CHAPTER 7  Papillary cystadenomas- protrudes into cystic

spaces

NEOPLASIA Polyps- benign/malignant projection above the mucosal

surface
Adenomatous polyps- has glandular tissue
Cancer
 2nd leading cause of death in the USA Malignant Tumors
 Many disorders with widely different natural 1. Infiltrates
histories and responses to treatments 2. Invades and destroys adjacent structures
Eg. Hodgkin lymphoma- curable; 3. Metastasize
Pancreatic adenocarcinoma- fatal
Examples:
Nomenclature Solid mesenchymal tissues (-sarcoma)
 Fibrosarcoma
Neoplasia means “new growth,” => neoplasm  Chondrosarcoma
Neoplasm  Leiomyosarcoma- sm. ms
 Aka tumor  Rhabdomyosarcoma- sk. Ms
 an abnormal mass of tissue
 growth exceeds and is uncoordinated with that of Arises from blood forming cells
the normal tissues and persists in the same  Leukemia
excessive manner after cessation of the stimuli  Lymphoma
which evoked the change
 disorder of cell growth that is triggered by a series Epithelial malignant neoplasms (-carcinoma)
of acquired mutations affecting a single cell and  Squamous cell carcinoma
its clonal progeny  Adenocarcinoma
 causative mutations give the neoplastic cells a  Renal cell carcinoma
survival and growth advantage, resulting in  Bronchogenic squamous cell carcinoma
excessive proliferation that is independent of
physiologic growth signals (autonomous) Undifferentiated malignant tumor
Oncology- study of tumors or neoplasms  Unknown tissue origin

Two basic components: Exceptions in nomenclature

1. neoplastic cell parenchyma  Synovioma
- basis of classification of tumors and their biologic  Melanoma
behavior  Mesothelioma
2. parenchymal component  Hepatoma
- growth and spread are dependent on the stroma  Seminoma

