cellular

adaptation

CELLULAR ADAPTATIONS OF GROWTH AND

DIFFERENTIATION

cellular adaptation- is the state between a normal

unstressed cell and the overstressed injured cell
- constantly adjusting their structure and function
to accommodate changing demands and
extracellular stresses.
- by definition - an adaptative process is
reversible
- Cells tend to maintain their intracellular milieu
within fairly narrow range of physiologic
parameters; that is, they maintain normal
homeostasis.

NORMAL CELL GROWTH

3 groups on the basis of their regenerative
capacity
1. Labile cells- continuously dividing cells- they continue
to proliferate, remain all the time in cell cycle
a. tissues that contain most labile cells include-epithelia such as -stratified squamous
epithelium of the skin, oral cavity, vagina
cervix, esophagus
-lining epithelial cell of the gland such as
salivary glands, pancreas biliary tract,
-columnar epithelium of uterus, fallopian tube,
-urinary epithelium
-lymphoid tissue, hematopoetic tissue

2.Stable cells- quiescent

- they are considered to be in G0 phase, may
undergo rapid proliferation after appropriate stimuli,
they may be recruited back to the cell cycle
- stable cells include:
a. parenchymal cell of virtually all glandular organs,
such as liver,kidney, pancreas,breast, lung
b.mesenchymal cells, such as
fibroblasts and smooth muscle cells
c. vascular endothelial cells

3. Permanent cells- non-dividing.

- These cells have left cell cycle and cannot undergo
mitotic division.
This group includes:
a. nerve cells
b. skeletal and heart muscle cells
These cells have no regenerative capacity.

CONTROL OF THE CELL CYCLE

a. Growth factors- low-molecular-weight proteins which

have similar mechanism of activity as hormones
-growth factors are produced by the cells and act either
on the cell itself (autocrine activity) or an the
neighbouring cells (paracrine action) by linking to cell
surface receptors
b. cyclins- are a family of proteins which see to coordinate
the journey of the cells through different parts of the cellcycle

Characteristics of Cancer cells

1. Exhibit Uncontrolled Growth (Immortality)
2. Abnormal DNA (Mutations)
3. Evasion of Apoptosis
4. Lack Differentiation
5. Lack Contact Inhibition
6. Lack Anchorage Dependence
7. Ability to Penetrate the Lamina
8. Angiogenesis

Deoxyribonucleic Acid(DNA)
is the hereditary material in humans and almost all other
organisms
The information in DNA is stored as a code made up of
four chemical bases:
1. adenine (A)
2. guanine (G)
3. cytosine (C)
4. thymine (T)

Genes
which make up our DNA, provide directions for producing
our body's proteins
These proteins are vital to survival- They provide function,
regulation and structure for our tissues and organs

Examples of protein functions

Function

Description
Antibodies bind to specific foreign particles, such as viruses and
bacteria, to help protect the body.

Example
Immunoglobulin G (IgG)

Enzyme

Enzymes carry out almost all of the thousands of chemical reactions

that take place in cells. They also assist with the formation of new
molecules by reading the genetic information stored in DNA.

Phenylalanine hydroxylase

Messenger

Messenger proteins, such as some types of hormones, transmit

signals to coordinate biological processes between different cells,
tissues, and organs.

Growth hormone

Structural component

These proteins provide structure and support for cells. On a larger

scale, they also allow the body to move.

Actin

Transport/storage

These proteins bind and carry atoms and small molecules within cells
and throughout the body.

Ferritin

Antibody

Two ways in which DNA can become mutated:

1. Mutations can be inherited- this means that if a parent
has a mutation in his or her DNA, then the mutation is
passed on to his or her children.
2. Mutations can be acquired- this happens when
environmental agents damage DNA, or when mistakes
occur when a cell copies its DNA prior to cell division.

Carcinogenesis
Three(3) Major Steps:
a. Initiation occurs rapidly and is heritable and irreversible.
Exposure to chemical, physical or biological agent
(Carcinogens)
escape normal enzymatic mechanism
alter the genetic structure of the cellular DNA
permanent damage
(mutation) to DNA.

DNA repair mechanism

Stops cycle for repair
function normally

initiate program death

apoptosis

b. Promotion is the event that causes proliferation of the

transformed cells from inititation even after long
latency period.
Repeated Exposure to cocarcinogens
Further mutation of oncogenes
Tumor suppressor genes mutate (p53)
Loss regulatory capacity

Malignant cell reproduce

Proliferation of Oncogenes

c. Progression. This refers to the additional cell divisions

that - initiated cells undergo (sometimes involving
additional mutations) that ultimately result in the
development of neoplasia.
- The tumor cell establishes own blood supply then
makes TAF (Tumor angiogenesis factor) which
stimulates capillaries and other blood vessels in the
area to grow new branches into the tumor for
nourishment.

d. Metastasis Cancer cells move from original location.

