BIOLOGY OF CANCER
AND TUMOR SPREAD
Chapter 9
First Medial Description :Egyptian
Text@ 2500BC-Imhotep
Mastectomy: Johannes Scultetus
(1595-1645)-fire, acid, leather binding
Tumor – 1922
“it is tissue overgrowth that is independent of
the laws governing the remainder of the
body”
“neoplastic overgrowth serves no useful
purpose to the organism”
Cancer




Modern: “uncontrolled clonal proliferation of cells
that can arise from virtually any cell type in the
body”
Derived from the Greek word for crab karkinoma
– Hippocrates (460 – 370 BC)
Malignant tumors
Tumor
 Also
referred to as a neoplasm – new growth
Clonal Proliferation of a Single
Cell
“Storm Troopers: Star Wars”
Benign vs. Malignant Tumors
Benign
Grow slowly
Malignant
Grow rapidly
Well-defined capsule
Not encapsulated
Not invasive
Well differentiated
Invasive
Poorly differentiated
Low mitotic index
High mitotic index
Do not metastasize
Can spread distantly
(metastasis)
Classification & Nomenclature

Benign
 Named
according to the tissue from which
they arise, and includes the suffix - “oma”
Lipoma
Glioma
Leiomyoma
Chondroma
Classification & Nomenclature
•
Malignant tumors
–
–
–
–
–
–
Named according to the cell type from which
they arise
Epithelial tissue – carcinoma
Ductal or glandular epithelium –
adenocarcinoma
Example: mammary adenocarcinoma
Connective tissue – sarcoma
Example: rhabdomyosarcoma
Lymphatics – lymphomas
Blood forming cells – leukemia
Classification & Nomenclature

Carcinoma in situ (CIS)
 Preinvasive
epithelial malignant tumors of glandular or
squamous cell origin that have not broken through the
basement membrane or invaded the surround stroma
 Cervix, skin, oral cavity, esophagus and bronchus
(epithelium)
 Stomach, endometrium, breast, large bowel (glandular)
Stages of Cancer Spread
“important component to diagnosis and treatment”
 Physical findings
 Laboratory tests – histological/biochemical/genetic
 Imaging studies
Breast Cancer
Cancer Cells

Transformation
 Autonomy
Cancer
cells: independent from normal
cellular controls
 Anaplasia
Loss of differentiation (specialization and
organization)
“without form” - pleomorphic
Cancer and Stem Cells

Stem cells self-renew
 Cell

divisions create new stem cells
Stem cells are pluripotent
 Ability
to differentiate into multiple different
cell types
Stem Cell
Cancer…a genetic disease

DNA
the cell)
 “normal

DNA**
 1.
RNA
Proteins(workhorse of
regulated growth”
RNA**
Proteins**
Plasma membrane **
 2. Intracellular enzyme system**
 3. Hormones/Growth factors**
“unregulated growth…colonal proliferation
** multiple mutations- how many?
Cancer…a genetic disease


DNA**
Example:
RNA**
 EarlyCDT-Lung
Proteins**(antigen)
(Oncoimmune)-blood test
6
cancer associated antigens (p53, +5)
 Autoantibodies…against abnormal proteins**
Medscape Medical News Sept 20,2010
Tumor Markers (DNA…RNA…Proteins)

Tumor cell markers (biologic markers) are
substances produced by cancer cells or that are
found on tumor plasma cell membranes, in the
blood, CSF, or urine
 Hormones
 Enzymes
 Genes
 Antigens
 Antibodies
Tumor Markers Table 9-2

Used
 Screen
and identify individuals at high risk
for cancer(CA-125, PSA, CEA, Bense Jones
protein)
 Diagnose specific types of tumors
 Observe clinical course of cancer
Types of Genetic Lesions in Cancer






Point mutation
Subtle alterations (insertions, deletions,
translocation)
Chromosome changes (aneuploidy and loss of
heterozygosity)
Amplification
Gene silencing
Exogenous sequences (tumor viruses)
Genetic Basis of Cancer

Cancer-causing mutations
 Disease
of aging (more mutation over time)
 Clonal proliferation or expansion
Mutation leads to a Darwinian
Survival advantage
(↑ growth or ↓ apoptosis)
 Multiple mutations are required before
cancer can develop (how many?)
Oncogenes and Tumor-Suppressor Genes

Proto-oncogene/Oncogenes
 Mutant
genes that in their non-mutant state direct
protein synthesis and cellular growth (accelerationpedal to the metal)

Tumor-suppressor genes
 Encoded
proteins that in their normal state negatively
regulate proliferation
 Also referred to as antioncogenes (put the brakes on)
Types of Mutated Gene:” 7 mechanisms”




