patho exam 4 Flashcards
Steps in the Development of Disease
etiology: cause of disease -
hypoxia & ischemia
toxins
infections
abnormal immune rxns
genetic abnormalities
nutritional imbalances
physical agents
pathogenesis: mechanisms of disease
biochemical changes
structural changes
abnormalities in cells & tissues
molecular
functional
morphologic
clinical manifestations
signs & symptoms of disease
Cellular Adaptation
Adapt to change in the internal environment
Adaptation includes changes in cells:
◼ Size
◼ Number
◼ Type
Changes may lead to
◼ Atrophy - decreased cell size
◼ Hypertrophy- increased cell size
◼ Hyperplasia- increased cell number
◼ Metaplasia - change from one adult cell type to another
◼ Dysplasia - cells of varying size, shape, and organization in a specific tissue
normal myocyte and its progression
ischemia leading to cell injury =
- reversibly injured myocyte - then cell death
adaptation: response to increased load:
- adapted myocyte hypertrophy
parts in a tissue
basement membrane
normal columnar epithelium
squamous metaplasia
Cell Injury and Death
Cell injury may be reversible or irreversible
healthy cell + insult/injury <-> cell injury -> death
Causes of cell injury
Hypoxia and ischemia
◼ Toxins
◼ Infectious agents
◼ Immunologic reactions
◼ Genetic abnormalities
◼ Nutritional imbalances
◼ Physical agents
Hypoxia and ischemia
◼ Hypoxia: oxygen deficiency
◼ Ischemia: reduced blood supply (thus O2)
◼ Among the most common causes of cell injury
◼ Deprive tissues of O2
◼ Essential for generating E for cell function and survival
◼ Ischemia also reduces the nutrient supply
- e.g., artery blockage, lung disease, anemia
Toxins
Multiple sources:
◼ Air pollutants, insecticides, carbon monoxide, asbestos, cigarette smoke, ethanol, drugs
Multiple mechanisms:
◼ Direct damage to cell
◼ Enzyme interference
◼ Protein denaturation
◼ Disrupt cellular osmotic/ionic balance
Infectious agents
◼ Viruses: DNA incorporation
◼ Bacteria: direct; exo-/endo-toxins
◼ Fungi
◼ Parasites
Immunologic Reactions
◼ The good: immune responses to injury and infection are absolutely essential
◼ The bad: autoimmune reactions against one’s own tissues, allergic reactions against environmental substances, excessive or chronic immune responses to microbes
◼ Problem: immune responses elicit inflammatory reactions (which are good), but inflammation can damage cells and tissues
Genetic abnormalities
◼ Chromosomal (e.g., Down Syndrome) or single nucleotide mutations (e.g., sickle cell anemia)
◼ Role in CA development
Cell injury consequence of:
◼ decrease (e.g., enzymes in inborn errors of metabolism) or increase in protein function
◼ accumulation of damaged DNA or misfolded proteins can trigger cell death.
Nutritional imbalances
Deficiencies
◼ Vitamins
◼ Minerals
◼ Protein
◼ Carbohydrate
◼ Fat
◼ Starvation: all nutrients deficient
Excesses
◼ Obesity
◼ Saturated fat
physical agents
Trauma/Mechanical forces
◼ Impact with other objects
Temperature extremes
◼ Low-intensity heat
◼ More intense heat
◼ Cold
Radiation
Electrical injuries
◼ Voltage, amperage, AC vs. DC
Physical Agent: Radiation injury
Ionizing radiation: High frequency
◼ Free radical formation
Ultraviolet radiation
◼ Sunburns -> skin CA
Nonionizing radiation: Lower frequency (IR, ultrasound, microwaves, laser energy)
Case: stresses and injury
◼ Homer Simpson has a terrible cold
◼ He starts a fire at his job in a nuclear power plant
◼ In attempting to put out the fire, Homer burns his hands and is exposed to ionizing radiation
◼ The nuclear plant is evacuated and Homer stands in the snow for 2 hours; he gets frostbite
◼ He is sent for treatment, where he develops a Clostridium infection in his burned hands
◼ What are the stressors on his cells and how are they causing cell damage?
