Reflection

Chapter 12Cancer Biology
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Cancer
Is derived from Greek word for “crab”—
karkinoma.
 Is another name for malignant tumor.
 Cancer is not a tumor.

➢ Is an abnormal growth resulting from uncontrolled
proliferation; it serves no physiologic function.
➢ Is also referred to as a neoplasm: New growth.
Link to video on Animated Introduction to Cancer Biology
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2
Benign vs. Malignant Tumors
3
Benign vs. Malignant Tumors
Benign
Malignant
Slow growth
Rapid growth
Well-defined capsule
Not encapsulated
Not invasive
Invasive
Well differentiated
Poorly differentiated: Anaplasia
Low mitotic index
High mitotic index
Does not metastasize
Can spread distantly (metastasis)
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4
Classification and Nomenclature

Benign tumors
➢ Are named according to the tissues from which they
arise and include the suffix, -oma.
• Lipoma: Fat
• Leiomyoma: Smooth muscle
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5
Classification and Nomenclature (Cont.)

Malignant tumors
➢ Are named according to the tissues from which they
arise.
• Malignant epithelial tumors: Carcinomas

Adenocarcinoma: Ducts or glands
• Malignant connective tissue tumors: Sarcomas
• Cancers of lymphatic tissue: Lymphomas
• Cancers of blood-forming cells: Leukemias
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6
Classification and Nomenclature (Cont.)

Carcinoma in situ (CIS)
➢ Are preinvasive epithelial malignant tumors of
glandular or squamous origin.
➢ Have not broken through the basement membrane or
invaded the surrounding stroma.
➢ Are not malignant.
➢ Three prognoses:
1. Can remain stable for a long time.
2. Can progress to invasive and metastatic cancers.
3. Can regress and disappear.
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7
Progression from Normal to Neoplasm
8
Classification and Nomenclature
Question 1
A nurse learns that an individual has benign
tumors. What does this mean?
The tumors
1. are poorly differentiated.
2. are encapsulated.
3. may develop anaplasia.
4. may spread to a distant location.
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9
Biology of Cancer Cells
Cancer is predominantly a disease of aging.
 Clonal proliferation or expansion occurs.

➢ Is due to a mutation; that is, a cell acquires characteristics
that allow it to have selective advantage over its
neighbors.
• Increased growth rate or decreased apoptosis

Multiple mutations are required before cancer
can develop.
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10
Transformation = process of accumulating
mutations leading cell to become a cancer cell
➢ Autonomy: cell no longer relies on extracellular signals to
control proliferation
➢ Lacks contact inhibition = grow and pile up
➢ Anchorage independent = grow without attachment to
surface
➢ Anaplasia = loss of tissue organization and proper
differentiation
➢ Immortal = acquire an abnormal lifespan with apparently
unlimited potential for proliferation
Instructor’s note
Please watch the instructor’s micro-lecture
prepared for you to better understand the genetic
mechanisms of carcinogenesis.
Link to Microlecture on Mechanisms of Carcinogenesis
12
Biology of Cancer Cells (Cont.)

Mutation
➢ Alteration in DNA sequence affecting expression or
function of a gene
➢ Point mutations: small-scale changes
➢ Driver mutations: “drive” progression of cancer
➢ Passenger mutations: random events

Gene amplification
➢ Repeated duplication of chromosome
➢ 10s or 100s of gene copies made
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13
Biology of Cancer Cells (Cont.)

Chromosome translocation
➢ Large changes in chromosome structure
➢ Piece of one chromosome is translocated to another
chromosome.

Clonal proliferation (clonal expansion)
➢ Cancer cell progeny can accumulate faster than
nonmutant neighbors.
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14
Biology of Cancer Cells (Cont.)

Malignant transformation
➢ Is the process during which a normal cell becomes a
cancer cell.
➢ Heterogeneous mixture of cancer cells
➢ Stroma: Tumor microenvironment
Cancer heterogeneity: due to proliferation and
mutation
 Cancer development is similar to wound healing.

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15
Oncogenes and Tumor-Suppressor
Genes

Three key genetic mechanisms have a role in
human carcinogenesis.
1. Activation of proto-oncogenes, resulting in
hyperactivity of growth-related gene products (called
oncogenes)
2. Mutation of genes, resulting in the loss or inactivity of
gene products that would normally inhibit growth
(called tumor-suppressor genes)
3. Mutation of genes, resulting in an overexpression of
products that prevent normal cell death or apoptosis,
thus allowing continued growth of tumors
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16
Oncogenes and Tumor-Suppressor
Genes (Cont.)

