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Cancer Mortality
2nd only to heart disease
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Cancer Frequencies
- Men-Prostate
- women-breast
- Deadly men-lung, prostate, colon
- deadly women-lung, breast, colon
- Men-1:2
- Women 1:3
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Neoplasm
- Any new and abnormal growth
- Neoplasm (n), Neoplastic (adj)
- Neoplasia: the formation of a neoplasm
- Specifically uncontrolled and progressive
- Neoplasm = Tumor
- "Benign" or "Malignant"
- i.e., “neoplasm” not necessarily “cancer”
- "Oncology" = Study of tumors
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Suffix "-oma"
- signifies benign tumor except MELANOMA
- Examples:
- Fibroma: fibrous tissue
- Adenoma: epithelial tumor of glands
- Papilloma: epithelial tumor forming finger-like projections
- Polyp: benign tumor that projects from mucosal surface
- Chondroma: benign tumor of cartilage
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Malignant Tumors
- Malignant tumor = cancer
- -Sarcoma: Malignancies of mesenchymal tissues (proceeded by descriptive name)
- Fibrosarcoma: fibrous tissue
- Angiosarcoma: blood vessels
- Chondrosarcoma: cartilage
- Leiomyosarcoma: smooth muscle
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Carcinoma: Cancers of epithelial origin
- Adenocarcinoma
- Form glandular patterns and/or derived from glandular cells
- Squamous cell carcinoma
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Denal Related Cancers
- Melanoma
- Osteosarcoma-Bone, Common with Paget’s disease
- Squamous cell carcinoma of skin or oral cavity
- -30,000 new oral malignancies per year
- -90% squamous cell
- -Risk factors:
- --Tobacco, alcohol, chronic irritation, HPV 16, sun
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Hyperplasia
- Increase number of normal cells
- Physiological vs. Pathological (e.g., BPH)
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Metaplasia
- Pathological event: Replacement of one differentiated (normal) cell with another differentiated (normal) cell
- Example: smokers: squamous metaplasia
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Dysplasia
Abnormal cells becoming disorganized (often pre-malignant)
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Anaplasia
Malignant cells lacking differentiation
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Benign V Malignant
- Proliferation
- Benign tumors grow slower than most malignant tumors (in general)
- Nevertheless, malignant or benign tumors can take years or decades to develop
- Invasion
- Benign tumors remain local, do not invade, often encapsulated
- Malignant tumors invade
- Metastasis
- Definition: Spread to secondary site
- Uncontrolled invasion and metastasis defines 'malignant'
- Metastatic lesions are often lethal events
- Differentiation
- Benign-well differentiated look like og cell
- malignant-range from anaplastic to well-differentiated
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Malignant Cells Histology
- Disorganized tissue architecture
- Loss of polarity
- Abnormal variations in size and shape of cell
- Often abnormal differentiation
- Abnormal shape & size of nucleus
- Often >1 prominent nucleolus
- Mitotic figures
- Invasion into stroma
- For carcinomas, invasion through the basement membrane
- Metastatic cells
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Adenomatous Polyps
- Colon polyps outgrowth of cells
- benign may or may not develop into malignancy
- adenomatous head with narrow stalk
- -colonoscopies- polyps removed
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adenocarcinoma
- cancer of colon
- appreciate that there is no normal lining of epithelial cells, abnormal architecture
- bottom right: looks nothing like normal cells/architecture of colon
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Lung: carcinoma in situ
- Lung atypical cells with thickened bronchial lining
- -disorganization, losing polarity; no stacking of epithelial cells bc of loss of basement membrane- no dependency on basement membrane or neighboring cells
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squamous cell carcinoma
- Tongue
- high power with pearls and intercellular bridges
- -nothing is normal, no normal polarity, cell to cell contact, or architecture; whorls of tumor cells- blue demarcates tumor cell nuclei; nuclei vary in shape and size
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Cancer 1st steps
- Initial 'hit'- Inherited mutation or polymorphism
- "Altered" cell stays alive - avoid apoptosis, , immune surveillance
- Overcome Proliferation controls
