BIOLOGY OF TUMOR

GROWTH
Dr. FX Ediati Triningsih MSc SpPA (K)
Department of Pathology
Gadjah Mada University School of Medicine

05/06/2014

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.
05/06/2014

The biology of tumor

Normal cells

Malignant cells
Changes:
Genotypic
Phenotypic

05/06/2014

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
05/06/2014

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
05/06/2014

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

05/06/2014

BIOLOGY OF TUMOR GROWTH

Most malignant tumors
normally passing four phases :
Transformation
Growth of transformed cells
Local invasion
Distant metastases

BIOLOGY OF TUMOR GROWTH

Multiple factors that influence tumor growth
1. Kinetics of tumor growth
2. Tumor angiogenesis
3. Tumor progression and heterogeneity

05/06/2014

BIOLOGY OF TUMOR GROWTH

Kinetics of tumor growth

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

05/06/2014

Kinetics of tumor growth

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.

05/06/2014

10

The doubling time of tumor cells

05/06/2014

11

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
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%
05/06/2014

12

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

05/06/2014

13

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

05/06/2014

14

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
- 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%
05/06/2014

15

Kinetics of tumor growth

Growth fraction

05/06/2014

16

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
05/06/2014

17

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)
05/06/2014

18

BIOLOGY OF TUMOR GROWTH

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.

05/06/2014

19

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.
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
05/06/2014

20

BIOLOGY OF TUMOR GROWTH

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
05/06/2014

21

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
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
05/06/2014

22

BIOLOGY OF TUMOR GROWTH

Tumor angiogenesis
Antiangiogenesis
Tumor cells also induced and produced antiangiogenesis molecules.
Tumor growth is controlled by the balance between
angiogenic factors and antiangiogenic factor (inhibit
angiogenesis).
Example of Antiangiogenesis :
Thrombospondin1
Angiostatin, endostatin, tumstatin
05/06/2014

23

BIOLOGY OF TUMOR GROWTH

Tumor Angiogenesis

05/06/2014

Dysorganized vessels within the tumor mass

24

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.
05/06/2014

25

Tumor angiogenesis compared to normal

blood vessel

Arterioles, capillaries, and veins are disorganized and unidentifiable.

05/06/2014

26

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.)

05/06/2014

27

BIOLOGY OF TUMOR GROWTH

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

05/06/2014

28

Tumor Progression and Heterogeneity

05/06/2014

29

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 cavities30
05/06/2014

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
05/06/2014

31

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

05/06/2014

32

Invasion Sequence of Basement

Membrane by Tumor Cells

05/06/2014

33

The

METASTATIC
CASCADE

05/06/2014

34

Mechanism of
metastasis development
within a primary tumor

05/06/2014

35

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

05/06/2014

36

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

05/06/2014

37

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, unresponsiveness to growth factors, or the presence
immune growth restraints
05/06/2014

38

CLINICAL RELEVANCES
OF TUMOR
Dr. FX Ediati Triningsih SpPA (K)
Department of Pathology
Gadjah Mada University School of Medicine

05/06/2014

41

CLINICAL RELEVANCES OF TUMOR

EFFECT OF TUMOR ON HOST

Tumors may affect host in several ways
Non-immunologic effect
Immunologic reaction

05/06/2014

42

non immunologic effect

CLINICAL FEATURES OF NEOPLASM
DEPEND ON

1. Anatomical location
morbidity/mortality: i.e. brain tumors intracranial pressure is increasing
2. Local effect
pressing surrounding tissue necrosis,
desmoplasia
3. Sistemic effect
hormone producing tumor and hormon-like
substance
05/06/2014

43

CLINICAL FEATURES OF NEOPLASM

2. Local Effects
Destruction of surrounding tissue
Circulation disturbances
Growth enlargement ulcer
Obstruction of hollow organs
Secondary infection
Nerve pressure
05/06/2014

44

CLINICAL FEATURES OF NEOPLASM

3. Systemic effect
Cachexia
Fever
Increased BSR
Anemia
Decreased body resistance
Increased tendency of thrombus
development
05/06/2014

45

OTHER

Clinical Manifestations of
Malignancy
Cachexia and wasting
Endocrine abnormalities
Paraneoplastic syndromes

05/06/2014

46

Cachexia & wasting

Origin is complex
Characterized by weakness, weight
loss, anorexia, anemia, infection, and
hypermetabolism
May be mediated in part by cachectin
(TNF-), a product of macrophages
that promote catabolism of fatty tissue
05/06/2014

47

Endocrine abnormalities
caused 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
05/06/2014

48

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
05/06/2014

49

Paraneoplastic syndrome
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
05/06/2014

50

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- , TNF- , IL-1 51
05/06/2014

PARANEOPLASTIC SYNDROMES

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
05/06/2014

52

PARANEOPLASTIC SYNDROMES

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 ?
05/06/2014

53

PARANEOPLASTIC SYNDROMES

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
05/06/2014

54

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

05/06/2014

55

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

05/06/2014

56

Astler-Coller

05/06/2014

57

Follicular adenoma & adenocarcinoma of colon

05/06/2014

58

In situ SCC

05/06/2014

59

Well differentiated SCC

05/06/2014

60

Pleomorphic Rhabdomyosarcoma

05/06/2014

61

PETANDA TUMOR
PETANDA

TUMOR YANG BERHUBUNGAN

Hormon
HCG
Kalsitonin
Katekolamin dan metabolit
Hormon ektopik

Tumor trofoblastik dan testis non-seminoma

Ca medular tiroid
Feokromositoma dan tumor yang berhubungan
Paraneoplastic syndrome

Antigen onkofetal
Alfa-fetoprotein
CEA

HCC, tumor testis sel benih non seminomatosa

Ca kolon, pankreas paru, gaster, mama

Isoenzim
Prostatic Acid Phosphatase
Neuron specific enolase (NSE)

Ca prostat
Ca sel kecil paru, neuroblastoma

Protein spesifik
Imunoglobulin
PSA

Mieloma multipel dan gamopati lain

Ca prostat

Musin & glikoprotein lain

CA-125
CA-19-9
CA-15-3
05/06/2014

Ca ovarium
Ca kolon, pankreas
Ca mama

62