Genes and Cancer - Part 1

Cancer as a Disorder of Somatic Cells

• Cancer arises from somatic cells, which are all body cells excluding gametes (eggs and sperm).
• Cancer involves malignant tumors, characterized by their ability to invade other tissues and cause harm.
• The term "malignant" signifies "bad" in several languages.
• The primary risk factor for cancer is age, as it takes time for mutations to accumulate.
• Heritable predispositions to cancer usually exhibit dominant patterns of inheritance, meaning that inheriting a mutated gene involved in cell cycle control can lead to cancer development.

Age and Cancer Risk

• The risk of cancer increases with age.
• Until around age 30-35, the cancer risk remains relatively low.
• After age 45, there is a significant increase in cancer risk.

Characteristics of Cancer

• Uncontrolled cell growth is a key characteristic of both benign and malignant tumors.
• Benign tumors:
  • Non-invasive and non-cancerous.
  • Encapsulated by a membrane.
  • Slow-growing.
  • Do not spread to other parts of the body.
  • Can often be surgically removed, resulting in the patient becoming cancer-free.
• Malignant tumors:
  • Cancerous.
  • Lack a surrounding membrane and are not encapsulated.
  • Fast-growing.
  • Can metastasize, meaning cells can break off and spread to other parts of the body.
• Metastasis:
  • Cancer cells from the primary tumor can travel through the circulatory or lymphatic systems to other areas of the body.
  • These cells can then exit the vessels and initiate new tumors.
  • Metastasis indicates a more advanced and difficult-to-control stage of cancer.

Causes of Cancer

• Mutations are the primary cause of cancer.
• Reasons for mutations:
  • Heritable predisposition: Inheritance of a mutated gene involved in cell cycle control or DNA repair.
  • Spontaneous mutations: Errors made by DNA polymerase during DNA replication.
  • Environmental and behavioral factors: Exposure to toxins and behaviors like smoking.
• Most cancers are sporadic, originating from accumulated mutations over time.
• Mutations usually occur in a single cell, and all subsequent offspring of that cell will carry the same mutation.
• While cancer itself isn't heritable, a predisposition to cancer can be inherited.

Heritable Predispositions to Cancer

• Early onset familiar breast cancer: Mutations in BRCA1 and BRCA2 genes (DNA repair genes).
• Hereditary nonpolyposis colorectal cancer: Inherited colon cancer requiring multiple mutations to manifest.
• Retinoblastoma: Cancer behind the eye caused by a mutation in a tumor suppressor protein.

Cancer Cells vs. Healthy Cells

• Cancer cells often have odd shapes.
• In healthy tissues:
  • Damaged cells are eliminated through apoptosis (cellular suicide).
  • The damaged cell receives signals to self-destruct, changes shape, dies, and is removed by macrophages.
• In cancer cells:
  • The elimination process fails.
  • Uncontrolled growth occurs, and offspring cells inherit the mutation and grow into abnormal shapes.
• Normal cells in a laboratory setting:
  • Require growth factors to divide.
  • Will divide and grow to cover the surface of a tissue culture flask when growth factors are present.
  • Will not divide without growth factors.
• Cancer cells in a laboratory setting.
  • Divide regardless of the presence of growth factors.

Tumor Suppressor Genes

• Functions inside the nucleus.
• RB, mutated in 40% of all cancers.
• p53, mutated in 50% of all cancers.
• Both suppress the cell cycle and prevent tumorous growth.

Proto-oncogenes

• Promote the cell cycle.
• RAS proteins. Activated by mutations in 20-30% of all cancers.
• SOK Kinase.
• RAS protein is normally active and inactive as part of cellular growth, but gets inactivated when a cell should not divide.

Regulation of the Cell Cycle

• Tumor suppressor proteins regulate the cell cycle at various checkpoints.
• G1 Checkpoint: A crucial checkpoint where cells can exit the cell cycle into G0 phase if something is wrong.
  • RAS and p53 are active at the G1 checkpoint.
• G2 Checkpoint: Located between the G2 phase and the mitotic phase to prevent cell division if there's an issue.
• Checkpoint at the End of Mitosis: Ensures chromosomes are properly separated.

