BIO 102 Cancer - Adrienne Alaie, PhD
Overview of Cancer Biology
Cancer is defined as a disease characterized by the uncontrolled proliferation of mutated cells, leading to the detriment of surrounding healthy cells.
Cell Communication in Multicellular Organisms
Cells in a multicellular organism engage in collaborative behavior, coordinating actions through signals.
Signals serve as social controls, influencing cell behaviors like resting, dividing, differentiating, or dying.
Disturbances in these signals can disrupt cellular harmony, leading to cancer.
Specific signals for cell behaviors:
Survival Signals: A, B, C
Division Signals: A, B, C, D, E
Differentiation Signals: A, B, C, F, G
Death Signals: Absence or alteration of signals
Many mammalian cells depend on both soluble signals and extracellular matrix (ECM) signals for growth and proliferation.
Definition of Cancer
Cancer: A disease where a single mutant clone of cells proliferates at the expense of neighboring cells.
Cancer cells behave selfishly, leading to uncontrolled growth and nutrient acquisition.
Mutations in critical genes related to cell division disrupt communication and responses to growth cues, undermining the overall organism's health.
Tumors often contain billions of cancer cells by the time they are diagnosed.
Social Responsibility of Cell Division
Normal cells divide mainly when the body requires it for:
Repair of tissues
Response to infection
Growth and development
Replacement of aging or damaged cells
Cell Division Signals:
Mitogens: Stimulatory extracellular signals that promote mitosis (from neighboring cells).
Growth Factors: Stimulate increases in cell mass, promoting the synthesis of macromolecules while inhibiting degradation.
Division Restrictions:
Quality control mechanisms ensure accurate cell division, monitored at various checkpoints during the cell cycle.
Cell Cycle Checkpoints
G1 Checkpoint:
Criteria to pass:
Mitogens are present.
Adequate cell size.
Sufficient nutrient availability.
DNA is undamaged.
Failure to meet conditions leads to cell arrest; If DNA is damaged, repair is attempted before moving to the S phase.
G2 Checkpoint:
Criteria to pass:
Adequate cell size.
Successful completion of chromosome replication.
Metaphase Checkpoint:
Criteria to pass:
All chromosomes must be properly attached to the mitotic spindle.
If conditions are unmet, cells undergo arrest and attempt to rectify issues before transitioning to the next phase.
If unresolved, apoptosis is triggered.
Definition of Tumor
Tumor: An increase in the number of cells, resulting from altered cell division and apoptosis rates.
Normal apoptosis and cell division maintain homeostasis.
Cancer results from an imbalance where some cells ignore signals for apoptosis and continue dividing.
Causes of Uncontrolled Cell Division
Each cancer type stems from distinct defect sets leading to uncontrolled division.
Mutations in proteins controlling the cell cycle and chromosomal stability are primary drivers of cancer.
Development Stages of Cancer:
Initiation: A mutation causes abnormal proliferation of a single cell.
Progression: More mutations accumulate, leading to selective proliferation of faster-dividing cells.
Cancer is ultimately a result of cumulative mutations and a disease associated with aging.
Normal Response of Cells to Signals
Normal cells appropriately respond to:
Growth stimulatory signals (growth factors and mitogens).
Signals that inhibit growth (contact inhibition).
Signals initiating apoptosis (programmed cell death).
Characteristics of Cancer Cells
Behavioral Alterations:
Many cancer cells ignore regulatory signals, leading to excessive division.
Altered responses to apoptotic signals.
Circumvention of replicative senescence (ability to divide indefinitely).
Genetic instability, leading to more mutations.
Invasiveness, allowing cancer cells to escape their home tissues.
Ability to survive and proliferate at foreign sites (metastasis).
Induction of angiogenesis to support tumor growth.
Experimental Evidence Related to Cell Division
Normal human connective tissue cells demonstrate the importance of growth factors. For example, fibroblast cultures survive and proliferate effectively in growth media supplemented with Platelet-Derived Growth Factor (PDGF).
Some cancer cells can proliferate without these growth factors, showing their different developmental pathways.
Mechanisms of Metastasis
Steps in the metastatic process:
Formation of a benign tumor.
Invasion of surrounding tissues, including blood vessels.
Adherence of cancer cells to the walls of target organs.
Escape from circulation and establishment of metastasis.
Cancer Cell Genetic Instability
Translocations and other chromosomal alterations are common in cancer cells, leading to instability and abnormal gene expression.
Cancer Critical Genes
Categories of Cancer Critical Genes:
Proto-oncogenes: Activate pathways for cell division.
Tumor suppressors: Slow down or stop the cell cycle.
DNA maintenance genes: Maintain genomic stability.
Proto-oncogenes are likened to a gas pedal (stimulatory), while oncogenes represent a stuck gas pedal (perpetuating growth).
Activation mutations promote overactivity that can lead to cancer.
Case Study: Chronic Myelogenous Leukemia (CML)
In CML, a fusion of chromosomes 9 and 22 leads to the formation of an active Bcr-Abl protein, an overactive tyrosine kinase that promotes unchecked proliferation.
Gleevec is an example of a targeted therapy inhibiting this produced protein.
Tumor Suppressors
Function: The "brake pedal" of the cell cycle; they slow down or halt progression upon detecting damage.
Mechanisms of Loss: Mutations can lead to complete loss of function.
Misregulated tumor suppressor function can lead to unregulated cell growth and malignancy.
Role of p53 in Tumor Suppression
p53 detects cellular stress and damage, regulating genes necessary for cell cycle arrest and apoptosis.
It accumulates under stress signals and performs critical functions such as:
Inducing cell cycle arrest via transcriptional modulation.
Initiating apoptotic signals when damage cannot be repaired.
Cancer Types and Genetic Mutations
Cancer risk not only depends on environmental factors but also genomic mutations and hereditary predispositions, such as in retinoblastoma, where mutated Rb genes lead to excessive cell growth.
Viral Inhibitors of Tumor Suppressors
Certain oncogenic viruses, like HPV, produce proteins that inactivate tumor suppressors such as p53 and Rb, facilitating unchecked proliferation.
Model of Cancer Formation: Multiple Hit Model
The progression of cancer involves a series of mutations leading ultimately to malignancy, often following a sequence: loss of tumor suppressors -> activation of oncogenes -> further mutations.
Metabolic Characteristics of Cancer Cells
Cancer cells often undergo lactic acid fermentation even in the presence of oxygen, differing from normal cells that prefer oxidative phosphorylation.
Increased glucose uptake is a characteristic of cancer cells for increased ATP production through anaerobic pathways.
Vascularization in Tumors
Angiogenesis, the formation of new blood vessels, is crucial for tumor survival, often mediated by secretion of Vascular Epithelial Growth Factor (VEGF).
Stem Cell Origin of Tumors
Not all cancer cells arise from stem cells. The origins and mutations can vary greatly between individuals and cancers.
Immune Evasion by Cancer Cells
Tumor cells can evade immune detection through down-regulation of MHC molecules or secretion of inhibitory factors that suppress T cell activation.
Cancer Immunotherapy Development
Mechanism of Action: Blocking CTLA-4 and PD-1 enhances T-cell activity against tumors.
YERVOY and OPDIVO are examples of antibodies that inhibit these pathways, thereby promoting robust anti-tumor responses.
Side Effects of Immunotherapy
While effective, these therapies can lead to autoimmune responses due to increased immune activity against normal tissues.
Conclusion
Understanding the mechanisms of cancer biology, including genetic mutations, cell cycle regulation, tumor biology, and immune interactions, is crucial for development of targeted therapies and novel treatments.