etiology
what caused the disease
the agent (virus, bacteria, prion)
pathogenesis
the beginning of the problem; the sequence of events from there
morphology
cellular changes that occur with the disease
a cell in the lungs that is exposed to smoke will change to a squamous cell to survive
clinical manifestations
#NAME?
diagnosis
putting the pieces of info together to come up with the problem
clinical course
how did the disease or problem evolve over time (acute vs. chronic); sudden onset vs. progressive onset
preclinical (no symptoms) vs clinical
pathophysiology
cellular and organ changes associated with the disease and the effect on the whole body
5 cellular responses to stress
1. atrophy
2.hypertrophy
3.hyperplasia
4.metaplasia
5. dysplasia
atrophy
cells actually get smaller in size. When the cell has less work to do it will shrink so that it is expending less energy .It is a way that the cell can still survive under stressful circumstances (like malnutrition) it gets more efficient as it does only
Hypertrophy
the cells get bigger as a result of increased work. It happens in the cells that cannot reproduce to take care of the increased work load. It is seen in cardiac and skeletal muscle tissue. When they get bigger they also increase their function. Think abou
Hyperplasia
the cells increase in number. This then only happens in cells that can reproduce like epithelial cells. We grow more cells as a result of a physiological response such as wound healing, or because of hormone stimulation (pregnancy). When the need ceases t
Metaplasia
is when a cell type is replaced by another cell type. It happens usually when there is an irritant around like with smoking. The cells will change into cells that can survive the irritation better..therefore you get squamous cells in the trachea in smoker
Dysplasia
the cells change shape size and appearance. The changes in the cells happen over time but since it is an adaptive response if the underlying cause is removed then the cells can revert back. If the cause is not removed then it is considered a precursor to
With cell injury there are two kinds of reversible changes cellular swelling and fatty changes. Which one is a more "ominous" sign of injury? What happens that makes the cells swell
fatty changes are more "ominous". After cell injury there is a disruption of cell membrane permeability. Sodium is allowed into the cell and where sodium goes water follows. While the cell swells its function is impaired but when the injurious agent is re
The extent of cell injury and death are dependent on the nature of the injury and the length of time that the cell was exposed to it. What are the 5 causes of cell injury?
1. Hypoxia: the cell will change from aerobic metabolism to anaerobic metabolism as it attempts to keep functioning. Lactic acid is produced and creates a reduction in the cellular pH which deleteriously effects the cell structure. It causes ischemia whic
There are three ways that most of the causes of cell injury seem to do their deeds what are they?
1. Decreased ATP associated with hypoxia/ cells swell and there is decreased functioning.
2. Free radicals damage cell membranes, damage DNA (maybe why they cause aging) damage enzyme systems and cell proteins. They are charged and as a result can start c
Can you differentiate between apoptosis and necrosis?
apoptosis is the normal/controlled destruction of cells. Necrosis is unregulated and as a result the enzymes that are used to digest the cell are released and injure the surrounding tissue
Cellular Adaptation
Allows the stressed tissue to survive or maintain function
Adaptation may include changes in size, number, type, or organization
Changes may occur singly or in combination
Can be reversible once the need for adaptation has ceased
2 types of Genes (sub cellular) Affect Adaptation:
House keeping" genes: affect normal functions of a cell
"Differentiation" genes: determine differential characteristics of a particular cell type. (squamous v columnar, heart v vessel, etc)
Often in adaptive cellular responses the house keeping genes rem
Disuse atrophy
usually associated with muscle cells, is related to lack of workload needed to maintain muscle size. This is done to conserve energy as less oxygen is used to maintain a smaller cell.
Normal Adaptive Responses are also called
physiologic responses
hormonal atrophy
from lack of a hormonal stimulus like menopause leads to atrophic changes in the reproductive organs and vaginal tissues
Denervation atrophy
from denervation, so the muscle doesn't get the neuro signal to contract and be used.
Persistent cell injury atrophy
from prolonged infection/inflammation can lead to cellular atrophy which allows the cell to survive because it needs less energy.
