NEOPLASIA
Normal cells
Malignant cells
Changes:
Neoplasia
• Neoplasia
new growth
• Neoplasm:
abnormal tissue mass growing
excessively and indefinitely without
coordination with normal tissue
coordination with normal tissue
• Behaviour:
progressive, useless,
• The tumor cells tend to replicate rather than to differentiate due to genetic alterations
(oncogene activation, anti-oncogene suppression, etc)
suppression, etc)
The Molecular basis of Cancer
• Nonlethal genetic damage lies at the heart of carcinogenesis
• 3 classes of normal regulatory genes: growth promoting (proto-oncogenes), anti-oncogenes (growth inhibiting / suppressor genes), apoptotic genes (regulate
programmed cell death) the principal targets of genetic programmed cell death) the principal targets of genetic damage.
• Misnomer
• Physiologic function: regulate cell growth (not to prevent tumor formation) apply brakes to cell
proliferation
• Discovered by studying rare disease such as • Discovered by studying rare disease such as
retinoblastoma
“Two-hit” Hypothysis of Oncogenesis
• In hereditary cases, one genetic change
(“first hit”)
is inherited from affected parent
present in all
somatic cells of the body
• The second mutation
(“second hit”)
occurs in one of
many retinal cells (which already carry the first
many retinal cells (which already carry the first
mutation)
Rb gene
Paradigm of:
tumor suppressor genes
2 broad categories regarding the functions:
Molecules that regulate nuclear transcription and cell cycle
• Cell surface: TGF-receptor, E-cadherin • Under plasma mebrane: NF-1
• Under plasma mebrane: NF-1 • Cytoskeleton: NF-2
• Cytosol: APC/β-catenin, PTEN, SMAD 2, SMAD 4
Molecules that regulate signal tranduction
TGF-
β
receptor
• Function: Growth inhibition
• Tumors associated with somatic mutation: Carcinoma of colon
E-cadherin
• Function:
Cell adhesion
• Tumors associated with somatic
mutation:
mutation:
Ca. gaster & breast
• Tumors associated with inherited
mutation:
NF-1
• Function:
Inhibition of ras signal transduction • Tumors associated with somatic mutation:
Schwannoma Schwannoma
• Tumors associated with inherited mutation: Neurofibromatosis type 1 and
NF-2
• Function:
Unknown
• Tumors associated with somatic mutation: Schwannoma and meningioma
Schwannoma and meningioma
• Tumors associated with inherited mutation: Neurofibromatosis type 2,
APC
• Function:
Inhibition of signal transduction
• Tumors associated with somatic mutation: Ca. of stomach, colon, pancreas;
Ca. of stomach, colon, pancreas; melanoma
Rb
• Function:
Regulation of cell cycle
• Tumors associated with somatic mutation: Retinoblastoma, osteosarcoma,
Retinoblastoma, osteosarcoma, Ca breast, colon, lung
p53
• The guardian of the genome
• Located on chromosome 17p13.1
• The most common target for genetic alteration in • The most common target for genetic alteration in
human tumors
p53
• Function:
Regulation of cell cycle & apoptosis in response to DNA damage
• Tumors associated with somatic mutation: • Tumors associated with somatic mutation:
Ca. gaster & breast
GROWTH
Most malignant tumors
“normally” passing four phases :
•
Transformation
•
Growth of transformed cells
•
Growth of transformed cells
•
Local invasion
Multiple factors that influence tumor growth
1. Kinetics of tumor growth
2. Tumor angiogenesis
2. Tumor angiogenesis
How long does it take to produce a clinically overt
tumor mass ?
This depends on three variables:
• The doubling time of tumor cells
Kinetics of tumor growth
• The doubling time of tumor cells
• Growth fraction
The doubling time of tumor cells
• Original transformed cell (+ 10u in diameter) must undergo at least 30 population
doublings to produce 109 cells (weighing +
1gm) ---- the smallest clinically detectable mass.
1gm) ---- the smallest clinically detectable mass.
