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  Well-differentiated squamous cell carcinomas of
structures the epidermis synthesize keratin
 Well-differentiated hepatocellular carcinomas
Hamartoma- disorganized benign masses; involves elaborate bile
normally found cells
Highly anaplastic
Choristoma- heterotopic rest of cells; cells are found on  new and unanticipated functions may emerge
different structures or locations beyond their  some tumors express fetal proteins
actual significance  less likely to have specialized functional activity
Eg.
Characteristics of Benign and Malignant Tumors Bronchogenic carcinomas
1. Differentiation- degree of resemblance to - may produce corticotropin, parathyroid-like
normal cells in morphology and fxn hormone, insulin, glucagon, and other hormones,
giving rise to paraneoplastic syndromes
Anaplasia
- lack of differentiation Metaplasia
- hallmark of malignancy - replacement of one type of cell with another type
- reversal of differentiation to a more primitive level - nearly always found in association with tissue
damage, repair, and regeneration.
Eg. - replacing cell type is better suited to local
Lipoma environment alteration
- tumor of benign adipocytes Eg.
- closely resembles normal adipocytes Esophagus- squamous to glandular epithelium
Adenocarcinoma of the thyroid due to gastroesophageal reflux
- well-differentiated
- normal appearing follicles Dysplasia
Squamous cell carcinoma - disordered growth
- may appear identical to normal squamous - loss in the uniformity of the individual cells and
epithelial cells orientation
- may exhibit pleomorphism and abnormal nuclear
Associated morphologic changes to anaplasia: morphology
 Pleomorphism - mitotic figures are more abundant
- variation in size and shape - architecture of the tissue may be disorderly
- Eg. Tumor giant cells, polymorphic nucleus, Eg.
hyperchromatic nuclei Dysplastic squamous epithelium
 Abnormal nuclear morphology Normal: progressive maturation of tall cells in the
- nuclei are disproportionately large for the cell basal layer to flattened squames on the surface
- variable nuclear shape Dysplastic: replacement of the epithelium by
- hyperchromatic basal-appearing cells with hyperchromatic nuclei
- abnormally large nucleoli
 Mitoses Carcinoma in situ
- many cells are in mitosis - preinvasive neoplasm
- high proliferative activity of the parenchymal - dysplastic changes in full thickness of the
cells epithelium, but does not penetrate the basement
- atypical, bizarre mitotic figures membrane
- exception: normal tissues may exhibit rapid - may persist for years before it becomes invasive;
turnover such as epithelial lining of the gut and eg carcinomas of the skin, breast and uterine
nonneoplastic hyperplasia cervix
 Loss of polarity
- Disorganized orientation of anaplastic cells Invasive tumor
 Other changes - tumor cells breach the basement membrane
- Increased blood supply
- large central areas of ischemic necrosis *Note: Severe epithelial dysplasia frequently antedates
the appearance of cancer
*Note: The better the differentiation of the transformed cell, Eg. Barrett esophagus and
the more completely it retains the Long-term cigarette smokers
functional capabilities of its normal counterpart
Eg. Dysplasia may be a precursor to malignant
 Benign neoplasms & well-differentiated transformation, it does not always progress to
carcinomas of endocrine glands secrete cancer
hormones characteristic of their origin
 Dysplasia often occurs in metaplastic epithelium,  Lymphatic spread
not all metaplastic epithelium is dysplastic - most common pathway for the initial
dissemination of carcinomas
2. Local Invasion - tumors do not have lymphatics; uses LV at the
tumor margin instead
Benign tumor - follows the natural routes of lymphatic drainage
- Sentinel lymph node- first node in a regional
Capsule lymphatic basin that receives lymph flow
- compressed fibrous tissue that separates the - Sentinel node mapping- injection of radiolabeled
tumor from the host tissue tracers or colored dyes, examination of frozen
- does not prevent tumor growth, makes the tumor sections to guide surgeon for therapy
palpable, moveable and easily excisable by - Enlargement of nodes may be caused by the
surgical enucleation spread and growth of cancer cells or reactive
hyperplasia
Fibroblast- deposits ECM upon activation by hypoxic Eg.
damage resulting from the pressure of the expanding  Carcinomas of the breast- axillary lymph nodes
tumor.  Cancers of the inner quadrants- nodes along
internal mammary arteries to infraclavicular and
Exception supraclavicular nodes
Hemangiomas- composed of tangled blood vessels, often  Carcinomas of the lung- perihilar
unencapsulated and permeate the site in which they arise tracheobronchial and mediastinal nodes
(e.g., the dermis of the skin and the liver); unresectable
when extensive  Hematogenous Spread
- typical of sarcomas but is also seen with
Malignant tumor carcinomas
- poorly demarcated from the surrounding normal - arteries- less penetrated than veins
tissue - venous invasion- follow the venous flow draining
- penetrate the wall of the colon or uterus the site of the neoplasm
- surgical resection difficult or impossible - tumor cells often rest in the first capillary bed they
- necessary removal of a considerable margin of encounter
normal tissues adjacent to the infiltrative - liver (portal area drainage) and lungs (caval blood
neoplasm to ensure complete local excision. flow) freq involved in hematogenous spread
Eg.
“Pseudoencapsulated” masses- malignant tumors that  Cancers proximal to vertebral column-
develop enclosing fibrous capsule that penetrates the paravertebral plexus; also involved in vertebral
margin and infiltrates the adjacent structures metastases of carcinomas of the thyroid and
prostate
3. Metastasis  Renal cell carcinoma- renal vein and its branches
- spread of a tumor to sites that are physically  Hepatocellular carcinoma- portal and hepatic
discontinuous with the primary tumor radicles
- reduces possibility of cure
*Note: Mere anatomic localization of the neoplasm and
Eg. natural pathways of venous drainage do not wholly
 Gliomas and basal cell carcinomas of the skin- explain the systemic distributions of metastases.
invades but rarely metastasize
 Blood cancers (leukemias and lymphomas, or Eg.
liquid tumors) have the capacity to travel to  Breast carcinoma- spreads to bone
distant sites; malignant  Bronchogenic carcinomas- spread to the
adrenals and the brain
Pathways of Spread
 Neuroblastomas- spread to the liver and bones
 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)
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
I. Self-sufficiency in Growth Signals:
Eight Fundamental Changes in Cancer Cell Oncogenes
Physiology
1. Self- sufficiency in growth signal Proto-oncogenes
- capacity to proliferate without external - normal cellular genes whose products
stimuli promote cell proliferation

