CHAPTER

16 Cell-Cycle Regulation
and Cancer

 Cancer is the second leading cause of death in Western countries, surpassed only by
heart disease. It strikes people of all ages, and one out of three people will experience a
cancer diagnosis sometime in his or her lifetime.
 Over the last 30 years, scientists have discovered that cancer is a genetic disease,
characterized by an interplay of mutant forms of oncogenes and tumor suppressor
genes leading to the uncontrolled growth and spread of cancer cells. While some of
these mutations may be inherited, most mutations that leads to a cancer occurs in
somatic cells that then divide and lead to tumors.
 The mutation that lead to cancer affect multiple cellular functions, including repair of
DNA damage, cell division, apoptosis, cellular differentiation, migratory behaviour, and
cell-cell contact.
 Cancer is clinically defined as a large number of complex disease, up to a hundred, that
behave differently depending on the cell types from which they originate. Cancer vary in
their;
-ages of onset
-growth rates
-invasiveness
-prognoses; and
-responsiveness to treatment.
 Two Fundamental properties of Cancer Cells
1. Abnormal cell growth and division (cell proliferation)
2. Abnormalities in the normal restraints that keep cells from spreading and
invading other parts in the body (metastasis)
---It is this combination of uncontrolled cell proliferation and metastatic spread that
makes cancer cell dangerous.
 Benign Tumor occurs when a cell simply loses genetic control over cell growth that will
cause it to grow into a multicellular mass.
 Malignant Tumors are difficult to treat and may become life threatening. It occurs when
the cells in the tumor also acquire the ability to break loose, enter the bloods stream,
invade other tissues, and form secondary tumors (metastases).
 Although malignant tumors may contain billions of cells, and may invade and grow in
numerous parts of the body, all cancer cells in the primary and secondary tumors are
clonal, meaning that they originated from a common ancestral cell that accumulated
numerous specific mutation.
 Cancer is a multistep process, requiring multiple mutation for a single mutation is not
sufficient to transform a normal cell into a tumor- forming (tumorigenic), malignant cell.
-the phenomenon of age-related cancer is another indication that cancer
develops from the accumulation of several mutagenic events in a single cell. The
incidence of most cancers rises exponentially with age.
 Each step in tumorigenesis (the development of a malignant tumor) appears to be the
result of one or more genetic alterations that release the cells progressively from the
controls that normally operate on proliferation and malignancy.
 Cancer cells show higher than normal rates of mutation, chromosomal abnormalities,
and genomic instability.
-many researchers believe that the fundamental defects in cancer cells is a
derangement of the cells’ normal ability to repair DNA damage. This loss of genomic
integrity leads to a general increase in the mutation rate in every gene, including specific
genes that control aspects of cell proliferation, programmed cell death, and cell-cell
contact. In turn, the accumulation of mutations in genes controlling these processes
leads to cancer.
 Mutator phenotype is the high level of genomic instability seen in cancer cells.
 Genomic instability in cancer cells manifests itself by the presence of gross defects such
as translocations, aneuploidy, chromosome loss, DNA amplification, and chromosome
deletions.
-cancer cells that are grown in cultures in the lab also show a great deal of genomic
instability.
 One of the fundamental aberrations in all cancer cells is a loss of control over cell
proliferation.
 Cell proliferation is the process of cell growth and division that is essential for all
development and tissue repair in multicellular organisms.
 Differentiated cells are those that are specialized for a specific function, such as a
photoreceptor cells of the retina or muscle cells of the heart.
 Normal regulation over cell proliferation involves a large number of gene products that
control steps in the cell cycle, programmed cell death, and the response of cells to
external growth signals. In cancer cells, many of the genes that control these functions
are mutated or aberrantly expressed, leading to uncontrolled cell proliferation.
 Cancer cells often have defects in signal transduction pathway. Sometimes, abnormal
signal transduction molecules send continuous growth signals to the nucleus even in the
absence of external growth signals. In addition, malignant cells may not respond to
external signals from surrounding cells--- signals that would normally inhibit cell
proliferation within a mature tissue.
 There are at least three distinct points in the cell cycles at which the cells monitors
externals signal and internal equilibrium before proceeding to the next stage of the
cell cycle. These are;
1. G1/S checkpoint, the cell monitors its size and determines if its DNA has been
damaged. If the cell has not achieved an adequate size, or if the DNA has
been damaged, further progress through the cell cycle is halted until these
 conditions are corrected. If the cell size and DNA integrity are normal, the
G1/S checkpoint is traversed, and the cell proceeds to S phase.

2. G2/M checkpoint, where physiological conditions in the cell are monitored

prior to entering mitosis. If DNA replication or repair of any DNA damage has
not been completed, the cell cycle arrests until these process are complete.

