Cancer metastasis:

Building a Framework

Oleh:
Fikri Akbar 1507101030168
Sarah Fadillah 1507101030257
Silvia Arga 1507101030223
Sri Hanifah Mea H 1507101030161
INTRODUCTION

Metastasis

Metastasis is a proccess when genetically

unstable cancer cells adapt to a tissue
microenvironment that is distant from the
primary tumor.
Metastasis steps
A Problem of evolution
 Metastasis emerges from the somatic evolution of
a genetically diversified cancer-cell population
under the selective pressures of an environment
Biological cascade of metastasis are:
1. Loss of cellular adhesion
2. Increased motility and invasiveness
3. Entry and survival in the circulation
4. Exit into new tissue
5. Eventual colonization of a distant site
The Early Origin Of Cellular
Heterogenety
 Evolutionary processes require a source of
heterogeneity within the population, from which
advantageous traits can be selected
 This heterogeneity is supplied by the intrinsic instability
of cancer genomes in the form of:
1. DNA mutations
2. Chromosomal rearrangements
3. Epigenetic alterations
Pressure That Select For An Aggressive
Phenotype
 The inappropriate proliferation of cells harboring oncogenic lesions is challenged
by multiple layers of mechanisms that suppress tumor formation
There are some mechanisms that suppress tumor formation:
1. Cell intrinsic
a. Genotoxic stress induced by oncogenes
b. Expression of growth inhibitory
c. Apoptotic and senescence pathways
d. Telomere attrition
Evasion of these tumor suppressive pathways is a hallmark of primary tumors
2. Tumor microenvironment
a. Extracellular matrix components
b. Basement membranes
c. Reactive oxygen species
d. The limited availability of nutrients and oxygen
e. Attack by the immune system
Pressure to make aggressive phenotype
Prerequisities For Metastasis
1. Tumor-initiating Capacity
 Normal cells constitute lineages that extend from stem
cells to terminally differentiated progeny. Stem cells have
the capacity to divide with at least one daughter retaining
the phenotype of the mother
 the long- term tumorigenic potential of some tumors
may rely on a small proportion of malignant cells
endowed with a similar capacity to indefinitely self renew.
 These tumor-initiating cells are sometimes referred to as
‘cancer stem cells’
2. Altered Cellular Adhesions