2. In sensitivity to growth-inhibitory signals Oncogenes

- unresponsive to molecules that inhibit
proliferation
- genes that promote autonomous cell
growth
- inactivation of tumor suppressor genes
- mutated or overexpressed versions of
3. Altered cellular metabolism proto-oncogenes that function
- metabolic switch to aerobic glycolysis autonomously, having lost dependence
(Warburg effect) on normal growth-promoting signals
- enables synthesis of macromolecules
and organelles that are needed for rapid Oncoproteins
growth - protein encoded by an oncogene that
drives increased cell proliferation through
4. Evasion of Apoptosis one of several mechanisms
- resistant to programmed cell death
Normal Growth Factor Signaling Pathways
5. Limitless replicative potential (Immortality) 1. GF binds to specific receptor
- unrestricted proliferative capacity 2. transient and limited activation of GF receptor
- stem-like property that allows cells to 3. signal transduction to nucleus via cytoplasmic
avoid cellular senescence and mitotic receptor proteins and secondary messengers or
catastrophe by cascade
4. induction and activation of nuclear regulatory
6. Sustained Angiogenesis factors that initiate DNA transcription
- induce angiogenesis for further growth 5. expression of factors that promote cell division
6. changes in gene expression resulting to survival
7. Ability to evade and metastasize and metabolic alterations that promote optimal
- cause of vast majority of cancer deaths cell growth

8. Ability to evade the host immune response

- exhibit alterations that allow evasion of Molecular Defects that Promote Cancer Cell
host immune response 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

* Genetic and epigenetic alterations that confer cancer

cell development maybe accelerated by genomic
instability and cancer-promoting inflammation.
 - 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

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

- 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  loss of function mutations in
- most commonly involved in human tumor suppressor genes that
tumors inhibit G1/S progression
- 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

