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Neoplasia process of new growth

Neoplasm Tumor BENIGN or MALIGNANT

Neoplasia I.trans

Cystadenoma glandular structures are

abnormally dilated

Homeostasis everything inside our body should be in a

state of balance

(Macroscopic) Polyp tumor visibly seen

projecting above mucosal cells

Cell death apoptosis

Cell division mitosis

Ex. Polyp in colon (wala syang tangkay?)

Sessile older, develops tangkay (stem)
Pedunculated

So anything na mag-iimbalance is TOO MUCH

DEATH OR TOO MUCH DIVISION.
Too much death immunodegenerative disorders,
immunodeficiency states, infertility
Too much cell proliferation autoimmune disorders
Neoplasia is a process of new growth growth of cells
fully elevated
Everything inside our body has check and balance,
REGULATORS, and yun ang nawawala as far as cancer is
concerned.
Anything that causes cell death, is inhibited.
Genetic mutation GAIN or LOSS of function
Neoplasia Neoplasm or TUMOR
Tumor disorganized growth
So pag may cancer ba, damay agad lahat ng cell?
No. It should start with a single cell. Either
physical, chemical agent, etc. Nag mutate ang
DNA.
Normal cell genetic mutation additional mutation
mitosis permanent TRANSFORMED CELL
multiplies bigger TUMOR PROGRESSION
NOMENCLATURE
-OMA : BENIGN
Tumors of mesenchymal origin
Ex. Fibroma fibroblasts
Chondroma cartilage (chondroblasts)
Osteoma osteoblasts (bone)
WHAT IS THE CELL OF ORIGIN favorite itanong sa lab
Tumors of epithelial origin
Consider three things:
1. Cell of origin
a. Glandular adenoma
2. Microscopic architecture
3. Macroscopic architecture (Gross)
Ex.
Cystadenoma
Cell of origin (CO): (adenoma) glandular
Cyst glands are abnormally dilated
Pwede ko pang idugtong ang papillary which
means fingerlike projections PAPILLARY
CYSTADENOMA
Serous cystadenoma
Serous type of secretion: WATERY

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Malignant
Mesenchymal in origin SARCOMA (fleshy)
Ex. Fibrosarcoma
Chondrosarcoma
Osetosarcoma
Liposarcoma adipose cells
Leiomyosarcoma & Rhabdomyosarcoma
MYO: muscle; LEIO: smooth muscle;
RHABDO: skeletal muscle
Epithelial in origin: CARCINOMA
With cyst: Cystadenocarcinoma
Fingerlike projections with dilated
glands: Papillary cystadenocarcinoma
Fingerlike projections WITHOUT dilated
glands: Papillary adenocarcinoma
Squamous cell: Squamous carcinoma
Urinary bladder: Transitional carcinoma
MIXED TUMORS: Certain tumors which are from a single
cell but when they differentiate, they have divergent
differentiations. TRUE NEOPLASM
Epithelial cell proliferation cartilage or
bones
PLEASE TAKE NOTE THAT MAJORITY OF NEOPLASMS,
INCLUDING MIXED TUMORS ARISE FROM SINGLE GERM
LAYER.
TERATOMA: arises from totipotential cells (ability to
grow different types of tissues forming in one cell)
- You may see tumors that arise from more
than one germ layer
- Benign form of the dermoid tumor
- INVOLES ECTODERMAL DIFFERENTIATION OF
TOTIPOTENTIAL CELLS
- MATURE BENIGN TERATOMA
- Can appear anywhere. But SUPER COMMON is
on ovary
Ex. Totipotential cell supposed to develop to
ovarian tissue but developed to ectodermal
derivatives, so when you open the ovary it will
contain hair, teeth, plenty of sebaceous glands
EXCEPTION TO THE RULE
Lymphoma malignant tumor of lymphoid tissues
Malignant Melanoma skin (CO: melanoma)
Basal Cell Carcinoma CO: basal cells of stratum
germinativum or stratum basale that