The doubling time of tumor cells
• Is the amount of time a tumor to double in cell numbers
• Doubling time for malignant tumor is not necessarily longer than normal cell origin. Benign tumors grow more slowly
Benign tumors grow more slowly
• One factor in doubling time is the number cells in the growth phase
The doubling time of tumor cells
Characteristics of tumor cells:
• Cells in the growth phase are the most
susceptible to chemotherapeutic agents
susceptible to chemotherapeutic agents
• Type of tumor vary in their doubling time,
The doubling time of tumor cells
A lesson to be learnt from the concept of doubling time / tumor growth is :
by the time a solid tumor is clinically detected, it has already completed a major portion of its life cycle
or,
When tumors are finally discovered, they have been
around for a long time, growing unnoticed because of their small size. By the time the tumor achieves a
Growth Fraction
• The proportion of tumor cells within the tumor cell population that are in replicative pool
• Tumor continue to grow cells leave the replicative pool, owing to:
- shedding or lack of nutrient - shedding or lack of nutrient - by differentiating
- reversion to G0
telomere length are essential for the
maintenance of replicative potential in
cancer cells
Cell production and loss
• Progressive growth of tumors and the rate of growth
is determined by how much cell production exceeds
cell loss
tumor cell kinetics
Cancer chemotherapy
• Most antineoplastic agents are mostly effective on cycling cells high growth fraction tumors are very sensitive to anti-cancer drugs
• Debulking the left cells ten to re-enter the cell • Debulking the left cells ten to re-enter the cell
cycle sensitive
Latent period of tumors
Tumor angiogenesis
Blood supply :
Tumor cannot enlarge beyond 2 mm in
diameter or thickness unless they are
vascularized. Presumably the 2 mm zone
vascularized. Presumably the 2 mm zone
represent the maximal distance across
Tumor angiogenesis
• Angiogenesis is not only for tumor growth, but also for metastasize
• Angiogenesis is a necessity for biological correlation of malignancy.
correlation of malignancy.
• Several studies have revealed a correlation between the extent of angiogenesis
(microvessel density) and the probable of
metastases in melanomas and cancer of the
Tumor angiogenesis
Effect of neovascularization
• Perfusion of supply nutrients, oxygen,
and newly formed endothelial cells
and newly formed endothelial cells
Tumor angiogenesis
How do growing tumors
develop blood supply
• Tumor contain factor that are capable of
affecting the entire series of events involved in the formation of new capillaries Tumor Associated Angiogenic Factors (TAAF) may in the formation of new capillaries Tumor Associated Angiogenic Factors (TAAF) may be produced by tumor cells or inflammatory cells (macrophage) that infiltrate tumors.
• TAAF : many, but two most important : VEGF and bFGF --- expressed in wide
Tumor angiogenesis
Antiangiogenesis
• Tumor cells also induced and produced antiangio-genesis molecules.
• Because angiogenesis is critical for the
growth and spread of tumors, much
attention is focused on the use of
angiogenesis inhibitors – therapy
angiogenesis inhibitors – therapy
• Success has been achieved in treating
fairly large tumors in mice by adm. of
Tumor progression and
heterogeneity
• Over period of time the tumor become more aggressive and acquire greater malignant potential tumor progression
• Most malignant tumor are monoclonal in origin • Most malignant tumor are monoclonal in origin
but by the time they become clinically
• Acclerated growth, invasiveness, ability to form distant metastasis
• Invasion and metastasis are biologic hallmark of malignancy
malignancy
Four steps of invasion
• Detachment of tumor cells
Tumor growth
• Tumor cells do not necessarily proliferate
more rapidly than their normal counterpart
• The major determinant of tumor growth is
• The major determinant of tumor growth is
The growth of cancer
• Tumor growth rates may be expressed as
doubling time
• Tumor angiogenesis refers to the
sprouting of new capillaries
sprouting of new capillaries
Tumor dormancy
• Often, metastatic tumors is not detectable at the time of the removal of a primary tumor
• Breast cancer and melanoma metastasis may remain dormant for many years