- Subscribe to Darwinian evolution i.e., induce more genetic / epigenetic alterations: ‘survival of the fittest’
- Become independent of environment and its neighboring cells
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Cancer 2nd Steps
- "dark side"
- Angiogenesis
- Clear a path for (tissue) invasion
- -Degrade extracellular matrix
- -Overwhelm normal cells
- Metastasis
- Enter blood system and/or lymphatics
- Cross extracellular matrix, endothelium and basement membrane
- Survive in a new environment
- Exit in new organ site
- Survive and thrive in a new environment
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Targets of genetic alterations include:
- Genes for cell proliferation
- Inactivation of growth suppression genes
- "Tumor suppressor genes"
- Activation of growth-promoting genes
- "Oncogenes"
- Genes that govern life / death decisions (apoptosis)
- Suppression of pro-apoptotic genes (tumor suppressor genes)
- Activation of anti-apoptotic genes (oncogenes)
- DNA repair genes
- Related to cell proliferation and survival
- Induces further genetic instability
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Uncontrolled Prolifereation
- Growth Factors
- Abnormal secretions
- Autocrine and/or paracrine
- Many of these factors are the ones you learned about in inflammation, immunity and/or tissue repair (e.g., PDGF, EGF, TGF-a)
- Abnormal receptor expression
- Abnormal receptor activation (ligand independent, self signaling)
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RAS
- 30% of human tumors have activated RAS
- Higher in colon and pancreatic cancers
- Drives cells to proliferate
- Activates signal transduction pathway
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ABL
- Activated by chromosomal translocation (Chrom. 9 & 22)
- Produces BCR-ABL fusion ("Philadelphia Chromosome")
- Chronic Myeloid Leukemia (CML)
- Tyrosine kinase
- BCR-ABL: cell proliferation
- ABL: promotes apoptosis
- BCR-ABL: no apoptosis
- Inhibited by Gleevec
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Proteins that regulate gene transcription
- MYC
- abnormal fusion, putting myc gene (transcription factor) under the regulation of an antibody gene (IgH)- bc these are B-cell tumors, when IgH gene was turned on, myc gene also turned on
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Cell Cycle Disruption
- Cancer
- there are a number of genes that turn on and off, that bring cell through cycle in normal cells, there are genes that halt cell cycle & put it into arrested stage
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Events necessary for normal proliferation
- Membrane receptor recognizes outside world
- -Soluble growth factor
- -Extracellular matrix
- Activation of growth factor receptor
- Transduction of signal
- -Via other proteins and second messengers in the cell
- Activation of proteins that regulate gene transcription
- Entry and progression through the cell cycle
- Exit from cell cycle
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Burkitt's Lymphoma
Activation of MYC
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Altered Cell cycle
- Most normal cells are not proliferating
- Proliferation occurs in stem cells / progenitor cells
- Normal cells tightly control the cell cycle
- Cancer cells by-pass check-points and blocks
- Cancer cells promote cell cycle progression
- Activation of genes important for cell cycle (oncogenes)
- Inhibition of cell cycle check-points (suppressor genes)
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Retinoblastoma gene (Rb)
- cancer is treated by removing the eyeball; retinoblastoma tumor, if not removed and spreads, is fatal
- First Tumor Suppressor gene discovered
- Normally expressed in all cells
- Critical for cell cycle control
- Deletion = cell cycle does not stop
- Both alleles need to be KO'd
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Retinoblastoma
- "small blue cell tumors" of childhood.
- Necrosis and dystrophic calcification are commonly seen within this tumor.
- At low magnification, two small calcification can be seen below center.
- The characteristic microscopic pattern is arrangement of the small blue cells into Flexner-Wintersteiner "rosettes" as shown here.
- -bottom left and right: cancer cells, vs normal retina on upper left
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Cancer "immortality"
- -stressful conditions for cancer cells: hypoxic conditions, avoid immune surveillance (immune system trying to kill it)
- -cancer cells can turn off the genes that normally trigger apoptosis, and increase anti-apoptosis proteins (like Bcl-2- KNOW)
- continue to grow
- resist the urge to die
- Under stressful conditions
- In a new environment, etc. etc.
