Unit IV Cellular Proliferation: Cancer

Malignant tumors
Named according to the tissues from which they arise
Malignant epithelial tumors are referred to as carcinomas
Adenocarcinoma and basal cell carcinoma
Malignant connective tissue tumors are referred to as sarcomas
Chondrosarcoma and osteosarcoma

Benign tumors
Named according to the tissues from which they arise
and include the suffix oma
Lipoma
Glioma
Leiomyoma
Chondroma

Cancer cells are named according to the cell type of origin:

Carcinomas- cancer of epithelial tissue
Adenocarcinoma- arise from ductal or glandular epithelium
Sarcomas- arise from connective tissues
Lymphoma- cancer of lymphatic tissue
Leukemia- cancer of blood-forming cells
Carcinoma in situ (CIS)- preinvasive epithelial tumor of
glandular or squamous cells
Anaplasia- the loss of differentiation

Classification and
Nomenclature
leukemias

Cancers of lymphatic tissue are lymphomas

Cancers of blood-forming cells are
Carcinoma in situ (CIS)Preinvasive

epithelial malignant tumors of glandular or

epithelial origin that have not broken
through the basement membrane or
invaded the surrounding stroma

Cancer Cells
Transformation
Cancer cells independence from normal cellular

controls
Anchorage independent
Immortal
Anaplasia

Pleomorphic

Stem cells self-renew

Cell divisions create new stem cells
Stem cells are multipotent
Ability to differentiate into multiple different cell types

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

Can be increased by noncancerous as well as

cancerous conditions

Cancer-Causing
Mutations

Cancer is predominantly a disease of aging

Clonal proliferation or expansion
Due to a mutation, a cell acquires

characteristics that allow it to have selective

advantage over its neighbors

Increased growth rate or decreased apoptosis

Multiple mutations required before cancer

can develop
Epigenetics

DNA chemically modified but not mutated

Gene Mutations That Alter

Growth
Signals
Growth factors
(autocrine stimulation) secreted
Increase in growth factor receptors
Signal from cell-surface receptor is mutated in

the on position
Mutation in the Ras intracellular signaling protein
Inactivation of Rb tumor suppressor
Activation of protein kinases that drive the cell
cycle
Mutation in the TP53 gene (tumor suppressor
gene)
Suppression of normal apoptosis
7

Oncogenes
Mutant genes that in their nonmutant state

direct protein synthesis and cellular growth

Tumor suppressor genes

Encode proteins that in their normal state
negatively regulate proliferation
Also referred to as anti-oncogenes
Proto-oncogene
Normal nonmutant gene that codes for cellular

growth

Mutation
of
Normal
Genes

Point mutations

Changes in one or few nucleotide base pairs

Chromosome translocation
Piece on one chromosome is transferred to
another
Gene amplification
Duplication of a small piece of chromosome
over and over
Results in an increased expression of an
oncogene

Telomeres and Immortality

Body cells are not immortal and can divide

only a limited number of times

Telomeres are protective caps on each
chromosome and are held in place by
telomerase
Telomeres become smaller and smaller
with each cell division
Cancer cells can restore telomeres, leading
to continued division

10

Oncogenesareactivated
Normalfunction:cellgrowth,genetranscription
Tumorsuppressorgenesareinactivated
Normalfunction:DNArepair,cellcyclecontrol,celldeath
Viruses: insertional mutagenesis

Chemicals: DNA adducts

UV and ionizing radiation: single

and double strand DNA breaks

Causes of cancer: - carcinogens, radiation, viruses, random

- hereditary vs. spontaneous tumors
- multi step process

Genes and gene products involved in cancer:

activation of proto-oncogenes to oncogenes (gain-of-function)
inactivation of tumor suppressor genes (loss-of-function)
altered activity of modulator genes

Genetics and Cancer

Exposure to mutagens
If the mutation occurs in somatic cells, it is not passed
to progeny
If the mutation occurs in germline cells, it can be passed
to future generations
Cancer-prone families
Chronic inflammation is an important factor in the

development of cancer
Causes cellular injury

Cytokine release from inflammatory cells

Free radicals
Mutation promotion
Decreased response to DNA damage

13

Viruses, Bacteria and Cancer

Hepatitis B and C viruses
Epstein-Barr virus (EBV)
Kaposi sarcoma herpesvirus (KSHV)
Human papillomavirus (HPV)
Human T cell leukemialymphoma virus (HTLV)