Compensatory hypertrophy
enlargement of remaining organ or tissue after a portion has been surgically removed or inactivated. Like a kidney (the other kidney will step up whe none is removed) or lobectomy of a liver
A swollen cell is not a hypertrophic cell
it just has more fluid in it not more functioning mass!
Normal physiologic hypertrophy
muscle cells with weight training
Abnormal pathologic hypertrophy
cardiomyopathy associated with disease processes like heart failure or pulmonary HTN
Hyperplasia can only occur in
cells capable of mitotic division
epidermis�calluses from a physical stimulus
*glandular tissue�breast from a hormonal stimulus
*intestinal tissue�liver regeneration after partial hepatectomy as a compensatory mechanism
CAN NOT occur in nerve, skeletal, o
Reversible cell injury
**Injured cells swell due to impaired cell membrane permeability�if the cell membrane is damaged it can't control the flow of substances through it�especially water which is passive
Injured cells can't regulate their volume!
Reversible:
cell swelling: cel
Irreversible cell injury
leads to cell death
Intracellular Accumulations
buildup of substances that stressed cells cannot immediately use or dispose of!
Intracellular Accumulations: stressed cells may fill up with
Unused foods
Lipids (fatty liver)
Glycogen (enzyme deficiency)
Abnormally folded proteins: Alzheimer & Parkinson disease
Pigments: bilirubin, coal dust
Calcium salts: valvular stenosis
Intracellular accumulations: mechanisms
over-production, impaired removal, exogenous exposure
normal body substances present in abnormally large amounts: fatty liver ds
Abnormal products from inside the body/inborn errors of metabolism: gout/uric acid
Products from outside the body: lead poison
Hypoxia
power failure
the cell is unable to get or unable to use oxygen. Without oxygen it cannot perform the basic functions. If prolonged leads to necrotic cell death
Physical: Most lead to hypoxia (low oxygen)�anaerobic leads to less energy production
-Trauma
Biologic Agents
Biologic agents cause cell injury in a variety of ways depending of the bacteria or virus.
Chemical: heavy metals and electrolyte abnormalities.
Ionizing Radiation: free radical production�this injury is often not reversible and leads to cell death!
Radia
Contact Inhibition and Tumors
cells start crowding so they stop dividing; tumors don't have contact inhibition so they just keep dividing
Mechanisms of injury
-Direct damage to proteins, membranes, DNA
-ATP depletion (characteristic of hypoxic & chemical/toxic injury)
-Free radical formation (impairment of antioxidant protective mechanisms)
-Increased intracellular calcium (Ca2+ /Mg2+ ATPase pump failure)
ATP depletion
caused by hypoxia
aerobic metabolism needs oxygen
-Aerobic metabolism stops less ATP is produced
--Na+/K+ ATPase cannot run fast enough
---Cell swells up with water
-Anaerobic metabolism used lactic acid produced
--Acid damages cell membranes, intracell
Free Radical Injury
#NAME?
Effects of Free Radical damage
Effects of reactive free radicals is wide-spread
Three types of effects are particularly important in cell injury
1. Lipid peroxidation
-loss of cell membrane integrity
-destroys the phospholipids in the cell membrane
2. Oxidative modification of proteins
Antioxidants
#NAME?
Impaired Calcium Homeostasis
Impaired calcium homeostasis is another complication of hypoxia/ischemia of the cell.
Enzymes meant to work on other things work on the cell instead and self destructs!
-Cell usually maintains low intracellular calcium
-When calcium is released into the c
Programmed cell death
apoptosis or "cell suicide"
-Removes cells that are being replaced or have "worn out"
-Removes unwanted tissue
-Normal process in the body
Apotosis is a protective mechanism. The cell identifies that is has a problem and the only way to keep the problem f
Necrotic cell death
Unregulated death caused by injuries to cells
Cells swell and rupture
Inflammation results
rupture of cell membrane leads to
-death of surrounding cells
-free radical formation
Process of apoptosis
Damaged or worn-out cells commit "suicide"
Turn on their own enzymes inside the cell, especially caspases (family of proteases)
Digest their own cell proteins and DNA fragmentation
Cell fragments digested by by WBCs
Can Be Caused By:
Signaling factor att
Dry gangrene
lack of arterial blood supply but venous flow can carry fluid out of tissue
-tissue tends to coagulate
circulatory issue which makes them higher risk for a secondary infection but they are NOT CAUSED by an infection
wet gangrene
lack of venous flow lets fluid accumulate in tissue
-tissue tend to liquefy and infection is likely
circulatory issue which makes them higher risk for a secondary infection but they are NOT CAUSED by an infection
gas gangrene
Clostridium infection produces toxins and H2S bubbles
gangrene definition
a large area of necrotic tissue
All gangrenes lead to NECROTIC cell death
Which of the following is the most common cause of cellular injury?
