CARcINOGENESIS

(The Overview of Molecular Basis of

Cancer Cell)
Dr. Ema Qurnianingsih, dr., M.Si
Dep. Biokimia Kedokteran Universitas Airlangga
 General aspects
• A neoplasm refers to any abnormal new growth of tissue 
may be benign or malignant in nature.
• The term “cancer” is usually associated with malignant
tumors.
• Cancer cells are characterized by certain key properties:
– proliferate rapidly
– display diminished growth control
– display loss of contact inhibition in vitro
– invade local tissues and spread, or metastasize, to other parts of
the body
– self-sufficient in growth signals and are insensitive to anti-
growth signals
– stimulate local angiogenesis
– often able to evade apoptosis.
• Non-lethal genetic damage is thought to be
the initiating event in carcinogenesis.
• There are principally four classes of genes,
which when mutated to cause gain-, or loss-
of-function or inappropriate regulation, can
result in the development of a tumor.
– Proto-oncogenes,
– Tumor suppressor genes,
– DNA repair genes,
– Genes regulating apoptosis or evasion of immune
surveillance
Harper’s Medical Biochemistry, 30th ed, 2015
Causes of genetic damage

• Genetic damage can be due to either

acquired or inherited mutations.
– acquired mutations due exposure to
environmental carcinogens (radiant energy,
chemicals, and certain oncogenic viruses)
– Inherited mutations due to familial conditions
that
– predispose to hereditary cancer.
Radiant Energy
• Ultraviolet rays, x-rays,and f-rays are mutagenic
and carcinogenic, through :
– Formation of pyrimidine dimer
– Formation of apurinic or apyrimidinic sites by
elimination of corresponding bases.
– Formation of single- or double-strand breaks or
cross-linking of DNA strand
– Additionally, x-rays and γ-rays can induce formation
of reactive oxygen species (ROS) that are mutagenic
Chemicals
• A wide variety of chemical compounds are carcinogenic.
• It is estimated that perhaps 80% of human cancers are
caused by environmental factors, principally chemicals.
• Chemical carcinogenesis comprises two
stages—initiation and promotion.
– Initiation is the stage where exposure to a
chemical causes irreversible DNA damage and is a
necessary initial event for a cell to become
cancerous.
– Promotion comprises the stage at which an
initiated cell begins to grow and proliferate
abnormally.

Harper’s Medical Biochemistry, 30th ed, 2015

Generation of ultimate carcinogen Rengarajan et al, Asian Pac J Trop Biomed, 2015

from Benzopyrene

(epoxy-7,8-dihydrobenzo(a)pyrene)

(dihydroxy-7,8-dihydrobenzo(a)pyrene)

(BPDE)
Oncogenic Viruses
• Approximately, 15 % of human cancer may be caused by
virus.
• In general, the genetic material of viruses is incorporated into
the genome of the host cell.
– In the case of RNA viruses,
• RNA  reverse transcription viral DNA integration
withhost DNA  results in various events such as
deregulation of the cell cycle, inhibition of apoptosis,
and abnormalities of cell signaling pathways.
• RNA viruses often carry oncogenes in their genomes
– DNA viruses often act by down regulating the expression
and/or function of tumor suppressor genes P53 and RB
and their protein products.
Harper’s Medical Biochemistry, 30th ed, 2015
Molecular biology of the cell, 5th ed, 2008
 Oncogen and Tumor Suppressor Gene
• An oncogene can be defined as an altered gene whose
product acts in a dominant manner to accelerate cell
growth or cell division.
• Oncogenes are generated by “activation” of normal
cellular proto-oncogenes; that is, genes encoding
growth stimulating proteins.
• A tumor suppressor gene produces a protein product
that normally suppresses cell growth or cell division.
• When such a gene is altered by mutation, the
inhibitory effect of its product is lost or diminished 
leads to increased cell growth or cell division.
Harper’s Medical Biochemistry, 30th ed, 2015
(A) Oncogenes act in a dominant manner: a gain-of-function mutation in a
single copy of the cancer-critical gene can drive a cell toward cancer.
(B) Mutations in tumor suppressor genes, on the other hand, generally act in a
recessive manner: the function of both alleles of the cancer-critical gene must be
lost to drive a cell toward cancer. Molecular biology of the cell, 5th ed, 2008
Harper’s Medical Biochemistry, 30th ed, 2015
Harper’s Medical Biochemistry, 30th ed, 2015
Harper’s Medical Biochemistry, 30th ed, 2015
Figure of Chart of the major signaling pathways relevant to cancer in human
cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
 Rb protein
• The tumor suppressor protein Rb, controls a key
point for cell cycle  serves as a brake restricts
entry into S phase by binding to and inhibiting
gene regulatory proteins (E2F), which are needed
to transcribe genes that encode proteins required
for entrance into S phase.