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downward growth to dermis. DOES NOT
METASTASIZE
Squamous Cell Carcinoma CO: epidermal cells
Leukemia CO: bone marrow
Glioma (Glioblastoma multiforme): Malignant
tumor of glial cells (support cells)
Seminoma of testes
Hepatoma/Hepatocellular Carcinoma: Malignant
HAMARTOMA
- Benign
- Disorganized cells that are native to a
particular location with neoplastic growth
- Chromosomal mutations
- Hamartoma of spleen
CHORISTOMA
- NOT NEOPLASTIC
- Ectopic location of normal cells
- Pancreatic tissue in stomach wall (gastric
mucosa will be a problem)
- Gastric mucosa in ileum: ulcerations in ileum
- Pancreatic tissue in gall bladder
PROPERTIES OF TUMORS
1. Component
- All tumors (benign or malignant) are made up
of PARENCHYMA (function of cell, in
neoplasm, this undergoes proliferation)
o Malignant Melanoma: CO:
melanocytes; Parenchyma?
Melanocytes
o Lipoma: Adipose cells
- Stroma: Supportive structures of
parenchyma, behavior of tumor & important
for survival of cancer cells, where you see
blood vessels
- Cancer cells are all metabolically active
o Each cancer cell has high
requirement for nutrient and oxygen
you need more blood supply
2. Differentiation
- How closely tumor cells resemble normal
cells
- Level of differentiations is inversely
proportional to behavior of tumor, so kapag
well differentiated sya mas okay kasi hindi
sya aggressive.
- Aggressive: higher growth rate, ability to
metastasize
- Cellular Pleiomorphism: variation in size &
shape of cells
- Nuclear Pleiomorphism: variation with size &
shape of nuclei as well as number of nuclei
present
- Hyperchromatic
- Anaplastic: lack of differentiation, primitive
forms of cells (MAJOR CHARACTERISTIC OF
MALIGNANT)

Neoplasia I.trans

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Malignant
- Angiogenesis (new blood vessel formation)
- Anaplastic
MICROSCOPIC FEATURES:
o Pleiomorphism
Cellular variation in size & shape
Nuclear size & shape, number
Hyperchromaticity darker staining
Increase in N:C ratio normal (1:3);
malignant (1:1) lumaki ang nucleus,
BAKIT? Because of active mitosis
Plenty of mitotic cells (atypical
looking)
Loss of polarity
METAPLASIA: change from one cell type
to another; reprograming of STEM
CELLS
DYSPLASIA: disorganized growth mainly
seen in epithelial tissues loss of
architectural orientation
Dysplasia within basement
membrane: PREINVASIVE
NEOPLASM or CARCINOMA IN SITU
UNENCAPSULATED (Benign is
CAPSULATED DUH)
Malignant tumors have 4 main tumors:
1. Cellular Pleomorphism
2. Nuclear changes (hyperchromaticity, increase
N:C, pleomorphism)
3. Atypical mitotic figures
4. Loss of polarity
MAJOR HALLMARKS:
1. Anaplasia
2. Rapid growth
3. Invasion
4. Metastasis MOST IMPORTANT
ALL TUMORS WILL METASTASIZE EXCEPT:
GLIOBLASTOMA & BASAL CELL CA
2 ADAPTIVE CHANGES THAT PREDISPOSE TO
MALIGNANCY: METAPLASIA & HYPERPLASIA
MALIGNANT THAT HAVE CAPSULE:
1. Leiomyoma - pseudoencapsulated
2. Hemangioma CO: blood vessel
Choriocarcinoma
Gestational trophoblastic disease
Abnormal proliferation of trophoblastic tissue
Areas of ischemic necrosis
Tuberculosis
Tumor Giant Cells
BENIGN TUMOR
- CAPSULATED because of slow growth rate
- needs 32x of doubling time to be palpable
needs to be 1GM pag nagging 1 GM na ang
weight, 12x double time na lang 1 KGM