Mechanisms of Cell Injury: General Principles
◼ Cell response depends on type of injury, its duration, and severity
◼ Consequences depend on the type of cell and its metabolic state, adaptability, and genetic makeup
◼ Usually results from functional and biochemical abnormalities in one or more essential cellular components
Mechanisms of cell injury
- Mitochondrial dysfunction and damage
- Oxidative stress
- Membrane damage
- Disturbance in calcium homeostasis
- ER stress
- DNA damage
Mechanisms of cell injury
image
- Mitochondrial Dysfunction and Damage
Mechanism of injury: Failure of oxidative phosphorylation, leading to decreased ATP generation and depletion of ATP in cells
◼ “Power failure” in cell
◼ Oxidative metabolism falters; cell reverts to
anaerobic metabolism (less efficient; less E)
◼ pH falls due to lactic acid accumulation
◼ Effects: clumping of nuclear chromatin; destruction of cell membranes, intracellular components
◼ Loss of E: failure of Na+/K+-ATPase membrane pumps
◼ Cells swell
Hypoxic cell injury
O2 deprivation
◼ Reduced aerobic metabolism ◼ Reduced ATP production
Reversible or irreversible, depending on:
◼ Degree of deprivation
◼ Metabolic needs of cells (high tissue O2 demands: Heart, brain, kidneys)
Hypoxic cell injury (cont.)
causes
◼ Low [O2] in air: “pure” hypoxia
◼ Respiratory disease
◼ Ischemia (decreased blood flow = circulatory disorders)
◼ Anemia
◼ Edema
1/24/2024
image
- Oxidative Stress
◼ Oxidative stress = cellular damage induced by the accumulation of reactive oxygen species (ROS), a form of free radical
◼ Free radicals: Chemical species with free (unpaired) electron in outer orbit
(smoke, radiation)
◼ Protection: antioxidants
◼ Highly unstable; very reactive
◼ Normal cellular reactions produce free radicals
(cellular respiration, Mfs)
◼ Extrinsic factors can produce free radicals
principle of free radicals involved in cell injury
- Membrane Damage
◼ Most forms of cell injury that end in cell death: characterized by increased membrane permeability → membrane damage
◼ Cell membranes may be damaged by: ROS, phospholipid biosynthesis, degradation, cytoskeletal abnormalities that disrupt the anchors for plasma membranes
◼ Most important sites of membrane damage: Mitochondrial membrane damage
Plasma membrane damage
Injury to lysosomal membranes
image
- Disturbance in calcium homeostasis
Importance of intracellular [Ca2+]
◼ Cellular messenger
◼ Stored in ER and mitochondria
Normally, intracellular [Ca2+] low vs. extracellular levels
◼ Maintained by Ca2+/Mg2+-ATPase exchange system
Toxins and ischemia can increase intracellular [Ca2+]
◼ Cell damage from activated enzymes: phospho- lipases, proteases, ATPases, endonucleases
- Endoplasmic Reticulum Stress
Protein synthesis in ER: chaperones enhance proper folding of newly synthesized proteins
◼ Process is imperfect; some misfolded polypeptides made
◼ Targeted for proteolysis by ubiquitination
Accumulated misfolded proteins in ER induce
protective cellular (adaptive) response = unfolded protein response
◼ Activates signaling pathways that increase the production of chaperones and retard protein translation, reducing levels of misfolded proteins
◼ If quantity of misfolded protein exceeds capacity of adaptive response, additional signals activate proapoptotic sensors →apoptosis (intrinsic, more later)
Unfolded Protein Response and ER Stress
image
- DNA Damage
DNA damage may result from:
◼ Exposure of cells to radiation or chemotherapeutic agents ◼ Intracellular generation of ROS
◼ Acquisition of mutations
If severe damage: may trigger apoptotic death
Damage to DNA sensed by intracellular sentinel proteins, which transmit signals that lead to the
accumulation of p53 protein
◼ p53 first arrests the cell cycle (at the G1 phase) to allow the
DNA to be repaired before it is replicated
◼ If the damage is too great to be repaired successfully, p53
triggers apoptosis, mainly by the mitochondrial pathway
Reversible cell injury
Two patterns visible under microscope: ◼ Cellular swelling
