Molecular biology of cancer
Prepared by Dr Budoromyi Obed , IM resident, PGY3
Facilitated by Dr Rubagumya Fidel, Oncologist

Introduction
• Cell numbers are a product of cell division that is
Mitosis and cell death that is apoptosis.
• Cancer can arise as a result of gene mutations that
affect the rate of mitosis as well as apoptosis , thereby
Leading to the accumulation of extra cells
• The cell cycle is controlled by proteins from inside
and outside the cell including the following

Introduction cont.
1. Intracellular cyclins and cyclin dependent kinase(CKDs) control the
checkpoints
2. Hormones or extracellular proteins from other cells (called growth
factor) signal target cell to divide
• Hormones(e.g. Growth hormone) or growth factors bind to receptor
proteins of target cell membrane. This triggers a molecular signaling
pathway. A series of linked proteins activate Cyclin-CKDs which allows
cells to pass cell cycle checkpoints and divide

Introduction cont.
• Cancer is a group of diseases caused by the uncontrolled
multiplication of abnormal cells in he body, a process called
neoplasia. Neoplasms usually form masses called tumors that may be
benign (non cancerous) or malignant (cancerous)
• Some become invasive (to surrounding tissue) and others
metastatic(travelling via blood/lymph to invade distant tissues)
• Cancer is the 2nd major killer in populations of developed countries
and cause of death in children

• Cancers are genetic disorders caused by accumulation of somatic
mutations (genes and chromosome) in cells of a person. Inherited
mutations give a predisposition for certain cancers.

Characteristics of cancers
• Cancer cells are genetically altered via gene or chromosome
mutations so
 They lack normal controls over cell division or apoptosis
They may express inappropriate genes( e.g. For telomerase, enzyme
that maintains length of DNA for continued division)
They are genetically unstable due to loss of DNA repair mechanism
(so are susceptible to radiation damage than normal cells )

• Cancer cells divide excessively (proliferate) and indefinitely
neoplasms.
• They live indefinitely i.e. do not show apoptosis
• They lose the normal attachment to other cells so become metastatic
(travelling via blood/lymph to invade distant sites).
• They secrete signals for angiogenesis (growth of blood vessels into
tumor)

Categories of cancers
Based on tissue type they arise from, cancers can be categorized as
• Carcinomas which are associated with skin, nervous system, gut, and
respiratory tract tissue.
• Sarcomas which are associated with connective tissue (such as
muscle) and bone
• Leukemias(related to sarcomas) are cancers of the blood.
• Lymphomas develop in glands that fight infection(lymph nodes and
glands).
• Myelomas start in the bone marrow

Causes of cancer
• There are Inherited mutations in genes that affect cell cycle, DNA
repair, or apoptosis. These mutations give a genetic predisposition for
cancer.
• Somatic mutations to these same genes caused by
 exposure to risk factors such as environmental
mutagens(carcinogenic chemicals, radiation), hormones and
weakening of immune system (as in AIDS).
Oncogenic (tumor) virus infections e.g. Epstein Barr virus (causes
Burkitt lymphoma and human papilloma virus (causes cervical
cancer). Tumor virus transform human cells into cancer by introducing

Viral cancer-causing oncogenes of host proto-oncogens
• Carcinogens are cancer-causing agents, while mutagens are agents
that change the genetic code in a cell. Almost all carcinogens are
mutagens

Theories of cancer genesis
• Standard dogma
Proto-oncogenes(Ras-melanoma)
Tumor suppressor genes(p53- various cancers)
• Modified dogma
There is a mutation in a DNA repair gene leading to the accumulation
of unrepaired mutations(xeroderma pigmentosum)
• Early-instability theory
Master genes required for adequate cell reproduction are disabled,
resulting in aneuploidy(Philadelphia chromosome)

