Trans 10- Neoplasia Flashcards
Neoplasia=
“new growth”
o Abnormal mass of tissue
o Uncontrolled, uncoordinated growth with that of the
normal tissue
o Persists in the same excessive manner after
cessation of stimuli
Premolecular era
o Disorder of cell growth that is triggered by a series of
acquired mutations affecting a single cell and its
clonal progeny
Modern era
neoplastic cells → survival and growth
advantage (excessive proliferation independent of
physiological growth)
Mutations
tumor cells arise from a single cell that has
incurred genetic changes (result to cells with the same
genetic makeup)
Clonal
o Parenchyma
o Where the classification of the tumor is usually based
on
o Cells that gained mutation and proliferated
o Determines the course of biological behavior
Neoplastic cells
o Connective tissue: serves as framework of the tumor
o Blood vessels: to supply nutrition
o Chronic inflammatory cells
o Surround the neoplastic cells
o Essential for growth and spread of the tumor
Stroma
§ Abundant collagenous stroma as stimulated by
parenchymal cells
§ Ex: Schirrous (stony hard) in breast cancer
Desmoplasia
- Localized and will not spread to other sites
- Can be surgically removed
- Name of cell type from which it originated ends in –oma
Benign neoplasms
In mesenchymal tumors, fibrous tissue
fibroma
In mesenchymal tumors, cartilage
chondroma
In epithelial tumors, derived from glands
adenoma
In epithelial tumors, finger-like projections from epithelial surface
papilloma
In epithelial tumors, form large cystic masses like in the ovary
cystadenoma
Exceptions:
these are malignant
melanoma and lymphoma
• “cancers” • Invade and destroy adjacent structures • Spread to distant sites through blood vessels and lymphatic vessels (metastasis) • Can cause instant death
malignant neoplasms
o Epithelial cell origin (from any of the three germ
layers)
carcinoma
tumor cells resemble
stratified squamous epithelium
squamous cell carcinoma
neoplastic epithelial cells grow in
glandular pattern
adenocarcinoma
o Sar = “fleshy”
o Arise in solid mesenchymal tissues
sarcoma
o Arise from blood-forming cells (literally WBCs) or
lymphocytes and their precursors
Leukemias or lymphoma
- Divergent differentiation of a single neoplastic clone
* With two lineages
mixed tumors
Contain epithelial components scattered within a
myxoid stroma with cartilage or bone
Mixed tumor of the salivary gland
from a single clone
producing both epithelial and myoepithelial cells
pleiomorphic adenoma
• Mature or immature cells or tissues belonging to more
than one germ cell layer
• From totipotent germ cells normally present in ovary,
testis or abnormal midline embryonic rests
• May contain variety of tissue types in an unorganized
arrangement
Teratoma
cystic tumor
lined by skin full of hair, sebaceous glands and tooth
structure
ovarian cystic teratoma
disorganized but benign masses of cells
indigenous to the involved site
Hamartoma
disorganized cartilage and
blood vessels
pulmonary hamartoma
heterotropic rest of cells
choristoma
eg nodule containing pancreatic tissue found in the
stomach, duodenum or small intestine mucosa
4 criteria to distinguish benign from malignant tumors:
o Differentiation and Anaplasia
o Rate of Growth
o Local Invasion
o Metastasis
extent to which tumor cells closely
resemble original cells.
differentiation
malignant tumors exhibit
anaplasia (total disarray of tissue architecture)
- lack of differentiation
- hallmark of poor differentiated malignancies
anaplasia
anaplasia is characterized by
§ Pleomorphism § Abnormal nuclear morphology § Abundant mitoses § Loss of polarity § Others: tumor giant cells, necrosis
replacement of a mature cell type with
another mature cell type
o normally reversible but may progress to neoplasia
metaplasia
Disordered growth
o premalignant condition (not yet a tumor, might be precedent to the pre-invasive cancer, carcinoma in situ, but may be reversible)
o loss of uniformity of individual cells and architectural orientation
o exhibits pleomorphic, hyperchromatic nuclei, and frequent mitoses, loss of polarity
dysplasia
are cohesive, expansile and form a connective tissue capsule making surgical enucleation
easy
benign tumors
are invasive, infiltrating and lacking of
well-defined capsule and plane of cleavage
malignant tumors
spread of tumor to other sites that are physically discontinuous with the primary tumor
metastasis
Unequivocally marks a tumor as
malignant
Almost all malignant tumors have the ability to
metastasize (Exception: glioma, basal cell carcinoma of the skin)
lymphatics invasion is most common in
carcinomas
hematogenous spread is most common in
sarcomas
§ favored by carcinomas originating from the kidney
§ Venous or arterial (more frequently through
veins)
§ Lung and liver are common sites because they
receive the systemic & venous outflow
Hematogenous spread
Differentiation: well-differentiated; typical structure
Rate of growth: gradual
local invasion: no
metastasis: no
benign
Differentiation: anaplastic; atypical structure
Rate of growth: rapid, erratic
local invasion: yes
metastasis: yes
malignant
Incidence of cancer in males
prostate > lung > colon/rectum
Incidence of cancer in females
breast >lung > colon/rectum
deaths in males
lung > prostate > colon/rectum
deaths in females
lung > breast > colon/rectum
Environmental factors that cause cancer
o Infectious agents (ex. HPV) o Smoking – single most important factor o Alcohol consumption o Diet o Obesity – higher death rates o Reproductive history o Environmental carcinogens
Carcinomas predominate in the
elderly
§ accumulation of somatic mutations
§ decline in immune competence
primitive malignancies in children
Wilms tumor retinoblastoma
acute leukemias rhabdomyosarcomas
§ Proliferation of cells to repair the damage
§ Increase in pool of tissue stem cells susceptible
to transformation
§ Activation of immune cells – reactive oxygen
species
§ ex. H. pylori – lymphoma
chronic inflammation
Gastric and colonic metaplasia
Barrett esophagus
Squamous metaplasia
bronchial and
bladder mucosa
Colonic metaplasia
pernicious anemia
presenc e of hyperplasia
endometrial hyperplasia
benign neoplasms
villous adenoma
-> 50% may progress to colonic adenocarcinoma
those with deficient T cell immunity
- oncogenic viruses
- lymphomas, sarcomas, carcinomas
Genetic predisposition and interactions between
environmental and inherited factors examples
BRCA1
BRCA2
Four basic principles of the molecular basis of cancer
non-lethal genetic damage
regulatory genes are involved
carcinogenesis is a multi-step process
monoclonal tumors
Genetic damage/mutation may be acquired by
the action of environmental agents (chemicals,
radiation and viruses) or it may be inherited
non-lethal genetic damage
These normal regulatory genes are the principle
targets of genetic damage.
