers but are
relatively uncommon in other
cancer types.

Mechanism of Ras activation
• The gene product (p21) is related to G protein that modulates the
activity of Adenylate cyclase and thus plays a key role in cellular
responses to many hormones and drugs.
• p21 has GTPase activity also to terminate the hormonal action.
• The mutations in p21 appear to affect its conformation and to
diminish its activity as a GTPase.

Mechanism of Ras activation
• The lowered activity of GTPase results in chronic stimulation of the
activity of Adenylate cyclase, which normally is diminished when GDP
is formed from GTP.
• The continuous stimulation of the activity of Adenylate cyclase can
result in several effects on cellular metabolism exerted by the
increased amount of c AMP affecting the activities of various cAMP
dependent protein kinases.
• These events shift the balance of cellular metabolism towards a state
favoring malignant transformation.

2) Gene Amplification
• Gene amplification is observed in
tumors in patients on Methotrexate,
an anticancer drug, an inhibitor of an
enzyme dihydrofolate reductase.
• Tumor cells can become resistant to
the action of this drug.
• The gene for dihydrofolate reductase
becomes amplified, resulting in an
increase in activity of the enzyme up
to 400 folds.

2) Gene Amplification
• Certain cellular oncogenes can also
be amplified in this manner and
can get activated.
• Increased amount of the products
of certain oncogenes, produced by
gene amplification may play a role
in the progression of tumor cells to
a more malignant state.

3) Chromosomal Rearrangement
• Chromosomal alterations provide important clues to the genetic
changes in cancer.
• The chromosomal alterations in human solid tumors such as
carcinomas are heterogeneous and complex and likely reflect selection
for the loss of tumor-suppressor genes on the involved chromosome.
• In contrast, the chromosome alterations in myeloid and lymphoid
tumors are often simple translocations.

3) Chromosomal Rearrangement
• A piece of one chromosome is split off
and joined to another chromosome.
• If the second chromosome donates
material to the second, the translocation is
said to be ‘Reciprocal’.
• The breakpoints of recurring
chromosome abnormalities usually occur
at the site of cellular oncogenes.

Burkitt's lymphoma
• The segment of chromosome 8 that breaks off
and moves to chromosome 14 contains C-MYC.
• The transposition places the previously inactive C-
MYC under the influence of the enhancer
sequences the genes coding for the heavy chains
of immunoglobulins.
• This juxta position results in activation of
transcription of C-MYC.
• There is greatly increase synthesis of C-MYC
coded DNA binding protein that acts to drive or
force the cell towards becoming malignant,
perhaps by an effect on the regulation of mitosis.

Philadelphia chromosome
• The Philadelphia chromosome abnormality is
detected in CML (Chronic myelogenous leukemia).
• This cytogenetic abnormality is generated by
reciprocal translocation involving the ABL
oncogene, a tyrosine kinase on chromosome 9,
being placed in proximity to the BCR (breakpoint
cluster region) on chromosome 22.

Philadelphia chromosome
• The consequence of expression of the fused BCR-ABL gene product is
the activation of signal transduction pathways leading to cell growth
independent of normal external signals.
• Normally C-ABL encodes a protein kinase. The juxta position results in
chimeric BCL-ABR m RNA, which encodes a fusion protein displaying
the increases tyrosine kinase activity.
• The increased activity transforms the normal cell to leukemic cell.

4) Insertional mutagenesis
• This process occurs in viral Oncogenesis.
• Certain viruses lack oncogenes but may cause cancer over a longer
period of time.
• When these viruses infect cells, a DNA copy (c DNA ) of their genome
is synthesized by the activity of reverse transcriptase enzyme and the
cDNA is integrated into the host genome.
• The integrated double stranded c DNA is called “Provirus”.