Functions of Tumor Suppressors

• Acts like 'brakes' to shut down or stop the cell cycle.
• p53 Tumor Suppressor:
  • Influenced by DNA damage, hypoxia, nutrient deprivation, oxidative stress, and oncogene expressions.
  • Triggers cell cycle arrest and apoptosis (cell suicide).
  • Involved in DNA repair, metabolism, and senescence (aging of the cell).

Retinoblastoma

• Caused by mutated RB protein.
• If there is a family history of retinoblastoma, genetic checks can assess the probability of a child inheriting the condition.
• Early detection allows for treatment to preserve eyesight and the eyeball.

Hereditary vs. Sporadic Retinoblastoma

• Hereditary: Inherited mutated RB gene, leading to predisposition.
• Sporadic: Requires two mutations to occur over a longer time.
• Retinoblastoma is usually associated with an inherited mutated RB gene.
• Gene Location: Chromosome 13 on the Q arm.
• Mechanism: Active RB gene inhibits the E2F transcription factor from binding to DNA and promoting transcription.
• Phosphorylation of RB protein causes it to detach from the transcription factor, allowing E2F to bind to DNA.

Overview of Growth Factor and RB Protein

• Growth Factor (e.g., PDGF) binds to a receptor on the cell surface.
  • The growth factor itself does not enter the cell.
• A cascade of events is initiated inside the cell, involving the RAS protein.
• RAS protein is located near the receptor.
• Kinases (proteins that phosphorylate and activate other proteins) are activated.
• In the nucleus, RB protein binds to the E2F transcription factor, inhibiting transcription.
• Stimulation of RAS and the kinase cascade leads to phosphorylation of RB.
• Phosphorylated RB detaches from the transcription factor.
• The transcription factor binds to DNA and activates transcription.

Proto-oncogenes

• Proto-oncogenes are like gas pedals in a car, while tumor suppressors are like brakes.
• Normal RAS gene can be turned on (activated) and turned off (inactivated).
• If the cell needs to divide, RAS gets activated.
• Leads to a signal transduction cascade.
• Initiates transcription factors that promote cell division.
• When the cell receives a signal to stop dividing, RAS gets inactivated, halting the cell cycle.

Mutant RAS Protein

• Remains active.
• Cannot be turned off.
• Leads to uncontrolled cell growth, forming a tumor because the signal for inactivation is not functional, and the cell keeps dividing.
• Normal proto-oncogenes (like RAS) promote the cell cycle under controlled conditions.
• Mutant RAS protein, however, remains in the "on" position, leading to uncontrolled growth.

Cell Growth in Tissue Culture Flasks

• Anchorage Dependence: Cells must adhere to the bottom of the dish to divide.
• Density-Dependent Inhibition: Cells stop dividing when they come into contact with neighboring cells, forming a single layer.
• In cancer cells, neither anchorage dependence nor density-dependent inhibition functions properly, leading to uncontrolled piling up of cells.

DNA Repair Genes

• DNA Damage Causes: Radiation, aging, UV light, chemicals, errors by DNA polymerase.
• DNA Repair Mechanism: Enzymes fix errors, eliminating mutated base pairs or wrongly incorporated nucleotides in the DNA.
• DNA Repair Failure: Mutations accumulate, leading to uncontrolled cell growth.
• Examples: BRCA1 and BRCA2 DNA repair genes. Mutations can't do their job, leading to breast cancer and ovarian cancer in women.

Development of Breast Cancer

• One cell not following cell cycle rules leads to abnormal growth.
• Tumor is encapsulated and benign, usually in the milk duct of the breast. It can be surgically removed.
• Invasion of cancer cells into neighboring tissue makes the tumor malignant.
• Cells can move to different places through the circulatory system or the lymphatic system, starting metastatic tumors.
• Exiting of cells from the blood vessels or lymphatic vessels allows the formation of new tumors in different parts of the body.
• Metastasis indicates a dire outlook.