◼ Impaired Na+/K+-ATPase pump, usually from hypoxia
◼ Fatty change: indicative of severe injury
◼ Many small vacuoles of fat in cytoplasm
◼ May be due to high fat load or reduced ability to metabolize fat
◼ Liver, heart, kidneys particularly susceptible
Cell death
Balance exists between death and proliferation
Cell death in two ways:
◼ Apoptosis: controlled cell destruction (“cell suicide”)
◼ Removes cells that are being replaced or have “worn out” ◼ Removes unwanted tissue
◼ Normal process in the body
◼ Necrosis: Unregulated death caused by injuries to
cells; death of organ or tissue that is part of a living
person
◼ Cells swell and rupture ◼ Inflammation results
necrosis
cell size
- enlarged (swelling)
nucleus
- pyknosis to karyorrhexis to karyolysis
plasma membrane
- disrupted
cellular contents
- enzymatic digestion; may leak out of the cell
adjacent inflammation
- frequent
physiologic or pathologic role
- invariably pathologic (culmination of irreversible cell injury)
apoptosis
cell size
- reduced (shrinkage)
nucleus
- fragmentation into nucleosome-sized fragments
plasma membrane
- intact; altered structure, esp. orientation of lipids
cellular contents
- intact; maybe released in apoptotic bodies
adjacent inflammation
- no
physiologic or pathologic role
- often physiological means of eliminating unwanted cells; may be pathologic after some forms of cell injury, esp. DNA & protein damage
Apoptosis
◼ Programmed cell death via controlled cell destruction
◼ Physiologic:
◼ Development, maturation, repair
◼ Pathophysiologic:
◼ Lack of apoptosis in proliferation of CA cells ◼ Hepatocyte death in hepatitis B and C
◼ Control Mechanism: unclear
Apoptosis, the process
◼ Controlled autodigestion via endogenous enzymes
◼ Cell shrinkage:
◼ Disruption of cytoskeleton
◼ Condensation of cytoplasmic organelles
◼ Disruption and clumping of
nuclear DNA
◼ Eventually nucleus breaks into
spheres
◼ Wrinkling of cell membrane
◼ Finally: division of cell into membrane-covered fragment
Necrosis
Necrosis: death of organ or tissue that is part of a living person
Unregulated:
◼ Enzymatic digestion of cell components
◼ Loss of membrane integrity
◼ Uncontrolled release of products into intracellular space
◼ Initiation of inflammatory response
Necrosis, different types
Liquefaction/liquefactive necrosis: e.g., center
of abscess
◼ Characterized by tissue softening
◼ Death of some cells but their catalytic enzymes
still functional
Coagulation necrosis: e.g., hypoxic
injury/infarct
◼ Transformation into gray, firm mass
◼ Acidosis, with resultant denaturation of proteins
Caseous necrosis: e.g., Tb granulomas
◼ Persistence of dead cells as soft, cheeselike debris
Necrosis, different types 2
Fat necrosis: Focal areas of fat destruction (due
to abdominal trauma or acute pancreatitis) ◼ Enzymes leak out of damaged pancreas, digest
peritoneal fat cells and their contents (e.g., stored
triglycerides)
◼ Released fatty acids combine w/ Ca2+: produce
grossly identifiable chalky white lesions
Fibrinoid necrosis: Special form of necrosis,
visible by light microscopy
◼ Seen in immune reactions, in which Ag/Ab
deposited bv walls, and in severe hypertension
Gangrene
Describes large area of necrotic tissue
2 classifications:
◼ Dry gangrene: lack of arterial blood supply but
venous flow can carry fluid out of tissue ◼ Tissue tends to coagulate
◼ Moist (wet) gangrene: lack of venous flow lets fluid accumulate in tissue
◼ Tissue tends to liquefy; infection likely ◼ Special type:
◼ Gas gangrene: Clostridium infection produces toxins and H2S bubbles
Autophagy
Autophagy (“self-eating”): lysosomal digestion
of the cell’s own components
◼ Survival mechanism during nutrient deprivation ◼ Enables starved cell to live by eating its own
contents and recycling these contents to provide nutrients and E
Intracellular organelles and cytosol sequestered
within an ER-derived double membrane
(phagophore); matures into autophagic vacuole ◼ Fuses w/ lysosomes: forms autophagolysosome
◼ Digests cellular components w/in
Autophagy
Cell Changes with Aging— Why?