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
G. Cyclin and Cyclin-dependent Kinases loss of heterozygosity
- progression of cells through cell cycle is - both alleles of a tumor-suppressor gene must be
regulated by CDKs which are activated mutated for carcinogenesis to occur
by binding to cyclin - heterozygous cells have adequate tumor suppressor
- CDK-cyclin complexes phosphorylate activity
crucial target proteins that drive cells - the mutation of the second normal tumor suppressor
forward through cell cycle leads to carcinogenesis
- CDK inhibitors silence CDKs and exert
negative control over cell cycle
- G1/S transition and G2/M transition are RB Gene
tightly regulated - governor of cell cycle
- defects in G1/S checkpoint is more - prototypic tumor-suppressor gene
important in cancer - product regulates the advancement of cells
 gain of function mutations in D through the G/S checkpoint
cyclin genes promote G1/S - sequestering E2F less efficiently, RB mutations
progression lead to increased E2F transcription factor activity
 allow cells to proceed in the cell cycle in the p53
absence of a growth stimulus - guardian of the genome
- prevents the propagation of genetically defective
- several oncogenic DNA viruses (e.g., human cells
papillomavirus [HPV]) synthesize proteins that - when cells are “stressed” (e.g., by damage to
bind to RB and displace the E2F transcription DNA), p53 undergoes post-translational
factors, thereby contributing to persistent cell phosphorylation, releasing it from an associated
cycling MDM2 protein that normally targets it for
degradation
RB contributes to the pathogenesis of the childhood tumor
retinoblastoma through a two-hit mechanism: - sensing of DNA damage is accomplished through
two protein kinases, ataxia-telangiectasia
 both normal RB alleles must be inactivated (i.e., two mutated (ATM), and ataxia-telangiectasia and
hits) for retinoblastoma to develop
Rad3-related (ATR)
 in familial cases (i.e., 40% of retinoblastomas), children
inherit one defective germ line copy of RB;
retinoblastoma develops when the remaining normal - unshackled p53 then acts as a transcription factor
RB gene undergoes somatic mutation. for additional genes (including miRNAs) that
 in sporadic cases, both normal RB alleles are lost by arrest the cell cycle and promote DNA repair
somatic mutation in a retinoblast
- if DNA can be repaired during the cell cycle arrest,
Anti-proliferative effect of RB is abrogated in cancers MDM2 transcription increases and p53 is
through: subsequently degraded, allowing the cell to
1. loss of function mutations affecting RB progress into S phase
2. gene amplification of CDK4 and cyclin D genes
3. loss of cyclin-dependent inhibitors
4. viral oncoproteins that bind and inhibit RB - 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)