Helicobacter pylori
Chronic infections are associated with:
Peptic ulcer disease
Stomach carcinoma
Mucosa-associated lymphoid tissue lymphomas

14

Three-Step Theory of
Invasion
Tumor cell attachment
Fibronectin and laminin
Degradation or dissolution of the matrix
Enzymes
Locomotion into the matrix
Invadopodia (pseudopodia)

15

Metastasis
Spread of cancer from a primary site of

origin to a distant site

Steps

Direct or continuous extension

Penetration into lymphatics, blood vessels, or
body cavities
Transport into lymph or blood
Transport to secondary sites
Entry and growth in secondary sites

16

Angiogenesis
Growth of cancerous colonies depends on

an adequate blood supply

Angiogenesis is the development of new
blood vessels
TP53 gene
Proangiogenic factors
Angiogenesis inhibitors

17

Distant Metastases
Metastasis often occurs in the first capillary

bed encountered by circulating cells

Organ tropism
Preferential growth of cancerous cells in

certain organs

Growth factors, chemokines, hormones, tissueselective homing receptors, and chemotactic

factors

18

Staging
Involves the size of the tumor, degree to

which it has invaded, and extent of spread

Stage 1

Cancer is confined to its organ of origin

Stage 2

Locally invasive

Stage 3

Regional structures

Stage 4

Distant sites

19

Clinical Manifestations of
Cancer
Pain
Little or no pain is associated with early

stages of malignancy
Influenced by fear, anxiety, sleep loss,
fatigue, and overall physical deterioration
Mechanisms

Pressure, obstruction, invasion of sensitive

structures, stretching of visceral surfaces, tissue
destruction, and inflammation

20

Clinical Manifestations of
Cancer
Fatigue
Subjective clinical manifestation
Tiredness, weakness, lack of energy,

exhaustion, lethargy, inability to

concentrate, depression, sleepiness,
boredom, and lack of motivation
Suggested causes

Sleep disturbance, biochemical changes from

circulating cytokines, secondary to disease and
treatment, psychosocial factors, level of activity,
nutritional status, and environmental factors
21

Clinical Manifestations of
Cancer
Syndrome of cachexia
Most severe form of
malnutrition
Present in 80% of cancer
patients at death
Includes:

Anorexia, early satiety, weight

loss, anemia, asthenia, taste
alterations, and altered protein,
lipid, and carbohydrate
metabolism

22

Clinical Manifestations of Cancer

Anemia
A decrease of hemoglobin in the blood
Mechanisms

Chronic bleeding resulting in iron deficiency, severe

malnutrition, medical therapies, or malignancy in bloodforming organs

Leukopenia and thrombocytopenia

Direct tumor invasion to the bone marrow causes
leukopenia and thrombocytopenia
Chemotherapy drugs are toxic to bone marrow
Infection
Risk increases when the absolute neutrophil and

lymphocyte counts fall

23

The steps of metastasis

Cancer Treatment
Immunotherapy
Theoretically, antitumor responses can

selectively eliminate cancer cells while

sparing normal cells
Immune memory is long lived
Numerous immunologic mechanisms are
capable of rejecting different types of cancer
Biologic response modifiers (BRMs)

25

Etiology of cancer
Viruses and Bacteria
DNA viruses- HepaB, Herpes, Papilloma
Virus
RNA Viruses- HIV
Bacterium- H. pylori
Body Defenses Against TUMOR
1. T cell System/ Cellular Immunity
Cytotoxic T cells kill tumor cells
2. B cell System/ Humoral immunity
B cells can produce antibody
3. Phagocytic cells
Macrophages can engulf cancer cell
debris

 > 100 different types of human cancer

20 % of the mortalities in industrialized nations
detection classification and localization therapy
imaging
histology
biomarkers

surgery
radiation
chemotherapy

Cancer
US Mortality,
2003

Epidemiology

1.

Heart Diseases

685,089

No. of % of all
deaths deaths
28.0

2.

