Chapter 20A: Cancer
Exam Information
Chapter 20 will be covered in the next three lectures.
Chapter 18 will not be included in part three of the exam.
A final review session will be held next Monday.
The exam is next Wednesday morning in the same lecture halls.
Introduction to Cancer
Cancer arises when normal cellular processes are disrupted, causing cells to behave erratically.
Dr. Vogelstein defines cancer as a genetic disease requiring multiple mutations.
These mutations lead to cellular multiplication and increased tumor size and malignancy.
A series of accumulated mutations, especially key cancer-driving mutations, are required for cancer development.
Historical Context
Carcinos/Carcinoma: Coined by Hippocrates to describe tumors with a crab-like appearance.
Cancer: Latin word for crab, used by Roman physician Celsus.
Oncos: Greek term by physician Glenn referring to tissue swelling, now used in oncology (study of cancers).
Key Properties of Cancer
Uncontrolled growth and proliferation.
Increased survivability, escaping normal bodily constraints.
Invasion and colonization of other tissues.
Hyperplasia: Increase in cell number, leading to tumors or neoplasms.
Tumor Classification
Benign: Non-invasive; can often be surgically removed.
Malignant: Invasive, spreading to surrounding tissues; true cancer.
Cancer stages range from 1 to 4, with grades varying by tissue and cancer type.
Metastasis: Advanced stage where cells break loose, enter the bloodstream or lymphatic system, forming secondary tumors.
Cancer Cell Characteristics
Unusual glucose uptake, revealed in PET scans using radioactive glucose (five-fluorodeoxyglucose).
Pale yellow areas in PET scans indicate regions of metastasis.
Classifications of Cancer
Carcinomas: Cancers of epithelial tissues (e.g., urothelial, adenocarcinomas).
Sarcomas: Cancers of connective tissues like bones, tendons, cartilage, muscle, and fat.
Leukemias: Cancers of the bone marrow where blood cells are produced.
Myelomas: Arise from plasma cells of bone marrow.
Lymphomas: Cancers of the lymphatic system involving lymphocytes.
Neuronal Cancers: Originating from the brain (e.g., glioblastomas, neuroblastomas).
Mixed-Type Cancers: Combinations, such as neuronal cancer metastasizing into epithelial cancer.
Specific Cell Type Cancers: Melanomas (melanocytes) and mesotheliomas (lung tissue).
Cancer Development
Cancer cells bypass normal proliferation controls and colonize other tissues.
Example: Mammary duct epithelial cells growing into the apical region, breaking through the tissue matrix to become malignant.
Cancer Incidence and Mortality
One in five people may develop cancer.
Epithelial carcinomas are highly prevalent.
New cases are shown in green, and deaths per year are shown in blue.
Digestive organs, lungs, and reproductive tracts show high prevalence.
Breast cancer has high new case rates but lower death rates compared to new cases detected.
Bone and connective tissue cancers have lower incidence rates in the U.S.
Tumor Growth
Tumor detection is not immediate; it requires a substantial cell population.
Visible on X-ray: cells.
First palpable: cells.
Patient death: cells.
These figures are examples and can vary based on tumor type and grade.
Clonal Origin of Tumors
Tumors develop from a single aberrant cell (monoclonal origin).
Cells gain mutations advantageous for survival and become cancerous.
Chronic myelogenous leukemia: Patients have a chromosomal aberration only in leukemic cells.
Translocation of chromosome 9 with chromosome 22 causes the expression of an oncogenic factor.
Philadelphia chromosome: Modified chromosome 22 with a fragment of chromosome 9.
Genetic Changes in Cancer Development
Inherited mutations: Germline mutations (sperm or egg cells) constitute less than 10% of tumors and increase cancer risk (e.g., BRCA mutations).
Somatic mutations: Mutations in body cells, not necessarily in the germline; most tumors have somatic mutations.
Epigenetic changes: Heritable changes in gene expression without changes in DNA sequence, such as chromatin modifications or methylation marks.
Cancer Incidence and Age
Cancer is a disease of age; likelihood increases with age.
Cancer prevalence increases significantly in individuals in their 60s, 70s, and 80s.
Caused by accumulation of mutations over a lifetime.
Environmental factors like smoking and radiation also play a significant role.
Malignant vs. Benign Tumors
Malignant tumors are dangerous because cells invade surrounding tissue.
Cancer Development Over Time
It takes time for cancer to develop, as seen in radiation exposure incidents (Hiroshima and Nagasaki).
