Cancer Biology: Oncogenes and Tumor Suppressors

Cancer Overview

• Multi-cellular organisms function as a society or ecosystem, where self-sacrifice (collaboration) outweighs survival of the fittest.
• Molecular disturbances disrupt this harmony, causing issues in multi-cellular societies.
• Cancer is a suitable topic to conclude a cellular and molecular biology course. It's an outcome of malfunctioning regulatory mechanisms in cells' normal behaviors when cells become non-cooperative or "selfish."

Cancer as Microevolution

• The human body contains more than 10¹³ cells, experiencing billions of mutations daily.
• DNA replication is highly accurate, but some mutations evade cell repair.
• Most genes likely experience mutations more than 10⁹ times per individual.
• The problematic aspects of cancer are not why mutations occur, but rather their infrequent occurrence.
• A mutation can provide a cell with an advantage to grow, divide, and outcompete neighbors, forming a mutated clone.
• This "selfish" behavior jeopardizes the overall organism's health.
• Mutation, competition, and natural selection, within a population of cells, can lead to malignant cancer.

Main Cancer Types

• Over 200 types of cancer are classified into four main categories.
• Carcinomas (~30% of human cancers) originate from epithelial cells.
• Sarcomas (rare in humans) arise from connective tissue (like bone, cartilage, and muscle).
• Leukemias/lymphomas originate from blood cells (hemopoietic cells).
• Neoplastic neuromas derive from nervous system cells (neurons and neuroglia).

Major Cancer Traits

• Hyperplasia: Excessive growth and proliferation of cells that form tumors.
• Metastasis: Cancer cells detach, travel through blood/lymphatics, and form secondary tumors (metastases).
• Benign tumors do not metastasize. Malignant tumors are cancerous.

Cancer Development & Factors

• Cancer develops through an accumulation of somatic mutations (not germline).
• The mutations must be inheritable, meaning they pass to progeny.
• Cells can have genetic or epigenetic changes (e.g., DNA sequence mutations or alterations in gene expression without DNA changes).
• Cancer requires multiple steps/mutations to develop over many years.
• Individuals with DNA repair defects accumulate mutations at a faster rate.

Cancer Cell Characteristics

• Genetically unstable: Exhibit increased mutation rates due to replication/repair/segregation errors.
• Defective control: Lose dependence on signals for survival, death, and differentiation.
• Abnormally invasive: Lack adhesion molecules, survive in unusual places, and secrete enzymes that break down the extracellular matrix (ECM).
• Absence of senescence: Cells proliferate indefinitely.
• Resistance to DNA damage: Display altered responses to DNA damage and stress.
• Heterogeneous: Tumors are made up of different clones with diverse combinations of mutations.

Cancer Cells - Unstable Genetics

• Cancer cells accumulate genetic changes at accelerated rates.
• Some cells struggle to repair DNA damage or regulate chromosome integrity.
• Genetic mutations may occur in DNA maintenance genes.
• Karyotypes show abnormalities in cancerous cells.

Factors Contributing to Instability

• Defects in DNA replication/repair.
• Defects in cell-cycle checkpoints.
• Mistakes during mitosis.
• Abnormal chromosome numbers.

Increased Cell Division/Apoptosis' Effect

• Increased cell division and decreased apoptosis increase the number of cells, thus increasing the potential for mutations.

Cancer Stem Cells

• Specialized cells, typically unable to divide, need constant replacement.
• Stem cells (precursors) generate replacement cells.
• Cancer stem cells arise from normal stem cells or differentiated cells, contributing to unlimited cell division.

Absence of Cell Senescence

• Normal cells have a limit on cell divisions before apoptosis starts.
• Telomere shortening triggers apoptosis in normal cells.
• Cancer cells overcome senescence by maintaining telomerase activity or changing cell cycle control pathways (e.g., failing to activate p53 pathway).

Steps in Metastasis

• Cells grow benignly in epithelial tissue.
• Cells become invasive and enter capillaries.
• Cancer cells travel via bloodstream, escaping blood vessels.
• Colonization of new sites (liver, etc.) for metastatic growth.

Two Types of Cancer Genes

• Proto-oncogenes: Code for proteins that promote normal cell proliferation.
• Mutant oncogenes: Become overactive, encouraging excessive proliferation (e.g., mutations on Ras, B-catenin).
• Tumor suppressor genes: Code for proteins that inhibit cell proliferation.
• Loss-of-function mutations on tumor suppressor genes lead to unchecked proliferation.

Oncogenes and Tumor Suppressors

• Proto-oncogenes can cause oncogenes by acquiring gain-of-function mutations.
• Tumor suppressor genes often need both copies to inactivate to cause cancer.

Converting Proto-oncogenes to Oncogenes

• Mutations in coding sequences, gene amplification, or chromosomal rearrangements can convert proto-oncogenes to oncogenes.
• Overactive oncogenes drive continuous cell proliferation even without signals.

Loss of Tumor Suppressor Gene Function

• Losing tumor suppressor gene function often involves both genetic and epigenetic changes.
• p53 is an important tumor suppressor gene in cell cycle-regulation, apoptosis, and DNA damage-repair.
• Mutations in many pathways result from p53 loss.

Why multiple mutations are needed for cancer development

• Complex regulatory systems and redundant backup processes prevent unchecked cell growth.
• Many regulatory systems must be impaired before a cell loses normal restraints and behaves as a cancer cell.

Development of Colorectal Cancer

• At least 5 mutations are needed in a lineage of cells for cancer development.
• APC is a crucial gene for colorectal cancer development.
• Cells lose cell-cell adhesion abilities and gain stem cell traits.
• Multiple mutations in p53, Ras, and Rb are involved.

Different Colorectal Cancer Patients

• Different colorectal cancer patients will have different combinations/mutations.
• Diversity in mutations impacts treatment response.

Current Cancer Treatments

• Prevention: Avoidance of known carcinogens.

• Early detection: Diagnostic tools like pap smears, mammograms.

• Treatments: Surgery, radiation, chemotherapy, immunotherapy, and gene therapy.

• Many treatments target cancer cells by damaging DNA leading to their death or halting their proliferation.

• Multidrug Treatments: Simultaneous use of multiple drugs may reduce tumor resistance, as it is highly improbable for tumors to develop resistance simultanesouly to two different drugs.

New Cancer Therapies

• Custom treatments: Tailored to the specific changes in a patient's cancer cells.
• Targeting mutated proteins: Inactivation of cancerous proteins without affecting normal cell function.

At-Home Exercises

• Leukemia, early-onset cancer - explanation for earlier onset needs provided
• Heavy smokers, industrial workers, delayed cancer onset - explanation for delayed progression needs provided
• Is cancer hereditary? - Explanation needs provided
• Choosing targets for cancer therapies (oncogenes vs. tumor suppressor genes) - explanation needs provided

iClicker Questions

• Malignant vs. Benign Tumors: Malignant cells invade other tissues.
• Converting Proto-oncogenes: Specific mutations, gene amplification, chromosomal rearrangements can turn proto-oncogenes to oncogenes, or causing the normal protein to be overproduced.
• False Statement About Mutations in Cancer - APC is a tumor suppressor, not a proto-oncogene