Angiogenesis & Metastasis

Dr. T. Ibnu Alferraly, M.Ked.PA, SpPA, D.Bioeth

2017
Angiogenesis
 What is angiogenesis

Angiogenesis is the formation of new blood vessels

from pre-existing vessels.

Angiogenesis is a normal process in growth and

development, as well as in wound healing.

However, this is also a fundamental step in the

transition of tumors from a dormant state to a
malignant state.
Angiogenesis is a process controlled by certain chemicals produced in the body.
Some of these chemicals stimulate cells to repair damaged blood vessels or form
new ones. Other chemicals, called angiogenesis inhibitors, signal the process to
stop.
 The balance hypothesis of the 'angiogenic switch'.

Angiogenesis is tightly controlled by the balance of two sets of counteracting

factors – angiogenic activators and inhibitors.
 The angiogenic process
The angiogenic process is a critical process for new cell and tissue growth 。

The 4 major steps of endothelial cells in

angiogenesis
1. Breaking through of the basal lamina that
envelopes existing blood vessels
2. Migration toward a source signal

3. Proliferation

4. Formation of tubes

Like most processes in homeostatic cellular systems, angiogenesis is a complex, highly

regulated system. A large number of pro-angiogenic growth factors have been identified, many
of which are capable of inducing all 4 of the above steps. One of the primary factors among
these is a protein known as VEGF.
aggregasi sel tumor merupakan usaha pertahanan
terhadap sel efektor antitumor host.

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• Ekstravasasi sel tumor yang bebas / tumor emboli melekat pada
endotel p.darah  menerobos basal membran  ke organ
parenkim (melalui mekanisme mirip dengan invasi)

• Tempat ekstravasasi & organ yang tersebar oleh metastasis

secara umum dapat diperkirakan dengan lokasi tumor primer
dan pengaliran (drainage) p.darah & limfatik.

• Sebagian tumor (spt. Kanker paru) cendrung melibatkan adrenal,

namun tidak pernah menyebar ke otot rangka

• Beberapa organ berkaitan dengan tampilan molekul perlekatan

(adhesion molecules) dengan sel tumor, dimana ikatan (ligands)
nya tertampil terutama pada endothel organ target.

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• Mekanisme lain dari tempat spesifik untuk homing adalah chemokines &
reseptornya.

• Chemokine berpartisipasi di dalam gerakan leukosit secara langsung

(chemotaxis).

• Sel kanker payudara mempunyai tampilan kuat untuk chemokine reseptor

CXCR4 & CCR7.

• Ikatan (ligands) untuk reseptor ini (contoh: chemokine CXCL12 & CCL21)
tertampil lebih kuat hanya pada organ tempat metastasis sel kanker payudara.
Ini mendasari penghambatan reseptor chemokine dapat membatasi
metastasis.

• Setelah ekstravasasi, peetumbuhan sel tumor tergantung pada penerimaan

stroma.
• Sel tumor mungkin gagal untuk bermetastasis ke jaringan target tertentu,
karena tidak tersedia lingkungan untuk pertumbuhan.
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 Molecular Genetics of Metastasis
• Teori progresif tumor progression menyokong bahwa :
• pertumbuhan tumor, sel individu mengalami sejumlah mutasi
secara acak, menghasilkan subklone dengan beragam kombinasi
mutasi.

• According to this hypothesis only a small subpopulation of the

tumor cells contains all the mutations necessary for metastasis.
• However, recent experiments, in which gene profiling of primary
tumors and metastatic deposits has been compared, challenge
this hypothesis.
• For example, a subset of breast cancers has a gene expression
signature similar to that found in metastases, although no clinical
evidence for metastasis is apparent.
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• In these tumors it seems that most if not all cells
develop a predilection for metastatic spread early,
during primary carcinogenesis.
• Metastases, according to this view, are not dependent
on the stochastic generation of metastatic subclones
postulated above.
• It should be noted, however, that gene expression
analyses like those described above would not detect a
small subset of metastatic subclones within a large
tumor. Perhaps both mechanisms are operative, with
aggressive tumors acquiring a metastases-permissive
gene expression pattern early in tumorigenesis that
requires some additional random mutations to
complete the metastatic phenotype 20
• One open question in the field is, are there genes whose principal
or sole contribution to tumorigenesis is to control metastases?

• This question is of more than academic interest, because if

altered forms of certain genes promote or suppress the
metastatic phenotype, their detection in a primary tumor would
have both prognostic and therapeutic implications.

• Metastasis is a complex phenomenon involving a variety of steps

and pathways described above. It is thought therefore that, unlike
transformation, in which a subset of proteins like p53 and RB
seem to play a key role, genes that function as "metastasis
oncogenes" or "metastatic suppressors" are rare.

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Among candidates for such metastasis oncogenes are SNAIL and
TWIST, which encode transcription factors whose primary function
is to promote a process called epithelial-to-mesenchymal
transition (EMT). In EMT, carcinoma cells down-regulate certain
epithelial markers (e.g., E-cadherin) and up-regulate certain
mesenchymal markers (e.g., vimentin and smooth muscle actin).
These changes are believed to favor the development of a
promigratory phenotype that is essential for metastasis. Loss of E-
cadherin expression seems to be a key event in EMT, and SNAIL
and TWIST are transcriptional repressors that promote EMT by
down-regulating E-cadherin expression. EMT has been
documented mainly in breast cancers; whether this is a general
phenomenon remains to be established
 SUMMARY
Invasi & Metastasis
• Kemampuan meninvasi jaringan merupakan sifat khas tumor ganas,

• Ada 4 langkah invasi :

1. Hilangnya hubungan antar sel

2. Hancurnya ECM
3. Melekatnya sel tumor terhadap komponen ECM
4. Migrasi sel tumor

• Hilangnya kontak antar sel disebabkan oleh tidak aktifnya E-cadherin melalui
berbagai jalur.

• Hancurnya basal membran & matriks interstisial diperantarai oleh enzim

proteolitik yang disekresi oleh sel tumor & sel stroma (spt. MMPs & cathepsins).

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• Enzim proteolitik melepasakan faktor pertumbuhan ke dalam
ECM  menimbulkan kemotaktik & fragmen angiogenik dari
cleavage of ECM glycoproteins.

• Tempat untuk metastatis berbagai tumor dapat diperkirakan dari

lokasi tumor primer.

• Sebagian besar tumor bermetastasis ke kapiler (terutama ke paru

& hati).

• Sebagian tumor menunjukkan organ kankernya, mungkin

menampilkan reseptor adhesion / kemokin, yang ikatannya
tertampil pada tempat metastasis.

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 Principle of Treatment
• Surgical therapy – early stage/debulk
• Chemotherapy
• Radiotherapy
• Immunotherapy
 It is easy to kill cancer
cells, but the challenge is
keeping the patient alive at
the same time…..!