Neoplasia

Chapter 7
1
Dr. Suha Saleh
Neoplasia
Means new growth

Implies abnormality of cellular
growth/tumor

Malignant neoplasm is cancer

Benign growth is generally easily cured

Malignant cancer may not be survivable

Cancer is associated with altered expression
of cellular genes
2
Benign vs. Malignant
Growth
Malignant Tumor

Can kill host if untreated
Confirmed by invasive or metastasizing nature
Tissue-specific differentiation (does not closely
resemble tissue type of origin)
Greater degree of anaplasia indicates aggressive malignancy
Grows rapidly, may initiate tumor vessel growth,
frequently necrotic, dysfunctional
3
Benign vs. Malignant Growth (Cont.)
4
Fig. 7-1
Benign vs. Malignant Growth (Cont.)
Benign Tumor
Does not have potential to kill host, but may be life-threatening
because of its location
Does not invade adjacent tissue or spread to distant sites
Many are encapsulated
More closely resembles original tissue type
Grows more slowly, little vascularity, rarely necrotic, often
retains original function
-oma suffix indicates benign tumor (adenoma)
-carcinoma, -sarcoma indicate malignant tumors
Carcinoma: malignant tumor of epithelial origin
(adenocarcinoma)
Sarcoma: malignant tumor of mesenchymal origin
Leukemia: malignant growth of white blood cells

5
Epidemiology and Cancer Risk Factors
Cancer is 2nd leading cause of death in the
U.S.

Most cancer deaths occur in individuals over
age 55

Men have 1:2 risk of developing cancer;
women have 1:3 risk

5-year survival rate: 66%
6
Epidemiology and Cancer Risk Factors
(Cont.)
7
Fig. 7-2
Epidemiology and Cancer Risk Factors
(Cont.)
One third of cancer-related deaths may be
attributable to lifestyle factors
Tobacco use
Nutrition
Obesity
Sun exposure (skin cancer)
Sexual exposure to HPV (cervical cancer)

Early screening aids in early detection
8
Tobacco Use
Death rate from lung cancer has dramatically
increased (may be directly related to
smoking)

Lung cancer: leading cause of death in men
and women; worst survival rate

Also linked to pancreatic, kidney, bladder,
mouth, esophageal, and cervical cancers
9
Tobacco Use (Cont.)
10
Fig. 7-3
Tobacco Use (Cont.)
Two types of carcinogens
Initiator (causes genetic damage)
Promoter (promotes tumor growth)

Tobacco smoke contains both types

Second-hand smoke also increases risk for
lung cancer
11
Tobacco Use (Cont.)
12
Fig. 7-4
Nutrition
Dietary factors believed to be related to
cancer risk

Fat
Fiber
Alcohol
Antioxidants
13
Genetic Mechanisms of
Cancer
Carcinogen
Potential cancer-causing agent

Proto-oncogene
Overactivity of cancer-critical genes contributes to cancer

Oncogene
Proto-oncogene in its mutant overexpressed form

Tumor suppressor gene
Too little gene activity; inhibits cell proliferation
Cancers may arise when tumor suppressor gene function is
lost or abnormally inhibited
14
Proto-Oncogenes
Normal cellular genes that can be
transformed into oncogenes by activating
(gain-of-function) mutations

Code for
Growth factors
Receptors
Cytoplasmic signaling molecules
Nuclear transcription factors
15
Proto-Oncogenes (Cont.)
16
Fig. 7-5
Growth Factors (Mitogens)
Small CellManufactured Peptides

Secrete into extracellular space

Diffuse to nearby cells

Interact with receptors on target cell surface

Activate signaling cascade; can produce
autocrine signaling
17
Growth Factor Receptors
Transmembrane proteins
Mitogen-binding area on outside of cell
Enzyme-activating area on inside of cell

Will bind with only one particular mitogen

Binding activates cell proliferation
18
Cytoplasmic Signaling Pathways
Involve numerous enzymes and chemicals
that normally function to transmit signals
from activated receptors at cell surface to cell
nucleus

Mutant proto-oncogene can activate pathway,
even when no signal received at cell surface
19
Transcription Factors
Proteins that must be assembled at the
promoter area to begin gene transcription

Normally sequestered and prevented from
indiscriminate activity until appropriate signals
cause their release

Mutations may cause overproduction of
transcription factors
20
From Proto-Oncogene to Oncogene
Proto-oncogenes become activated oncogenes when
mutations alter their activity so that proliferation-
promoting signals are generated inappropriately