Secretion of growth factors (autocrine stimulation)
Increased growth factor receptors (HER2/neu)
Signal from cell-surface receptors is mutated to the
“on” position
Mutation in the ras intracellular signaling protein –
(cell growth without growth factors) : “kinase”
“all lead to increase growth”
Types of Mutated Genes
Types of Mutated Genes:”7 mechanisms”



Inactivation of Rb tumor suppressor(tumor
suppression) inherited
Activation of protein kinase* that drive the cell
cycle (oncogene)
Mutation in the p53 gene (# apoptosis)-tumor
suppression gene 17p13.1
 *-PO4: activates and amplifies enzymatic processes over and
over…
Types of Mutated Genes:Bowel
Cancer
Question: How many mutations
does it take to cause cancer?

“Cancer Genome Atlas”-breast cancer 127
mutations
 Driver
mutations: 11-15 (average=13)-directly
cause growth and survival of the cancer; hit
oncogenes/tumor suppression genes; limited number
exist
 Bystander/passenger
mutations: accidental
copying of DNA; no impact on the biology of cancer
Driver Mutations

“Core metabolic pathway leads to dysregulation
of any tumor”
 One
or more proto-oncogene/tumor suppression
gene may skip mutation, but others mutations
activate the core pathway
CANCER
Angiogenesis (core pathway)


Growth of new blood vessels
Advanced cancers can secrete angiogenic factors
(VEGF)
Telomeres and Immortality: core





Body cells are not immortal and can only divide a
limited number of times (double about 50 times Hayflick Limit: 1961)
Telomeres are protective cap on each chromosome
and are held in place by telomerase (germ cells &
stem cells) enzyme
Telomeres become smaller and smaller with each
cell division- “somatic cells” – quit dividing/die
Telomerase enzyme: rebuilds telomeres
Nobel Prize 2009:Blackburn, Greider, Szostak
Telomeres and Immortality
Mutations of Normal Genes → Cancer Genes

Point mutation (most common)
 Change
of one or a few nucleotide base pairs
 ras gene (pancreatic, colon)

Chromosome translocation
A
piece on one chromosome is transferred to another
 t(8;14) Burkitt Lymphoma
 t(9;22) chronic myeloid leukemia (Philadelphia
chromosome – 1960)
Mutations of Normal Genes → Cancer Genes

Chromosome amplification
 Duplication
of a small piece of chromosome
(DNA) over and over
 Result in ↑ expression of an oncogene
 N-myc oncogene @ 25% amplification
Mutation of Normal Genes
Oncogenes and Tumor-Suppressor Genes

Oncogenes
 Mutant
genes that in their non-mutant state direct
protein synthesis and cellular growth (jammed
acceleration)

Tumor-suppressor genes
 Encoded
proteins that in their normal state negatively
regulate proliferation
 Also referred to as antioncogenes (put the brakes on)
Mutations of Normal Genes →Cancer Genes

Tumor-suppression genes(“inherited”)
 Unregulated
cellular growth (put on the brakes) Rb gene
(inactivated) → retinoblastoma, lung, breast, bone
 Two
hits or mutations to inactivate the genes(Rb)
 Childhood
retinoblastomas: 2 forms-inherited(2-6
mo.)/sporadic(2-4 yrs)
 De Gouvea(1872)-Brazilian Ophthmol. :young boy & his 2
daughters= cancer can be inherited
Mutations of Normal Genes → Cancer Genes

Loss of heterozygosity
 Loss
of a chromosome region in one chromosome
 Unmasks mutation in the other locus of a tumor
suppression gene
Mutation of Normal Genes: Tumor
Suppression Genes
Mutations of Normal Genes → Cancer Genes

Gene silencing
 No
mutation or change in DNA sequence
 Whole regions of chromosomes are shut off
while the same regions in other cells remain
active
 Shuts off critical tumor suppression genes
Mutations of Normal Genes → Cancer Genes

Caretaker genes(“inherited”)
 Encode
for proteins that are involved in repairing
damaged DNA (UV or ionizing radiation, chemicals and
drugs)
 Loss lead to increase mutation rates

Chromosome instability
 Increase
in malignant cells
 Results in chromosome loss, loss of heterozygosity and
chromosome amplification
 Loss
of tumor suppression genes with
overexpression of oncogenes
Genetics and Cancer-Prone Families

Somatic cells – most cancers
 Exposure
to mutagen
 Defect in DNA repair
 Not inherited

Germ line cells (sperms and eggs)
 Vertical
transmission of cancer causing genes
 Tumor suppression and caretaker genes
 One mutant allele (mom or dad), loss of heterozygosity
in some cells → tumors
Viruses and Cancer