 normallysubject to proteasomal degradation in
the setting of DNA Damage; but often found to be
stabilized and overexpressed in drug-resistant
INTRINSIC PATHWAY – DNA Damage (mostly in cancers.
Cancers) p53
Stimuli - withdrawal of survival factors, stress, and injury  important pro-apoptotic protein that induces
 mitochondrial outer membrane permeabilization apoptosis in cells that be unable to repair DNA
by BAX and BAK pro-apoptotic proteins damage
 BH3-only proteins (BAD, BID, PUMA) promote  actions mediated by transcriptional activation of
apoptosis by sense death-inducing stimuli and BAX and PUMA
promote apoptosis by neutralizing the actions of  (cancer) mutations directly affecting component
anti-apoptotic proteins like BCL2 and MCL1 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  Has BCR-ABL fusion gene from transformed
 Immortal cells and limitless capacity to replicate hematopoietic stem cell with capacity for self-
renewal (e.g. colonic crypts)
INTRRELATED FACTORS: Acute Myeloid Leukemia
1) EVASION OF SENESCENCE  cancer stem cells arise from more differentiated
 DNA damage accumulation hematopoietic progenitors that acquire an
 upregulation of tumor suppressors p53 and abnormal capacity for self-renewal because of
INK4a/p16 PML-RARA fusion protein
 maintain RB in a hypophosphorylated state
 RB-dependent G1/S cell cycle checkpoint is VI. Angionesis
disrupted
 cell cycle arrest Tumor - cannot enlarge beyond 1 to 2 mm in diameter
 Senescence  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
(See 7-34)
Local Balance of Angiogenic and Antiangiogenic
2) EVASION OF MITOTIC CRISIS Factors:
 Bridge-fusion breakage cycle  Relative lack of oxygen due to hypoxia
 p53 dysfunctional, nonhomologous endjoining stabilizes HIF1α
pathway is activated and join the “naked” ends of  activating transcription of the proangiogenic
two chromosomes results in new stranded double cytokines VEGF and bFGF guiding the growth of
DNA breaks pulled apart at anaphase new vessels toward the tumor
 Cells in crisis reactivate telomerase  Mutations involving tumor suppressors and
 May arise from stem cells and continue oncogene
expressing telomerase  p53 stimulate expression of antiangiogenic
 Alternative lengthening of telomerase molecule thrombospondin-1 repressing
depends on DNA recombination expression of proangiogenic molecule VEG
 provide more permissive environment for
3) SELF RENEWAL angiogenesis.
 Express telomerase resistant to mitotic crisis and  VEGF transcription
avoiding genetic alterations that trigger  RAS-MAP kinase pathway + gain-of-function
senescence mutations in RAS or MYC upregulate VEGF
 MYC mutations converts somatic cell into a cell production
who can de-differentiate stem cell-like state  bFGF and VEGF elevated levels detected serum
 CA cells can repopulate from non-stem cell and urine
populations
Bevacizumab - a monoclonal antibody; neutralizes
Divisions: VEGF activity and approved for use in treatment of
 Symmetric Division – both daughter cells multiple cancers
remain stem cells; may occur during  can prolong life only a few at very high financial
embryogenesis/stress cost
 Asymmetric division - only one daughter cell
remains a stem cell; in non–stem cell daughter INVASION AND METASIS
proceeds differentiation  complex interactions between cancer cells and
pathway losing “stemness” but gaining one or normal stroma; major causes of cancer-related
more functions in the process morbidity and mortality
Chronic Myelogenous Leukemia (CML) 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
  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

VASCULAR DISSEMIATION and HOMING of TUMORS

Tumor cells - within the circulation tend to aggregate in ORGAN TROPISM

clumps
- bind and activate coagulation factors, resulting to emboli  Tumor cells - have adhesion molecules whose
- Arrest and extravasation of tumor emboli at distant sites ligands are expressed preferentially on the
involves adhesion (integrins, laminin receptors and endothelial cells of the target organ.
proteolytic enzymes) to the endothelium followed by
basement membrane egress  Chemokines - important role in determining the
target tissues for metastasis.
CD44 adhesion molecule - expressed on normal T  E.g Breast CA cells express - receptors CXCR4
lymphocytes; used by these cells to migrate to selective and CCR7.
sites in lymphoid tissues
 Target tissue – nonpermissive
The site at which circulating tumor cells leave the environment/unfavorable soil for growth of tumor
capillaries to form secondary deposits is related to  E.g. skeletal muscle and spleen – well-
anatomic location and vascular drainage of the vascularized but rarely sites of metastasis.
primary tumor and the tropism of particular tumors
for specific tissue
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 Antitumor Effector Mechanisms