4) Insertional mutagenesis
Based on the site of viral insertion, two
mechanism are involved –
a) Promoter Insertion– The cDNA copies
of retroviruses are flanked at both ends
by sequences named as long terminal
repeats. These sequences are important
in proviral integration and they can act
as promoters of transcription
• The provirus becomes integrated near the myc
gene.
• The myc gene is activated by an upstream,
adjacent long terminal repeat acting as a
promoter, resulting in transcription of its
product in such cells.
• A B cell tumor is formed.
• By a similar mechanism human C-MYC gene is
activated causing colorectal carcinoma.

b) Enhancer Insertion
• In some cases the provirus is inserted downstream from the myc gene,
or upstream from it but oriented in the reverse direction, nevertheless
the myc gene becomes activated.
• Such activation is due to the enhancer sequences present in the long
terminal repeat sequences of the retroviruses.

Proto-oncogenes to Oncogenes

Product of oncogenes
1) They act on key intracellular pathway involved in growth control.
2) They act as DNA binding proteins to affect the control of the cell
cycle
3) The product of certain oncogenes act as growth factors or imitate
the action of an occupied growth factor receptors.

Tumor suppressor genes

Tumor suppressor genes
Tumor suppressor genes are
also called “Anti-oncogenes
or recessive oncogenes”.
RB1 genes
BRCA1 gene
BRCA2 gene
P 53 gene
P TEN gene

RB1 gene
• This gene is involved in the formation of Retinoblastoma,
• a malignant tumor of retinal neuroblasts,
• which are precursor cells of photoreceptor cells in the retina.
• In some cases, the tumor is inherited,
• in others it does not appear to be hereditary in nature.

Function of RB1 gene product
• It is a nuclear protein to regulate the cell cycle.
• It binds to certain viral proteins to inactivate them.
• It also binds to certain transcription factors that are active in the S
phase of the cell cycle and thus slows cell cycling.
• Mutations in the genes are responsible for Retinoblastoma,
Osteosarcoma and certain other human tumors.

Function of RB1 gene product
• In hereditary case of retinoblastoma, the first mutation exists in the
germ cell lines and the second is acquired during the life time in
retinoblasts.
• This phenomenon is called “Loss of heterozygosity”. Since initially
before mutations the individuals were heterozygous in the region of
RB gene- one normal and other mutated allele.
• Knudson hypothesis postulates that the development of
retinoblastoma depends upon two mutations
• In sporadic (Non-hereditary cases) both mutations occur in the
retinoblasts, both are acquired during the life time of an individual.

Functions of BRCA-1 gene
• This gene encodes DNA binding protein with a special motif to
exclusively bind DNA and the product therefore may function as a
transcription factor.
• The gene product also appears to be involved in gene repair.
• Cells defective in BRCA1 possesses numerous cytological and
biological features that have been correlated with perturbation in the
maintenance of chromosome stability.
• BRCA1 has been shown to function in Double Strand Break repair

Functions of BRCA-1 gene
• BRCA1 has been reported to interact with as many as 50 proteins.
• Women who inherit a mutated allele of this gene from either parent
have at least a 60–80% lifetime chance of developing breast cancer and
about a 33% chance of developing ovarian cancer.
• Men who carry a mutant allele of the gene have an increased
incidence of prostate cancer and breast cancer.

BRCA-2 gene
• This gene has been localized to chromosome 13q12
• it is also associated with an increased incidence of breast cancer in
men and women.

P53 gene
• The p53 mutation is present in nearly 40% of human breast cancers
as an acquired defect.
• The p53 tumor suppressor gene acts as the ‘Guardian of the
Genome’.
• It encodes a protein of molecular weight 53 kDa.
• This protein is nuclear in location and is subjected to phosphorylation
and dephosphorylation.

Functions of P53 gene
• It acts as a transcriptional activator regulating certain genes involved in the
cell cycle
• It acts as G1 check point control for the DNA damage.
• If excess damage to the DNA has occurred, it causes inhibition of the cell
cycle, allowing time for repair.
• p53 also participates in apoptosis. It hastens the death of the potentially
dangerous cells which have the potential to become cancer cells.
• Besides all this p53 also combines with certain viral proteins.
• Mutations in the p53 gene are the most common genetic alterations in
human cancer and are frequent in Breast, colon and lung cancers.