Mixed tumors
desmoplasia- formation of an abundant collagenous 1. Divergent differentiation of a single neoplastic
stroma clone
scirrhous- stony hard. Eg, breast cancer
Ex. Mixed tumor of salivary gland
- contain epithelial components scattered within
Benign tumors (-oma); cystic, torsion
a myxoid stroma that may contain islands of
1. remain localized
cartilage or bone
2. does not metastasize 2. capable of producing epithelial and myoepithelial
3. can be surgically removed
cells
Examples: Pleomorphic adenoma- from single germ layer
Tumors of mesenchymal cells
 Fibroma Teratoma- contains recognizable mature or immature
 Chondroma cells or tissues belonging to more than one germ
Tumors derived from glands cell layer
 Adenoma - Totipotential germ cells of the ovary and
Renal tubular cells in clustered small glands testis
Ex. Ovarian cystic teratoma
Benign epithelial neoplasms - Dermoid cysts
 Papillomas - Differentiates along ectodermal lines to
 Cystadenomas- ovary create a cystic tumor lined by skin replete
 with hair, sebaceous glands, and tooth
structures
Hamartoma- disorganized benign masses; involves
normally found cells
Choristoma- heterotopic rest of cells; cells are found on
different structures or locations beyond their
actual significance
Characteristics of Benign and Malignant Tumors
1. Differentiation- degree of resemblance
normal cells in morphology and fxn
Anaplasia
- lack of differentiation
- hallmark of malignancy
- reversal of differentiation to a more primitive level
Eg.
Lipoma
- tumor of benign adipocytes
- closely resembles normal adipocytes
Adenocarcinoma of the thyroid
- well-differentiated
- normal appearing follicles
Squamous cell carcinoma
- may appear identical to normal squamous
epithelial cells
Associated morphologic changes to anaplasia:
 Pleomorphism
- variation in size and shape
- Eg. Tumor giant cells, polymorphic nucleus,
hyperchromatic nuclei
 Abnormal nuclear morphology
- nuclei are disproportionately large for the cell
- variable nuclear shape
- hyperchromatic
- abnormally large nucleoli
 Mitoses
- many cells are in mitosis
- high proliferative activity of the parenchymal
cells
- atypical, bizarre mitotic figures
- exception: normal tissues may exhibit rapid
turnover such as epithelial lining of the gut and
nonneoplastic hyperplasia
 Loss of polarity
- Disorganized orientation of anaplastic cells
 Other changes
- Increased blood supply
- large central areas of ischemic necrosis
*Note: The better the differentiation of the transformed cell,
the more completely it retains the
functional capabilities of its normal counterpart
Eg.
 Benign neoplasms & well-differentiated
carcinomas of endocrine glands secrete
hormones characteristic of their origin
 Well-differentiated squamous cell carcinomas of
the epidermis synthesize keratin
 Well-differentiated hepatocellular carcinomas
elaborate bile
Highly anaplastic
 new and unanticipated functions may emerge
 some tumors express fetal proteins
 less likely to have specialized functional activity
Eg.
Bronchogenic carcinomas
to - may produce corticotropin, parathyroid-like
hormone, insulin, glucagon, and other hormones,
giving rise to paraneoplastic syndromes
Metaplasia
- replacement of one type of cell with another type
- nearly always found in association with tissue
damage, repair, and regeneration.
- replacing cell type is better suited to local
environment alteration
Eg.
Esophagus- squamous to glandular epithelium
due to gastroesophageal reflux
Dysplasia
- disordered growth
- loss in the uniformity of the individual cells and
orientation
- may exhibit pleomorphism and abnormal nuclear
morphology
- mitotic figures are more abundant
- architecture of the tissue may be disorderly
Eg.
Dysplastic squamous epithelium
Normal: progressive maturation of tall cells in the
basal layer to flattened squames on the surface
Dysplastic: replacement of the epithelium by
basal-appearing cells with hyperchromatic nuclei
Carcinoma in situ
- preinvasive neoplasm
- dysplastic changes in full thickness of the
epithelium, but does not penetrate the basement
membrane
- may persist for years before it becomes invasive;
eg carcinomas of the skin, breast and uterine
cervix
Invasive tumor
- tumor cells breach the basement membrane
*Note: Severe epithelial dysplasia frequently antedates
the appearance of cancer
Eg. Barrett esophagus and
Long-term cigarette smokers
Dysplasia may be a precursor to malignant
transformation, it does not always progress to
cancer
 Dysplasia often occurs in metaplastic epithelium,
not all metaplastic epithelium is dysplastic
2. Local Invasion
Benign tumor
Capsule
- compressed fibrous tissue that separates the
tumor from the host tissue
- does not prevent tumor growth, makes the tumor
palpable, moveable and easily excisable by
surgical enucleation
Fibroblast- deposits ECM upon activation by hypoxic
damage resulting from the pressure of the expanding
tumor.
Exception
Hemangiomas- composed of tangled blood vessels, often
unencapsulated and permeate the site in which they arise
(e.g., the dermis of the skin and the liver); unresectable
when extensive
Malignant tumor
- poorly demarcated from the surrounding normal
tissue
- penetrate the wall of the colon or uterus
- surgical resection difficult or impossible
- necessary removal of a considerable margin of
normal tissues adjacent to the infiltrative
neoplasm to ensure complete local excision.
“Pseudoencapsulated” masses- malignant tumors that
develop enclosing fibrous capsule that penetrates the
margin and infiltrates the adjacent structures
3. Metastasis
- spread of a tumor to sites that are physically
discontinuous with the primary tumor
- reduces possibility of cure
Eg.
 Gliomas and basal cell carcinomas of the skin-
invades but rarely metastasize
 Blood cancers (leukemias and lymphomas, or
liquid tumors) have the capacity to travel to
distant sites; malignant
Pathways of Spread
 Seeding of Body Cavities and Surfaces
- Malignant neoplasm penetrates into a natural
“open field” lacking physical barriers, such as the
peritoneal cavity, pleural, pericardial,
subarachnoid, and joint spaces
Eg.
Appendiceal carcinomas or ovarian carcinomas-
fill the peritoneal cavity with a gelatinous
neoplastic mass (pseudomyxoma peritonei)
 Lymphatic spread
- most common pathway for the initial
dissemination of carcinomas
- tumors do not have lymphatics; uses LV at the
tumor margin instead
- follows the natural routes of lymphatic drainage
- Sentinel lymph node- first node in a regional
lymphatic basin that receives lymph flow
- Sentinel node mapping- injection of radiolabeled
tracers or colored dyes, examination of frozen
sections to guide surgeon for therapy
- Enlargement of nodes may be caused by the
spread and growth of cancer cells or reactive
hyperplasia
Eg.
 Carcinomas of the breast- axillary lymph nodes
 Cancers of the inner quadrants- nodes along
internal mammary arteries to infraclavicular and
supraclavicular nodes
 Carcinomas of the lung- perihilar
tracheobronchial and mediastinal nodes
 Hematogenous Spread
- typical of sarcomas but is also seen with
carcinomas
- arteries- less penetrated than veins
- venous invasion- follow the venous flow draining
the site of the neoplasm
- tumor cells often rest in the first capillary bed they
encounter
- liver (portal area drainage) and lungs (caval blood
flow) freq involved in hematogenous spread
Eg.
 Cancers proximal to vertebral column-
paravertebral plexus; also involved in vertebral
metastases of carcinomas of the thyroid and
prostate
 Renal cell carcinoma- renal vein and its branches
 Hepatocellular carcinoma- portal and hepatic
radicles
*Note: Mere anatomic localization of the neoplasm and
natural pathways of venous drainage do not wholly
explain the systemic distributions of metastases.
Eg.
 Breast carcinoma- spreads to bone
 Bronchogenic carcinomas- spread to the
adrenals and the brain
 Neuroblastomas- spread to the liver and bones
Epidemiology of Cancer
- causative link between smoking and lung cancer  Environmental Factors
- high dietary fat and low fiber in the development - Dominant risk factors for most cancers
of colon cancer
- remarkable geographic variation in the incidence  Infectious Agents
of specific cancers HPV- cervical carcinoma
- developing world
men: lung, stomach, and liver  Smoking
women: breast, cervix, and lung Lung cancer deaths
- Decreased use of tobacco products - reduction in
lung cancer deaths  Alcohol Consumption
- Improved detection and treatment- decrease in Carcinomas of the oropharynx, larynx, and
death rates for colorectal, female breast, and esophagus and, by the development of alcoholic
prostate cancer cirrhosis, hepatocellular carcinoma
- Papanicolaou (Pap) smear test- decline deaths Alcohol + tobacco- cancers in the upper airways
caused b*y cervical cancer and digestive tract
- Reduction in unknown dietary carcinogens-
decline in deaths from stomach cancer  Diet
- Race: Colorectal carcinoma, prostate
African Americans had the largest decline in carcinoma, and breast carcinoma
cancer mortality
Hispanics have a lower frequency of the most  Obesity
common tumors Weight is strongly associated with cancer risk

 Reproductive history
Cancers of the breast and endometrium-
Estrogen stimulation, if unopposed by
progesterone
Cancers of the breast- timing and number of
pregnancies

 Environmental carcinogens
ultraviolet [UV] rays, smog, well water in
Bangladesh (arsenic), medication (methotrexate),
asbestos, grilled meat, high-fat diet, alcohol
 - possess the cancer-enabling property of
genomic instability
colonic villous adenoma- if untreated
rare: uterine leiomyomas
pleomorphic adenoma
does no progress at all: lipoma