• Normally, inhibition by Rb is relieved by the

phosphorylation of Rb by cyclin-dependent kinases
(Cdks) Rb releases its inhibitory grip on the E2F
proteins.

Figure of Chart of the major signaling pathways relevant to cancer in human

cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
 Rb protein...
• The p16 (INK4) protein-which is produced
when cells are stressed-inhibits cell-cycle
progression by preventing the formation
of an active cyclin D-Cdk4 complex.

• Deletion or inactivation of the p16 gene is

common in many forms of human
cancer.

• In cancers in which mutations do not

inactivate the pl6 gene, DNA methylation
of its regulatory region often silences the
gene epigenetic change contributing to
theofdevelopment
Figure Chart of the majorof cancer.pathways relevant to cancer
signaling in human
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Figure of How Rb controls cell cycle entry contains both
protooncogenes and tumor suppressor gene

Molecular biology of the cell, 5th ed, 2008

Figure of Chart of the major signaling pathways relevant to cancer in human
cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
 p53 Protein
• p53 gene  p53 protein is so critical, because its
multifaceted function :
• in cell-cycle control,
• in apoptosis,
• and in maintenance of genetic stability
 all aspects of the fundamental role of the p53
protein in protecting the organism against the
consequences of cell damage and the risk of
cancer.

• Under normal condition, p53 amount is very little

(degraded after synthesized), because it is not
Figureessential
of Chart of for normal
the major development.
signaling pathways relevant to cancer in human
cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
 p53 protein..
• p53 level is increased by special circumtances
(hypoxia, exposed to treatment leading to DNA
damage, etc)  limit the damage, through :
• Cell cycle arrest
• Senescence
• apoptosis

• p53 protein performs its job mainly by acting as a

gene regulatory protein.

• The most common mutations observed in p53 in

human tumors are in its DNA-binding domain 
where they cripple the ability of p53 to bind to its
FigureDNA
of Chart of the sequence
target major signaling pathways
(exp. generelevant
for p21)to cancer in human
cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
 p53 protein..

• P21  inhibits Cdk complex required for progression

through cellcycle  prevents cell enters S phase and
replicating its DNA.

• p53 promotes apoptosis, through :

• Stimulation of genes expression responsible for
apoptosis
• It binds to and inactivate Bcl2 (anti-apoptotic
protein)

Figure of Chart of the major signaling pathways relevant to cancer in human

cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
 p53 protein..

• In summary, p53 helps multicellular organism to cope

safely with DNA damage aand other cell stresses.
• The loss of p53  promote cancer, because :
• It allows cells with DNA damage  cell cycle.
• It allows them to escape apoptosis.
• By permitting dividing of cells with damaged
chromosomes  genetic instability of cancer
cells.
• It makes some cancer cell resistant to anticancer
drugs and irradiation.

Figure of Chart of the major signaling pathways relevant to cancer in human

cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
Figure of simplified mechanism of apoptosis

Harper’s Medical Biochemistry, 30th ed, 2015

Harper’s Medical Biochemistry, 30th ed, 2015
Figure of Chart of the major signaling pathways relevant to cancer in human
cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
PI 3-kinase / Akt pathway
• Cell proliferation needs more than progression
through cell cycle, it also requires cell growth, which
involved complex anabolic processes  cancer cells
grows continuesly  requires heritable changes that
not only disregulate cell cycle progression, but also
provoke cell growth

• PI 3-kinase / Akt pathway is critical for cell growth 

in cancer cell, it is activated by mutation  cell can
grow in the absence of such signals  stimulates
protein synthesis, increases glucose uptake via mTOR
Figureand production
of Chart ofsignaling
of the major acetyl coA for cell
pathways lipidto synthesis
relevant cancer in human
cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
Figure. Cells may require two types of signals to proliferate.
Molecular biology of the cell, 5th ed, 2008
 Warburg effect, two hypotheses:
• The increased ratio of glycolysis to aerobic respiration was likely
due to defects in the mitochondrial respiratory chain  recent
studies : reprogrammed mitochondrial respiration typically
observed in tumor cells, influences :
• The self-sustaining proliferative growth factor signaling.
• Genetic changes in specific metabolic enzyme-encoding genes and other
genes.
 shunting of glucose chemical energy for building up the cellular biomass
of proteins, lipids, nucleic acids, etc  cancer cell proliferation

• The enhanced glycolysis enabled cancer cells to preferentially

proliferate in the reduced oxygen tension often seen in tumors 
many solid tumors have localized areas of poor blood supply 
anaerobic glycolysis lactic acid and local acidosis  tumor cells
invades more easily.
• The low oxygen tension in areas of tumors with poor blood supply 
hypoxia-inducible factor-1(HIF-1)  up-regulates—activities of genes
controlling synthesis of glycolytic enzymes.
Harper’s Medical Biochemistry, 30th ed, 2015
Harper’s Medical Biochemistry, 30th ed, 2015
 Colorectal Cancers
• Many types of tumors have been analyzed for genetic
changes  One of the most informative areas : the
development of colorectal cancer by Vogelstein and
colleagues.