Is it programmed into cells?
◼ Telomeres become too short; cell can no
longer divide
Is it the result of accumulated damage?
◼ Older cells have more DNA damage
◼ Older cells have more free radicals
◼ Cells lose the ability to repair their telomeres
Aging: what we know
Results from combination of multiple and progressive cellular alterations
◼ Accumulation of DNA damage and mutations
◼ Replicative senescence: reduced capacity of cells to divide secondary to progressive shortening of chromosomal ends (telomeres)
◼ Defective protein homeostasis: loss of normal proteins and accumulation of misfolded proteins
Exacerbated by chronic diseases, especially those associated with prolonged inflammation, and by stress; slowed down by calorie restriction and exercise
Cellular aging: causes & mxms
Telomeres and senescence
Concept Map of Major Terms in Pathophysiology
STRESSOR
- Interferes with normal cell function
CELL INJURY or ADAPTATION or COUNTERATTACK
CELL INJURY
- Decreases cell function
ADAPTATION
- Cell or system reacts to restore normal function
COUNTERATTACK
- Cells and systems react to reduce or remove the stressor
cell injury to HEALING
healing
- Repairs injury
CELL INJURY or ADAPTATION or COUNTERATTACK can all go to signs & symptoms
SIGNS: Can be detected or measured
SYMPTOMS: The patient can feel
COMPLICATIONS: Occur when injury, adaptation, and counterattacks act as new stressors
Inflammation
◼ Reaction of vascularized tissue to local injury
◼ Reaction develops in
steps:
1. recognition of the
offending agent;
2. recruitment of blood cells
and proteins to the site;
3. removal of the offending
agent;
4. regulation of the
reaction;
5. repair of injured tissue
Inflammation: Causes
Many and varied
◼ Response to infectious microorganisms
◼ Trauma
◼ Surgery
◼ Caustic chemicals
◼ Heat and cold extremes
◼ Ischemic damage to tissues
◼ Immune rxns (hypersensitivity, autoimmunity)
Acute vs. Chronic Inflammation
Difference dependent upon:
◼ Persistence of injury
◼ Clinical symptoms
◼ Nature of the inflammatory response
Acute:
◼ Accumulation of fluid and plasma components in
tissue
◼ Intravascular stimulation of platelets ◼ Presence of PMNs
Chronic:
◼ Lymphocytes, plasma cells, macrophages
acute inflammation
onset
- fast: minutes to hours
cellular infiltrate
- mainly neutrophils (PMNs)
tissue injury
- usually mild and self-limited
fibrosis
- none
local & systemic signs
- prominent
chronic inflammation
onset
- slow: days
cellular infiltrate
- monocytes/macrophages; lymphocytes
tissue injury
- may be significant
fibrosis
- maybe severe and progressive
local & systemic signs
- variable; usually modest
Acute Inflammation
Short: minutes to days
Hallmarks:
◼ Rubor (redness)
◼ Dolor (pain)
◼ Calor (heat)
◼ Tumor (swelling)
◼ Functio laesa (loss of function)
Anything ending in –itis: describes an inflammatory state
Acute inflammation (cont.)
Outcomes:
◼ Resolution
◼ Abscess
◼ Scar
◼ Persistent inflammation
Stages:
◼ Vascular (hemodynamic) stage
◼ Cellular stage
Acute inflammation (cont.)
