2 Blok9 Biologi Tumor Untad2011

05/06/2014 1

Dr. FX Ediati Triningsih MSc SpPA (K)

Department of Pathology

Gadjah Mada University School of Medicine

BIOLOGY OF TUMOR

GROWTH

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Neoplasia• Neoplasia new growth

• Neoplasm: abnormal tissue mass growing

excessively and indefinitely without

coordination with normal tissue

• Behaviour: progressive, useless,

independent from surrounding tissue,

unrelated to host needs, parasitic,

autonomic.

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The biology of tumor

Normal cells

Malignant cells

Changes:• Genotypic

• Phenotypic

Carcinogenesis

• Basically : the changes of norma – malignant cell

• Carcinogenesis is a multistep process at both the

phenotypic and the genotypic levels, resulting from the

accumulation of multiple mutations

• Phenotypic : excessive growth, invasion, metastase -

over periode of time – reffered as tumor progression

• Genotype : changes of genes cause by mutation, not

only genes for growth but also for angiogenesis, invasion

and metastase

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Six basic factors to ascertain the physiologycal

changes of a normal - malignat cells

• Self sufficiency- produce their own growth

signal-consequence of oncogen activation

• Intensitivity toward growth inhibitor - TGF alpha

and CDKs (Cyclin dependent Kinase)

• Avoid apoptosis- inactivation of p53 and

activation of anti apoptotic gene – BCL2

• Unlimited replication- immortal- telomer

• Continuing angiogenesis-VEGF and FGF

• Ability to invade and metastase

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BIOLOGY OF TUMOR GROWTH

• The tumor cells tend to replicate rather than to differentiate due to genetic alterations (oncogene activation, anti-oncogene suppression, etc)

• Most tumors are of monoclonal origin


Most malignant tumors “normally” passing four phases :

• Transformation

• Growth of transformed cells

• Local invasion

• Distant metastases

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Multiple factors that influence tumor growth

1. Kinetics of tumor growth

2. Tumor angiogenesis

3. Tumor progression and heterogeneity

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How long does it take to produce a clinically overt tumour mass ?

This depends on three variables:

• The doubling time of tumor cells

• Growth fraction

• Cell production and loss


Kinetics of tumor growth

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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.

• In contrast, only 10 further doubling cycles are required to produce a tumor containing 1012 cells (weighing + 1 kg), which is usually the maximal size compatible with life.

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• 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

• 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%

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Characteristics of tumor cells:

• Cells in the growth phase are the most susceptible to chemotherapeutic agents

• Type of tumor vary in their doubling time, and the same type of tumor varies from patient to patient

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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

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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

- by differentiating

- reversion to G0

• most cells within cancer remain in the G0 phase

• In some rapidly growing tumors, the growth

fraction is approximately 20%

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Growth fraction

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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

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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 tend 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)

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Tumor angiogenesis

Blood supply :

Tumor cannot enlarge beyond 2 mm in

diameter or thickness unless they are

vascularized. Presumably the 2 mm zone

represent the maximal distance across

which oxygen and nutrients can diffuse

from blood vessels.

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Tumor angiogenesis

• Angiogenesis is not only for tumor growth, but also for metastasize

• Angiogenesis is a necessity for biological 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

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Tumor angiogenesis

Effect of neovascularization

• Perfusion of supply nutrients, oxygen,

and newly formed endothelial cells

stimulate the growth of adjacent tumor

cells by secreting polypeptides such as

IGF, PDGF, GM-CSF, and IL-1

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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 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

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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

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Tumor Angiogenesis

Dysorganized vessels within the tumor mass

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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.

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Tumor angiogenesis compared to normal

blood vessel

Arterioles, capillaries, and veins are disorganized and unidentifiable.

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Angiogenesis

• Because angiogenesis is critical for the

growth and spread of tumors, much

attention is focused on the use of

angiogenesis inhibitors – therapy

• Success has been achieved in treating

fairly large tumors in mice by adm. of

endostatin and tumstatin (anim.exp.)