Cancer

556,902

22.7

3.

Cerebrovascular diseases

157,689

6.4

4.

Chronic lower respiratory diseases

126,382

5.2

5.

Accidents (Unintentional injuries)

109,277

4.5

6.

Diabetes mellitus

74,219

3.0

7.

Influenza and pneumonia

65,163

2.7

8.

Alzheimer disease

63,457

2.6

1.

Nephritis

42,453

1.7

34,069

1.4

Rank Cause of Death

10. Septicemia

Prostate

33%

Lung & bronchus

13%

Colon & rectum

Men Women
720,28 679,510
31%
0

Breast

12%

Lung & bronchus

10%

11%

Colon & rectum

Urinary bladder

6%

6%

Uterine corpus

Melanoma of skin

5%

4%

Non-Hodgkin
lymphoma

4%

Melanoma of skin

Non-Hodgkin
lymphoma

4%

Kidney

3%

3%

Thyroid

Oral cavity

3%

3%

Ovary

Leukemia

3%

2%

Urinary bladder

Pancreas

2%

2%

Pancreas

18%

22%

All Other Sites

All Other Sites

2006 Estimated US Cancer Deaths*

Lung & bronchus

31%

Colon & rectum

10%

Men Women
291,27 273,560 26%
15%
0

Breast

Prostate

9%

Pancreas

6%

6%

Pancreas

Leukemia

4%

6%

Ovary

Liver & intrahepatic

bile duct

4%

4%

Leukemia

Esophagus

4%

3%

Non-Hodgkin
lymphoma

3%

Uterine corpus

2%

Multiple myeloma

2%

Brain/ONS

Non-Hodgkin
lymphoma

3%

Urinary bladder

3%

Kidney

3%

All other sites

23%

ONS=Other nervous system.

Source: American Cancer Society, 2006.

10%

Lung & bronchus

23%

Colon & rectum

All other sites

HVB/HCV- Hepatocellular carcinoma

Herpes viruses (Epstein-Barr)- Burkit lymphoma, nasopharyngeal
carcinoma
Papilloviruses- HPV-16, 18.31.33- Kaposi sarcoma, Cervical
Retroviruses- HTLV-1 Lymphoma, adult T-cell leukemia
H. pilori i more than a half of world population- peptic cancer,
gastric MALT lymphoma

 general changes:

- loss of division limits (immortality)

- uncontrolled proliferation

genetic changes:

- point mutations
- chromosomal changes

structural changes:

- less organized cytoskeleton

- increased membrane fluidity

biochemical changes:

- altered protein expression

- altered protein modification

Phenotype of a cancer
The Six Hallmarks of Cancer
cell
Self-sufficient growth signals
Constitutively activated growth factor signalling

Resistance to anti-growth signals

Inactivated cell cycle checkpoint

Immortality

Inactivated cell death pathway

Resistance to cell death

Activated anti- cell death signalling

Sustained angiogenesis

Activated VEGF signalling

Invasion and metastasis

Loss of cell-to-cell interactions, etc.

What can cancer therapies

target?
Classic cancer therapies target rapidly

dividing cells
Target the DNA
Ionizing radiation
Chemotherapy

Many side effects

Hair loss
Weakened immune
system
Problems with GI tract

Risk factors for cancer: (some are

controllable; some are not)
1. Heredity: 5 10% of cancers; documented with
some breast and colon cancers
2. Age: 70% of all cancers occur in persons > 65
3. Lower socio-economic status
4. Stress
Leads to greater wear and tear on body in general
5 Diet: certain preservatives in pickled, salted
foods; fried foods; high-fat, low fiber foods; charred
foods, high fat foods, diet high in red meat
6. Occupational risk: exposure to know
carcinogens, radiation, high stress
7. Infections, especially specific organisms and
organ (e.g. papillomavirus causing genital warts and
leading to cervical cancer)

Sun Exposure (radiation) e.g. skin cancer

Theories of Carcinogenesis
1.
Cellular Mutation
a. Cells begin to mutate (change the DNA to
unnatural cell reproduction)
2.
Oncogenes/Tumor Suppressor Genes Abnormalities
a. Oncogenes are genes that promote cell
proliferation and can trigger cancer
b. Tumor suppressor genes normally suppress
oncogenes but are damaged
3.
Exposure to Known Carcinogens
a. Act by directly altering the cellular DNA
(genotoxic)
b. Act by affecting the immune system (promotional)
4.
Viruses

viruses break the DNA chain and mutates the

normal cells DNA
Epstein-Barr virus
Human papilloma virus
Hepatitis virus

5.