 Immunodeficiency states
- Immunodeficient patients
- T-cell immunity deficit
- caused by oncogenic viruses:
 Age lymphomas
- Most carcinomas occur >55 yo due to carcinomas
accumulation of somatic mutations associated sarcomas
with the emergence of malignant neoplasms sarcoma-like proliferations
- decline in immune competence
- Women: aged 40 to 79  Genetic Predisposition and Interaction Between
- Men: aged 60 to 79 Environmental and Inherited Factors
Common carcinomas among children: - cancer may be an inherited trait due to germline
Acute leukemia mutations
Neoplasms of the central nervous system - Tumors with a well-defined inherited component-
risk of developing the tumor can be influenced by
Common neoplasms of infancy and childhood: nongenetic factors
Neuroblastoma Eg. Inherited mutated copies of the BRCA1
Wilms tumor or BRCA2 tumor suppressor genes-
Retinoblastoma changes in reproductive history
Acute leukemias - Genetic factors can influence the development of
Rhabdomyosarcomas environmentally induced cancers
Eg. polymorphism in one of the P-450 loci
 Aquired Predisposing Conditions confers an inherited susceptibility to lung
 Chronic Inflammation cancers in cigarette smokers
- increase the pool of tissue stem cells =>
transformation
Molecular Basis of Cancer: Genetic and
- ROS production => genotoxic
- Inflammation mediators promotes bystander cell Epigenetic Alterations
survival
- Leads to metaplasia => oncogenic mutations 1. Nonlethal genetic damage
Eg. - Environmental exposure
Helicobacter pylori gastritis- gastric cancer Exogenous agents:
viruses, chemicals
 Precursor Lesions Endogenous agents:
- Localized morphologic changes products of cellular metabolism
- Arise in epithelial surfaces => carcinoma - Inherited in the germline
- do not inevitably progress to cancer; detection - Random
reduces risk of developing cancer 2. Clonal expansion of the tumor
- arise in the setting of chronic inflammation => - Inherited DNA alterations passed to daughter
metaplasia cells
Eg. - Identified by:
- Barrett esophagus DNA sequencing- point mutations
- squamous metaplasia of the bronchial Chromosomal analyses-
mucosa- smoking chromosomal translocation
- squamous metaplasia of the bladder 3. Mutation of 4 Normal Regulatory Genes:
mucosa- schistosomiasis infection  Proto-oncogenes
- colonic metaplasia of the stomach- - Cause excessive increase or new
pernicious anemia, chronic atrophic gastritis function of affected gene prod
- endometrial hyperplasia- sustained - “gain-of-function”
estrogenic stimulation of the endometrium  Tumor suppressor genes
- leukoplakia- thickening of squamous - recessive
epithelium; oral cavity or on the penis or vulva; - “loss-of-function”
=>squamous carcinoma - Exception: haploinsufficiency- loss of 1
- benign neoplasm => malignancy allele reduces the activity of the
encoded protein
  Apoptosis-regulating genes
- result in less death
- enhanced survival of the cells
- “gain-of-function” mutation in apoptosis
suppressor genes
- “loss-of-function” mutation in apoptosis
promoter genes
 DNA repair genes
- Loss of function impairs the ability of to
recognize and repair nonlethal genetic
damage
- Mutator phenotype- mutations at an
accelerated state; genomic instability
4. Carcinogenesis thru accumulation of
complementary mutations over time
 Cancer Hallmarks
- excessive growth
- local invasiveness
- metastases
 Driver mutations- dev malignant phenotype
- Initiating mutation- 1st driver mutation
- Persistence arise from cancer stem cells
with the capacity of self-renewal
 Acquisition of genomic instability
- Loss-of-function mutations in genes that
maintain genomic integrity
- Increase likelihood of acquiring in driver
mutations, and passenger mutations
which have no phenotypic consequence

Further Genetic Evolution

- Competition for access to nutrients and niches
- Subclones overgrow predecessors
- Tumor progression- tendency to become more
aggressive over time
- Clonal in origin => genetically heterogenous
constituents

2 types of mutations:
1. Mutations present in all tumor sites, presumably
present in the founding cell at the moment of
transformation
2. Unique mutations likely acquired after
transformation

Selection of the Fittest Cells

- Natural history of cancer
- Changes in tumor behavior after therapy
- Tumors that recur after chemotherapy or
radiotherapy tend to be resistant if the same
therapy is given again

Epigenetic Aberrations
- potentially reversible by drugs that inhibit DNA-
or histone-modifying factors
1. DNA Methylation- silence gene expression
2. Modification of histones- may enhance or
dampen gene expression
Cellular and Molecular Hallmarks of Cancer
Eight Fundamental Changes in Cancer Cell
Physiology
1. Self- sufficiency in growth signal
- capacity to proliferate without external
stimuli
2. In sensitivity to growth-inhibitory signals
- unresponsive to molecules that inhibit
proliferation
- inactivation of tumor suppressor genes
3. Altered cellular metabolism
- metabolic switch to aerobic glycolysis
(Warburg effect)
- enables synthesis of macromolecules
and organelles that are needed for rapid
growth
4. Evasion of Apoptosis
- resistant to programmed cell death
5. Limitless replicative potential (Immortality)
- unrestricted proliferative capacity
- stem-like property that allows cells to
avoid cellular senescence and mitotic
catastrophe
6. Sustained Angiogenesis
- induce angiogenesis for further growth
7. Ability to evade and metastasize
- cause of vast majority of cancer deaths
8. Ability to evade the host immune response
- exhibit alterations that allow evasion of
host immune response
* Genetic and epigenetic alterations that confer cancer
cell development maybe accelerated by genomic
instability and cancer-promoting inflammation.
I. Self-sufficiency in Growth Signals:
Oncogenes
Proto-oncogenes
- normal cellular genes whose products
promote cell proliferation
Oncogenes
- genes that promote autonomous cell
growth
- mutated or overexpressed versions of
proto-oncogenes that function
autonomously, having lost dependence
on normal growth-promoting signals
Oncoproteins
- protein encoded by an oncogene that
drives increased cell proliferation through
one of several mechanisms
Normal Growth Factor Signaling Pathways
1. GF binds to specific receptor
2. transient and limited activation of GF receptor
3. signal transduction to nucleus via cytoplasmic
receptor proteins and secondary messengers or
by cascade
4. induction and activation of nuclear regulatory
factors that initiate DNA transcription
5. expression of factors that promote cell division
6. changes in gene expression resulting to survival
and metabolic alterations that promote optimal
cell growth
Molecular Defects that Promote Cancer Cell
Growth
A. Growth Factors
- normal cells require growth factor
stimulation for growth via paracrine
signaling
- cancer cells synthesize own growth factors
to which they are sensitive creating an
autocrine loop
example:
glioblamstomas: PDGF and
PDGF receptor kinases
sarcomas: TGF-α and EGFR
- autocrine loop is an important pathogenic
element
 - transmembrane protein with an extracellular
ligand-binding domain and a cytoplasmic
tyrosine kinase domain

- binding of specific growth factor on the

extracellular domain elicits a conformational
change that activates the receptor

- activated receptor in turn autophosphorylates

tyrosine residues on its own tail serving as a
site for recruitment for a number of signaling
molucules including RAS and PI3K