Oncogenes
➢ Are 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.
➢ Are also referred to as anti-oncogenes.

Proto-oncogenes
➢ Are normal nonmutant genes that code for cellular
growth.
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17
Oncogenes and Tumor-Suppressor
Genes (Cont.)

Oncogene activation
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18
Evading Growth Suppressors
Secretion of growth factors (autocrine stimulation)
 Increase of growth factor receptors
 Mutation of the signal from cell surface receptor in the
“on” position
 Mutation in the Ras intracellular signaling protein
 Inactivation of retinoblastoma protein (Rb) tumor
suppressor
 Activation of protein kinases that drive the cell cycle
 Mutation in the TP53 gene (tumor-suppressor gene)

➢ Suppression of normal apoptosis
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19
Caretaker Genes

Caretaker genes
➢ Are responsible for the maintenance of genomic
integrity.
➢ Encode proteins that are involved in repairing
damaged DNA, such as the damage that occurs with
errors in DNA replication, mutations caused by
ultraviolet or ionizing radiation, and mutations caused
by chemicals and drugs.
➢ Loss of function of caretaker genes leads to
increased mutation rates.
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20
Genomic Instability
Results from epigenetic silencing (modulation of
gene).
 Mutations in caretaker genes that protect
genome and DNA repair increase genomic
instability and risk of cancer


Link to Instructor’s recording on Genomic
Instability
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21
Genomic Instability (Cont.)

Chromosome instability (CIN) also appears to be
increased in malignant cells.
➢ May be caused by malfunctions in the cellular
machinery that regulates chromosomal segregation at
mitosis.
➢ Results in a high rate of chromosomal loss, as well as
a loss of heterozygosity and chromosomal
amplification; each of these events can accelerate the
loss of tumor-suppressor genes and the
overexpression of oncogenes.
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22
Genomic Instability (Cont.)
Gene expression networks can be regulated by
changes in miRNAs or miRs.
 Oncomirs are miRs that stimulate cancer
development and progression.
 Chromosome instability: increased in malignant
cells causing high rate of chromosome loss,
heterozygosity, and amplification

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23
Genomic Instability
Question 2
Chromosome instability may result in the
overexpression of
1. tumor-suppressor genes.
2. heterozygosity.
3. oncogenes.
4. point mutations.
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24
Telomeres and Immortality
Body cells are not immortal and can divide only
a limited number of times (Hayflick limit).
 Telomeres: Are protective caps on each
chromosome that are held in place by a
telomerase.
 Telomeres become smaller and smaller with
each cell division.
 Cancer cells can activate telomeres, leading to
continued division.

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25
Telomeres and Immortality (Cont.)
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26
Instructor’s note
Now that you are familiar with the genetic mechanisms of carcinogenesis through the micro-lecture,
the next few slides will focus on the major cellular adaptations that occur with cancer.
1. Angiogenesis
2. Changes in cell metabolism
3. Role of inflammation and TAMs (tumor-associated macrophages)
4. Immune Evasion
27
Angiogenesis
Is the growth of new vessels.
 Is also called neovascularization.
 Advanced cancers can secrete angiogenic
factors to facilitate feeding of the tumor.

➢ Vascular endothelial growth factor (VEGF)
➢ Basic fibroblast growth factor (bFGF)
Link to Instructor’s recording on Angiogenesis
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28
Angiogenesis (Cont.)

Process
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29
Cancer Metabolism

Cancer cells perform glycolysis.
➢ Allows lactate and its metabolites to be used for the
more efficient production of lipids and other molecular
building blocks needed for rapid cell growth.
➢ Reverse Warburg effect: cancer cells generate large
amounts of ATP.
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30
Inflammation as a Cause for
Cancer
Chronic inflammation: Is an important factor in
the development of cancer.
 Active inflammation predisposes a person to
cancer.

➢ By stimulating a wound-healing response that
includes proliferation and new blood vessel growth

Susceptible organs
➢ Gastrointestinal (GI) tract, pancreas
➢ Thyroid gland
➢ Prostate, urinary bladder
➢ Pleura, skin
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31
Inflammation as a Cause for
Cancer (Cont.)