Free radical-induced injury
Chemical injury
Hypoxia
Dysplasia
HYPOXIA
Hypoxia is caused by decreased oxygen in the environment, decreased hemoglobin, decreased red blood cells, or cardiovascular collapse and is the most common cause of cellular injury. Chemical injury and free radicalinduced injury are two other typ
Which of the following terms best describes death of a cell from hypoxia, generally as a result of ischemia in the lower extremities?
Coagulative necrosis
Liquefactive necrosis
Fat necrosis
Gangrenous necrosis
Gangrenous necrosis
Gangrenous necrosis typically occurs in lower extremities when blood vessels are blocked and ischemia occurs. Hypoxia then ensues and bacteria invade. Coagulative necrosis occurs primarily in the kidneys, heart, and adrenal glands and
Inflammation is
An automatic response to cell injury
Purpose of inflammation
#NAME?
Overview of Inflammation
#NAME?
Vascular stage =
hemodynamic stage
Damaged cells release inflammatory mediators: local response
Vascular stage and cellular stage
Damaged cells release inflammatory mediators: systemic responses
white blood cell response and acute-phase response
Cardinal manifestations of inflammation
#NAME?
Acute local inflammation: Vascular Stage
This the local response at the area that is injured
Remember your Cardinal Manifestations!
Bradykinin=Swelling & Pain
Histamine & Seratonin=vasoactive leads to dilation of arterioles and increases permeability of venules
-Prostaglandins and leukotrienes a
What mechanism causes the redness (erythema) associated with the inflammatory process?
I could also ask what causes the heat, swelling, & pain associated with inflammation!
Prostaglandins
Leukotrienes
Arachidonic acid
All of the above
a and b
a and b
Prostaglandins and leukotrienes cause vasodilation, which brings more blood to the injured/affected area. The symptoms caused by this vasodilation are redness/erythema and warmth.
Kinds of Exudate:
serous
plasma, watery, clear, low protein content (blister); indicates early inflammation
Kinds of Exudate:
Hemorrhagic
vessel damage or leakage of reds cells from capillaries; indicates bleeding
Kinds of Exudate:
Fibrinous
large amounts of fibrin, thick & sticky; indicates more advanced inflammation
Kinds of Exudate:
Membranous
develop on mucous membranes; necrotic cells in fibropurulent exudate
Kinds of Exudate:
Purulent
pus, which is composed of WBCs, proteins, & tissue debris; may lead to formation of an abscess; indicates a bacterial infection
Exudate
When capillaries become more permeable it allows fluid to escape into the tissue and create exudate�this is a local response
Cellular Stage
-White blood cells enter the injured tissue:
--Destroying infective organisms
--Removing damaged cells
--Releasing more inflammatory mediators to control further inflammation and healing
-How do they enter the injured area?
--Leukocytes express adhesive p
Granulocytes
Neutrophils
Eosinophils
Basophils
Mast cells
Monocytes
Macrophage
Neutrophils
primary phagocyte; most numerous, arrives early/first; short life-span = need for rapid replacement = leukocytosis; mature cells emigrate to tissues for phagocytosis
-can form psuedopods making them highly mobile
-Only live 24-48 hours, then die by apopto
Eosinophils
contain granules toxic to parasites
Basophils
granules include histamine & vasoactive agents; involved in hypersensitivity reactions (IgE receptors)
important for allergic reactions mediated by IgE
-precursors to Mast cells
Mast cells
release chemical mediators & chemotactic factors
don't fully develop til leave vascular space and lodge in tissues esp lung, GI tract, & skin---so where do we see allergic responses???