PTEN gene
• Acquired mutations in PTEN occur in about 10% of the cases.
• The gene appears to be located on chromosome 10 and appears to
be an important ‘tumor suppressor’.
• When mutated it allow the cells to grow out of the control and
become malignant.
• This gene is also called “MMAC1”, Mutations in this gene also play an
important role in the aggressiveness of the tumor.

Tumor markers

Tumor markers
• Tumor markers are hormones, enzymes, peptides or proteins
abnormally synthesized and released by the cancer cells, or are
produced by the host cells in response to cancerous growth.
• Tumor markers may be present in the body fluids, blood, cell
membranes or in the cytoplasm of the cell.

Clinical significance of tumor markers
Tumor markers are used as diagnostic and prognostic agents. They are
used -
• For screening of cancer in asymptomatic individuals
• As an adjunct in clinical staging of the cancerous condition
• For monitoring during cancer treatment
• For early detection of recurrence of the cancerous process.

Examples of tumor markers
S.N. Tumor marker Significance
1. Carcinoembryonic antigen (CEA) Gastrointestinal cancer, ovarian, breast, cervical and lung
cancers. Best marker of colorectal carcinoma.
2. Alpha feto protein (AFP) Germ cell tumor and hepatocellular carcinoma
3. Tissue polypeptide antigen. Colonic cancer, breast and prostatic cancer
4. CA-125 Mainly ovarian cancer, but may also be elevated in endometrial
cancer, fallopian tube cancer, lung cancer, breast cancer and
gastrointestinal cancer
5. CA-15-3 Breast cancer
6. CA-19-9 Mainly pancreatic cancer, but also colorectal cancer and other
types of gastrointestinal cancers.
7. β-HCG Gestational trophoblastic and germ cell tumors of testes and
ovaries24/12/2020 OurBiochemistry 52

Examples of tumor markers
S.N. Tumor marker Significance
8. MAP(Mitogen activated protein kinase) Breast cancer
ACTH Lung cancer, Medullary carcinoma of thyroid and
pancreatic carcinoma
9. Calcitonin Medullary carcinoma of thyroid
10. Catecholamines Pheochromocytoma
11. Gastrin- Gastrinoma
12. Insulin Insulinoma
13. Glucagon- Glucagonoma
14. Serotonin Carcinoid syndrome24/12/2020 OurBiochemistry 53

Anticancer drugs

The goal of cancer treatment
• The goal of cancer treatment is first to eradicate the cancer.
• If this primary goal cannot be accomplished, the goal of cancer
treatment shifts to palliation, the amelioration of symptoms, and
preservation of quality of life while striving to extend life.

Types of Cancer treatment
• Surgery,
• Radiation therapy (including photodynamic therapy),
• Chemotherapy (including hormonal therapy and molecularly targeted
therapy), and
• Biologic therapy (including immunotherapy and gene therapy)
• Surgery and radiation therapy are considered local treatments,
though their effects can influence the behavior of tumor at remote
sites.
• Chemotherapy and biologic therapy are usually systemic treatments.

Commonly Used Chemotherapy Agents
1) Direct DNA-Interacting Agents
• Cyclophosphamide
• Cisplatin
• Chlorambucil
• Mechlorethamine
• Melphalan
• Carmustine
• Lomustine
• Ifosfamide
• Procarbazine

2) Antitumor antibiotics
• Bleomycin
• Actinomycin D
• Mitomycin C
• Etoposide
• Doxorubicin
• Idarubicin
• Epirubicin

3) Indirect DNA-Interacting Agents
Antimetabolites
• 6-Mercaptopurine
• 6-Thioguanine
• Azathioprine
• 2-Chlorodeoxyadenosine
• Hydroxyurea
• Methotrexate
• 5-Fluorouracil
• Cytosine arabinoside
• Azacytidine
• Asparaginase

4) Antimitotic agents
• Vincristine
• Vinblastin
5) Naturally occurring anticancer substances
1) Vitamin A and Beta Carotene
2) Vitamin E
3) Ascorbic acid
4) Selenium
5) Zinc

Question 1
Mutation in which of the following proteins accounts for the most
common genetic alterations in the development of cancer ?
a) Ras
b) Bcl2
c) p53
d) p10