Examples
➢ Those with ulcerative colitis for 10 years or more have
up to a 30-fold increase in developing colon cancer.
➢ Hepatitis B (HBV) or hepatitis C (HCV) increase the
risk of liver cancer.
➢ H. pylori increases the risk of stomach cancer.
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32
Inflammation as a Cause for
Cancer (Cont.)

A tumor-associated macrophage (TAM) is the
key cell that promotes tumor survival.
➢ Develops the capacity to block cytotoxic T cell and
natural killer (NK) cell functions.
➢ Produces cytokines that are advantageous for tumor
growth and spread.
➢ Secretes angiogenesis factors.
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33
Immune System and Cancer (Cont.)

Link to video on
Tumor Immunology
and Immunotherapy
From Kumar V et al: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015,
Saunders.
Copyright © 2017, Elsevier Inc. All rights
reserved.
34
Immune System and Viral-Associated
Cancers
Tumor associated antigens: oncogenes,
antigens from oncogenic viruses, oncofetal
antigens, and altered glycoproteins and
glycolipids
 Immune surveillance hypothesis
 Immunotherapy hypothesis

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35
Immune System and Viral-Associated
Cancers (Cont.)

Immunotherapy can be either active or passive.
➢ Active: Immunization with tumor antigens to elicit or
enhance the immune response against a particular
cancer
➢ Passive: Injecting the patient diagnosed with cancer
with antibodies or lymphocytes directed against the
tumor-associated antigens
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36
Immune System and Viral-Associated
Cancers (Cont.)

Several viruses have been associated with
human cancer.
➢ Human papillomavirus (HPV)
➢ Epstein-Barr virus (EBV)
➢ Kaposi sarcoma herpesvirus (KSHV or HHV8)
➢ Human T-cell lymphotropic virus type I (HTLV-1)
➢ Hepatitis B (HBV)
➢ Hepatitis C (HCV)
➢ Cervical cancer
➢ Hepatocellular carcinoma
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37
Instructor’s note
The next few slides deal with cancer invasion and metastasis. They
highlight the main changes that occur in tumor cells for them to detach
from the original tumor and spread to a distance location to establish a
new tumor in the new location.
Link to Instructor’s recording on cancer invasion and metastasis
38
Cancer Invasion and Metastasis
Metastasis: Is the spread of cancer cells from
the site of the original tumor to distant tissues
and organs through the body.
 Is a complex process that requires cells to have
many new abilities.

➢ Spread
➢ Survive
➢ Proliferate in distant locations
➢ Destination must be receptive to growth of cancer
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39
Cancer Invasion and Metastasis (Cont.)

Invasion: Local spread
➢ Is a prerequisite for metastasis and the first step in
the metastatic process.
➢ Cancer often spreads first to regional lymph nodes
through the lymphatic system and then to distant
organs through the bloodstream.
➢ Invasion then requires that the cancer attach to
specific receptors and survive in the specific
environment.
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40
Cancer Invasion and Metastasis (Cont.)
Cancer cells secrete protease.
 Proteases digest the extracellular matrix and
basement membranes.

➢ Create pathways through which cells can move.
Metastatic cells must be able to withstand the
physiologic stresses of travel in the blood and
lymphatic circulation.
 Metastatic cells must then survive in a new
environment.

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41
Cancer Invasion and Metastasis (Cont.)

Epithelial-mesenchymal transition (EMT)
➢ Many epithelial-like characteristics (e.g., polarity,
adhesion to basement membrane) are lost.
➢ Migratory capacity increases.
➢ Resistance to apoptosis increases.
➢ Dedifferentiation to a stem cell-like state favors
growth in foreign microenvironments and the
establishment of metastatic disease.
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42
Cancer Invasion and Metastasis (Cont.)
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43
Cancer Invasion and Metastasis
Question 3
Epithelial-mesenchymal transition (EMT)
produces which result?
1. Increased resistance to apoptosis
2. Adherence to basement membranes
3. Decreased migratory capacity
4. Promotion of angiogenesis
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44
Instructor’s note
The next few slides deal with cancer invasion and metastasis and highlight the main
changes that occur in tumor cells to detach from the original tumor and spread to a
distance location and establish a new tumor in the new location.
45
Clinical Manifestations of Cancer

Paraneoplastic syndromes
➢ Symptom complexes are triggered by a cancer but
are not caused by direct local effects of the tumor
mass.
➢ Are caused by biologic substances released from the
tumor (e.g., hormones) or by an immune response
triggered by the tumor.
➢ Can be life-threatening.
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46
Clinical Manifestations of Cancer (Cont.)