- Invading, in blood stream, in other organs (metastases)
- Endogenous "clocks" (telomers) are turned off
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IgH
- chromosomal translocation which places the Bcl-2 gene next to the immunoglobulin heavy chain locus.
- This fusion gene is deregulated, leading to the transcription of excessively high levels of anti-apoptopic bcl-2 protein
- This decreases the propensity of these cells for undergoing apoptosis.
- Bcl-2 is another representative example of breakage and rearrangement of chromosomes so that genes that shouldn’t be close together, are- promotor for IgH is next to Bcl-2 gene;
- net effect: drive proliferation and prevent cell death > lymphoma
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p53
- Guardian Gene
- Commonly mutated genes in human cancers
- Tumor suppressor gene
- p53 Monitors stress
- e.g., DNA damage, hypoxia (decreased oxygen)
- p53 is a transcription factor
- Normal Functions include:
- Proliferation
- cell cycle arrest or cell cycle 'pause' (G1 arrest)
- Regulation of apoptosis
- DNA repair
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DNA Damage Control
- BRCA1 and ATM genes- regulate control of DNA damage
- BRCA 1 gene- involved in breast & other types of cancer; mutations affect how cells can repair their DNA
- ATM gene- rendered unfunctional, so that DNA damage is not repaired properly > mutations of cancer cells, some of which are advantageous to help cells bc more aggressive
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Cancer Cell Summary
- Initial 'hit'
- Transformed cell must stay alive
- Overcome proliferation controls and checks
- Darwinian evolution
- Survival of the fittest (constant genetic modifications)
- Independence from environment & neighboring cells
- Bring in its own nourishment (Angiogenesis)
- Tissue invasion
- Metastasis
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Cancer Mechanisms
- Non-lethal genetic events
- Principal Targets of genetic alterations include:
- Genes important for cell proliferation
- -Activation of proliferation (“oncogenes”)
- -Suppression / deletion of cell cycle blocks (“tumor suppressor genes”)
- Alterations in genes that govern life / death decisions (apoptosis)
- -Suppression of pro-apoptotic genes (“tumor suppressor genes”)
- -Activation of anti-apoptotic genes (“oncogenes”)
- Increased genetic instability via DNA repair genes
- -Related to cell proliferation and survival
- -Induces further genetic instability
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Cancer Uncontrolled Proliferation
- Genes that promote autonomous growth ("oncogenes")
- Review: Events necessary for normal proliferation
- Membrane receptors
- Activation of growth factor receptor
- Transduction of signal
- Activation of proteins that regulate gene transcription
- Entry and progression through the cell cycle
- Exit from cell cycle (i.e., halt proliferation)
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Metastasis
- Don't memorize-not easy for metastasis
- Tumor cells detach from each other because of reduced adhesiveness, and cells then attach to the basement membrane via the laminin receptors and secrete proteolytic enzymes, including type IV collagenase and plasminogen activator.
- Degradation of the basement membrane and tumor cell migration follow
- must break through basement membrane travel through blood stream, lymphatics, peritoneal or other cavities; must break through connective tissue, basement membrane, go into hostile liquid environment (blood stream, etc), then once it gets to its new location, must recruit blood supply (angiogenesis)
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Carcinogens
- Radiation
- Ultraviolet (sun light)
- Ionizing radiation
- x-rays, g rays, a-particles, b-particles)
- Chemicals
- Alkylating agents (e.g., chemotherapy drugs)
- Solvents (e.g., benzopyrene)
- Aflatoxin B1 (from peanuts)
- Nitrosamines
- Inorganic fibers
- Asbestos
- Cigarette smoke (second-hand)
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Carcinogenic Virii
- Ebstein-Barr virus (EBV)
- Herpes virus
- e.g., African Burkitts lymphoma, B cell lymphoma
- HIV
- Depletes immune surveillance
- Tumors include: lymphoma, Kaposi's sarcoma (Herpes Virus-8)
- Hepatitis B virus (HBV)
- Liver cancer
- Helicobacter pylori (H. pylori)
- Gastric carcinoma, gastric lymphomas
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HPV
- Cervical cancer
- inactivate p53 and Rb
- vaccination exists
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