1. Extension tumors secrete enzymes that open up
areas of surrounding tissue
2. Penetration enzymes make large pores in blood
vessels allowing entrance thus circulating through
body
3. Release clumps break off into blood vessels for
transport
4. Invasion Tumor cells circulate through the blood and
enter tissues at remote sites & invade surrounding
tissues

Cellular Adaptive Responses

Hypertrophy
Hyperplasia
Metaplasia
Dysplasia
Atrophy

Cellular Adaptive Responses

1. HYPERTROPHY
- increase in the size of individual cells if sufficient
number of cells is involved-increase in size of the
entire organ
- mainly seen in cells which have no capacity for
mitotic division
Types:
a. physiologic hypertrophy - hypertrophy may occur
as an adaptation to increased demand or to
specific hormonal stimuli.
b. pathologic hypertrophy - abnormal ( pathologic )
hypertrophy occurs in the absence of an appropriate
stimuli of increased demand, usually does not revert
back to normal

2. HYPERPLASIA

-increase in number of cells in organ or tissue which

may thus increase its volume
- Hyperplasia can occur only in cell population capable
of dividing
Capacity for hyperplastic growth-depends on cell type:
a. high capacity - epidermis, intestinal epithelium, hepatocytes, fibroblasts, bone marrow cells etc
b. Blow or no capacity-nerve cell, skeletal and cardiac
muscle
c. intermediate capacity-bone, cartilage, smooth muscle

Physiological causes of hyperplasia

a. hormonal -proliferation of glandular epithelium in
female breast at puberty and during pregnancy
b.cell loss- regeneration of squamous epithelium in wound
healing- regeneration of squamous epithelium
in wound healing
c. compensatory - hyperplasia of one kidney
associated with developmental hypoplasia of the
other one

Pathological causes of hyperplasia

a. hormonal - endometrial hyperplasia is associated
with irregular, often excessive uterine bleeding
- endometrial hyperplasia may progress
into atypical hyperplasia- significantly
higher risk of cancer
b. cell destruction- in ulcerative colitis- the colonic
mucosa undergoes repeated ulcerations, cell
loss and regeneration and hyperplasia

3. METAPLASIA
- results from abnormal differentiation

- reversible
- is the conversion of one cell type to another cell type
not usually found in the involved tissue
4. ATROPHY
- is a decrease in the size of tissue or organ resulting
from
decrease either in the size of individual cells or in the
number of cells composing the tissue
5. DYSPLASIA
- The enlargement of an organ or tissue by the
proliferation
of cells of an abnormal type

Cell Adaptation

Two Types of Cell Death

1. Necrosis- when damage to membranes
is severe, enzymes leak out of
lysosomes, enter the cytoplasm, and digest the cell
2. Apoptosis- when a cell is deprived of
growth factors or the cells DNA or proteins
are damaged beyond repair, the cell kills
itself

Acquired
(Environmental)
DNA damaging
agents:
Chemicals
Radiations
virus

Normal Cell

DNA Damage

Failure of DNA Repair

Mutation the in the genome

of Somatic Cells
Activation of Growth
promoting Oncogenes

Inactivation of tumor
supressor genes

Unregulated cell proliferation

Inherited mutations in:

Genes affecting DNA
Repairs
Genes afftecting cell
growth or apoptosis

Alterations in genes
that regulate Apoptosis
Decreased apoptosis

Clonal Expansion
Angiogenesis

Additional Mutation

Escape from immunity

Tumor progression

Malignant Neoplasm

Invasion and
Metastasis

Tumor Markers
The cancer cells have ability to produce some substances
tumor cell markers that are found on tumor cell
membranes and in cytoplasm.
These substances may be detected in the blood, urine or
spinal uid.
Immunochemical analysis of serum levels of tumor cell
markers enabled us:
1. to identify individuals at high risk of cancer
2. to diagnose the specic type tumor
3. to follow the clinical course of malignant disease
4. to assess eectiveness of therapy

 Tumor markers are developed over time as the cell become

less differentiated
- this distinguished malignant from benign cell of the
same tissue type
- may be useful in measuring the extent of disease
- tracking the course of illness during treatment or
relapse
Tumor cell markers includes:
- antigens
- enzymes
- hormones