Cachexia
➢ Is the most severe form of malnutrition.
➢ Leads to protein-calorie malnutrition and progressive
wasting.
➢ Manifestations
• Anorexia, early satiety, weight loss, anemia, asthenia, taste
alterations, and altered protein, lipid, and carbohydrate
metabolism
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47
Clinical Manifestations of Cancer (Cont.)

Diagnosing and staging
➢ Involves the size of the tumor, the degree to which it
has invaded, and the extent of the spread.
• Stage 1

Is confined to its organ of origin.
• Stage 2

Is locally invasive.
• Stage 3

Has advanced to regional structures.
• Stage 4

Has spread to distant sites.
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48
Clinical Manifestations of Cancer (Cont.)

Staging using the World Health Organization
TNM system
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49
Clinical Manifestations of Cancer
Question 4
A tumor that has advanced to regional
structures is in which Stage?
1. Stage 1
2. Stage 2
3. Stage 3
4. Stage 4
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50
Tumor Markers
Are substances produced by benign or
malignant cells.
 Are found on or in a tumor cell, in the blood, in
the spinal fluid, or in urine.

➢ Hormones
➢ Enzymes
➢ Genes
➢ Antigens
➢ Antibodies
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51
Tumor Markers (Cont.)

Liver and germ cell tumors
➢ Secrete a protein known as alpha fetoprotein (AFP)
into the blood.

Prostate tumors
➢ Secrete prostate-specific antigen (PSA) into the
blood.

If a tumor marker, itself, has biologic activity:
➢ Symptoms are expressed.
➢ A phenomenon known as a paraneoplastic syndrome
occurs.
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52
Tumor Markers (Cont.)

Tumor markers are used to
➢ screen and identify individuals at high risk for cancer.
➢ diagnose specific types of tumors.
➢ follow the clinical course of cancer.
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53
Tumor Markers
Question 5
Which factor indicates a recurrence of prostate
cancer?
1. Decrease in PSA
2. Increase in PSA
3. False negative
4. False positive
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54
Instructor’s Note
The next few slides cover the treatment for cancer.
Link to video on Cancer Therapies
55
Surgery
Is a definitive treatment of cancers that do not
spread beyond the limits of surgical excision.
 Palliative: Is indicated for the relief of symptoms.
 In selected high-risk diseases, surgery plays a role
in the prevention of cancer.

➢ Mutations of the APC gene have close to a 100% lifetime risk
of colon cancer: Colectomy.
➢ Women with BRCA1/2 mutations have a significantly
increased risk of breast and ovarian cancer: Prophylactic
mastectomy or bilateral salpingo-oophorectomy or both.
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56
Surgery (Cont.)
Must achieve adequate surgical margins; that is,
surgery must get it all.
 Surgeon provides critical staging information.

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57
Radiation Therapy
Is used to kill cancer cells while minimizing the
damage to normal structures.
 Ionizing radiation

➢ Damages cells by imparting enough ionizing radiation to
cause molecular damage to the DNA.
➢ Causes irreversible damage to normal cells.
• Lifetime radiation dose

Brachytherapy
➢ Seeds are implanted.
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58
Chemotherapy
Eradicates enough tumor cells to enable the body’s
natural defenses to eradicate the remaining cells.
 Can be a single-agent or combination chemotherapy.
 Induction chemotherapy: Causes shrinkage or the
disappearance of tumors.
 Adjuvant chemotherapy: Is administered after the
surgical excision with a goal of eliminating
micrometastases.
 Neoadjuvant chemotherapy: Is administered before
localized (surgical or radiation) treatment.

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O pts
Assignment Details
22FABIOL434430 PATHOPHYSIOLOGY
Not Submitted
Due
Oct 1 at 11:59 PM
Submission Types
Text Entry
Submission & Rubric
Description
I encourage everyone to participate. This assignment
enables you to think about the content for the week
and also to let me know where you are having
trouble. I may use reflections as a bonus opportunity
for Exam 2.
Week 5: Biology of Cancer (due Oct 1)
1. Why do you think it is important for your career
to learn about the biology of cancer?
2. What was the most fascinating aspect of
biology of cancer you learned this week?
3. Was there an objective you needed more
clarification on for this week?
4. After exam 1, did you make any adjustments to
how you approach the weekly material for this
course?
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