Oncogenes introduced to host cell by retrovirus
Proto-oncogene within cell suffers a mutagenic event
DNA sequence may be lost/damaged and allows proto-
oncogene to become abnormally active
Error in chromosome replication causes extra copies of
proto-oncogene in the genome
21
From Proto-Oncogene to Oncogene
(Cont.)
22
Fig. 7-6
From Proto-Oncogene to Oncogene
(Cont.)
Retrovirus
HIV
Kaposis sarcoma

Epstein-Barr virus
Burkitt lymphoma

Human T-lymphocyte virus type 1
Adult T-cell leukemia/lymphoma

Composed of RNA

Contains reverse transcriptase enzyme
Directs synthesis of a DNA copy of viral RNA
23
From Proto-Oncogene to Oncogene
Transcription Factors
24
Fig. 7-7
Tumor-Suppressor Genes
Contribute to cancer only when not present

Both copies of tumor suppressor genes are
inactivated when cancer develops

One can inherit a defective copy of tumor
suppressor gene from 1 or both parents
25
Tumor-Suppressor Genes (Cont.)
26
Fig. 7-8
Rb Gene
Codes for large protein in cell nucleus (pRb) that is
the master break for the cell cycle

Blocks cell division
Binding transcription factors
Inhibits T factors from transcribing genes that initiate cell
cycle

Can be induced to release transcription factors when
sufficiently phosphorylated

An inactivating mutation of the Rb gene removes 1
major restraint on cell division
27
Rb Gene (Cont.)
28
Fig. 7-9
p53 Gene
Most common tumor-suppressor gene defect
identified in cancer cells
More than of all types of human tumors lack
functional p53

Inhibits cell cycling

Accumulates only after cellular (DNA)
damage

Binds to damaged DNA and stalls division
29
p53 Gene (Cont.)
30
Fig. 7-10
p53 Gene (Cont.)
May direct cell to initiate apoptosis

Allows genetically damaged/unstable cells to
survive and continue to replicate

Chemotherapy/radiation
Damages target cell to trigger p53-mediated cell
death

Cancer cells that lack functional p53 may be
resistant to chemotherapy/radiation
31
BRCA1 and BRCA2 Genes
Breast cancer genes

Family history and inherited defect in BRCA1
increases risk of breast and ovarian cancer
32
BRCA1 and BRCA2 Genes (Cont.)
33
Fig. 7-11
Multistep Nature of Carcinogenesis
Initiation
Promotion
Progression
34
Multistep Nature of Carcinogenesis
(Cont.)
35
Fig. 7-12
Multistep Nature of Carcinogenesis
(Cont.)
36
Fig. 7-13
Initiation
Initiating events
Genetic mutations
Inappropriately activate proto-oncogenes
Inactivate tumor suppressor genes

Proliferation
Required for cancer development
(nonproliferating cells cannot cause cancer)

Each type of cancer has its own combination
of mutations that lead to malignancy
37
Initiation (Cont.)
38
Fig. 7-14
Initiation (Cont.)
Complete carcinogens
Capable of initiating cell damage as well as
promoting cellular proliferation

Partial carcinogens
Promoters that stimulate growth
Incapable of causing genetic mutations sufficient
to singly initiate cancer
39
Promotion
Stage during which mutant cell proliferates
Activation of another oncogene
Inactivation of tumor suppressor gene
Nutritional factors
Infection

Regulated by many hormonal growth factors
(hormones may be promoters for certain
cancers)
Estrogen
Testosterone
40
Progression
Mutant, proliferating cells begin to exhibit
malignant behavior

Malignant cells commonly produce
telomerase (an enzyme that repairs telomeres
and may be a key for attaining immortality)

Cells whose phenotype gives them a growth
advantage proliferate more readily

Requires multiple steps

41
Progression (Cont.)
42
Fig. 7-15
Metastasis
Process by which cancer cells escape their
tissue of origin and initiate new colonies of
cancer in distant sites

Specialized enzymes and receptors enable them to
escape their tissue of origin and metastasize
43
Metastasis (Cont.)
44
Fig. 7-16
Patterns of Spread
Cancer cells generally spread via circulatory
or lymphatic systems

Tumor markers help identify parent tissue of
cancer origin
Rely on some retention of parent tumor
characteristics
Some released into circulation
Others identified through biopsy
Enzymes typically used as tumor markers
Help track tumor activity
45
Angiogenesis
Process by which cancer tumor forms new
blood vessels in order to grow

Usually does not develop until late stages of
development

Triggers are not generally understood

Inhibition of angiogenesis is important
therapeutic goal
46
Grading and Staging of
Tumors
To predict clinical behavior of malignant
tumor and guide therapeutic management

Grading
Histologic characterization of tumor cells
Degree of anaplasia
3 or 4 classes of increasing degrees of malignancy
47
Grading and Staging of Tumors (Cont.)
Staging
Location and patterns of spread within the host
Tumor size, extent of local growth, lymph node
and organ involvement, distant metastasis

