CM11 -Oncogenesis

Biomedical Sciences I

What is cancer?

A heterogeneous group of disorders caused by uncontrolled cell division resulting in overgrowth of cells with genetic mutations that confer them advantage over normal cells.

• Cancer is a genetic disease, but it is NOT inherited

What are the characteristics of cancer cells?

• Non-differentiated

• Abnormal nuclei

• Do not undergo apoptosis

• No contact inhibition

• Disorganized, multilayered

• Undergo metastasis and angiogenesis

What are the characteristics of non-cancer cells?

• Differentiated

• Normal nuclei

• Undergo apoptosis

• Contact inhibition

• One organized layer

What are the main risk factors for oncogenesis?

• Genetic predisposition

• Environmental factors:

  • Tobacco

  • Diet

  • Obesity

  • Alcohol

  • Ultraviolet (UV) radiation

  • Ionizing radiation

  • Pollutants

• Viral infections

• Age

What is the “multi-hit” model of cancer?

• Cancer develops from an accumulation of mutations in multiple genes over time.

• An initial malignant cell arises after critical mutations.

• Mutations can be:

  • Passenger mutations: neutral, not driving cancer progression

  • Driver mutations: directly contribute to cancer development

What is clonality in cancer?

All cancer cells in a tumor are clones of a single original malignant cell.

What is autonomy in cancer?

The ability to override normal regulatory mechanisms.

What are the hallmarks of cancer?

• Sustained proliferative signaling

• Avoiding immune destruction

• Evading growth suppressors

• Enabling replicative immortality

• Tumor promoting inflammation

• Activating invasion and metastasis

• Genomic instability (mutator phenotype)

• Inducing angiogenesis

• Resisting cell death

• Deregulating cellular energetics

Which types of genes are commonly mutated in cancers?

• Proto-oncogenes

• Tumor-suppressor genes

• Cell cycle controlling genes

• Apoptotic genes

• DNA repair genes

• Telomerase-regulating genes

• Genes that promote vascularization

• MicroRNA genes (post-transcriptional regulators)

What do tumor suppressor genes do?

• Suppress inappropriate cell proliferation

• Induce repair of damaged DNA

• They are recessive-acting genes (both copies must be lost/mutated for effect)

• Loss-of-function mutations cause cancer → Loss of heterozygosity (LOH)

What is BRCA1?

• Tumor suppressor gene

• Normal function: DNA repair and transcription factor

• Cancer in which gene is mutated: breast and ovarian cancer

What is p53 and what happens when it is mutated?

• Tumor suppressor gene that regulates cell division

• Encoded by TP53 gene

• When mutated, causes many types of cancer

What is Retinoblastoma (RB) and what happens when it is mutated?

• A tumor suppressor gene that regulates cell division

• Mutation causes uncontrolled cell cycle progression and cancer.

What is the Li-Fraumeni syndrome?

• Caused by a germline mutation in TP53, the gene encoding p53.

• Increases risk of colon, breast, and brain cancers

• 50% of carriers develop cancer by age 30.

What are proto-oncogenes?

Normal genes responsible for basic cellular functions such as growth factors, receptors, intracellular kinases, and transcription factors.

What are oncogenes?

Mutated forms of proto-oncogenes that stimulate cell division.

• They act as dominant genes → only one mutated copy is needed.

• Gain-of-function mutations → cancer development.

What is the myc gene?

• Proto-oncogene that encodes for a transcription factor

• Mutates into an oncogene that causes lymphomas, leukemias, neuroblastoma

What is the ras gene?

• Proto-oncogene that encodes for GTP binding and GTPase

• Mutates into an oncogene that causes many types of cancer

What are the mechanisms of oncogene activation?

• Promoter/enhancer insertion

• Gene amplification

• Point mutations

• Chromosomal translocations

These can create abnormal proteins, new proteins, or excessive amounts of proteins

What is Burkitt’s Lymphoma?

A cancer caused by chromosomal translocation

How can viruses cause cancer?

• Both DNA and RNA viruses can cause cancer.

• Mechanisms include:

  • Introducing a new “transforming” gene into the host cell

  • Altering expression of host genes

  • Mutating or rearranging proto-oncogenes

  • Inserting strong promoters near proto-oncogenes

  • Inducing impaired DNA repair and chronic inflammation

How do cell cycle regulatory genes contribute to cancer?

• Normal cycling of cyclins and cyclin-dependent kinases (CDKs) regulates checkpoints.

• Mutations that allow unregulated passage from G1 to S phase are oncogenic in 80% of human cancers.

What signaling pathway is commonly altered in cancer?

The Ras/MAPK pathway.

What types of cancer-related mutations can occur in signal transduction pathways?

Mutations in:

• Growth factors

• Growth factor receptors

• Adaptor proteins

• Kinases

• Transcription factors

What is the role of Ras-GTP in a healthy vs cancerous individual?

Normal:

• Ras-GDP = inactive

• Ras-GTP = active → controlled growth, proliferation, and migration

Cancerous:

• Ras-GTP is the dominant state

• Causes uncontrolled growth, proliferation and migration → cancer

Why do cancer cells often have higher mutation rates?

• Low replication fidelity (DNA copied inaccurately)

• Inefficient DNA repair

• Defective DNA repair systems can produce double-strand breaks, leading to chromosomal rearrangements.

• Loss-of-function in DNA repair genes = cancer.

What is the role of telomerase in cancer?

• Telomerase is normally active only in germ cells and stem cells.

• In 90% of tumors, telomerase is reactivated, allowing cells to become immortal.

• Most common noncoding mutations in cancer: mutations in the proximal promoter of the human telomerase reverse transcriptase (hTERT) gene, which encodes the catalytic subunit of telomerase.

What is apoptosis?

Programmed cell death, a regulated energy-dependent process in which cells self-destruct.

What are the steps of apoptosis?

• Initiation: triggered by death receptors (TNF1-R), growth factor deprivation, or loss of mitochondrial integrity.

• Signal integration: balance of pro-apoptotic vs. anti-apoptotic signals determines outcome.

• Execution: mediated by caspases (proteases that dismantle the cell).

How do cancer cells bypass apoptosis?

By inactivating caspases, preventing programmed cell death.

What role does methylation play in cancer?

• Methylation status of DNA is influenced by lifestyle and environmental exposures.

• This is part of epigenetics (heritable gene expression changes not caused by DNA sequence changes).

• Aberrant methylation can silence tumor suppressor genes or activate oncogenes.

What is angiogenesis?

New blood vessel formation by endothelial cells and the extracellular matrix

Why do tumors need angiogenesis?

• Tumors larger than 1 mm³ require new blood vessels for oxygen and nutrients.

• Angiogenic factors: promote angiogenesis (VEGF, TGF-β, bFGF, IL-8)

• Angiogenesis inhibitors: interferons.

What is invasion in cancer?

• A defining feature of malignancy.

• Malignant cells disrupt the basement membrane and penetrate the underlying stroma.

• Mechanisms:

  • Loss of adhesion to basal membrane (low E-cadherin expression).

  • Local extracellular matrix degradation/proteolysis (high matrix metalloproteinases, MMPs).

What is metastasis in cancer?

• Spread of malignant cells to distant sites through tissue barriers.

• Steps:

  • Intravasation: cancer cells enter the bloodstream.

  • Extravasation: cells exit circulation and invade new extracellular matrix.