Smoking-related cancers take 20-30 years to develop.
Stages of Tumor Progression
Squamous epithelial cells of the uterine cervix: Progression from low-grade intraepithelial neoplasia to high-grade and invasive carcinoma.
Low-grade intraepithelial neoplasia: Epithelial cells start dividing, causing hyperplasia.
High-grade intraepithelial neoplasia: Number of cells increases, disrupting tissue integrity.
Invasive carcinoma: Cells invade the stromal layer and extracellular matrix.
Natural Selection in Tumors
Tumor cells follow the principles of natural selection, favoring mutations that give them a survival advantage.
Clonal evolution: Cells accumulate mutations, adapting to the environment to enhance survival, leading to dangerous proliferation.
Cancer is a microevolutionary process.
Clonal Expansion
Initiating mutation leads to the first clonal expansion.
Subsequent mutations make cells more advantageous.
Multiple independent mutations lead to further clonal expansions.
This results in multiple parallel clonal expansions, making cancer treatment difficult due to the varied genetic identities within the same tumor.
Genetic Instability in Cancer
Breast cancer cells show abnormal chromosome numbers (e.g., 48 instead of 46).
Fragments of different chromosomes attach to others, causing rearrangements.
Karyotypes of colon cancer display various genetic instabilities.
Cancers can have abnormal karyotypes, which are more common, or normal karyotypes with advantageous point mutations.
Chromosome Segregation Defects
Aneuploidy (changes in chromosome number) is caused by defects in chromosome segregation.
Cancer cells bypass the spindle assembly checkpoint, leading to abnormal chromosome numbers in daughter cells.
Lagging chromosomes can either be gained or lost in daughter cells, leading to aneuploidy.
Lagging chromosomes can form micronuclei, which fragment and integrate into other chromosomes (chromothrypsis).
Single Mutation and Cancer
A single mutation is not enough to convert a normal cell to a cancer cell.
Cancer requires additional mutations to support a key, defining mutation.
Cancer Risk and Cell Division Rate
Lifetime cancer risk is correlated with the division rate of the cell of origin.
More stem cell divisions lead to higher susceptibility to mutations and cancer.
Lifetime cancer risk increases in organs with higher stem cell division rates (e.g., skin, colorectal).
Cancer Stem Cells
Some cancers may have cancer stem cells with self-replication and differentiation properties.
Cancer stem cells can give rise to new tumors, unlike transit amplifying cells.
Targeting these stem cells during treatment is crucial to prevent recurrence.
Key Attributes of Cancer Cells
Altered homeostasis: Imbalance between cell division and cell death.
Ability to bypass normal constraints and grow under constant stress.
Evasion of cell death signals and altered cellular metabolism.
Manipulation of the tissue microenvironment to promote cell survival.
Ability to escape the tissue of origin and proliferate in new sites (metastasis).
Survival and Stress
Cancer cells have an abnormal ability to survive stress and DNA damage.
Normal cells undergo apoptosis when stressed, but cancer cells continue to survive.
They can even produce their own growth factors (autocrine signaling).
Contact Inhibition
Cancer cells lack contact inhibition, allowing them to grow on top of each other.
Transformed cells form foci, indicating cells growing in multiple layers.
Escape from Cell Death Signals
Cancer cells avoid cell death signals, surviving even when extruded into the lumen.
They can also escape from the basal epithelial region, becoming more invasive.
Replicative Senescence
Cancer cells escape replicative senescence due to their ability to maintain telomere length.
Telomeres are repeat sequences at the ends of chromosomes that shorten with each cell division.
Once telomeres become too short, cells normally enter senescence or die.
Cancer cells reactivate telomerase, allowing them to bypass this limit and divide indefinitely.
Telomerase complex includes RNA template and catalytic enzyme (TERT).
Telomerase activity is high in fetal liver but decreases in healthy liver, increasing again in liver cancer.
Warburg Effect
Cancer cells rely more on glycolysis than oxidative phosphorylation, even in the presence of oxygen.
Tumor cells uptake a lot of glucose, like other proliferative tissues.
The glucose is shunted to glycolysis, producing lactate, with only a small amount going to oxidative phosphorylation.
Tumor Microenvironment
Tumors manipulate their surrounding microenvironment to support their growth.
Stroma includes extracellular matrix, immune cells, fibroblasts, and blood vessels.
Tumors induce angiogenesis to ensure oxygen supply.
Metastasis Stages
Cells grow as a benign tumor.
They become invasive and enter a capillary.
Survive in the blood vessel.