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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

but by the time they become clinically

evedent, their constituent cells are extremely

heterogenous

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Tumor Progression and Heterogeneity

Behaviour of tumors

• The most important property of malignant tumors is

the ability to invade and metastasise

• Invasion is the most important criteria for

malignancy

• Invasion is due to abnormal cell motility, reduced

cellular cohesion, and production of proteolytic

enzyme

• Metasatasis is the process of formation of distant

secondary tumors

• Common routes of metastasis include lymphatic

channels, blood vessels, and through body cavities05/06/2014 30

INVASION

• The invasivness of malignant neoplasms

is determined by the properties of the

neoplastic cells within them.

• Factors influencing are :

- abnormal of increased cellular motility

- secretion of proteolytic enzymes

- decreased cellular adhesion

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Malignant potential

• Invasion and metastasis are biologic hallmark of

malignancy

Four steps of invasion

• Detachment of tumor cells

• Attachment of tumor cells to matrix components

• Degradation of ECM

• Migration of tumor cells

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Invasion Sequence of Basement Membrane by Tumor Cells

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The

METASTATIC

CASCADE

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Mechanism of

metastasis development

within a primary tumor

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Resume

Tumor growth

• Tumor cells do not necessarily proliferate

more rapidly than their normal counterpart

• The major determinant of tumor growth is

clearly the fact that more cells are produced

than die in a given time

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Resume

The growth of cancer

• Tumor growth rates may be expressed as

doubling time

• Tumor angiogenesis refers to the

sprouting of new capillaries

• Tumor dormancy accounts for interval

before the appearance of metastasis

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Resume

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

• It is not known whether they remain in G0

phase of cell cycle for prolonged period of time or whether they do not grow because interference with angiogenesis, unrespon-siveness to growth factors, or the presence immune growth restraints

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CLINICAL RELEVANCES OF TUMOR

Dr. FX Ediati Triningsih SpPA (K)

Department of Pathology

Gadjah Mada University School of Medicine

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CLINICAL RELEVANCES OF TUMOR

EFFECT OF TUMOR ON HOST

Tumors may affect host in several ways

• Non-immunologic effect

• Immunologic reaction

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non immunologic effectCLINICAL FEATURES OF NEOPLASM

DEPEND ON

1. Anatomical location

morbidity/mortality: i.e. brain tumors intra-

cranial pressure is increasing

2. Local effect

pressing surrounding tissue necrosis,

desmoplasia

3. Sistemic effect

hormone producing tumor and hormon-like

substance

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CLINICAL FEATURES OF NEOPLASM

2. Local Effects

• Destruction of surrounding tissue

• Circulation disturbances

• Growth enlargement ulcer

• Obstruction of hollow organs

• Secondary infection

• Nerve pressure

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CLINICAL FEATURES OF NEOPLASM

3. Systemic effect

• Cachexia

• Fever

• Increased BSR

• Anemia

• Decreased body resistance

• Increased tendency of thrombus development

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OTHER

Clinical Manifestations of Malignancy

• Cachexia and wasting

• Endocrine abnormalities

• Paraneoplastic syndromes

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Cachexia & wasting

• Origin is complex

• Characterized by weakness, weight

loss, anorexia, anemia, infection, and

hypermetabolism

• May be mediated in part by cachectin

(TNF-α), a product of macrophages

that promote catabolism of fatty tissue

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Endocrine abnormalitiescaused by endocrine gland tumors hormones variety of syndromes

A.Pituitary abnormalities:1. Prolactinoma amenorrhea, infertility, galactorrhea

2. Somatotropic (acidophilic) adenoma gigantism in children, acromegali in adult

3. Corticotropic (most often basophilic) adenoma Cushing disease

B.Adrenocortical abnormalities:- adrenogenital syndrome, Conn syndrome, Cushing

syndrome (adreno-cortical tumor)