- oncogenic versions of receptors presents

growth-factor independent tyrosine kinase
activity

Oncogenic Mutations of Clinical Importance:

ERBB1
- encodes the epidermal growth factor receptor
(EGFR)
- point mutations found in lung adenocarcinoma

ERBB2
- encodes for HER2
- amplified in certain breast carcinomas leading to
overexpression of HER2 receptor and
constitutive tyrosine kinase activity

Gene Rearrangements
- activate other tyrosine kinase receptors such as
ALK
- deletion on chromosome 5 fuses part of ALK
gene with EML4 in lung adenocarcinoma
- ALK-EML4 fusion gene encodes ALK-EML4
protein with constitutive tyrosine kinase activity

C. RAS Mutations
- most common type of abnormality involving
proto-oncogenes in human tumors

- 15-20% of all human tumors express mutated

RAS proteins

- membrane-associated small G proteins that

bind guanosine nucleotides (guanosine
triphosphate [GTP] and guanosine
diphosphate [GDP]

- normally flip back and forth between an

B. Growth Factor Receptors
- large number of oncogenes encode for
growth factor receptors
tyrosine kinase
- most important in cancer
excited signal-transmitting state in which they
are bound to GTP and a quiescent state in
which they are bound to GDP
- stimulation of receptor tyrosine kinases by
growth factors leads to exchange of GDP for
GTP and subsequent conformational changes
that generate active RAS, which in turn
stimulates both the MAPK and PI3K/AKT arms
of the receptor tyrosine kinase signaling
pathway
 - downstream kinases phosphorylate and
activate a number of cytoplasmic effectors as
well as several transcription factors that turn
on genes that support rapid cell growth
- activation of RAS is transient because RAS
has an intrinsic GTPase activity that is
accelerated by GTPase-activating proteins
(GAPs)
- GAPs prevent uncontrolled RAS activity
E. Alterations in Non-receptor Kinases
- normally localize to cytoplasm or nucleus
- mutations take form of chromosomal
translocations or rearrangements resulting to
fusion of genes encoding constitutively active
tyrosine kinase
- example of which involves ABL tyrosine
kinase in chronic myelogenous leukemia and
acute lymphoblastic leukemia

- gain of function of RAS proteins should be

mimicked by loss-of function mutations in
GAPS

D. Oncogenic BRAF and PI3K Mutations

- besides RAS other downstream factors
also contribute to cancer cell growth via
gain of function mutations

BRAF Mutations
- serine/threonine protein kinase that sits
on top of a cascade of other
serine/threonine kinases of the MAPK
family
- stimulate each of the downstream
pathways and activate transcription
factors

PI3K Mutations
- very common in certain cancer
- heterodimer comprised of a regulatory
subunit and a catalytic subunit
- in normal circumstances, PI3K is
recruited by receptor tyrosine kinase
activation to plasma membrane
associated signaling protein complexes
- activates a cascade of serine/threonine
kinases including AKT, which is a key
signaling node

mTOR
- sensor of cellular nutrient status
- activated by AKT
- stimulates protein andlipid
synthesis - in other instances tyrosine kinases may be
BAD activated by point mutations that abrogate
- pro-apoptotic protein function of negative regulatory domains that
- inactivated by AKT normally hold enzyme activity in check
,
FOXO transcription factor - example is tyrosine kinase JAK which
- promote apoptosis participate in the JAK/STAT pathway which
- negatively regulated by AKT transduces mitogenic signals from GF and
phosphorylation cytokine receptors that lack tyrosine kinase
activity
- PI3K is negativel regulated by a
“braking” factor called PTEN, a tumor F. Transcription Factors
suppressor gene whose function is lost - ultimate consequence of deregulated mitogenic
through mutation or epigenetic silencing signaling pathways is inappropriate and
in many cancers, particularly continuous stimulation of nuclear transcription
endometrial carcinomas factors that drive growth-promoting genes
MYC Oncogene
- most commonly involved in human
tumors
- normally, MYC protein concentrations
are tightly controlled at the level of
transcription, translation and protein
stability
Role in Normal and Neoplastic Cell Growth
a. activate expression of genes involved in
cell growth
b. upregulate telomerase expression
c. reprogram somatic cells into pluripotent
cells
G. Cyclin and Cyclin-dependent Kinases
- progression of cells through cell cycle is
regulated by CDKs which are activated
by binding to cyclin
- CDK-cyclin complexes phosphorylate
crucial target proteins that drive cells
forward through cell cycle
- CDK inhibitors silence CDKs and exert
negative control over cell cycle
- G1/S transition and G2/M transition are
tightly regulated
- defects in G1/S checkpoint is more
important in cancer
 gain of function mutations in D
cyclin genes promote G1/S
progression
 loss of function mutations in
tumor suppressor genes that
inhibit G1/S progression
II. Insensitivity to Growth Inhibition: Tumor
Suppressor Genes
- cancer can also arise by inactivation of tumor
suppressor genes that normally inhibit cell
proliferation
- protein products of tumor suppressors can be
transcription factors, cell cycle inhibitors, signal
transduction molecules, receptors, or factors
involved in DNA damage repair gene
loss of heterozygosity
- both alleles of a tumor-suppressor gene must be
mutated for carcinogenesis to occur
- heterozygous cells have adequate tumor suppressor
activity
- the mutation of the second normal tumor suppressor
leads to carcinogenesis
RB Gene
- governor of cell cycle
- prototypic tumor-suppressor gene
- product regulates the advancement of cells
through the G/S checkpoint
- sequestering E2F less efficiently, RB mutations
lead to increased E2F transcription factor activity
 allow cells to proceed in the cell cycle in the
absence of a growth stimulus
- several oncogenic DNA viruses (e.g., human
papillomavirus [HPV]) synthesize proteins that
bind to RB and displace the E2F transcription
factors, thereby contributing to persistent cell
cycling
RB contributes to the pathogenesis of the childhood tumor
retinoblastoma through a two-hit mechanism:
 both normal RB alleles must be inactivated (i.e., two
hits) for retinoblastoma to develop
 in familial cases (i.e., 40% of retinoblastomas), children
inherit one defective germ line copy of RB;
retinoblastoma develops when the remaining normal
RB gene undergoes somatic mutation.
 in sporadic cases, both normal RB alleles are lost by
somatic mutation in a retinoblast
Anti-proliferative effect of RB is abrogated in cancers
through:
1. loss of function mutations affecting RB
2. gene amplification of CDK4 and cyclin D genes
3. loss of cyclin-dependent inhibitors
4. viral oncoproteins that bind and inhibit RB
p53
- guardian of the genome
- prevents the propagation of genetically defective
cells
- when cells are “stressed” (e.g., by damage to
DNA), p53 undergoes post-translational
phosphorylation, releasing it from an associated
MDM2 protein that normally targets it for
degradation
- sensing of DNA damage is accomplished through
two protein kinases, ataxia-telangiectasia
mutated (ATM), and ataxia-telangiectasia and
Rad3-related (ATR)
- unshackled p53 then acts as a transcription factor
for additional genes (including miRNAs) that
arrest the cell cycle and promote DNA repair
- if DNA can be repaired during the cell cycle arrest,
MDM2 transcription increases and p53 is
subsequently degraded, allowing the cell to
progress into S phase
- If DNA damage cannot be repaired, p53 induces
cellular senescence by altering E2F signaling
pathways, or it can induce apoptosis by
increasing transcription of pro-apoptotic genes
- p53 is mutated in more than 50% of all human
cancers
- patients with germ line p53 mutations (Li-
Fraumeni syndrome) have a higher risk of
malignancy (e.g., leukemias, sarcomas, breast
cancer and brain tumors) due to inactivation of
the normal allele (i.e., LOH) in somatic cells
- p53 can also be functionally inactivated by
products of DNA oncogenic viruses
 - current non-invasive tumor imaging (i.e., positron
emission tomography [PET] scans) takes
advantage of the metabolic hyperactivity by
visualizing uptake of non-metabolizable glucose
analogue