Answer
• p53

Question
Which of the following is the most commonly mutated oncogene in
cancer?
a) p53
b) abl
c) ras
d) myc
e) BRCA1

Answer
c) ras

Question
A 47-year-old man, with no known family history of cancer, develops
changes in his bowel habits, with occasional blood in stools. A
colonoscopy and biopsy confirms the diagnosis of adenocarcinoma of
the colon.
The tumor is found to have mutation in the ras protein. Which of the
following correctly defines this protein?
a) A non receptor tyrosine kinase
b) A nuclear transcription protein
c) A GTP binding protein
d) A growth factor

Answer
• A GTP binding protein

Question
• A 53-year-old man presents to the physician because he is fatigued and not
“feeling himself”.
• Routine blood tests show a WBC count of 85,000/Ml.
• Molecular studies suggest that he has Chronic myelogenous leukemia.
• Which of the following translocations is associated with this disorder ?
• t (8;14)
• t (11;14)
• t(9;22)
• t(15;17)

Answer
• t(9;22)

Question
A 23-year-old woman is seen for a lump in her breast that she palpated
on self beast examination.
History reveals that her mother and her aunt both had breast and
ovarian cancer.
Given this presentation, you suspect the patient may have a mutation
in which of the following genes involved in DNA repair?

Question
a) BRCA-1
b) ras
c) bcl-2
d) p 53
e) Rb

Answer
a) BRCA-1 gene

Question
A 56-year-old woman is recently diagnosed with breast cancer. She
undergoes a lumpectomy and a lymph node dissection, which shows
that there are tumor cells that have migrated to the lymph nodes.
He oncologist recommended the chemotherapy including an agent that
inhibits the provision of folic acid which is required for the synthesis of
purines and pyrimidines.
Which of the following agents should be the drug of first choice?

Question
a) Cyclophosphamide
b) Busulfan
c) Methotrexate
d) Etoposide
e) Vinblastin

Answer
c) Methotrexate

Question
A 78-year-old male was brought to emergency with difficulty in passing
urine and weight loss. The attending urologist suspected carcinoma
prostate. Which of the following molecular marker would help in the
confirmation of diagnosis?
a) Carcinoembryonic antigen (CEA)
b) Alpha feto protein(AFP)
c) Tissue specific antigen
d) Alkaline phosphatase
e) Acid phosphatase

Answer
• e) Acid phosphatase

Question
A 23-year-old man was diagnosed with metastatic liver disease. The
grain storage facility outside his house was contaminated with aflatoxin
B. In addition, which of the following might act as a co carcinogen in
the development of patient's cancer?
a) Human T cell lymphotrophic virus (HTLV-1)
b) Hepatitis B virus
c) Asbestos
d) Epstein Barr virus
e) Aniline dyes

Answer
• b) Hepatitis B virus

Question
• An 82-year-old woman presented to her primary care physician with a
10-year history of episodic confusion and somnolence.
• The episodes occurred about twice a year, typically in the morning,
just after waking.
• They lasted minutes and were relieved when she ate her breakfast or
had juice.
• Her admission laboratory value of glucose level was 36 mg/dl and
plasma insulin was highly raised. What is the possible diagnosis for
this patient?

Question
a) Hypothyroidism
b) Hypopituitarism
c) Diabetes mellitus
d) Von Gierke's disease
e) Insulinoma.

Answer
• e) Insulinoma.

Question
A 54-year-old postmenopausal woman, presented to internist for care
of hot flashes that had returned 2 years after menopause.
The symptoms occurred mostly after meals, when she drank wine, or
when she went for running.
There was history of hypertension and frequent diarrheas also.
The 24-hour urine levels of 5-HIAA (5-hydroxyindoleacetic acid), a
breakdown product of serotonin was found to be highly elevated.
What is the probable diagnosis for this patient?

Question
a) Pheochromocytoma
b) Carcinoid tumor
c) Hartnup disease
d) Hyperpituitarism
e) Medullary carcinoma of thyroid gland

Answer
• b) Carcinoid tumor

Thank you

Cancer

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