• Mutations in 4 types of genes cause cancer
Proto oncogenes genes that code for normal proteins used un cell
division (growth factors, membrane receptors for growth factors,
signaling proteins like ras proto-oncogene mutates 30% of cancer
Tumor suppressor genes that code for proteins that help prevent
uncontrolled cell division by blocking key steps e.g. DNA
replication(Retinoblastoma susceptibility RB gene. P53 gene mutates
in more than 50 % of cancers
DNA repair genes
Genes for apoptosis

Oncogenes and Protooncogenes
• Oncogenes are mutated forms of cellular proto-oncogenes.
• Proto-oncogenes code for cellular proteins which regulate normal cell
growth and differentiation
• There are five types of proteins encoded by proto oncogenes that
participate in control of cell growth
Class I growth factors
Class II Receptors for growth factors and hormones
Class III Intracellular signal transducers
Class IV Nuclear transcription factors

Class V Cell-cycle control proteins
• When Cellular proto-oncogenes are mutated and activated, the result
is
Overproduction of growth factors
Flooding of the cell with replication signals
Uncontrolled stimulation in the intermediary pathways
Cell growth by elevated levels of transcription factors

Chromosomal rearrangements or
translocations

Gene amplification

Tumor suppressor genes
• They inhibit cell division and prevent cancer
• They bind to checkpoints proteins to stop the cell cycle and prevent
cell division if DNA is damaged
• They stop division of mutated cells until mistakes in DNA are repaired
by enzymes.
• They keep most mutations from being passed on to daughter cells
and developing into cancer
• If the genes for TS proteins mutate the brake on cell division are
removed cancers may results.
• The 2 most important are the P53 and RB proteins

P53
• Phosphorylated p53 activates transcription of p21 gene
• P21 cdk inhibitor(binds cdk-cyclin complex—inhibiting kinase activity)
• Cell cycle arrested to allow DNA to be repaired
• If damage cannot be repaired, there is cell death(apoptosis)
• Disruption/deletion of p53 protein leads uncorrected DNA damage
and uncontrolled cell proliferation which in turn leads to cancer

RB protein
• RB protein controls cell cycle moving past G1 Check point
• RB protein binds regulatory transcription factor E2F
• E2F required for synthesis of replication enzymes
• E2F-RB bound no transcription/replication
• Growth factor leads to Ras pathway leads to G1cdk-cyclin synthesized
• Active G1dk-cyclin kinase phosphorylates RB
• Phosphorylated Rb cannot bind E2F results into S phase leads to
disruption/deletion of RB gene , inactivation of RB protein and
uncontrolled cell proliferation which leads to cancer

DNA repair genes
• These are genes that ensure each strand of genetic information is
accurately copied during cell division of the cell cycle
• Mutations in DNA repair genes lead to an increase in the frequency of
mutations in other genes, such as proto-oncogenes suppressor genes
• Examples include breast cancer susceptibility genes(BRCA1 and
BRCA2). Hereditary non polyposis colon cancer susceptibility
genes(MSH2,MLH1,PMS1,PMS2) have DNA repair functions.
• Their mutation will cause tumorigenesis.

Pathogenesis of Metastasis
• Cells in a primary tumor develop the ability to escape and travel in
the blood.
• Tumor cells secrete enzymes to break down extracellular matrix and
gain access to blood vessels.
• In blood, they can escape attack by immune cells by attaching to
platelets.
• Tumor cells attach to capillary walls and secrete more enzymes to
digest their way out and grow in a new location(metastasis) forming a
secondary tumor

Malignant versus benign tumors

References
• Uptodate /2023/etiology of cancers.
• Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6
and E6-AP complex functions as a ubiquitin-protein ligase in the
ubiquitination of p53. Cell 1993; 75:495
• Havre PA et al p53 inactivation by HPV16 E6 results in increased
mutagenesis in human cells. Cancer Res 1995,55.4420
• Brehm A et al. The E7 oncoprotein associates with Mi2 and histone
deacetylase activity to promote cell growth. EMBO J 1999,18,2449