Vascular stage:
◼ Transient vasoconstriction
◼ Rapid vasodilation of arterioles and venules supplying injured area
◼ Increased permeability of vessel endothelial cell barrier
Cellular stage:
◼ PMNs initially
◼ Macrophages later
Increased vascular permeability
Circulating PMNs
Chemotactic factors
to
Margination & adherence
to
Emigration
to
Chemotactic migration
to
Phagocytosis
Leukocyte migration
Inflammatory mediators
Tissue injury
*Trauma
*Ischemia
*Neoplasm
*Infection
*Particle (e.g., asbestos)
Vasoactive mediators
*Histamine
*Serotonin
*Bradykinin
*Anaphylatoxins
*Leukotrienes/prostaglandins *Platelet activating factor
Chemotactic factors
*C5a
*Lipoxygenase products (e.g., LTB4) *Formylated products
*Lymphokines *Monokines
◼ Vasoactive mediators
◼ Histamine
◼ Serotonin
◼ Bradykinin
◼ Anaphylatoxins
◼ Leukotrienes/prostaglandins ◼ Platelet activating factor
to
Increased vascular permeability
to
edema
Chemotactic factors
◼ Histamine
◼ Serotonin
◼ Bradykinin
◼ Anaphylatoxins
◼ Leukotrienes/prostaglandins ◼ Platelet-activating factor
to
Recruitment and stimulation of inflammatory cells
can either go to acute inflammation or chronic inflammation
Acute inflammation
*PMNs
*Macrophages
Chronic inflammation
*Macrophages
*Lymphocytes
*Plasma cells
Vasoactive mediators
plasma
- Complement activation: Anaphylatoxins (C3a, C5a)
◼ Hageman factor activation: Bradykinin
cell
◼ Mast cell/basophil degranulation:
Histamine
◼ Platelets: Serotonin
◼ Inflammatory cells: Leukotrienes, prostaglandins, platelet-activating factor
Chemotactic factors
plasma
◼ Complement activation: C5a, C3a
cell
◼ Cell membrane phospholipids:
Lipoxygenase products (e.g., LTB4)
◼ Inflammatory cells: Chemokines = Lymphokines, monokines
◼ Bacterial and mitochondrial: Formylated products
Vascular Response
Arachidonic acid released from injured cell membranes
to
Cyclooxygenase/ Lipoxygenase pathways
Prostaglandins/ leukotrienes
to
vasodilation and increased capillary permeability
histamine released from injured cells
can go to Vasodilation and increased capillary permeability
Vasodilation and increased capillary permeability can go to calor (heat) or rubor (redness)
Vasodilation and increased capillary permeability to exudate
exudate to tumor or dolor (pain)
exudate to toxin dilution
exudate to Decreased blood flow out of injured area
Cellular Response
Phagocytes enter injured area by:
- margination
- pavementing
- emigration
- chemotaxis
chart (how do you study this ah….)
Origins of inflammatory mediators
Principal Inflammatory Mediators
histamine
- sources: mast cells, basophils, platelets
- actions: vasodilation, increased vascular permeability, endothelial activation
prostaglandins
- sources: mast cells, leukocytes
- actions: vasodilation, pain, fever
leukotrienes
- sources: mast cells, leukocytes
- actions: increased vascular permeability, endothelial activation chemotaxis, leukocyte adhesion, and activation
cytokines (ex: TNF, IL-1, IL-6)
- sources: macrophages, endothelial cells, mast cells
- actions: local: endothelial activation (expression of adhesion molecules); systemic: fever, metabolic abnormalities, hypotension (shock)
chemokines
- sources: leukocytes, activated macrophages
- actions: chemotaxis, leukocyte activation
platelet-activating factor
- sources: leukocytes, mast cells
- actions: vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
complement
- sources: plasma (produced in the liver)
- actions: leukocyte chemotaxis and activation, direct target killing (membrane attack complex), vasodilation (mast cell stimulation)
kinins
- sources: plasma (produced in the liver)
- actions: increased vascular permeability, smooth muscle contraction, vasodilation, pain