Monocytes
-Monocytes become Macrophages (mononuclear phagocytes)
-Largest WBC; long life-span; important role in chronic inflammation
-Trigger immune responses
Lymphocytes & Plasma Cells
Smallest, help fuel and sustain chronic inflammation
Plasma cells develop from activated B lymphocytes and produce antibodies
Cellular Stage: Leukocytes Enter the Injured Area
#NAME?
Chemotaxis
Movement of cells along a chemical gradient
primarily attracts neutrophils and eosinophils
chemotactic factors
released by mast cells
complement
Steps of Leukocyte Activation & Phagocytosis
1. Recognition & Adherence: receptor is activated
2. Phagosome formation: Engulfment : phagosome formation, essentially the particle is brought into the macrophage
3. Phagolysosome fusion: lysosomal enzymes and free radicals
4. Intracellular killing
Plasma derived mediators
Bradykinin: leads to increased capillary permeability and pain,
Cell derived mediators
-Histamine & Serotonin: leads to dilation of arteries & permeability of venules
-Platelet-activating factor: leads to platelet activation as well as stimulates neutrophils, monocytes, endothelial cells, & vascular smooth muscle
-Cytokines
--TNF-alpha & IL
Cell derived mediators cont
: from mast cells found out in tissue especially mucous membranes, bronchioles, & skin! (think allergic reactions and where we see them)
Histamine & serotonin are vasoactive amines and affect blood vessel tone, stored in mast cells, one of 1st mediators r
Systemic manifestations of inflammation
-White blood cell response (leukocytosis)
--Bacterial: neutrophilia
--Parasitic & allergic: eosinophilia
--Viral: neutropenia & lymphocytosis
--Overwhelming or poor immune system: leukopenia
-Acute-Phase Response
--Acute-phase proteins (fibrinogen, CRP, &
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 pathoge
Pyrexia
-Purpose:
--Adaptive response to infection or tissue injury
--Growth rate of microorganisms is inhibited
--Immune function is enhanced
-Mechanism: cytokine-induced upward displacement of the set point of the hypothalamic thermoregulatory center
-Causes: p
Fever in Pediatrics
The severity of the fever does not indicate the severity of the illness in a child!
Febrile seizures are usually result of sudden change in internal temp
Fever in Geriatrics
Due to a disturbance in the functioning of the thermoregulatory center elderly can have:
-Slight elevations with severe illness.
-No fever or a low body temp with an infection.
Tell whether the following statement is true or false:
Body temperature is controlled through negative feedback loops.
True
When the body senses a change out of the norm (as illustrated in the previous slides), it activates mechanisms that oppose that change (vasodilation and sweating with increased temperatures; vasoconstriction and shivering with decreased temperatures)
If a fever is a response that helps vasodilate and bring WBC to the site of infection then why is it critical to control fever in a person with heart disease?
Because a fever also increases metabolic rate and increased oxygen need which leads to increased heart rate. A weak heart may not be able to accommodate this increased need.
A 1 degree celcius rise in temp leads to a 15 bpm increase in heart rate!
Chronic Inflammation
-Inflammation lasting 2 weeks or longer
-Will see lymphocytosis & activated macrophages!
-Causes:
--Unsuccessful acute inflammatory response
--Low grade persistent infections or irritants
--Obesity
-Can lead to:
--Cancer formation
--Granulomatous formatio
Nonspecific chronic inflammation
#NAME?
Granulomatous inflammation
#NAME?
Phases of Wound healing
1. inflammatory
2. proliferative
3. remodeling
Tissue generation and repair: inflammatory phase
(Hemostasis�your body is trying to prevent further injury...let us keep the damage right here. What are the vascular and cellular phases?)Another application from the earlier lecture...Steroids interrupt the inflammatory process correct? But since inflamm
Tissue generation and repair: proliferative phase
builds new tissue to fill the space. Starts after 2-3 days-- can take a few weeks. You are bringing in the Extracellular matrix�support tissue, collagen/ fibrin. Building new blood vessels (angiogenesis�anytime you see genesis it means the beginning of) I
Tissue generation and repair: remodeling phase
now you break down the cells that are not necessary in the functioning of the area�take away the Stromal cells and leave the parenchymal tissue. As for the builder�the scaffolding can be returned to home depot, and the muding is sanded down to make the wa
What messes with wound healing?