3. M checkpoint occurs during mitosis. At this checkpoint, both the successful

formation of the spindle-fiber system and the attachment of spindle fibers to
the kinetochores associated with the centromeres are monitored. If spindle-
fibers are not properly formed or attachment is inadequate, mitosis is
arrested.
 In addition to regulating the cell cycle at checkpoints, the cell controls progress through
the cell cycle through two classes of protein:
1. Cyclins- are a family of proteins that control the progression of cells through
the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes. A class of
proteins that fluctuate in concentration at specific points during the cell cycle
and that regulate the cycle by binding to a kinase.
2. Cyclin-dependent kinases (CDKs)- are a family of protein kinases first discovered
for their role in regulating the cell cycle. They are also involved in regulating
transcription, mRNA processing, and the differentiation of nerve cells.[1] They
are present in all known eukaryotes, and their regulatory function in the cell
cycle has been evolutionarily conserved.
--The cell synthesizes and destroys cyclin proteins in a precise pattern during the cell
cycle. When a cyclin is present, it binds a specific CDK, triggering activity of the CDK/
cyclin complex. The CDK/cyclin complexes then selectively phosphorylate and activate
other proteins that in turn bring about the changes necessary to advance the cell
through the cell cycle.
 Both cell-cycle checkpoints and cell cycle control molecules are genetically regulated. In
general, the cell cycle is regulated by an interplay of genes whose products either
promote or suppress cell division. Mutation or mix-expression of any of the genes
controlling the cell cycle contribute to the development of cancer in several ways.
 If DNA replication, repair, or chromosome assembly is aberrant, normal cells halt their
progress through the cell cycle until the condition is corrected. This reduces the number
of mutations and chromosomal abnormalities that accumulate in nomal proliferating
cells.
 Apoptosis or programmed cell death-the second line defense initiate by the cell if DNA
or chromosomal damage is so severe, that repair is impossible.
-is a genetically controlled process whereby the cell commits suicide.
-is also initiated during normal multi-cellular development in order to eliminate certain
cells that do not contribute to the final adult organism.
 The steps in apoptosis are the same for damaged cells and for the cells eliminated
during development: Nucleus DNA becomes fragmented, internal cellular structures are
 disrupted, and the cell dissolves into small spherical structures known as apoptotic
bodies. In the final step, the apoptotic bodies are engulfed by the immune system’s
phagocytic cells.
 A series of proteases called carpases are responsible for initiating apoptosis and for
digesting intracellular components.
 By removing damaged cells, programmed cell death reduces the number of mutations
that are propagated to next generation, including those in cancer-causing genes.
 Two general categories are mutated or mis-expressed in cancer cells;
1. Proto-oncogenes- are genes whose product are important for normal cell
functions, especially cell growth and division. They do this by encoding
transcription factors that stimulate expression of other genes, signal
transduction molecules that stimulate cell division, or cell-cycle regulators that
move the cell through the cell cycle.
2. Tumor suppressor genes- are those whose products normally regulate cell-cycle
checkpoints and initiate the process of apoptosis. In normal cells, proteins
encoded by tumor suppressor genes halt progress through the cell cycle in
response to DNA damage or growth suppression signals from the extracellular
environment. When the tumor cells suppressor genes are mutated or
inactivated, cells are unable to respond normally to cell-cycle checkpoints, or
are unable to undergo programmed cell death if DNA damage extensive.

Some Proto-oncogenes and Tumor Suppressor Genes

Proto- Normal Function Alteration in Cancer Associated Cancer
oncogenes
Ha-ras Signal transduction molecule, Point mutation Colorectal, bladder,
binds GTP/GDP many types

c-erbB Transmembrane growth factor Gene amplification, Glioblastomas, breast

receptor point mutation cancer, cervix

c-myc Transcription factor, regulates Translocation, Lymphomas,

cell-cycle, differentiation, amplification, point leukemias, lung
apoptosis mutations cancer, many types

c-kit Tyrosine kinase, signal Mutation Sarcomas

transduction

RaRa Hormone-dependent Chromosomal Acute promyelocytic

transcription factor, translocation with PML leukemia
differentiation gene, fusion product

E6 HPV infection Cervical cancer

 Human papillomavirus encoded
Cyclins oncogene, inactivates p53 Gene amplification, Lung, esophagus,
overexpression many types
Bind to CDKs, regulates cell-cycle
CDK2, 4 Overexpression, Bladder
mutation
Cyclin-dependent kinases,
regulate cell-cycle phases.
Tumor Normal Function Alteration in Cancer Associated Cancers
Suppressor
p53 Cell-cycle checkpoints, apoptosis Mutation, inactivation Brain, lung,
by viral oncogene colorectal, breast,
products many types
RB1 Cell-cycle checkpoints, binds E2F
(Retinoblastoma Mutation, deletion, Retinoblastoma,
1) inactivation by viral osteosarcoma, many
oncogene products types