6.

7.

8.

Drugs and Hormones

a. Sex hormones often affect cancers of the
reproductive systems (estrogen in some breast
cancers; testosterone in prostate cancer)
b. Glucocorticoids and steroids alter immune system
Chemical Agents
a. Industrial and chemical
b. Can initiate and promote cancer
b. Examples: hydrocarbons in soot ; arsenic in
pesticides; chemicals in tobacco
Physical Agents
a. Exposure to radiation
Ionizing radiation found in x-rays, radium, uranium
UV radiation
Sun, tanning beds
Immune function
1. Protects the body from cancerous cells
2. Increased rate of cancer in immunocompromised
patients

Effects of Cancer

1. Disturbed or loss of physiologic functioning,

from pressure or obstruction
a. Anoxia and necrosis of organs
b. Loss of function: bowel or bladder
obstruction
c. Increased intracranial pressure
d. Interrupted vascular/venous blockage
e. Ascites
f. Disturbed liver functioning
G. Motor and sensory deficits
Cancer invades bone, brain or compresses
nerves
h. Respiratory difficulties
a.
b.

Airway obstruction
Decreased lung capacity

2.

3.
4.
5.

Hematologic Alterations: Impaired function of blood

cells
1. Secondary to any cancer that invades the bone
marrow (leukemia)
2. May also be caused by the treatment
a.Abnormal wbcs: impaired immunity
b.Diminished rbcs and platelets: anemia and clotting
disorders
Infections: fistula development and tumors may
become necrotic; erode skin surface
Hemorrhage: tumor erosion, bleeding, severe anemia
Anorexia-Cachexia Syndrome: wasting away of client
a.Unexplained rapid weight loss, anorexia with
altered smell and taste
b.Catabolic state: use of bodys tissues and muscle
proteins to support cancer cell growth

Paraneoplastic Syndromes: ectopic sites with

excess hormone production
a. Parathyroid hormone (hypercalcemia)
b. Ectopic secretion of insulin (hypoglycemia)
c. Antidiuretic hormone (ADH: fluid retention)
d. Adrenocorticotropic hormone (ACTH)
7. Pain: major concern of clients and families
a. Types of cancer pain
1. Acute: symptom that led to diagnosis
2. Chronic: may be related to treatment or to
progression of disease
b. Causes of pain
1. Direct tumor involvement including
metastatic pain
2. Nerve compression
3. Involvement of visceral organs
6.

8.
Physical Stress: body tries to respond and
destroy neoplasm
a. Fatigue
b. Weight loss
c. Anemia
d. Dehydration
e. Electrolyte imbalances
9.
a.
b.
c.
d.

Psychological Stress
Cancer equals death sentence
Guilt from poor health habits
Fear of pain, suffering, death
Stigmatized

Tumor
Cell
Markers

Cancer cells produce biological substances

that can be detected on tumor plasma
membranes or in the blood, spinal fluid or
urine
Detection through analysis can help
Screen, diagnose, mark tumor progression

These biologic markers include

Hormones, enzymes, genes, antigens, antibodies

Not used alone as a diagnostic test of

cancer

Tumor markers: specific proteins which

indicate malignancy
a. PSA (Prostatic-specific antigen): prostate
cancer
b. CEA (Carcinoembryonic antigen): colon
cancer
c. Alkaline Phosphatase: bone metastasis
4 Direct Visualization
a. Sigmoidoscopy
b. Cystoscopy
c. Endoscopy
d. Bronchoscopy
e. Exploratory surgery; lymph node biopsies
to determine metastases