I mentioned steroid use, but what else can you imagine? What about malnutrition?
What is the difference between primary and secondary intention of wound healing?
Primary has no tissue loss�not much to replace
Look at the normal cell cycle and how the body protects us from the formation of abnormal cells?
The earlier in the cell replication that an alteration occurs the less differentiated the cell will be (think about classifications of dysplasias)
Tumor suppressor genes get rid of the errors and thus stops the errors from proliferating, if there is a mut
If the body is always checking for abnormalities how is it that mutations happen? What is oncogenesis
There has to be multiple changes in a cell to create a cancer cell (we do such a good job keeping the mutations out).
Oncogenesis is protogenesis gone bad!
Oncogenes are the bad guys they promote autonomous cell growth in cancer cells; The malignant cell
Differentiate between benign and malignant growths
Benign tumors grow by expansion, they proliferate slower than their malignant counterparts, are encapsulated, and are differentiated some, can perform some normal functions.
Malignant: spread by invasion and infiltration through lymph and blood supply, ra
How does a malignancy spread and support itself?
Cells escape and travel through the lymph and blood system they can adhere to a new area and then establish their own blood supply (angiogenesis)
Remember Oma means benign, sarcoma/carcinoma is malignant
Know about the staging and grading of tumors
Grading: tumor cell differentiation grade I the most differentiated, grade IV the least differentiated
Staging looks at the disease progression T=tumor size, N=lymph involvement, M=Mets
Parenchymal tissue
functioning cells of organ
Stromal tissue
supporting connective tissue, blood vessels, nerve fibers, extracellular matrix.
Cell proliferation
: increasing cell numbers by mitotic division
Cell differentiation
: cells become specialized in structure and function
Normally, the number of cells produced =
the number of cells that die
The total number of cells in the body remains constant
Gene Mutations are
errors in duplication, rearrangement, or deletion of genetic material.
Most gene mutations can be repaired.
Teratogenic means
abnormality in development of fetus�most susceptiple during first 8 weeks because rapid division of cells
Check points and cyclins
the inspectors that make sure the division is going as planned�if a mutation or problem occurs it corrects it or aborts the process!
3 Proliferative capacities of tissues
1. continuously doubling or labile
2. stable
3. permanent tissues
Continuously doubling or labile
: cells continue to divide and replicate throughout life.
-Surface Epithelial: Skin, oral cavity, vagina, cervix,
-Columnar epithelium: GI tract, uterus,
-Transitional epithelium: urinary tract, bone marrow
stable tissue
only go into cell cycle if it must (injury)
-kidney, liver, smooth muscle of vessels, fibroblasts
-key for wound healing
Permanent tissues
not capable of mitotic cell division: brain and cardiac & skeletal muscle
If destroyed are replaced with fibrous scar tissue
--new research may prove this not quite accurate with peripheral nerve..
Stem cells
Incompletely differentiated throughout life
3 Properities of stem cells
Self-renewal (can undergo numerous mitotic division while maintaining an undifferentiated state)
Asymmetric replication (after each cell division one is differentiated and one remains undifferentiated)
Differential potential (potency) (pluripotent can dif
What causes stable cells to enter the cell cycle and divide?
growth factors
Growth factors
Small hormonelike proteins that increase cell size and cell division
cells divide only when they are told to do so by
growth factors
Process of growth factor
a hormone growth factor attaches to specific receptore on cell which turns on proteins and eventually causes the cell to divide
SPECIFIC
Extracellular Matrix
ECM is secreted locally and assembles a network of spaces surrounding tissue cells
basement membranes and interstitial matrix
(the basement membrane of the kidney is critical to it's functioning)
Provides turgor to soft tissue and rigidity to bone
When ba
Components of ECM
Fibrous structural proteins
Water-hydrated gels
Adhesive glycoproteins
Healing by Connective Tissue Repair: Phases of Repair
Angiogenesis and ingrowth of granulation tissue; they are leaky vessels when newly formed so edema occurs
Emigration of fibroblasts and deposition of extracellur matrix. Fibroblasts and collagen synthesis (provides strenghth)
Maturation and reorganization
Cutaneous Wound Healing: primary intention
sutured surgical incision; no tissue loss
If deep large surgical cut then have to suture the different layers�muscle, fascia, & skin�fat does not suture well so large risk for dehiscence on obese abdominal surgeries!