Tumor Markers

Tumor Growth

1. Cell Cycle time

- The duration of these cell cycle phases varies
considerably in different kinds of cells. For a typical
rapidly proliferating human cell with a total cycle time of
24 hours, the G1 phase might last about 11 hours,
S phase about 8 hours, G2 about 4 hours, and M about
1 hour.
- the length of G0 phase is the major factor in
determining the cell cycle time

2. Doubling time- the lenght of time it takes for a tumor to

double in size
- average doubling time for most primary solid tumors is
approximately 2 months
- fast growing tumors 1 month
- slow growing 1 year
- clincally undetectable until it has doubled 30 times
and contains more than 1 billion cells
- factors affecting doubling:
a. Cell cycle time
b. Growth fraction
c. Cell loss

3. Growth Fraction is the ratio of the total number of cells to

the number of dividing cells
- relationship between cancer
cells proliferating and those cells resting.

DEVELOPMENT OF CANCER
First Mutation

Fourth Mutation

Tumor
formation

Angiogenesis

Second Mutation

Third Mutation

Invasion

Metastasis

1. DNA of a normal cell

This piece of DNA is an exact copy of the DNA from

which it came. When the parent cell divided to create
two cells, the cell's DNA also divided, creating two
identical copies of the original DNA.

2. Mutation of DNA

Here is the same section of DNA but from another cell. If you
can imagine that DNA is a twisted ladder, then each rung of the
ladder is a pair of joined molecules, or a base pair. With this
section of DNA, one of the base pairs is different from the
original.
This DNA has suffered a mutation, either through mis-copying
(when its parent cell divided), or through the damaging effects
of exposure to radiation or a chemical carcinogen.

3. Genetically altered cell

Body cells replicate through mitosis, they respond to

their surrounding cells and replicate only to replace
other cells. Sometimes a genetic mutation will cause a
cell and its descendants to reproduce even though
replacement cells are not needed.
The DNA of the cell highlighted above has a mutation
that causes the cell to replicate even though this
tissue doesn't need replacement cells at this time or at
this place.

4. Spread and second mutation

The genetically altered cells have, over time, reproduced

unchecked, crowding out the surrounding normal cells. The
growth may contain one million cells and be the size of a
pinhead. At this point the cells continue to look the same as the
surrounding healthy cells.
After about a million divisions, there's a good chance that one
of the new cells will have mutated further. This cell, now
carrying two mutant genes, could have an altered appearance
and be even more prone to reproduce unchecked.

5. Third mutation

Not all mutations that lead to cancerous cells result in the cells
reproducing at a faster, more uncontrolled rate. For example, a
mutation may simply cause a cell to keep from self-destructing. All
normal cells have surveillance mechanisms that look for damage
or for problems with their own control systems. If such problems
are found, the cell destroys itself.
Over time and after many cell divisions, a third mutation may arise.
If the mutation gives the cell some further advantage, that cell will
grow more vigorously than its predecessors and thus speed up the
growth of the tumour.

6. Fourth mutation

The new type of cells grow rapidly, allowing for

more opportunities for mutations. The next
mutation paves the way for the development of
an even more aggressive cancer.
At this point the tumour is still contained.

7. Breaking through the membrane

The newer, wilder cells created by another mutation are

able to push their way through the epithelial tissue's
basement membrane, which is a meshwork of protein
that normally creates a barrier. The invasive cells in this
tumour are no longer contained.
At this point the cancer is still too small to be detected.

8. Angiogenesis

Often during the development of earlier stages of the tumour,

or perhaps by the time the tumour has broken through the
basement membrane (as pictured above), angiogenesis takes
place. Angiogenesis is the recruitment of blood vessels from
the network of neighbouring vessels.
Without blood and the nutrients it carries, a tumour would be
unable to continue growing. With the new blood supply,
however, the growth of the tumour accelerates; it soon
contains thousand million cells and, now the size of a small
grape, is large enough to be detected as a lump

9.Invasion and dispersal

The tumour has now invaded the tissue beyond the

basement membrane.
Individual cells from the tumour enter into the network of
newly formed blood vessels, using these vessels as
highways by which they can move to other parts of the
body. A tumour as small as a gram can send out a million
tumour cells into blood vessels a day.

 What makes most

tumours so lethal is
their ability to
10. Tumour cells travel - metastasize -- that is,
establish new tumour
metastasis
sites at other locations
throughout the body.
Secondary tumours.
Metastasis is now
underway, as tumour
cells from the original
cancer growth travel
throughout the body.
Most of these cells will
die soon after entering
the blood or lymph
circulation.