Cancer Treatment
Chemotherapy
Use of nonselective cytotoxic drugs that target vital

cellular machinery or metabolic pathways critical to

both malignant and normal cell growth and replication
Goal

Eliminate enough tumor cells so the bodys defense can

eradicate any remaining cells

Compartments

1: cells undergoing mitosis and cytokinesis

2: cells capable of entering the cell cycle in the G 1 phase

3: cells not dividing or that have irreversibly left the cell

cycle
Cells

in compartment 3 will die a natural death

45

Cancer Treatment
Ionizing radiation
Damages cells by imparting enough ionizing radiation to
cause molecular damage, especially to DNA-killing
cancerous cells
Causes irreversible damage to normal cells

Lifetime radiation dosage

Brachytherapy
Seed implants

Surgery
Biopsy and lymph node sampling

Sentinel nodes

Debulking surgery
Palliative surgery

46

Classes of Chemotherapy Drugs

1.
Alkylating agents
1. Action: create defects in tumor DNA
2. Examples: Nitrogen Mustard, Cisplatin
2.
Antimetabolites
1. Action: similar to metabolites needed for
vital cell processes
Counterfeit metabolites interfere with cell
division
2. Examples: Methotrexate; 5 fluorouracil
3. Toxic Effects: nausea, vomiting, stomatitis,
diarrhea, alopecia, leukopenia
3.
Antitumor Antibiotics
1. Action: interfere with DNA
2. Examples: Actinomycin D, Bleomycin
3. Toxic Effect: damage to cardiac muscle

4.

Antimiotic agents
1. Action: Prevent cell division
2. Examples: Vincristine, Vinblastine
3. Toxic Effects: affects neurotransmission,
alopecia, bone marrow depression
5.
Hormone agonist
1. Action: large amounts of hormones upset the
balance and alter the uptake of other hormones
necessary for cell division
2. Example: estrogen, progestin, androgen

6. Hormone Antagonist
1. Action: block hormones on hormone-binding

tumors (breast, prostate, endometrium; cause tumor

regression
Decreasing the amount of hormones can decrease
the cancer growth rate
Does not cure, but increases survival rates
2. Examples: Tamoxifen (breast); Flutamide
(prostate)
3. Toxic Effects: altered secondary sex characteristics
7. Hormone inhibitors
Aromatase inhibitors (Arimidex, Aromasin)

Prevents production of aromatase which is needed for

estrogen production
Used in post menopausal women
Side effects
Masculinizing effects in women
Fluid retention

Managing side effects of chemotherapy

A. Nausea and vomiting
80% of patients will develop it
Antiemetics such as Zofran, Tigan,
Compazine as well as Ativan to control the
symptoms
Monitor for dehydration and need for IV fluids
B. Bone marrow suppression
Decreased number of RBC
Leads to hypoxia, fatigue
Hgb 9.5-10 gm/dl require oral iron supplements
Hgb below 8 gm/dl require transfusion
May use Epogen to stimulate RBC production

MANAGEMENT OF ALOPECIA

Alopecia begins within 2 weeks of therapy

Regrowth within 8 weeks of termination
Encourage to acquire wig before hair loss
occurs
Encourage use of attractive scarves and
hats
Provide information that hair loss is
temporary BUT anticipate change in
texture and color

COLON CANCER
PATHOPHYSIOLOGY
Benign neoplasm DNA alteration

malignant transformation malignant

neoplasm cancer growth and invasion
metastasis (liver)
Sigmoid colon is the most common site
Predominantly adenocarcinoma
If early 90% survival
34 % diagnosed early
66% late diagnosis

COLON CANCER
ASSESSMENT FINDINGS

1. Change in bowel habits- Most

common
2. Blood in the stool
3. Anemia
4. Anorexia and weight loss
5. Fatigue
6. Rectal lesions- tenesmus, alternating D
and C

Breast Cancer

RISK FACTORS
1. Genetics- BRCA1 And BRCA 2
2. Increasing age ( > 50 yo)

3. Family History of breast cancer

4. Early menarche and late menopause
5. Nulliparity
6. Late age at pregnancy
7. Obesity
8. Hormonal replacement
9. Alcohol
10. Exposure to radiation

Breast Cancer
ASSESSMENT FINDINGS
1. MASS- the most common location is the
upper outer quadrant
2. Mass is NON-tender. Fixed, hard with
irregular borders
3. Skin dimpling
4. Nipple retraction
5. Peau d orange