C.Ovarian abnormalities:1. Granulosa-theca cell tumor hyperestrinism

2. Sertoli-Leydig cell tumor excess androgen production

D. Trophoblastic tissue abnormalities:- mole & choriocarcinoma excess hCG

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Paraneoplastic syndrome

• Symptom complexes in cancer-bearing

patients that cannot readily be explained,

either by local or distant spread of the

tumor or by the elaboration of hormones

indigenous to the tissue from which the

tumors arose

• Incidence: 10 % of patients with advance malignancy

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Important to recognize several problems:

1. Earliest manifestation of occult

neoplasm

2. In the patient: may represent significant problems and may even

be lethal

3. They may mimic metastatic disease and therefore confound treatment

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PARANEOPLASTIC SYNDROMES

ENDOCRINOPATHIES

• Cushing syndrome:

Small cell Ca of lung, pancreatic Ca, neural

tumors ACTH or ACTH-like substance

• Syndrome of inappropriate ADH secretion:

Small cell Ca of lung, intra-cranial neoplasms

ADH or atrial natriuretic hormones

• Hypercalcemia:

Lung SCC, breast Ca, renal Ca, adult T-cell

leukemia / lymphoma, ovarian Ca parathyroid

hormone related peptide, TGF- α, TNF- α, IL-1

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ENDOCRINOPATHIES

• Hypoglycemia:

Fibrosarcoma, other sarcoma, LCC insulin or insulin-like substance

• Carcinoid syndrome:

Bronchial adenoma (carcinoid), pancreatic Ca, gastric Ca serotonin, bradykinin, histamin (?)

• Polycythemia:

Renal Ca, cerebellar hemangioma, LCC erythropoietin

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Nerve and muscle syndromes

• Myasthenia: bronchogenic Ca immunologic

• Disorders of the central & peripheral nervous system:breast Ca immunologic

Dermatologic disorders

• Acanthosis nigricans: gastric Ca, lung Ca, uterine Ca

• Dermatomyositis: bronchogenic Ca, breast Ca immunologic (?)

Osseous, articular, and soft tissue changes

• Hypertrophic osteoarthropathy and clubbing of the fingers:bronchogenic Ca ?

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Vascular and hematologic changes

• Venous thrombosis (Trousseau phenomenon):pancreratic Ca, bronchogenic Ca, other cancers tumor products (mucin that activate clotting)

• Nonbacterial thrombotic endocarditis: advanced cancers hypercoagulability

• Anemia: thymic neoplasm ? (unknown)

Others

• Nephrotic syndrome: various cancers tumor antigen, immune complexes

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Staging & Grading

• Grading of cancer is based on the degree of

differentiation of the tumor cells and the number of

mitosis (correlated with the aggressiveness of the tumor)

• The staging of cancer is based on the size of the primary

lesion, its extent of spread to regional lymphnode, and

the presence or absence of blood borne metastases

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T(tumor)N(nodule)M(metastasis)

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Astler-Coller

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Follicular adenoma & adenocarcinoma of colon

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In situ SCC

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Well differentiated SCC

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Pleomorphic Rhabdomyosarcoma

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PETANDA TUMOR YANG BERHUBUNGAN

Hormon

HCG

Kalsitonin

Katekolamin dan metabolit

Hormon ektopik

Antigen onkofetal

Alfa-fetoprotein

CEA

Isoenzim

Prostatic Acid Phosphatase

Neuron specific enolase (NSE)

Protein spesifik

Imunoglobulin

PSA

Musin & glikoprotein lain

CA-125

CA-19-9

CA-15-3

Tumor trofoblastik dan testis non-seminoma

Ca medular tiroid

Feokromositoma dan tumor yang berhubungan


HCC, tumor testis sel benih non seminomatosa

Ca kolon, pankreas paru, gaster, mama

Ca prostat

Ca sel kecil paru, neuroblastoma

Mieloma multipel dan gamopati lain

Ca prostat

Ca ovarium

Ca kolon, pankreas

Ca mama

PETANDA TUMOR

Documents

2 Blok9 Biologi Tumor Untad2011