Implicated
 Hepatitis
B & C viruses*
 Epstein-Barr Virus (EBV)
 Kaposi’s Sarcoma Herpes Virus (KSHV)
 Human Papillomavirus (HPV)*
 Human T cell Leukemia – Lymphoma Virus (HTLV)
*80% virus-linked cancers
Bacterial Causes of Cancer

Helicobacter pylori
 Chronic
infections associated with:
Peptic ulcer disease
Stomach carcinoma
Mucosa-associated lymphoid tissue
lymphoma
Immunity and Cancer

Surveillance – “nonself”
 Viral-induced
cancers
Immune defect –
HIV /immunosuppressants
↑ viral cancers
Organ transplant – immunosuppression –
little or no ↑ in prevalent cancers
So → ?
Immunity and Cancer

Chronic inflammation – “complex”
 Cytokine
release form inflammatory cells – may
promote growth
 Free radicals
 Mutation promotion
 ↓ response to DNA damage

Diseases
colitis – 30x ↑
 Liver – HBV/HBC - ↑ risk
 Lung cancer – chronic asthma ↑66%
 Ulcerative
Cancer Progression and Metastasis

Metastasis – “a defining characteristic of cancer”
 Localized
 Breast

5 year survival > 90% - local
5 year survival < 3% - metastatic
Pattern of spread
 Vascular,

may be cured(“in situ”)
:
lymphatic and natural tissue planes
Selectivity
 Breast
to bone, not kidney or spleen
 Lymphomas to spleen, not bone
Distant Metastasis
Cancer cells must detach(invade) and migrate from its
primary location
 Survive passage through the body
 Attach, invade and multiply while stimulating
angiogenesis
Thus:
#1. Vast majority of cancer cells do not have the
ability to form metastasis
“appropriate cancer “seed” and a permissive “soil”

Therapy for Cancer

Surgery (1800-1900s)
 Halsted
Radical vs simple mastectomy vs local excision
+ radiation

Chemotherapy 3 to 7 drugs (ALL)
 Bone


marrow transplant-maximum chemotherapy
Radiation to tumors(Hodgkin’s lymphoma)
Targeted: mutated gene’s protein
 Breast
cancer +Her-2 membrane receptor:
antibody:Herceptin
 CML: kinase signal
inhibitor: Gleevec
Why do the cancer cells become
resistant to chemo/targeted therapy?


A few stem cells of the cancer mutate and
produce a new protein product that specific
chemo/targeted therapy can no longer inhibit and
kill.
A new generation of resistant cancer cells
evolves
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
Mechanism
•
–
Pressure, obstruction, invasion of sensitive structures,
stretching of visceral surfaces, tissue destruction and
inflammation
Priorities of treatment
1. Control
– rapid and complete (patient)
2. Prevention – of recurrence
Clinical Manifestations of Cancer
 Fatigue
 Tiredness,
weakness, lack of energy, exhaustion,
lethargy, inability to concentrate, depression, sleepiness,
boredom, lack of motivation and
↓ mental status
 Most frequently reported symptom – cancer/treatment
 Mechanism – poorly understood
Clinical Manifestations of Cancer
• 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
Mechanism – multifactoral
•
•
•
Hormones (leptin)
Neuropeptides
Pro-inflammatory cytokines
Cachexia
Clinical Manifestations of Cancer
 Anemia
 Decreased
amount of hemoglobin in the blood
 Mechanisms
 Chronic
bleeding resulting in Fe deficiency, severe
malnutrition, medial therapies or malignancy in
blood forming organs
 Suppression of erythropoietin on the bone marrow
 rHuEPO
Clinical Manifestations of Cancer
 Leukopenia and thrombocytopenia
 Direct
tumor invasion to the bone marrow
 Chemotherapy toxic to bone marrow

Infection
 Risk
increases when the absolute neutrophil and
lymphocyte counts fall
ANC = WBC x (% neurophils + % bands), if < 1000
protective → isolation)
[Table 10-3 Review]
Clinical Manifestations of Cancer
 Paraneoplastic syndromes
 Symptom
complex unexplained by local or distant
spread of the tumor or by the effects of hormones
released by the tissues from which the tumor arose
 10% of individuals
 Earliest
symptoms of an unknown cause
 May represent serious and life threatening problems
 May mimic cancer progression and interfere with
appropriate treatment.
[Table 10-4] Review
Side Effects of Cancer Treatment
“targeting the most rapidly growing cells”
 Gastrointestinal tract
 Oral
ulcers, malabsorption and diarrhea
 Nausea and vomiting → antiemetic therapy
 Supplemental nutrition (enteral or parenteral)

Bone marrow
– ↓RBC with fatigue
 Platelets – bleeding
 White blood cells – infection (ANC)
 Anemia