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Criteria for Metastasis:
1. Lack of Differentiation
2. Aggressive local invasion
3. Rapid growth
4. Size the bigger, the more likely to
metastasize
- Enters VEIN not artery because has thinner
wall and easier to penetrate
- Enters arteries only in LUNGS because of
normal shunting of arterial & venous
circulation
PATHWAYS OF SPREAD
1. Lymphatics
- Initial spread for carcinoma
- Most common
- SENTINEL NODE first & initial to drain
2. Hematogenous
- Typical of sarcomas
- Veins
- Lungs, liver, bone, brain & adrenal glands
- LUNGS: high oxygen supply & dual supply
3. Direct seeding
CANCER EPIDEMILIOGY
- US statistics
- Most common in men (decreasing order)
o Prostate
o Lungs
o Colorectal
- Most common in women (decreasing order)
o Breast
o Lungs
o Colorectal
- Most common DEATH cancer: LUNGS
- In developing countries
o Men: Lungs, Stomach, Liver
o Women: Breast, Cervix, Lungs
o Women in 30s: regular papsmear
- In children: Leukemia, CNS tumors (posterior
fossa)
- Carcinogenic bacterium: H. pylori (Chronic
gastritis)
- In Hep. B: Hepatocellular Carcinoma
- Parasites: Schistosoma japonicum: Liver
carcinoma
ACQUIRED PREDISPOSING CONDITIONS
1. Chronic inflammation
- Increased cell division
- Inflammation stimulates stem cells
- Release of ROS binds to DNA release of
chemical mediators prolongs survival
- Hep B & C hepatocellular
- Alcoholism Cirrhosis
2. Precursor lesions
- Patients with benign or inflammation
- Chronic GERD Barrett esophagus Cancer
of esophagus

Neoplasia I.trans

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- Smoking metaplasia squamous cell CA

- Endometrial hyperplasia
- Villous adenoma in colon
3. Immunodeficiency states
- Deficits in T cell immunity
- Main defense in virus & tumor cells: Cell
mediated (CD8)
MOST BENIGN DOES NOT GO TO MALIGNANT MOST
ESPECIALLY LIPOMA
MOLECULAR BASIS
1. Non lethal genetic damage lies in the heart of
carcinogenesis
- If the damage is lethal, cells die, no cancer
2. Single precursor cell
- Neoplastic growths are monoclonal, nonneoplastic are polyclonal
3. Oncogenes
- Proto-oncogenes: Normal cell, genes that are
involved in cell growth, cell division, cell
survival
o Products: Growth factors, growth
receptors, signal transducers,
transcription activators
o WHAT TYPE OF MUTATION SHOULD
HAPPEN IF PROTO-ONCOGENE IS
INVOLVED: Gain of function
o Tumor suppressor genes: Gatekeeper
o P53: TRUE GUARDIAN
First checkpoint: G1-S (cell
cycle arrest & repair genes)
Second checkpoint: G2-M
(pro-apoptotic genes or
cellular senescence)
Loss of function of proapoptotic gene & BH3
Cancer
- Oncogenes: Mutated
4. Driver Mutations: additional mutation that
enhance the malignant phenotype
5. Passenger mutations: secondarily acquired during
the series of mutation
6. Survival of the fittest
7. Genetic changes exogenous source
8. Epigenetic changes: randomly occur during
division, not an effect of exogenous source
a. DNA methylation silencing of gene (Loss
of function)
b. Histone modification
i. Histones maintains structure &
integrity of DNA
Again, ano ang 3 hallmarks ng malignancy?
--- END OF PART 1 ----

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Neoplasia I.trans

PART 2
1.
2.
3.
4.

Oncogene
Tumor Suppressor Gene
DNA repair genes
???