Principal Actions of AA Metabolites in Inflammation
vasodilation:
- eicosanoids: prostaglandins PG12 (prostacyclin), PGE1, PGE2, PGD2
Vasoconstriction
- eicosanoids: thromboxane A2, Leukotrienes C4, D4, E4
increased vascular permeability
- eicosanoids: leukotrienes C4, D4, E4
Chemotaxis, leukocyte adhesion
- eicosanoids: leukotriene B4
Outcomes of Acute Inflammation
Acute inflammation
- injury: tissue necrosis, bacterial infection, toxins, trauma
- vascular changes: vasodilation, increased vascular permeability
healing: resolution & scarring (fibrosis)
resolution:
clearance of harmful stimuli, clearance of mediators and acute inflammatory cells, replacement of injured cells, normal function
scarring:
loss of function, connective tissue, fibroblasts
or from acute inflammation, the cell can go to chronic inflammation and then can go to scarring
with chronic inflammation
- chronic infectious
- persistent injury
- autoimmune and allergic disease
Inflammation and Healing
The inflammatory response
◼ Acute inflammation
◼ Chronic inflammation
◼ Manifestations of inflammation
Tissue repair and wound healing
◼ Tissue repair
◼ Wound healing
Chronic inflammation
Long and self-perpetuating: weeks to years
◼ Contains and removes pathologic agent/process
Characteristic cells:
◼ Macrophages
◼ Lymphocytes
◼ Fibroblasts: increased risk of scarring and deformity than acute inflammation
Typical causative agents:
◼ Recurrent or progressive acute inflammation
◼ Low-grade, persistent irritants, with the inability to penetrate deeply or spread rapidly
Chronic inflammation
Two patterns:
◼ Nonspecific chronic inflammation ◼ Granulomatous inflammation
Inflammation and Healing
The inflammatory response
◼ Acute inflammation
◼ Chronic inflammation
◼ Manifestations of inflammation
Tissue repair and wound healing
◼ Tissue repair
◼ Wound healing
Inflammation Manifestations
Local
◼ Swelling
◼ Exudates: serous, hemorrhagic, fibrinous, membranous, purulent (suppurative)
◼ Abscess
◼ Ulceration
Systemic
◼ Acute-phase response
◼ Alterations in WBC count
◼ Fever
Acute-phase response
Leukocytes release interleukins and tumor necrosis factor
◼ Affect thermoregulatory center → fever
◼ Affect central nervous system → lethargy
◼ Skeletal muscle breakdown
Liver makes fibrinogen and C-reactive protein
◼ Facilitate clotting
◼ Bind to pathogens
◼ Moderate inflammatory responses
Tissue Regeneration and Repair
tissue regeneration: repair of injured tissue with cells of same parenchymal type
◼ Parenchymal tissue ◼ Stromal tissue
◼ Labile cells
◼ Stable cells
◼ Permanent (fixed) cells
Connective tissue repair: scar tissue substituted for parenchymal cells of injured tissue
Wound healing
Healing depends upon extent of tissue loss and occurs via:
◼ Primary intention
◼ Secondary intention
Phases of healing:
◼ Inflammatory phase: just seen
◼ Proliferation phase: Angiogenesis and growth of granulation tissue; emigration of fibroblasts and deposition of extracellular matrix
◼ Remodeling phase: Maturation and reorganization of the fibrous tissue
Factors Affecting Wound Healing
◼ Malnutrition
◼ Blood flow and O2 delivery
◼ Impaired inflammation and immune responses
◼ Infection, wound separation, foreign bodies
◼ Age
Cell differentiation and growth
Cell cycle
◼ G1: RNA and protein synthesis and cell
growth; variable time*
◼ S: DNA synthesis w/ 2 sets of chromosomes; 10 – 20 hours
◼ G2: premitotic; 2 – 10 hours
◼ M: mitosis; 0.5 – 1 hour
◼ G0: resting phase; variable time*
- Duration is dependent upon tissue type
Cell cycle
Labile cells: cells that continuously multiply and divide throughout life. Labile cells replace the cells that are lost from the body.