Adhesions form when scarring sticks la
Cutaneous wound healing: secondary intention
larger wounds which have a greater loss of tissue and contamination
road rash
Cutaneous Wound Healing: Inflammatory Phase
-Begins at time of injury & prepares the environment for healing.
-Hemostasis
-Vascular & cellular phases of inflammation
--Vascular: vessel constriction & clotting
--Cellular: phagocytic white cells remove debris
(doesn't this sound like Acute local infl
Cutaneous Wound Healing: proliferative Phase
-Usually begins within 2-3 days after injury & may last as long as 3 wks
-Building of new tissue to fill the wound space
-Fibroblast�granulation tissue
--Fibroblast are the key cells and they are needed to form granulation tissue�this tissue becomes the f
Cutaneous Wound Healing: remodeling phase
Begins ~ 3wks after injury & may last up to 6 months
Remodeling of tissue by simultaneous synthesis of collagen & lysis by collagenous enzymes
--never reach full tensil strength�with sutures 70% when removed only 10% and then after several weeks only 70-8
Factors That Affect Wound Healing
-Malnutrition
--slows healing process
--need adequate stores of fat, carbohydrate, protein, vitamins & minerals
--Vitamins A, C, B, & K play essential role
-Blood flow & oxygen delivery
--Impaired blood flow delays inflammatory response
--Molecular oxygen
Wound Healing in the Elderly
-Age-related changes:
--A decrease in dermal thickness
--A decline in collagen content
--Loss of elasticity
-Elderly are more vulnerable to chronic wounds, such as pressure, diabetic, and ischemic ulcers as compared to younger persons
Why do we need to know about Cancer?
Cancers develop in approximately 35% of US citizens Cancer (over half a million deaths in the US each year)
Any cancer, untreated, will eventually kill the patient.
Approximately 25% of US citizens die of cancer
Slightly more men than women die, since bre
Neoplasia definition and characteristics
Neoplasms proliferate to form new tissue
They do not wait for signals (growth factors) from the body that the new tissue is needed
They ignore signals to stop dividing
They often do not mature normally (differentiate) to do the "job" the tissue is suppose
Naming neoplasms
Names are derived from the type of parenchymal (functional) tissue type from which the growth originated
Benign tumors: "oma"
Malignant tumors (cancers):
Epithelial tissue: tissue name + "carcinoma"
Mesenchymal tissue: tissue name + "sarcoma"
Examples:
Ep
Benign Neoplasms
Contain cells that look like normal tissue cells (fairly differentiated)
May perform the normal function of the tissue (like secreting hormones)
This may lead to over or under secretion
Usually have a capsule around them
Usually do not invade neighboring
Malignant Neoplasms
Contain cells that do not look like normal adult cells
These cells divide rapidly, so:
Tumors grow quickly
Cells mutate faster and can change type
The tumor does not have clear boundaries and sends "legs" out into surrounding tissue (the word cancer means
Normal cell growth controlled by:
#NAME?
neolasia means
new growth
Tumor cells: characteristics
Develop from mutations (DNA alt) that occur during differentiation�usually more than 1 mutation!
Proliferate rapidly to form new tissue
Autonomous: do not wait for signals from the body that the new tissue is needed & ignore signals to stop dividing
Anapl
Tumor cell characteristics cont
They do not die off (apoptosis) to keep the # of total cells constant, they are immortal.