Reasons for cell sufficiency

1. Mutation of Proto-oncogenes
- Proto-oncogenes products involved in cell
division, growth, activates cell cycle
o Growth factors
o Growth receptor
o Signal transducer send signal to
nucleus to divide (Inner leaflet of
plasma membrane)
o Transcription activators
o DNA transcription
- Oncogenes - mutated products
o Loss of internal components
o Gain of function to continue cell
division, growth
Overexpression more
product than normal
Gene accumulation more
copies of gene than normal
2. Dysregulation of cell cycle genes
MOST COMMON MUTATED PATHWAY Receptor
Tyrosine Kinase Pathway
GF bind to GF receptor Signal transducer
Cell division
When cell divides, increase need for
nutrients for the cell (lipids, etc)
MOST COMMON MUTATED SIGNAL TRANSDUCER: RAS
- RAS must undergo PHOSPORYLATION for
activated (GTP GDP)
- RAS RAF (MAPKKMAPK) PI3K
AKT mTOR (senses cell nutrients)
protein synthesis, lipid synthesis,
glycolytic factors/enzymes (NET
EFFECT) Cell growth
- RAF transcription factors
- MAPK CYCLIN D bind to CDK4 cell
cycle
- Inactivation of RAS
o GTPase: inactivates
o GAP (GTPase activating protein)
- MUTATION: Gain of function
Loss of function of inhibitors
- Increased function of RAS
- Inhibition of regulators
o Loss of function of GAP activity
Neurofibromin
Neurofibromatosis
- Downstream targets of RAS
o RAF activities of MAPK
RAS - RAF - MAPK
GAIN OF FUNCTION

PTEN
o
o
o
PI3K
o
o
o

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RAF activity depends on

activation of RAS

Inhibit PI3K
COWDEN SYNDROME
Mutation: LOSS OF FUNCTION
Loss of function of PTEN PTEN
inhibition of apoptosis
Mutation of RAS PI3K AKT
mTOR
Inhibition of apoptosis

GROWTH FACTORS
- Paracrine activity
- Released by: Inflammatory, endothelial
- GF receptor to be activated must undergo
DIMERIZATION
- Cancer:
o Cancer cells produce GF
o Autocrine
o Always dimerized GF receptors =
always activated continuous
signaling
TRANSCRIPTION FACTORS
- MYC most important transcription
activator
o NORMAL FUNCTION
+ Cyclin D binds to CDK
cell cycle
rRNA
protein synthesis
+ glycolytic enzymes for
glutamine metabolism K
ATP = cell survival
telomerase - cell
senescence
Reprogram cells
pluripotent stem cells
o MUTATION limitless replication
Mutated GF receptor RAS
MAPK MYC
GAIN OF FUNCTION OF
CYCLIN D maraming
magbibind kay CDK4 cell
cycle ribosome assembly
protein supply ATP
telomerase
cancer stem cells
Burkitts lymphoma
translocation
Activation of MYC
RAS
RAF
MAPK
MYC = P27 (CDK inhibitor)
CDK inhibitor so
CDK4 is free to bind

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to cyclin D = cell
cycle
MYC = E2F (Elongation
factor 2)
transcription
P27 - CD4 - CDK - activation of
G1 - RB gene - EF 2 G1S phase
RB: retinoblastoma gene;
gatekeeper of G1-S
Controls activity of
EF-2

DYSREGULATION OF CELL CYCLE GENE (Cyclin & CDK)

- Components of cell cycle
1. CDK inhibitor
a. CIP throughout the cycle
b. INK 4 MOST CRUCIAL; G1 only;
PRIMARY INHIBITOR ON BINDING
OF CD4 to CDK
RB gene gatekeeper
2. Checkpoints:
o G1S
Damage to DNA
MOST CRUCIAL
CDK inhibitor
Binding of cyclin D
MUTATION
Loss of function of CDK
inhibitor
Loss of function of RB
o G2M
- MUTATIONS:
o GAIN OF FUNCTION OF CYCLIN D & CDK4
= cell cycle
o LOSS OF FUNCTION OF CDK INHIBITOR =
P16 Pancreatic Ca
o LOSS OF FUNCTION OF RB
-