• These workers analyzed various oncogenes, tumor

suppressor genes, and certain other relevant genes in
samples of normal colonic epithelium, dysplastic
epithelium of various stages of adenomatous polyps,
and of adenocarcinomas.
Molecular biology of the cell, 5th ed, 2008
• In colorectal cancers, certain sets of mutations are particularry
common and they occur in a characteristic order
• mostly, in activating mutation of Apc gene appears to be a very
early step (is detected at same high frequency in small benign
polyps as in large malignant tumors)
• inherited changes that lead to genetic and epigenetic instability
are likely to arise early in tumor progressiion  drive the later
steps
• Activating mutations in K-Ras gene occurs later  proliferation
without anchorage to stratum
• Loss of Smad4 tumor suppressor gene, inactivating mutation of
p53 come later  loss of p53 function allows cancer cells to
accumulate additional mutations and avoid apoptosis and cell
cycle arrest
In colon cancer;
• mutations that activate specific oncogenes
• Mutations that inactivate specific tumor suppressor
genes
correlate with the steps of tumour progression.

But ;
• Different combinations of mutations
• Epigenetic changes
are found in different types of cancer and even in
different patients with same type of cancer
 refflecting random way in which these inherited
chenges occur, but many of same types of changes are
encountered repeatedly.
 GROWTH FACTORS & ABNORMALITIES OF THEIR
RECEPTORS & SIGNALING PATHWAYS PLAY MAJOR ROLES
IN CANCER DEVELOPMENT

• Growth factors can act in an endocrine, paracrine, or

autocrinemanner and affect a wide variety of cells to
produce a mitogenic response.

• Growth factors produce their effects by interacting with

specific receptorson cell surfaces, initiating various
signaling events.

• Growth factors interact with specific receptors to

stimulate specific signaling pathways that serve to
increase or decrease the activities of various genes that
affect cell division.
Interaction of PDGF with its receptor
 stimulates phospholipase C (PLC) 
splits PIP
2 into IP3 and DAG  Increased IP3
stimulates the release of intracellular
Ca2+, and DAG activates PKC.
 Hydrolysis of DAG  release
arachidonic acid  stimulate
production of prostaglandins and
leukotrienes  various biologic
effects

Exposure of target cells to PDGF 

can result in rapid (minutes to 1–2 h)
activation of certain cellular proto-
oncogenes (eg, MYC and FOS) 
participate in stimulation of mitosis via
effects on the cell cycle.

Harper’s Medical Biochemistry, 30th ed, 2015

Figure of Chart of the major signaling pathways relevant to cancer in human
cells, indicating the cellular locations of some of the Proteins modified by
mutation in cancers Molecular biology of the cell, 5th ed, 2008
 Epigenetics in Cancer

• There is growing evidence that epigenetic

mechanisms are involved in the causation of
cancer.

• Such mechanisms produce non-mutational

changes that affect regulation of gene
expression :
• Methylation of specific cytosine bases 
turning off certain genes.
• Changes from normal in methylation/demethylation of cytosine
• Post translational modifications of histones  also affect gene
expression.
• Mutations affecting the structures of protein complexes (eg, the
SWI/SNF complexes) involved in chromatin remodeling  can also
affect gene transcription.
 Cancer Metastasis

• It has been estimated that about 85% of the

mortality associated with cancer results from
metastasis.
• Metastasis is a complex process, and its molecular
bases are yet to be fully elucidated.
 arrest in the
nearest small
The earliest event is detachment of tumor cells capillary bed
from the primary tumor.
Decreases in the amounts of E-cadherin, a
molecule of major importance in the adhesion
of many normal cells, may help to account for
the decreased adhesiveness of many cancer
cells.

if they survive host defense mechanisms,

they grow at variable rates.

The proteinase enzymes that are expressed by

cancer cells are capable of degrading proteins
in the basement membrane and in the ECM,
such as collagen and others, facilitating the
spread of tumor cells.
To ensure growth,
metastatic cells need
an adequate blood
supply,
Harper’s Medical Biochemistry, 30th ed, 2015
Harper’s Medical Biochemistry, 30th ed, 2015
Harper’s Medical Biochemistry, 30th ed, 2015
Harper’s Medical Biochemistry, 30th ed, 2015
Harper’s Medical Biochemistry, 30th ed, 2015