- phenomenon is most likely explained by the

increased need of proliferating tumors to shunt
important precursor molecules into new lipid and
nucleotide synthesis rather than into energy
generation

- may also explain the role of apparent oncogenes

and tumor suppressor genes that affect
intracellular energy sensing and/or metabolic
pathways more than cell turnover

- Quiescent cells rely mainly on the Krebs cycle

for ATP production; if starved, autophagy (self-
eating) is induced to provide a source of fuel.

- When stimulated by growth factors, normal cells

markedly upregulate glucose and glutamine
uptake, which provide carbon sources for
synthesis of nucleotides, proteins and lipids.

- In cancers, oncogenic mutations involving

growth factor signaling pathways and other
key factors such as MYC deregulate these
metabolic pathways, an alteration known as the
Warburg effect.

III. Growth Promoting Metabolic Alterations: IV. Evasion Of Programmed Cell Death
The Warburg Effect
(Apoptosis)
- cancer cells preferentially utilize glycolysis for APOPTOSIS – protective response to pathologic
energy generation rather than the more energy conditions; barrier that must be surmounted by cancer to
efficient mitochondrial oxidative phosphorylation develop
pathways—even in the presence of adequate
oxygen ACCUMULATION OF NEOPLASTIC CELLS:
1) from activation of growth-promoting oncogenes
- originally described by Otto Warburg in 1931 or inactivation of growth-suppressing tumor
(hence the name) suppressor genes
2) mutations in the genes that regulate apoptosis
  BAX and BAK are activated, form pores in
APOPTOTIC SIGNALS: mitochondrial membrane
1) DNA Damage  Cytochrome c leaks into the cytosol & binds to
2) Deregulation of potent oncoproteins (e.g. MYC) APAF1
3) Anoikis or Loss of Basement Membrane  activating Caspase 9
Adhesion  activates Caspase 3
 cleaves DNA and other substrates
BIOCHEMICAL PATHWAYS LEADING TO  cell death.
APOPTOSIS
Caspases - held in check in healthy cells by members of
the inhibitors of apoptosis protein (IAP) family

EXTRINSIC PATHWAY – signal through CD95/Fas

death receptor

Process:
 CD95/Fas binds to CD95L/FasL ligand
 trimerization of receptor and cytoplasmic death
domains
 attract the intracellular adaptor protein FADD
 recruits Procaspase 8
 activated to Caspase 8 by cleavage into smaller
subunits
 activates downstream executioner AND cleave
and activate BH3-only protein BID (intrinsic
pathway)

OR

 High levels of FLIP protein

 bind death-induced signaling complex
 prevent activation of caspase 8.

 Hematopoietic and solid tumors

 overexpress at least one member of the BCL2
family of antiapoptotic proteins suggesting
suggesting evasion of apoptosis

 Chemotherapy and Radiation therapy

 kill cancer cells mainly by inducing apoptosis via
the intrinsic pathway and overexpression of BCL2
family

 MCL-1 (BCL-2 family member)

INTRINSIC PATHWAY – DNA Damage (mostly in
Cancers)
Stimuli - withdrawal of survival factors, stress, and injury
 mitochondrial outer membrane permeabilization
by BAX and BAK pro-apoptotic proteins
 BH3-only proteins (BAD, BID, PUMA) promote
apoptosis by sense death-inducing stimuli and
promote apoptosis by neutralizing the actions of
anti-apoptotic proteins like BCL2 and MCL1
 normallysubject to proteasomal degradation in
the setting of DNA Damage; but often found to be
stabilized and overexpressed in drug-resistant
cancers.
p53
 important pro-apoptotic protein that induces
apoptosis in cells that be unable to repair DNA
damage
 actions mediated by transcriptional activation of
BAX and PUMA
 (cancer) mutations directly affecting component
proteins, and loss of sensors of genomic integrity