11. Metastasis

To form a secondary tumour, a tumour cell needs to

leave the vessel system and invade tissue. The cell must
attach itself to a vessel's wall. Once this is done, it can
work its way through the vessel and enter the tissue.
Although perhaps less than one in 10,000 tumour cells
will survive long enough to establish a new tumour site, a
few survivors can escape and initiate new colonies of the
cancer.

Grading versus Staging

Cancer grading and staging
Cancer is graded upon the resemblance to
normal cells = G
(The higher the number, the worse the grade of cancer) i.e.
G1, G2, G3, G4

Staging is based upon

the presence of a primary tumor = T
involvement in lymph nodes = N
and appearance of metastasis = M
Numbers of the stage range from
x = none to 3 or 4 for each letter

TNM Classification System

A. Primary tumor
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis carcinoma in-situ
T1, T2, T3, T4 increasing size and/or local extent of the primary
tumor
B. Regional lymph node metastasis
Nx Regional LN cannot be assessed
N0 No regional LN metastasis
N1, N2, N3 Increasing involvement of regional LN
C. Distant metastasis
Mx Distant metastases cannot be assessed
Mo No distant metastases
M1 Distant metastases

Grading versus Staging

Is this a high grade or low grade cancer?
Case study
Julie has a breast lump in her right breast, and has also
found one in her right armpit. Biopsy and lumpectomy
were performed. The tumor was graded G3, T2, N2, M1.

Detection

Lab tests for cancer

Ultrasounds to determine size
CT scan with contrast the golden standard
Genetic markers BRCA 1 and BRCA 2
Tumor markers:
CEA general carcinogenic antigen
PSA prostate antigen
CA-125 ovarian
CA-25,27 breast
HER 2 NEU breast tissue needed

Oncology
Lab tests for cancer
Liver function tests
CBC with differential count
Renal function tests
PET scan looks for metastasis using a radioactive
glucose solution
PT, PTT, Fibrinogen, Fibrin levels

Oncology
Lab tests for cancer

Pathology slide of tumor:

(Should be kept for a period of years)
Determines type of tumor
Source of tumor
Aggression of tumor whether fast growing,
differentiated, or non-differentiated
Used to determine tumor growth factors and
susceptibility to certain chemotherapies

Cancer Warning Signs and

Symptoms
C change in bowel habits sign of colorectal cancer
A sore that does not heal on the skin or in the mouth could
be malignant
Unusual bleeding or discharge from rectum, bladder or
vagina could be colorectal, prostate, bladder or cervical
cancer
Thickening of breast tissue or a new lump in breast
Indigestion or trouble swallowing cancer of the mouth
throat esophagus or stomach.
Obvious changes to moles or warts could be skin cancer
Nagging cough or hoarseness that persists for four to six weeks
could be cancer of lung or throat cancer.

Detection and Prevention of Cancer

Primary Prevention: Nurses play a key
role in cancer prevention
Avoidance of Known carcinogens
Modification of associated factors
Removal of at risk tissues
Chemo prevention

Detection and Prevention of Cancer

Secondary Prevention:
Promotion of cancer screenings
Gene therapy for cancer prevention

Quiz
August 2

It is the state between a normal unstressed cell and the

overstressed injured cell.
a. Metastasis
b. Oncogenesis
c. Cell adaptation
d. apoptosis

2. A stratified squamous epithelium of the

skin is what group of the cell growth on
the basis of their regenerative capacity:
a. labile
b. Quiescent
c. stable
d. permanent

3. The following are characteristics of a cancer cell except:

a. Exhibit Uncontrolled Growth (Immortality)
b. Abnormal DNA (Mutations)
c. Apoptosis
d. Lack of Differentiation

4 5 What are the two ways in which DNA can

become mutated?
6. The stage in carcinogenesis when the abnormal cell
starts to divide, may be stimulated by environmental
changes, hormones, drugs, or irritants.

7. These substances produced by the cancer cells that

are found on tumor cell membranes and in cytoplasm
which may be detected in the blood, urine or spinal uid.
8. The duration of G1 phase for a typical rapidly
proliferating human cell with a total cycle time.

9. An average doubling time for most primary solid tumors

which are fast growing?
10-12. Staging of cancer is based upon the presence TNM ,
which stands for:
13. When should screening of cervical cancer starts?
14 20. The seven warning signs and symptoms of cancer.