TNM system most widely used

Results of staging determine treatment
modality
48
Grading and Staging of
Tumors
Fig. 7-17
Effects of Cancer on the Body
Depends on location of tumor and extent of
metastasis

Early stages may be symptomatic

Tumor increases in size and spreads; more
symptoms become apparent
Effects of Cancer on the Body (Cont.)
Fig. 7-18
Warning Signs of Cancer
Change in bowel or bladder habits
A sore that does not heal
Unusual bleeding or discharge
Thickening or lump in breast or elsewhere
Indigestion or difficulty swallowing
Obvious change in wart or mole
Nagging cough or hoarseness
Warning Signs of Cancer in
Children
Continued, unexplained weight loss
Headaches with vomiting in the morning
Increased swelling or persistent pain in bones or joints
Lump or mass in abdomen, neck, or elsewhere
Development of whitish appearance in pupil of the eye
Recurrent fevers not caused by infections
Excessive bleeding or bruising
Noticeable paleness or prolonged tiredness
Pain
Common and feared complication

May be due to metastasis, tissue
destruction/inflammation

May be caused by cancer treatment

Usually controlled with analgesics
Cachexia and Immune System Deficits
Cachexia
Overall weight loss and generalized weakness
Loss of appetite (anorexia)
Increased metabolic rate
Nausea/vomiting

Immune system suppressed by cancer cell
secretions

Some cancers can elude immune system
detection
Bone Marrow Suppression
Contributes to anemia, leukopenia, and
thrombocytopenia

Due to invasion and destruction of bone
marrow cells, poor nutrition, and
chemotherapy

Anemia: Deficiency in circulating red blood
cells
Leukopenia
Deficiency in circulating white blood cells
Primary cause
Malignant invasion of bone marrow
Contributing factors
Malnutrition
Chemotherapy

Opportunistic organisms can only infect
immunocompromised host

Infections difficult to manage, prevent
Thrombocytopenia
Deficiency in circulating platelets
Important mediators in blood clotting
Predispose to life-threatening hemorrhage

Anemia, leukopenia, thrombocytopenia can
all be managed by blood replacement therapy
Other Effects
Hair loss and mucositis
Complications of chemotherapy and radiation
therapy
Mucositis primary source of cancer pain and anorexia
May provide a portal for infection

Paraneoplastic syndromes
Hypercalcemia
Cushing syndrome secondary to ACTH secretion
Hyponatremia and water overload secondary to
excess ADH secretion
Cancer Therapy
Early detection best prognosis for cure

Mainstays of therapy
Surgery
Radiation therapy
Chemotherapy
Drug therapy

Emerging therapies
Immunotherapy
Targeted molecular therapies
Stem cell transplantation
Cancer Therapy (Cont.)
Fig. 7-19
Surgery
Majority of patients with solid tumors are
treated surgically

Main benefit: removal of tumor with minimal
damage to other body cells

Lymph nodes biopsied and/or removed

Commonly accompanied by radiation
therapy or chemotherapy
Radiation Therapy

Kills tumor cells by damaging nuclear DNA

Kills cells that are nonresectable due to location,
missed by surgery, or undetected

May not kill cells directly, but initiates apoptosis

Small doses of radiation over several treatments
(difficult to kill at once because cells on different
cycles)

Some normal cells killed during radiation therapy
Drug Therapy
Systemic administration of anticancer
chemicals to treat cancers known or
suspected to be disseminated in the body

Finds cancer cell targets in the body

Most are cytotoxic

Not selective for tumor cells (normal cell
death may also occur)
Drug Therapy (Cont.)
Most effective on rapidly dividing cells
Several courses ensure all cancer cells killed
Serious side effect: bone marrow suppression
Immunotherapy
Primarily involves use of:
Interferons
Glycoproteins produced by immune cells in response to
viral infection
Interleukins
Peptides produced and secreted by white blood cells
Monoclonal antibodies
Antibodies with identical structure that bind with
specific target antigens

Generally used as adjuncts to surgery,
irradiation, and chemotherapy
Gene and Molecular Therapy
May have high therapeutic potential

May be used to suppress overactive oncogenes or
replenish missing tumor suppressor function

Current uses
Genetic alteration of tumor cells to make them more
susceptible to cytotoxic agents or immune recognition
Genetic alteration of immune cells to make them more
efficient killers of tumor cells

Can be directed at cells other than cancer cells
Stem Cell Transplantation
Used to manage life-threatening disorders in
which patients bone marrow cannot
manufacture white blood cells, red blood cells, or
platelets

Also applied to other malignancies and to
nonmalignant disorders

Provides a method to restore bone marrow
function after high-dose irradiation or
chemotherapy