Normal cells Malignant cells

  

PATHOBIOLOGY OF

NEOPLASIA

Department of Pathology

_{Gadjah Mada University School of Medicine}

  Blok Biomedis, 6 Maret 2009 [12] dr. Harijadi

  

Changes:

  

The pathobiology of neoplasia

Normal cells

Malignant cells

• Genotypic • Phenotypic

  

Neoplasia

• Neoplasia  new growth

• • Neoplasm: abnormal tissue mass growing

  excessively and indefinitely without coordination with normal tissue coordination with normal tissue

• Behaviour: progressive, useless,

  independent from surrounding tissue, unrelated to host needs, parasitic, autonomic.

PATHOBIOLOGY OF TUMOR GROWTH

• The tumor cells tend to replicate rather than to differentiate due to genetic alterations (oncogene activation, anti-oncogene suppression, etc) suppression, etc)
• Most tumors are of monoclonal origin

  CARCINOGENESIS: 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.

• DNA repair genes, affect cell proliferation or survival indirectly by influencing the ability of the organism to repair non-lethal damage of other genes.

• • Carcinogenesis is a multi-step process at both the genetic

  and phenotypic level

• 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
• Knudson Hypothesis  as a paradigm for two-hit

  hypothesis of oncogenesis  apply substantiated by other suppressor gene, and now can be formulated in more precise terms, using retinoblastoma as paradigm

  

CANCER SUPPRESSOR GENES

“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)
• In sporadic case, both mutations (hits) occur somatically within a single cell  tumor

CANCER SUPPRESSOR GENES: Rb gene

  Paradigm of: two hit hypothysis of carcinogenesis

  

Role of RB as Cell-cycle Regulator

Virtually all cancers show dysregulation of the cell cycle by affecting the four genes

(red asterisk)

  

Sub-cellular location of protein product 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: • Under plasma mebrane: NF-1 NF-1
• Cytoskeleton: NF-2
• Cytosol: APC/

  β-catenin, PTEN, SMAD 2, SMAD 4 Molecules that regulate signal tranduction

• • Nucleus: Rb, p53, WT-1, p16(INK4a), BRCA-1,

  BRCA-2

  

Selected tumor-suppressor gene involved in human neoplasm

TGF- β receptor

• Function: Growth inhibition
• Tumors associated with somatic mutation:

  Carcinoma of colon

• Tumors associated with inherited mutation:

  Unknown

  

Selected tumor-suppressor gene involved in human neoplasm

E-cadherin

• Function:

  Cell adhesion

• Tumors associated with somatic mutation: mutation:

  Ca. gaster & breast

• Tumors associated with inherited mutation:

  Familial gastric cancer

  

Selected tumor-suppressor gene involved in human neoplasm

NF-1

• Function:

  Inhibition of ras signal transduction

• • Tumors associated with somatic mutation:

  Schwannoma Schwannoma

• • Tumors associated with inherited mutation:

  Neurofibromatosis type 1 and sarcomas

  

Selected tumor-suppressor gene involved in human neoplasm

NF-2

• Function:

  Unknown

• • Tumors associated with somatic mutation:

  Schwannoma and meningioma Schwannoma and meningioma

• • Tumors associated with inherited mutation:

  Neurofibromatosis type 2, acoustic schwannoma & meningioma

  

Selected tumor-suppressor gene involved in human neoplasm

APC

• Function:

  Inhibition of signal transduction

• • Tumors associated with somatic mutation:

  Ca. of stomach, colon, pancreas; Ca. of stomach, colon, pancreas; melanoma

• • Tumors associated with inherited mutation:

  Familial Adenomatous Polyposis coli; colon cancer

  

Selected tumor-suppressor gene involved in human neoplasm

Rb

• Function:

  Regulation of cell cycle

• • Tumors associated with somatic mutation:

  Retinoblastoma, osteosarcoma, Retinoblastoma, osteosarcoma, Ca breast, colon, lung

• • Tumors associated with inherited mutation:

  Retinoblastoma, osteosarcoma

  

Selected tumor-suppressor gene involved in human neoplasm

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
• A little over 50% of human tumors contain mutation in this gene

  

Selected tumor-suppressor gene involved in human neoplasm

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

• • Tumors associated with inherited mutation:

  Li-Fraumeni syndrome Multiple carcinoma and sarcoma

PATHOBIOLOGY OF TUMOR GROWTH Most malignant tumors

  

“normally” passing four phases :

Transformation •

• Growth of transformed cells • Growth of transformed cells
• Local invasion
• Distant metastases

Multiple factors that influence tumor growth

  1. Kinetics of tumor growth

  2. Tumor angiogenesis

  2. Tumor angiogenesis

  3. Tumor prgression and heterogeneity

  

Kinetics of tumor growth

How long does it take to produce a clinically overt tumor mass ? This depends on three variables:

• The doubling time of tumor cells • The doubling time of tumor cells
• Growth fraction
• Cell production and loss

  

Kinetics of tumor growth

The doubling time of tumor cells

  Original transformed cell (+ 10u in diameter) • must undergo at least 30 population

  9

  doublings to produce 10 cells (weighing + 1gm) ---- the smallest clinically detectable 1gm) ---- the smallest clinically detectable mass. mass.

  In contrast, only 10 further doubling cycles • are required to produce a tumor containing

  12

  10 cells (weighing + 1 kg), which is usually the maximal size compatible with life.

  

The doubling time of tumor cells

  

Kinetics of tumor growth

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

• Another factor, is the number of cells that die and never replicated, that is, most cells in a tumor, much more than 90%

  

Kinetics of tumor growth

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,

  and the same type of tumor varies from

  patient to patient

  

Kinetics of tumor growth

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

clinically noticeable size, its rate of growth will become more clinically noticeable

  

Kinetics of tumor growth

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 G
>most cells within cancer remain in the G phase
• In some rapidly growing tumors, the growth fraction is approximately 20%

  Kinetics of tumor growth

Growth fraction

  

Telomerase activities and maintenance of

telomere length are essential for the

maintenance of replicative potential in

cancer cells cancer cells

  

Kinetics of tumor growth

Cell production and loss

• • Progressive growth of tumors and the rate of growth

  is determined by how much cell production exceeds cell loss
• In tumors with relatively high growth fraction, the imbalance is large  more rapid growth

  

The important clinical implication of

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

• Most tumor cells leave replicative pool

   latent period (months/years before a tumor becomes clinically detectable)

  

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 which oxygen and nutrients can diffuse from blood vessels.

BIOLOGY OF TUMOR GROWTH 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

  breast,lung,colon and prostate

Tumor angiogenesis Effect of neovascularization

• Perfusion of supply nutrients, oxygen, and newly formed endothelial cells and newly formed endothelial cells stimulate the growth of adjacent tumor

  cells by secreting polypeptides such as

  IGF, PDGF, GM-CSF, and IL-1

BIOLOGY OF TUMOR GROWTH 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 in the formation of new capillaries  Tumor Associated Angiogenic Factors (TAAF) may 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 variety of tumor  elevated levels can be detected in the serum and urine

BIOLOGY OF TUMOR GROWTH Tumor angiogenesis

  

Antiangiogenesis

• Tumor cells also induced and produced antiangio- genesis molecules.
• Tumor growth is controlled by the balance between angiogenic factors and antiangiogenic factor (inhibit angiogenesis).

   Example of Antiangiogenesis : Thrombospondin1 Angiostatin, endostatin, tumstatin

  

Tumor Angiogenesis

Dysorganized vessels within the tumor mass

Tumor angiogenesis compared to normal blood vessel

  

The tumor vasculature is formed from circulating endothelial precursor

cells and existing host vessel. Myofibroblasts give rise to pericytes at

the periphery of the vessels. The tumor vessels are unstable and leaky.

  

Tumor angiogenesis compared to normal

blood vessel

Arterioles, capillaries, and veins are disorganized and unidentifiable.

Angiogenesis

• 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 endostatin and tumstatin (anim.exp.)

  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 evedent, their constituent cells are extremely heterogenous

  

Tumor Progression and Heterogeneity

  

Malignant potential

• 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
• Attachment of tumor cells to matrix components
• Degradation of ECM
• Migration of tumor cells

  Invasion Sequence of Basement

Membrane by Tumor Cells

  The METASTATIC CASCADE

  Mechanism of metastasis development within a primary tumor

  

Resume

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 clearly the fact that more cells are produced than die in a given time

  

Resume

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 accounts for interval before the appearance of metastasis

  

Resume