Process:
 BH3 proteins “overwhelms” anti-apoptotic
BCL2/BCL-XL/MCL1 barrier
V. Stem Cell-Like Properties Of Cancer Cells
 Immortal cells and limitless capacity to replicate
INTRRELATED FACTORS:
1) EVASION OF SENESCENCE
 DNA damage accumulation
 upregulation of tumor suppressors p53 and
INK4a/p16
 maintain RB in a hypophosphorylated state
 RB-dependent G1/S cell cycle checkpoint is
disrupted
 cell cycle arrest
 Senescence
(See 7-34)
2) EVASION OF MITOTIC CRISIS
 Bridge-fusion breakage cycle
 p53 dysfunctional, nonhomologous endjoining
pathway is activated and join the “naked” ends of
two chromosomes results in new stranded double
DNA breaks pulled apart at anaphase
 Cells in crisis reactivate telomerase
 May arise from stem cells and continue
expressing telomerase
 Alternative lengthening of telomerase
depends on DNA recombination
3) SELF RENEWAL
 Express telomerase resistant to mitotic crisis and
avoiding genetic alterations that trigger
senescence
 MYC mutations converts somatic cell into a cell
who can de-differentiate stem cell-like state
 CA cells can repopulate from non-stem cell
populations
Divisions:
 Symmetric Division – both daughter cells
remain stem cells; may occur during
embryogenesis/stress
 Asymmetric division - only one daughter cell
remains a stem cell; in non–stem cell daughter
proceeds differentiation
pathway losing “stemness” but gaining one or
more functions in the process
Chronic Myelogenous Leukemia (CML)
 Has BCR-ABL fusion gene from transformed
hematopoietic stem cell with capacity for self-
renewal (e.g. colonic crypts)
Acute Myeloid Leukemia
 cancer stem cells arise from more differentiated
hematopoietic progenitors that acquire an
abnormal capacity for self-renewal because of
PML-RARA fusion protein
VI. Angionesis
Tumor - cannot enlarge beyond 1 to 2 mm in diameter
 maximal distance across which oxygen, nutrients,
and waste can diffuse from blood vessels
 not entirely normal; vessels are leaky and dilated,
have a haphazard pattern of connection
Neovascularization - dual effect:
1) Perfusion - supplies needed nutrients and oxygen
2) Newly formed endothelial cells stimulate the
growth of adjacent tumor cells by secreting
growth factors, such as insulin-like growth factors
(IGFs) and PDGF
Blood Supply - balance is skewed in favour of promoters
Angiogenic switch
- increased production of angiogenic factors and/ or
loss of angiogenic inhibitors
- Produced by the tumor cells / by inflammatory cells
(e.g., macrophages) / stromal cells
Local Balance of Angiogenic and Antiangiogenic
Factors:
 Relative lack of oxygen due to hypoxia
stabilizes HIF1α
 activating transcription of the proangiogenic
cytokines VEGF and bFGF guiding the growth of
new vessels toward the tumor
 Mutations involving tumor suppressors and
oncogene
 p53 stimulate expression of antiangiogenic
molecule thrombospondin-1 repressing
expression of proangiogenic molecule VEG
 provide more permissive environment for
angiogenesis.
 VEGF transcription
 RAS-MAP kinase pathway + gain-of-function
mutations in RAS or MYC upregulate VEGF
production
 bFGF and VEGF elevated levels detected serum
and urine
Bevacizumab - a monoclonal antibody; neutralizes
VEGF activity and approved for use in treatment of
multiple cancers
 can prolong life only a few at very high financial
cost
INVASION AND METASIS
 complex interactions between cancer cells and
normal stroma; major causes of cancer-related
morbidity and mortality
INVASION OF ECM
  Carcinoma must first breach => basement  Stromal
membrane => interstitial connective tissue => cells
penetrating the vascular basement membrane => produce
circulation
Steps:
Step 1: Dissociation of cancer cells from one another
 result of alterations in intercellular adhesion
molecules
 lost of E-cadherin function reducing cells’ ability
to adhere to each other; facilitates their
detachment from the primary tumor; advance into
the surrounding tissues
 epithelial tumors: adenocarcinomas of colon,
stomach, and breast
Step 2: Degradation of the basement membrane and
interstitial connective tissue
 secreting proteolytic enzymes themselves / by
inducing stromal cells (e.g., fibroblasts and
inflammatory cells) to elaborate proteases (matrix
metalloproteinases (MMPs), cathepsin D, and
urokinase plasminogen activator)
 MMPs regulate tumor invasion by remodeling
insoluble components of the basement
membrane and interstitial matrix
Step 3: Invasion involves changes in attachment
of tumor cells to ECM proteins
 Loss of adhesion in normal cells leading to
induction of apoptosis but tumor cells are
resistant to this form of cell death
 matrix modified to promote invasion and
metastasis.
Step 4: Locomotion propelling tumor cells through
the degraded basement membranes and zones of
matrix proteolysis.
 Autocrine motility factors stimulates cells attach
to the matrix at the leading edge detach from the
matrix at the trailing edge, and contract the actin paracrine effectors of cell motility, (e.g.
cytoskeleton to ratchet forward hepatocyte growth factor/scatter factor - binds to
 cleavage products of matrix components (e.g., the receptor tyrosine kinase MET on tumor cells)
collagen, laminin) and growth factors (e.g., IGFs
I and II) have chemotactic activity for tumor cells

VASCULAR DISSEMIATION and HOMING of TUMORS
Tumor cells - within the circulation tend to aggregate in
clumps
- bind and activate coagulation factors, resulting to emboli
- Arrest and extravasation of tumor emboli at distant sites
involves adhesion (integrins, laminin receptors and
proteolytic enzymes) to the endothelium followed by
basement membrane egress
CD44 adhesion molecule - expressed on normal T
lymphocytes; used by these cells to migrate to selective
sites in lymphoid tissues
The site at which circulating tumor cells leave the
capillaries to form secondary deposits is related to
anatomic location and vascular drainage of the
primary tumor and the tropism of particular tumors
for specific tissue
 Most metastases occur in the first capillary bed
available to the tumor, not all:
 Prostatic carcinoma - spreads to bone
 Bronchogenic carcinomas - adrenals and the
brain
 Neuroblastomas - liver and bones
ORGAN TROPISM
 Tumor cells - have adhesion molecules whose
ligands are expressed preferentially on the
endothelial cells of the target organ.
 Chemokines - important role in determining the
target tissues for metastasis.
 E.g Breast CA cells express - receptors CXCR4
and CCR7.
 Target tissue – nonpermissive
environment/unfavorable soil for growth of tumor
 E.g. skeletal muscle and spleen – well-
vascularized but rarely sites of metastasis.
Tumor cell dormancy – prolonged survival of
micrometastasis without progression (e.g. melanoma,
breast and prostate cancer)
 secrete cytokines, growth factors, and ECM
molecules that act on the resident stromal cells
make the metastatic site habitable for the cancer
cell.
 E.g. Breast Cancer Metastases To Bone - secrete
parathyroid
hormone-related protein (PTHRP)
stimulating osteoblasts to make RANK ligand
(RANKL) => activate osteoclasts => degrade
bone matrix and release growth factors (IGF
and TGF-β)