The cells vary in size and shape (pleomorphism)
Genetically unstable: aneupoloidy
Growth Properties
loss of contact inhibition, cohesiveness, and adhesion
Altered ce
Tumor growth depends on
1. number of cells actively dividing
2. duration of the cell cycle
3. number of cells being lost
Growth fraction
ratio of dividing cells to resting cells in a tissue mass
doubling time
length of time it takes for the total mass of cells in a tumor to double
As the growth fractions increases the doubling time
decreases
A tumor is usually undetectable until it has doubled 30 times and contains more than 1 billion (109) cells
After 35 doublings the tumor contains over 1 trillion cells (1012) which is sufficient to kill the host
Critical to the treatment process�
Invasion
Cancer: "crablike"
Enzymes
Seeding
Synthesizes and secretes enzymes that break down proteins allowing it to infiltrate
Seeding: tumor erodes and sheds cells (may occur during surgery and allow a few cells to remain behind and grow in new area where they s
Metastasis definition
Spread of cancer from a primary site of origin to a distant site
Cancer cells that get into the blood or lymph systems eventually exit this and start to grow in the new site�the cancer cells secrete enzymes that allow them to invade and move!
2 ways cancer cells metastasize
Lymphatic Spread
Sentinel node: initial node
Hematogenous Spread
Lymphatic Spread: Occurs in nodes that drain the lymph from the original site of cancer cells; always occurs in the first node before progressing. Some cancers almost always metastasize this
Hematogenous spread
Typical of sarcomas
Enzymes breakdown the ECM and allow it into the blood stream
Adhesion to vascular wall needed for exit
Self growth factors at new site
Angiogenesis: promotes new circulation to cancer cells
Chemokines: chemo attractant cytokines (infla
How do tumors start? regarding stimulus/stressor
Cancer cells may initiate because of a stimulus/stressor but unlike normal compensatory changes of cells once the stimulus goes away the cancer cells continue to multiply and grow.
Because they are rapidly dividing they need a big blood supply to bring th
Teratogenic
Teratogenic means abnormality in development of fetus�most susceptiple during first 8 weeks because rapid division of cells.
Neoplastic growth and growth factors
Neoplastic growths don't listen to growth factors and often secrete their own so they stay in the cell cylce and continue to divide.
Cyclins
#NAME?
Cell cycle is dependent on:
� Proto-oncogenes: growth promoting regulatory genes
� Anti-oncogenes: growth inhibiting tumor suppressor genes
� Apotosis: genes that trigger cell suicide
� DNA repair genes
Proto-oncogenes
The normal genes that code for normal proteins used in cell division
Growth factors
Growth factor receptors
G proteins
Enzymes that produce second messengers
Genes that turn the production of these proteins on and off
Oncogenes :
Mutated Proto-oncogenes
They still code for the proteins needed for cell division
But they might produce
Too much of the protein
An abnormal protein
Protein that turns on all by itself
Protein that is made when it is not needed
Protein that cannot turn ce
Genetic Events leading to Oncogenes Formation
Point mutation
Chromosonal translation
Gene amplification
True or False:
Oncogenes code for normal proteins used in cell division.
False
The statement describes proto-oncogenes. Oncogenes are mutated proto-oncogenes that code for abnormal proteins
Tumor-Suppressor Proteins: (Cyclins)
checkpoints usually stop the division of mutated cells
keep most mutations from developing into cancer
proteins that control the checkpoints are called tumor-suppressor proteins
Cyclins
Cyclin-dependent kinases
Cyclin inhibitors (p53: codes for a protein
Genetic events leading to loss of Tumor-Suppressor Gene Function
P53 gene: "guardian of the genome"
Halts the cell cycle of genetically damaged cells
Senses damage and helps repair
If mutated can lead to several types of cancer
RB (retinoblastoma) gene
If inherited carrier only needs one mutation to come out
If not inh
Micro RNA genes
regulate gene expression
They might block protein translation
Can be a oncogene it target is tumor suppressor gene
Can be a tumor suppressor gene if target is oncogene
Carcinogenesis: process, cause, risk factors
Multi-step process
Molecular aspects of cell transformation (oncogenesis)
Growth & spread of the tumor mass
Cause
No single factor, often multiple gene mutations
Interactions between multiple risk factors or repeated exposure to a single carcinogenic agen
Oncogenesis Tumor Cell Transformation: 3 stage process
1. Initiation
Exposure of cells to carcinogenic agent that causes irreversible damage to DNA most commonly by highly reactive free radical species
2. Promotion
Activation of oncogenes by a promoter agent resulting in unregulated accelerated growth of init
Carcinogenesis: cause
no single cause-usually a multi gene mutation
Carcinogenesis: the transformation from normal to cancerous
Carcinogenesis: common factors
Hereditary
Hormones
Obesity
Immunologic Mechanisms
Chemical carcinogens
Radiation
Viral & Microbial Agents
Chemical Carcinogens
Direct reacting agents or indirect reacting agents!