 viruses produce proteins that are recognized as Cell-mediated immunity - dominant antitumor
foreign by the immune system; produced by mechanism in vivo:
latent DNA viruses
 competent immune system plays a role in  Cytotoxic T lymphocytes - ear protective role
surveillance against virus-induced tumors against virus-associated neoplasms (e.g., EBV-
 Human papilloma virus (HPV) and Epstein-Barr and HPV-induced tumors)
virus (EBV) - CD8+ T cells and “gene signature” associated
with CD8+ CTLs => better prognosis
Oncofetal antigens  Natural killer cells -lymphocytes capable of
 proteins that are expressed at high levels on destroying tumor cells without prior sensitization;
cancer cells and in normal developing (fetal) first line of defense lyse a wide range of human
tissue tumors after activation with IL-2 and IL-15
 increased in tissues and in the circulation in  Macrophages - potent activator is interferon-γ
various inflammatory conditions (secreted by T cells and NK cells)
 no evidence that oncofetal antigens are important
inducers or targets of antitumor immunity Immune Surveillance and Escape
 sufficiently specific - markers that aid in tumor - neoplasms are aggressive lymphomas composed of
diagnosis and clinical management mature B cells
 e.g. Carcinoembryonic antigen (CEA) and α- - e.g. X-linked recessive immunodeficiency disorder
fetoprotein (AFP) (X-linked lymphoproliferative syndrome) - mutations
 in the gene encoding an adapter protein, SAP,
Cell type–specific differentiation antigens participates in NK and T-cell signaling pathway
 specific for particular lineages or differentiation - EBV infection (boys) - evolves into a chronic or
stages of various cell types sometimes fatal form of infectious mononucleosis or,
 typically normal self-antigens, and therefore they even worse, a lymphoma comprised of EBV-infected
do not induce immune responses in tumor- B cells
bearing hosts
 potential targets for immunotherapy and for Mechanisms used by Tumor Cells to escape or evade
identifying the tissue of origin of tumors the immune system in immunocompetent hosts:
 e.g. Antibodies against CD20 - transmembrane
protein expressed on the surface of all normal Selective outgrowth of antigen-negative variants
mature B cells; broad cytocidal activity against  Loss or reduced expression of MHC
mature B-cell lymphomas and leukemias molecules
- fail to express normal levels of HLA class I molecules
Monoclonal antibodies – covalently coupled to drugs, escaping attack by cytotoxic T cells. Such cells,
toxins, or radiochemicals; guided missile that delivers however, may trigger NK cells
a therapeutic warhead to cancers expressing
particular surface antigens  Activation of immunoregulatory pathways
 CD30 - T cell lymphomas and Hodgkin - engaging normal pathways of immune regulation that
lymphomas serve as “checkpoints” in immune responses
- prevents sensitization but also may induce long-live
See Fg. 7-39 unresponsiveness in tumor-specific T cells
- downregulate expression APCs (e.g. dendritic cells) - DNA-repair genes - not oncogenic, but abnormalities
=> fail to engage CD28 => instead activate the greatly enhance the occurrence of mutations
inhibitory receptor CTLA-4 on effector T cells
- “checkpoint blockade” - treatments remove the Defects in three types of DNA-repair systems
“brakes” imposed by tumors on host anti-tumor
immune responses can be highly effective in treating  Mismatch Repair
cancer Microsatellite instability – hallmarks; tandem repeats
of one to six nucleotides found throughout the
 Secretion of immunosuppressive factors by genome; unstable and increase or decrease in length
cancer cells in tumor cells, creating alleles not found in normal
TGF-β – potent immunosuppressant cells of the same patient.
Galectins - skew T-cell responses; to favor Hereditary Nonpolyposis Colon Cancer Syndrome -
immunosuppression autosomal dominant disorder; predominantly the
Interleukin-10, prostaglandin E2, tryptophan, cecum and proximal colon
and VEGF - inhibit the diapedesis of T cells from - defects genes encoding DNA mismatch repair
the vasculature into the tumor bed proteins acting as “spell checkers
- proofreading function lost, errors gradually
 Induction of regulatory T cells (Tregs) accumulate throughout the genome
- tumors produce factors that favor the development of
immunosuppressive regulatory T cells =>  Nucleotide Excision Repair
immunoevasion Xeroderma Pigmentosum - exposure to UV light in
sun rays causes cross-linking of pyrimidine residues,
Immunomodulatory agents - antibodies that block CTLA- preventing normal DNA replication; cancer of the skin
4 and PD-1 potential of modern cancer immunotherapy
 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
Genomic Instability
proteases)
 Removal of growth suppressors
Genetic aberrations - increase mutation rates and
- growth of epithelial cells is suppressed by cell-cell
expedite the acquisition of driver mutations; required
and cell-ECM interactions
for transformation and subsequent tumor
- Proteases - degrade the adhesion molecules;
progression
removing a barrier to growth
- both copies of the DNA repair gene are lost;
 Enhanced resistance to cell death
haploinsufficiency of at least a subset of these genes
Anoikis - cell-cell interactions lead to a particular
may also promote cancer
form of cell death
- born with such inherited defects in DNArepair
Tumor-associated macrophages may prevent
proteins are at a greatly increased risk of developing
anoikis
cancer
 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