Molecular Genetics of Metastasis Development

Metastatic Phenotype Arises:

 Clonal evolution model – mutations accumulate
in genetically unstable cancer cells and tumor
become heterogeneous
 Metastasis signature - most if not all cells
develop a predilection for metastatic spread
during early stages of carcinogenesis
 Metastatic signature is necessary but not
sufficient for metastasis - additional mutations
are needed for metastasis to occur Role of Stromal Elements in Metastasis
 Capacity for metastasis - involves properties
intrinsic to cancer cells, characteristics of their Macrophages (in the stroma) - secrete matrix-
microenvironment (components of the stroma, degrading proteases, cleavage of ECM proteins can
presence of infiltrating immune cells, and release latent angiogenic factors and growth factors
angiogenesis) likeTGFβ
 tumor cells must co-opt these and use them to
Metastasis Oncogenes or Metastasis Suppressor promote their growth and invasion
Genes  potential targets in cancer treatment
 gene whose loss promotes the development of
metastasis without an effect on the primary tumor Evasion of Host Defense
 downregulate E-cadherin expression
SNAIL and TWIST - encode transcription factors Cancer immunoediting - ability of the immune system to
whose primary function is to promote epithelial-to- shape and mold the immunogenic properties of tumor
mesenchymal transition (EMT; mainly documented in cells leads to darwinian selection of subclones that are
Breast CA) which downregulates epithelial markers best able to avoid immune elimination
(e.g., E-cadherin) and upregulate certain
mesenchymal markers (e.g., vimentin and smooth How does a Lymphocyte Detect CA Cells?
muscle actin).
 Tumor Antigens - elicit an immune response
Classes:

Products of mutated genes

- neoplastic transformation of mutated genes encode
variant proteins that have never been seen by the immune
system and are thus recognized as nonself.
- “passengers mutations” - neutral in terms of cancer cell
fitness and thus unrelated to the transformed phenotype
=> may fall in the coding sequences of genes and give
rise to protein variants that serve as tumor antigens
=> may enter class I MHC antigen-processing pathway
and be recognized by CD8+ T cells, or class II antigen-
processing pathway (recognized by CD4+ T cells)
- Cancer patients - circulating CD4+ and CD8+ T cells
respond to peptides derived from mutated oncoproteins
(RAS, p53, and BCR-ABL)
Overexpressed or aberrantly expressed cellular
proteins
E.g tyrosinase - expressed only in normal melanocytes
and melanomas
cancer-testis antigens - encoded by genes that are silent
in all adult tissues except germ cells; sperm do not
express MHC class I antigens; tumor specific.
MAGE-1 - expressed on 37% of melanomas and a
variable number of lung, liver, stomach, and esophageal
carcinomas
Tumor antigens produced by oncogenic viruses
 viruses produce proteins that are recognized as
foreign by the immune system; produced by
latent DNA viruses
 competent immune system plays a role in
surveillance against virus-induced tumors
 Human papilloma virus (HPV) and Epstein-Barr
virus (EBV)
Oncofetal antigens
 proteins that are expressed at high levels on
cancer cells and in normal developing (fetal)
tissue
 increased in tissues and in the circulation in
various inflammatory conditions
 no evidence that oncofetal antigens are important
inducers or targets of antitumor immunity
 sufficiently specific - markers that aid in tumor
diagnosis and clinical management
 e.g. Carcinoembryonic antigen (CEA) and α-
fetoprotein (AFP)
 in the gene encoding an adapter protein, SAP,
Cell type–specific differentiation antigens
 specific for particular lineages or differentiation
stages of various cell types
 typically normal self-antigens, and therefore they
do not induce immune responses in tumor-
bearing hosts
 potential targets for immunotherapy and for
identifying the tissue of origin of tumors
 e.g. Antibodies against CD20 - transmembrane
protein expressed on the surface of all normal
mature B cells; broad cytocidal activity against
mature B-cell lymphomas and leukemias
Monoclonal antibodies – covalently coupled to drugs,
toxins, or radiochemicals; guided missile that delivers
a therapeutic warhead to cancers expressing
particular surface antigens
 CD30 - T cell lymphomas and Hodgkin
lymphomas
See Fg. 7-39
Antitumor Effector Mechanisms
Cell-mediated immunity - dominant antitumor
mechanism in vivo:
 Cytotoxic T lymphocytes - ear protective role
against virus-associated neoplasms (e.g., EBV-
and HPV-induced tumors)
- CD8+ T cells and “gene signature” associated
with CD8+ CTLs => better prognosis
 Natural killer cells -lymphocytes capable of
destroying tumor cells without prior sensitization;
first line of defense lyse a wide range of human
tumors after activation with IL-2 and IL-15
 Macrophages - potent activator is interferon-γ
(secreted by T cells and NK cells)
Immune Surveillance and Escape
- neoplasms are aggressive lymphomas composed of
mature B cells
- e.g. X-linked recessive immunodeficiency disorder
(X-linked lymphoproliferative syndrome) - mutations
participates in NK and T-cell signaling pathway
- EBV infection (boys) - evolves into a chronic or
sometimes fatal form of infectious mononucleosis or,
even worse, a lymphoma comprised of EBV-infected
B cells
Mechanisms used by Tumor Cells to escape or evade
the immune system in immunocompetent hosts:
Selective outgrowth of antigen-negative variants
 Loss or reduced expression of MHC
molecules
- fail to express normal levels of HLA class I molecules
escaping attack by cytotoxic T cells. Such cells,
however, may trigger NK cells
 Activation of immunoregulatory pathways
- engaging normal pathways of immune regulation that
serve as “checkpoints” in immune responses
- prevents sensitization but also may induce long-live
unresponsiveness in tumor-specific T cells
- downregulate expression APCs (e.g. dendritic cells)
=> fail to engage CD28 => instead activate the
inhibitory receptor CTLA-4 on effector T cells
- “checkpoint blockade” - treatments remove the
“brakes” imposed by tumors on host anti-tumor
immune responses can be highly effective in treating
cancer
 Secretion of immunosuppressive factors by
cancer cells
TGF-β – potent immunosuppressant
Galectins - skew T-cell responses; to favor
immunosuppression
Interleukin-10, prostaglandin E2, tryptophan,
and VEGF - inhibit the diapedesis of T cells from
the vasculature into the tumor bed
 Induction of regulatory T cells (Tregs)
- tumors produce factors that favor the development of
immunosuppressive regulatory T cells =>
immunoevasion
Immunomodulatory agents - antibodies that block CTLA-
4 and PD-1 potential of modern cancer immunotherapy
Genomic Instability
Genetic aberrations - increase mutation rates and
expedite the acquisition of driver mutations; required
for transformation and subsequent tumor
progression
- both copies of the DNA repair gene are lost;
haploinsufficiency of at least a subset of these genes
may also promote cancer
- born with such inherited defects in DNArepair
proteins are at a greatly increased risk of developing
cancer
- DNA-repair genes - not oncogenic, but abnormalities
greatly enhance the occurrence of mutations
Defects in three types of DNA-repair systems
 Mismatch Repair
Microsatellite instability – hallmarks; tandem repeats
of one to six nucleotides found throughout the
genome; unstable and increase or decrease in length
in tumor cells, creating alleles not found in normal
cells of the same patient.
Hereditary Nonpolyposis Colon Cancer Syndrome -
autosomal dominant disorder; predominantly the
cecum and proximal colon
- defects genes encoding DNA mismatch repair
proteins acting as “spell checkers
- proofreading function lost, errors gradually
accumulate throughout the genome
 Nucleotide Excision Repair
Xeroderma Pigmentosum - exposure to UV light in
sun rays causes cross-linking of pyrimidine residues,
preventing normal DNA replication; cancer of the skin
 Recombination Repair
- hypersensitivity to certain kinds of DNA-damaging
agents, such as ionizing radiation (Bloom syndrome
and ataxia-telangiectasia)
- Mutations: BRCA1 and BRCA2- 25% of cases of
familial breast cancer
- BRCA1 mutations - epithelial ovarian cancers,
prostate cancer
- BRCA2 - breast cancer in both men and women,
cancer of the ovary, prostate, pancreas, bile ducts,
stomach, melanocytes, and B lymphocytes
Cancers Resulting from Mutations Induced by
Regulated Genomic Instability: Lymphoid Neoplasms
- Antigen-induced cytosine deaminase (AID) -
catalyzes both immunoglobulin gene class switch
recombination and somatic hypermutation; errors
during antigen receptor gene assembly and
diversification
Cancer-Enabling Inflammation
- wounds that do not heal
- signs: anemia, fatigue, cachexia
 Release of factors that promote proliferation
- filtrating leukocytes and activated stromal cells
secrete a wide variety of growth factors (EGF and
proteases)
 Removal of growth suppressors
- growth of epithelial cells is suppressed by cell-cell
and cell-ECM interactions
- Proteases - degrade the adhesion molecules;
removing a barrier to growth
 Enhanced resistance to cell death
Anoikis - cell-cell interactions lead to a particular
form of cell death
Tumor-associated macrophages may prevent
anoikis
 Stromal cell– cancer cell interactions increase the associated with the loss of particular tumor
resistance of cancer cells to chemotherapy, suppressor genes
presumably by activating signaling pathways that - deletions involving chromosome 13q14, the site of
promote cell survival the RB gene and deletion of the VHL tumor
Inducing angiogenesis suppressor gene on chromosome 3p
- Induced by inflammatory cells release of VEGF
 Gene Amplication
Activating invasion and metastasis - Overexpression of oncogenes may also result from
- Proteases - from macrophages foster tissue invasion reduplication and amplification of their DNA
by remodeling the ECM sequences.
- TNF and EGF - directly stimulate tumor cell motility (1) double minutes multiple small
- TGF-β - promote epithelial-mesenchymal transitions; extrachromosomal structures (2) homogeneous
key event in the process of invasion and metastasis staining regions
Evading immune destruction
- TGF-β and a number of other factors - favor the NMYC - amplified in 25% to 30% in neuroblastoma; poor
recruitment of immunosuppressive T regulatory prognosis
cells or suppress the function of CD8+ cytotoxic T ERBB2 - 20% of breast cancers.
cells HER2 receptor encoded by ERBB2 - effective therapy
- macrophages - produce cytokines that promote for this molecular subset of breast cancers
angiogenesis, fibroblast proliferation, and collagen
deposition; invasive cancers  Chrymothrypsis
- e.g. Murine cancer - contain mainly alternatively - dramatic chromosome catastrophes/chromosome
activated (M2) macrophages shattering
COX2 inhibitors - decrease the incidence of colonic - DNA repair mechanisms are activated in affected
adenomas; approved for treatment of patients with familial cells haphazard way => chromosome
adenomatous polyposis rearrangements => resulting in the loss of some
Dysregulation of Cancer-Associated Genes chromosome segments
- 1% - 2% of cancers as a whole; up to 25% of
 Chromosomal Changes osteosarcomas and other bone cancers
-chromosomes may be gained or lost; changes in
chromosome number (aneuploidy) and structure
are generally considered to be late phenomena
-leukemias, lymphomas, sarcomas, carcinomas

 Chromosomal Translocations
- Translocations (most common), inversions,
amplifications, and even small deletion can activate
proto-oncogenes
Translocations can activate proto-oncogenes in
two ways:
By promoter or enhancer substitution
- protooncogene expression by swapping its
regulatory elements with those of highly expressed
gene
By formation of a fusion gene
- coding sequences of two genes fused in part or in
whole, leading to the expression of a novel chimeric
protein

Burkitt lymphoma - overexpression of a proto-oncogene

caused by translocation is exemplified
Philadelphia chromosome - characteristic of CML; an
oncogenic BCR-ABL fusion gene on the derivative
chromosome 22
Acute promyelocytic leukemia (APML) - reciprocal
translocation between chromosomes 15 and 17 that
produces a PML-RARA fusion gene

 Deletions
- prevalent structural abnormality in tumor cells.
Deletion of specific regions of chromosomes is