Both form highly reactive free radical species
Examples:
tobacco products & cigarette smoke (produce polycyclic hydrocarbons)
Alcohol (modifies the metabolism of carcinogens in the liver & esophagus; enh
Radiation Oncogenesis
Ionizing Radiation
Effects of ionizing radiation well documented in atomic bomb survivors
High incidence of leukemia & malignant epitheliomas of the skin
Attacks rapidly dividing cells: blood, GI, skin, fetal
Ultra-violet Radiation
Low-energy rays that do
Oncogenic Viral & Microbial Agents
A virus that can induce cancer
Enter a host cell & become incorporated into its chromosomal DNA
Five viruses implicated in human carcinogenesis
1. Human papilloma virus (HPV): squamous cell carcinoma of the cervix
2. Epstein-Barr Virus (EBV): Burkitt's ly
Clinical Manifestations of cancer
Changes in organ function
organ damage, inflammation, and failure
Local effects of tumors: compress & erode blood vessels
bleeding, compression of nerves or veins, gastrointestinal obstruction
SVC syndrome, portal hypertension
Ectopic hormones secreted by
Changes in Organ Function (with cancer)
Organ failure
Benign tumors may cause overproduction of normal organ secretions
Malignant tumors may occasionally cause overproduction (as in thyroid cancer), but more commonly decrease production of normal organ secretions
Local Effects of Tumor Growth
Bleeding
Compression of blood vessels
Superior vena cava syndrome
Portal hypertension
Compression of lymph vessels
Edema, ascites, effusion
Compression of hollow organs
Compression of nerves
Pain, paralysis
Bleeding�that is why we do a guiac screening tes
Generalized Effects of Cancer
Cancer cachexia syndrome
Weight loss
Muscle wasting
Weakness
Anorexia
Anemia
Usually seen with solid tumors -protein wasting
Paraneoplastic Syndromes
Cancer cells produce
hormones or hormone-like proteins
proteins that affect clotting
Paraneoplastic neurologic disorders
Thyroid tumors can produce hormones
Cancer Cells can produce hormones including: ADH, ACTH, PTH-related protein
Why do malignant tumors usually cause a reduction in the amount of hormones the affected organ produces?
Organ damage
Inflammation of the organ
Organ failure
All of the above
a and c
All of the above
Effects of malignant tumors on the organ system include inflammation and damage, which ultimately lead to organ failure. In all cases the organ cannot function optimally, and is unable to secrete the normal/typical amount of hormones
Immune Surveillance Most tumors express antigens that can be recognized by T cells...
TSAs: tumor specific antigens; found only on tumor cells
TAAs: tumor associated antigens; found on tumor cells & normal cells
Macrophages are important in tumor immunity as antigen-presenting cells to initiate the immune response and as potential effector
Tumor Markers
Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found on plasma cell membranes, in the blood, CSF, or urine
Hormones
Enzymes
Genes
Antigens
Antibodies
Antigens expressed on the surface of tumor cells or substances
Tumor Markers: value and useful markers
Value of a marker depends on
Sensitivity: apparent early; few false negatives
Specificity: specific for specific cancer; not elevated in other diseases
Proportionality: level accurately reflects growth of the tumor
Feasibility: methods available, easy to
Types of Cancer Treatment
Surgery�targeted
Radiation�targeted
Chemo�in blood stream goes everywhere, some more targeted than others
Hormone�targeted
Biotherapy�using the immune system to fight the cancer--interferon
Incidence and Types of Childhood Cancer
The incidence of childhood cancers is greatest during the first years of life
Embryonal tumors
Neuroblastoma
Retinoblastoma
Wilms tumor