P53 IMPORTANT REGULATOR OF

CHECKPOINTS
Damage to DNA cell cycle
arrest
Activates DNA repair gene
o MUTATION: LOSS OF FUNCTION OF P53

REMEMBER PAG TUMOR SUPPRESSOR GENES LAGI LOSS

OF FUNCTION

Neoplasia I.trans

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INSENSITIVITY TO GROWTH INHIBITORS

- Mutations involving Tumor Suppressor Genes
1. RB
-

Loss of function (mutated)

Gatekeeper of G1-M
CyclinD - CDK4 - RB
Autosomal dominant
o Every generation may phenotypic
abnormality
- Autosomal recessive
o DNA repair genes mutation
- Familial Breast Ca, Colonic Ca
o No pattern, but will always come out of
generation
- Two-Hit Hypothesis
o TSG two alleles
o Inherited form
Inherit 1 mutated allele
Need 1 more allele to be mutated
somatic cells
o Sporadic form
Two alleles are mutated already
o Bottomline: two alleles should be
mutated
- G1-S
- Active RB: Hypophosphorylated
o No need to divide
o EF-2 binds to RB
o EF-2 cannot cause translation no G1-S
- Inactive RB: Hyperphosphorylated (FOR
CANCER)
o Cell division
o EF-2 released from RB G1-S
- CDK & CYCLIN D = hyper RB
- Certain virus neutralize RB
o HPV 2 oncoproteins E6, E7
E6 degrades p53
E7 binds RB
2. P53 TRUE GUARDIAN/POLICEMAN
- Supposed to activate DNA repair genes
- Regulates progression
- DNA repair = apoptosis/senescence
- MOST COMMON TARGET
- Both alleles somatic sporadic
- Inherited: Li Fraumeni syndrome
o One allele only
o AUTOSOMAL DOMINANT
- MDM2 regulates p53 degradation
- Mutations:
o GAIN OF FUNCTION MDM2, MDMX LOSS
OF FUNCTION P53
- ATM/ATR genes
o Sensors of damage
o Causes phosphorylation MDM2 Loss of
function P53 NORMAL FUNCTION
- P14
o P14 binds to MDM2 inactivation of
MDM2
- P21 cell cycle arrest

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o CDK inhibitor
3. APC
- Gatekeeper of colonic CA
- Tight junctions
o E cadherin
o B catenin
- Controls B catenin pathway
o
APC B catenin nucleus
MYC
o B-catenin = loss of contact inhibition,
aggregation of cells
- Wnt signaling APC no destruction
complex no B-catenin degradation B
catenin nucleus MYC, cyclin D cell
division
- Loss of E-cadherin
o Invasion
o Disaggregation
o Inherited
o Germline loss of function Familial
Gastric Ca
o E-cadherin
SNAIL inhibitor
B-catenin silence E-cadherin
-

TGF-B
o Inhibits proliferation
o Promotes angiogenesis
o NORMAL: Type I & II (SMAD) x MYC
o PANCREATIC CA
NF1 (neurofibromin) inactivates RAS
NF 2 (Merlin) contact inhibition
o Merlin contact inhibition
WT1 devpt of kidney & gonads
o WT1 WILMS TUMOR, RENAL
MALIGNANCY
PATCHE (PTCH)
o Inactivates HEDGEHOG no
transcription
o Gorlin
VHL ubiquitin ligase
o O2 no hypoxia VHL no
transcription
o No VHL transcription VEGF
STK11 polyps 61 Jeghers

Neoplasia I.trans

GAIN
CDK4
Cyclin D
E6
MDM2, MDMX
B-catenin
Wnt signaling
SNAIL
Hedgehog
VEGF

LOSS
CDK Inhibitor
CIP
INK4
RB gene
P53
P16
P14
P21
APC
E-cadherin
TGF-B
SMAD
PTEN
PTCH
VHL

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