Cyclins
- ensure the cell has made proteins needed for chromo-some separation
- check for correct DNA duplication
- measure whether the cell is large enough to divide
RB
Role in regu- lating G1–S check- point of cell cycle
Cell differentiation and growth
Cell proliferation: process by which cells divide and reproduce
3 general types of cells with regard to differentiation
◼ Highly differentiated
◼ Progenitor cells
◼ Stem cells
Cell differentiation and growth
Cell differentiation: Orderly, stepwise process
Progenitor cells: partially differentiated, replace mature cells of same cell lineage
Stem cells:
◼ Unipotent - red blood cell
◼ Oligopotent - myeloid cell
◼ Pluripotent - stem cell, can becom anything
Terminology
Tumor: any condition leading to swelling but often used to mean neoplasm
Neoplasm: abnormal mass of tissue in which growth exceeds, and is uncoordinated with, that of normal tissues
◼ Benign: well-differentiated cells, clustered together in a single mass; usually do not cause death
◼ Malignant: less well differentiated, can break loose (metastasize); death if untreated or uncontrolled
◼ -oma: suffix added to parenchymal tissue type to denote tumor name
Terminology
Benign
- Cell characteristics: Well- differentiated; resemble cells in tissue of origin
- Rate of growth: Progressive and slow; may stop or regress
- Mode of growth: Expansion w/o invasion; usually encapsulated
- Metastasis: No
Malignant
- Cell characteristics: undifferentiated; Undifferentiated, w/ anaplasia and atypical structure; little or no resemblance to tissue of origin
- Rate of growth: Variable, depends on the level of differentiation
- Mode of growth: invasive; sends out processes to infiltrate surrounding tissues
- Metastasis: yes
Benign vs. Malignant
◼ When differentiated, “working” cells mutate, they form differentiated “working” tumors— benign tumors
◼ When undifferentiated, rapidly dividing cells mutate, they form rapidly dividing tumors—malignant tumors
Cancer cell characteristics
Fail to undergo normal cell proliferation and differentiation
◼ Believed that cancer cells develop from mutations occurring during differentiation
◼ Mutations early in process: tumor poorly differentiated and highly malignant
◼ Mutations later in process: tumor more fully differentiated and less malignant
◼ Grading of tumor based upon degree of differentiation and number of proliferating cells
Gleason grading: prostate
look at histology to see what they look like anxd to seeif they look like normal cells
◼ Loss of contact inhibition
◼ Loss of cohesiveness and adhesion
◼ Impaired cell-cell communication
◼ Expression of altered tissue antigens
◼ Production of degradative enzymes - Allowing invasion and metastasis
cancer: hallmarks and enabling factors
deregulatinng cellular energetics
sustaining proliferative signaling
inducing angiogenesis
resisting cell death
genomic instability (mutator phenotype)
activing invasion and metastaus
tumro promoting inflammation
enabling immortality
evading growth suppressors
avdoing immune destruction
Tissue invasion and metastasis
Seeding
◼ Entering body cavity
Metastasis
◼ Leave 1o tumor
◼ Invade ECM
◼ Enter blood/lymph
◼ Survive blood/lymph
◼ Location for growth
◼ Invade tissue & grow
Tumor Growth
Depends upon:
◼ Number of cells dividing
◼ Duration of cell cycle
◼ Number of cells being lost compared to number being produced
Tumor growth due to increased number of dividing cells
◼ Cells don’t die on schedule
◼ Lack growth factors for entering Go phase
Growth limited by blood supply and nutrients
Oncogenesis
genetic mxm whereby normal cells are transformed into cancer cells
Proto-oncogenes
◼ Growth stimulating regulatory genes
◼ Usually encode growth factors or second messengers that stimulate growth
Tumor suppressor genes (anti-oncogenes)
◼ Growth inhibiting regulatory genes
Genes controlling apoptosis
DNA repair genes
chart
TSG mutation
image
Cancer cell transformation by chemicals
◼ Multi-step process whereby normal cells become cancer cells
◼ Initiation
◼ Promotion
◼ Progression
Cancer risk factors
◼ Interactions among multiple risk factors or repeated exposure to carcinogens necessary for cancer to develop
◼ Hereditary
◼ Hormones
◼ Obesity
◼ Chemical carcinogens
◼ Radiation
◼ Viruses
◼ Immune dysfunction
Clinical Manifestations of Cancer
◼ Changes in organ function (e.g., organ damage, inflammation, and failure)
◼ Local effects of tumors (e.g., compression of nerves or veins, gastrointestinal obstruction)
◼ Tissue integrity: nonspecific signs of tissue breakdown (e.g., protein wasting, bone breakdown)
◼ Paraneoplastic syndromes: Ectopic hormones secreted by tumor cells
Clinical Manifestations of Cancer (cont.)
Cancer cachexia
◼ Weight loss
◼ Muscle wasting
◼ Weakness
◼ Anorexia
◼ Anemia
Cancer treatment
◼ Surgery
◼ Radiation
◼ Chemotherapy
◼ Hormonal
◼ Biotherapy (immunotherapy, biologic
response modifiers)
◼ Targeted
◼ Transplantation
◼ Hyperthermia
◼ Photodynamic
Genetic analysis: identify mutations for drug targets
Using molecular information to guide CA therapy