APC Cell-cell interaction Mutation Colorectal cancers,

brain, thyroid

Bc12 Apoptosis regulation Overexpression blocks Lymphomas,

apoptosis leukemias

BRCA2 DNA repair Point mutation Breast, ovarian,

prostate cancers

 There are more than 200 oncogenes and tumor suppressor genes now known, and
more likely be discovered as cancer research continues.
 Cancer is a genetic disorder affecting cell adhesion.
 Cancer cells must also acquire the features of metastasis, which include the ability
to disengage from the original tumor site, to enter the blood or lymphatic system, to
invade surrounding tissues, and to develop into secondary tumors.
 In order to leave that the site of the primary tumor and invade other tissues, tumor
cells must be dissociate from other cells and digest components of the extracellular
matrix and basal lamina, which normally contain and separate tissue.
 Proteolytic enzymes such as metalloproteinasses are present at higher than normal
levels in highly malignant tumors and are not susceptible to the normal controls
conferred by regulatory molecules such as tissue inhibitors of metalloproteinasses
(TIMPs).
 In appropriately expressed cell adhesion and proteinase enzymes may assist
malignant tumor cells by loosening the normal constraints on cell location and
creating holes through which the tumor cells can pass into and out of the circulatory
system.
 Although the vast majority of human cancers are sporadic, a small fraction (1-2
percent) have an hereditary or familial components.
- At present, about 50 forms of hereditary cancer are known.
- Most inherited cancer-susceptibility genes, though transmitted in a Mendelian
dominant fashion, are not sufficient in themselves to trigger development of a
cancer.
- At least one other somatic mutation in the other copy of the gene must occur in
order to drive a cell toward tumorigenesis.
 Loss of heterozygosity is the phenomenon whereby the second, wild-type, allele is
mutated in a tumor.
 Although loss of heterozygosity is an essential first step in expression of these
inherited cancers, further mutations in other proto-oncogenes and tumor
suppressor genes are necessary for the passage of the tumor cells to fully
malignancy.
 Viruses contribute to cancer in both human and animals.
 Most cancer-causing animal viruses are RNA viruses known as retroviruses because
they transform cells into cancer cells, they are known as acute transforming
retroviruses.
- The first of these acute transforming retroviruses was discovered in 1910 by
Francis Peyton Rous. Rous was studying sarcomas (solid tumors of muscles, bone, or
fat) in chicken, and he observed that extracts of these tumors caused the formation
of new sarcomas when they were injected into tumor-free chickens.
- Several decades later, the agent within the extract that caused the sarcomas was
identified as a retrovirus and was named the Rous Sarcoma Virus (RSV).
 When a retrovirus infects a cell, its RNA genome is copied into DNA by the reversed
transcriptase enzymes, which is brought into the cell with the infecting virus. The
DNA copy then enters the nucleus of the infected cell, where it integrates at random
into the host cell’s genome. The integrated DNA copy of the retroviral RNA is called a
provirus.
 A retroviral may cause cancer in two different ways;
1. The proviral DNA may integrate by chance near one of the cell’s normal proto-
oncogenes. The strong promoters and enhancers in the provirus then stimulate
high levels or inappropriate timing of transcription of the proto-oncogene,
leading to stimulation of whole cell proliferation.
2. A retrovirus may pick up a copy of a host proto-oncogene and integrate it I to its
genome. The new viral oncogene may be mutated during the process of transfer
into the virus, or it may be expressed at abnormal levels because it is now under
control of viral promoters.
  Retroviruses that carry to those viral oncogenes can infect entrance form normal
cells into tumor cells.
 So far, no acute transforming retroviruses have been identified in human.
 However, RNA and DNA viruses contribute to the development of human cancers in
a variety of ways. It is thought that, worldwide about, about 15 percent of cancers
are associated with viruses, making virus infection the second greatest risk factor for
cancer, next to tobacco smoking.
 The most significant contributors to virus-induced cancers are the papillomaviruses
(HPV 16 and 18), human T-cell leukemia virus (HTLV-1), hepatitis B virus, and
Epstain-Barr virus.
 Like other risk factors for cancer, including hereditary predisposition to certain
cancers, virus infection alone is not sufficient to trigger human cancers. Other
factors, including DNA damage or the accumulation of mutations in one or more of a
cell’s oncogenes and tumor suppressor genes, are required to move a cell down a
multistep pathway to cancer.
 Because viruses are comprised solely of a nucleic acid genome surrounded by a
proteinaceous coat, viruses must utilize the host cell’s biosynthetic machinery in
order to reproduce themselves. As most viruses need the host cell to be in an
actively growing state in order to assess the host’s DNA synthetic enzymes, these
viruses often contain genes encoding products that stimulate the cell-cycle.
 If the virus does not kill the host cell, the potential exist for a loss of a cell cycle
control and the beginning of tumorigenesis.
Human Viruses Associated with Cancer
Virus Cancer oncogenes Mechanism
Human Cervical cancer E6, E7 Inhibit p53 and pRB
Papillomavirus 16, 18 tumor suppressors

Hepatitis b virus Liver cancer HBx Signal transduction,

stimulates cell cycle

Epstein-Barr virus Burkitt’s lymphoma, Unknown Unknown

naso-pharyngeal

Human herpesvirus 8 AIDS-related Kaposi’s Several possible Unknown

sarcoma

Human T-cell Adult T-cell leukemia pX Stimulates cell cycle

leukemia virus
 Dalubhasaan ng Lunsod ng San Pablo
San Jose, San Pablo City
2014-2015

Written Report in
Genetics

Submitted by: Submitted to:

Myra D. Soriano Mr. Alvaro Dioquino
BSEd III- Biological Science Instructor

January 22, 2015