Regulatory genes are involved
§ Cancer is a multi-step process at both the
phenotypic and genetic levels resulting from the
accumulation of multiple mutations
§ Cancer does not develop right away because
numerous processes are involved.
carcinogenesis is a multi-step process
§ Are monoclonal wherein they arise from one
clonal cell
§ A tumor is formed by the clonal expansion of a
single precursor cell that has incurred genetic
damage.
Monoclonal tumors
o Non-lethal genetic damage at the heart of
carcinogenesis
o May be caused by environmental agents or
spontaneously occur
Mutation
Four classes of genes that are targets of genetic damage
- Proto-oncogenes and oncogenes
- Tumor suppressor genes (anti-onco genes)
- Apoptosis genes
- DNA-Repair genes
§ Normal function is to PROmote cell PROliferation
§ Activation to oncogenes->excessive cell
proliferation
Ø Over-expression of proteins
Ø Gene amplification
Ø Constitutive activation
Ø Ex. eRB-2, ras, abl, mvc
Proto-oncogenes and oncogenes
Normal function is to INHIBITcell proliferation
§ Damage (“inactivation”) leads to inability to
suppress cell division
§ P-53- involved in tumor formation
§ Rb-13- associated with retinoblastoma
§ APC- adenomatous polypoid gene- polyp in GI
tract
Tumor suppressor genes (anti-onco genes)
involved in tumor formation
P-53
associated with retinoblastoma
Rb-13
adenomatous polypoid gene- polyp in GI
tract
APC
§ Genes that regulate apoptosis
§ Bcl-2 (anti-apoptosis gene); overexpression leads
to tumorigenesis, involved in gastric lymphoma
§ Bax, bud (pro-apoptosis gene): inactivation leads
to tumorigenesis
Apoptosis genes
-anti-apoptosis gene
-overexpression leads
to tumorigenesis, involved in gastric lymphoma
Bcl-2
-pro-apoptosis gene
-inactivation leads
to tumorigenesis
Bax, bud
is a multi-step process: present on both
the phenotypic and genotypic level.
Carcinogenesis
are needed to produce a
malignant cell (the more defects, the more
malignant/aggressive the cell)
Multiple genetic alterations
8 key changes associated with cancer:
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitor signals
- Altered cell metabolism
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasize
- Ability to evade host immune response
tumor cells undergo a metabolic
switch -> Synthesis of macromolecules and
organelles
Warburg effect
Increased glucose leads to increased lactose
conversion
glycolytic pathway
o Inactivation of P-53
o Activation of anti-apoptotic genes
evasion of P-53
Continuous expression of
telomerase
Evasion of mitotic crisis
ability to continually produce stem cells
self-renewal
Biological hallmarks of malignant tumors
ability to invade and metastasize
Two steps in the ability to invade and metastasize
§ Invasion of basement membrane
§ Vascular dissemination, homing and colonization
Invasion of basement membrane
downregulation of E-cadherin
activation of proteinases
loosening up of
tumor cells
downregulation of E-cadherin
degradation
of basement membrane
MMP’s, cathepsin D,
urokinase, plasminogen activator)
3 Types of DNA repair systems
§ Mismatch repair
§ Nucleotide excision repair
§ Recombination repair
o Familiar cancer: cecum and proximal colon
o Defect in DNA mismatch repair system (“proofreader”)
o Hallmark: microsatellite system instability (also 15% of sporadic cancers)
Hereditary Non Polyposis Cancer Syndrome
mismatch repair genes
MSH2, MLH1
o Increases risk for skin cancer after UV exposure
(formation of pyrimidine dimers)
o Defect in nucleotide excision repair
Xerdoerma Pigmentosum
developmental defects and multiple tumors
Bloom syndrome
neural symptoms
ataxia telangiectasia
bone marrow aplasia
fanconi anemia
chromosomal changes:
Translocation and inversion
Lymphomas, Leukemias, Sarcomas, Carcinomas
chromosomal changes:
deletions
Rb gene: Retinoblastoma
Malignancy: Chronic Myeloid Leukemia
Translocation:
BCR / ABL
Malignancy: Burkitt Lymphoma
Translocation:
C-MYC / IGH
Malignancy: Mantle Cell Lymphoma
Translocation:
CCND1 / IGH
Malignancy: Follicular Lymphoma
Translocation:
IGH / BLC2
Malignancy: Ewing’s Sarcoma
Translocation:
EWSR1 / FLI1
Multiple copies of proto-oncogene à protein
overexpression
gene amplification
N-MYC gene
neuroblastoma
HER2 gene
breast cancer
o Reversible heritable changes in gene expression without mutation or change in DNA sequence
o Silencing of the gene by methylation or histone
modification
Epigenetic Changes
carcinogenic agents
- chemical
- radiation
- viruses