 Carcinoma cells almost invariably show diminished

intercellular adhesiveness
 In many instances, epithelial tumors lose E-cadherin-
mediated adhesions as they progress toward
malignancy
 Diverse alterations in adhesive properties allow cancer
cells to disobey the rules of tissue architecture and to
advance in their malignant progression
3. Cell Motility
Metastasis fundamentally involves the movement of cells from one site to
another
Components of this cell motility involve in metastatic progression:
1. Dynamic cytoskeletal changes
2. Cell-matrix interactions
3. Localized proteolysis
4. Actin-myosin contractions
5. Focal contact disassembly
 Nodes of regulation include small GTPases (such as Rho, cdc42, and Rac)
 integrin-containing focal adhesion assembly and disassembly, secreted and
plasma membrane-tethered proteases, and the actomyosin contractile machinery.
 Growth-factor signaling, such as that mediated by HGF through the Met receptor,
can modulate many of these activities either directly or indirectly
 4. Resistance To Extracellular Death Signals
 Cell death:
1.Nutrien deprivation
2.Hypoxia
3.Alteration in extracellullar adhesion
4.Change in cell shape during invasion
5.Exposure to novel stromal microenvironments
 Expression of potent anti apoptotic effectors (BCL2, BCL-X, XIAP)
make them highly resistant to death stimuli=> enhance metastasis
 Loss of caspase 8 expression (apoptotic initiator) by making tumor
cells more resistant to stress from loss adhesion=> invasion and
metastasis
5. Disruption Of The Basement Mebrane And
Extracellular Matrix
 Basement membran: Glicoprotein and proteoglican (Type 4
Colagen, Laminin, Perlecan)
 Tumor cells that are able to proteolytically disrupt the basement
membrane can progress to overt malignancy and metastasis
 To facilitating tumor invasion, extracellular protease may
generate a diverse array of bioactive cleaved peptides=>
modulate migration, cancer cells proliferation and survival,
tumor angiogenesis.
 Beyond The Basement Membrane:
enemies and accomplices
 Markers of strumal cell co option in tumor: fibrosis, leucocytic infiltration,
angiogenesis, limfangiogenesis => increase of metastasis relapse
Ex: 1) NK, T and B limphocyte blunted during progression of neoplasma by
imunosupresive cytokine (TGF beta, IL 10, IL 23).
Cytokine that mediate chronic inflamation facilitate both tumor initiation
and metastatis
2) Macrophage induce angiogenesis by secreting vasoactive factors ,
protease, and growth factor to facilitate tumor cell proliferation, survival,
and invasion.
Highways To Life In Transit
Distant Organs
 Cancer cells must invade  Using blood platelets as
tumor associated vasculature shields.
to gain access to distant sites
of body. (angiogenesis)  Malignancies induce
(dominant) hipercoagulable state
 Lymphatic vessels designed to
collect interstitial fluid
effusions and carry them to
lymph nodes into
hematogenous circulation
Getting Out: extravasation
1. Ezrin protein (osteosarcoma cells)
2. VEGH induced extravasation (induced
disruptions in endothelial cell junction)
Metastatic extravasation
Patterns of Colonization
 Based on observations of Stephen Padget: cancer cell would only
colonize organ microenvironment that were compatible with
their growth.
 Metastatic cells will only attack the organs the capability to it.
Ex: 1. Breast cancer, => the brain, bone, liver, lungs, which
actually has no direct blood flow to the breast
2. Prostat cancer => bone (dominan), visceral (rare)
3. Uveal melanoma => liver
4. sarcoma => lungs
Generating a Viable Niche
 The process usually involves the mobilization
metastases from hematopoietic progenitors derived
from bone marrow to the circulation and going to
the target organs for colonizes triggered by
hormonal factors are enumerated in the initiation of
primary tumor cells
Generating a Viable Niche
 Hematopoietic cells to identify cancer cells as VEGFR1 (first
receptor in the process of forming new blood vessels that serve to
stimulate the development of angiogenesis), CD133, CD34 and c-Kit
 When VGEFR1 bblocked -> will express antibodies propitious
progenitor cell metastasis. Who were inoculated subcutaneously lung
carcinoma is propagated through the bone marrow will only be
spread on the area alone and spread to the organ that has the same
type of cell types. (Meaning it can not spread to the receptor does not
pick the same organs with organs. While melanoma is recruited by
progenitor he would spread to target organs and will metastasized
widely. Thus, bone marrow cells would cause changes in specific
organs (metastasized).
In a State of Dormancy
 The most tumor cells that have undergone extravasation
can not be effectively extended. For some kinds of
carcinoma, tumor cells can be detected in the bone
marrow sum prior to the development of metastases.
 acquisition of an angiogenic stimulus that is effective in
secondary relevant microenvironment could solve the
inactivity imposed by limited access to blood vessels. In
other cases, disseminated tumor cells remain active in
microenvironments where angiogenesis does not appear
to be rate limiting.
Becoming Organ Specific
 To be able to rise up and spread to new organs, tumor
cells must have the productive capacity to be able to
interact with the new environment in order to stimulate
growth and survival. Because the microenvironments
(group of cells) smaller than the different organs, such
as the requirement to have cancer cells in the organ
metastasis can, and mediators specific organ metastases
were not always the same.
 Site-specific mediators of metastais

Becoming Organ Specific

 1. Colonizing Bone
 Bone metastases can make the two conditions: osteoblastic
and osteolytic.
 Osteoblast (prostate cancer): Wnt, BMP through the
induction of Runx2 (a "master" transcription factor in
osteoblast lineage), RANKL
 Osteoclast (breast cancer): M-CSF, RANKL, IL-6,IL-8, IL11
2. Colonizing the Lungs

 Pulmonary involvement may be that our entire cardiac output circulates

through the lung-cappilary network.
 Metastatic cells must survive and grow in this unique microenvironment, which
contains highly organized extracellular matrix and specialized cell types for the
purpose of respiration.
 Cancer cells are inoculated directly into the venous circulation to force the
seeding of the lungs.
 protein ezrin appears to be facilitate tumor-cell extravasation into the lung
parenchyma, and its expression correlates negatively with overall survival in
osteosarcoma patients
3. Colonizing the Brain
 Metastatic colonization of the brain, although less frequent than metastasis to other
organs, bodes and alarmingly poor prognosis.
 Metastatic cells may either colonize the brain parenchyma or thrive along the
leptomeninges, which represents the most aggressive form of this disease.

4.Colonizing the Liver

 Gastrointestinal malignancies tend to metastasize first to the liver, presumably due to
direct perfusion through the portal vein. Other primary tumors can metastasize to the
liver through the systemic vasculature, including breast cancer, uveal melanoma, and
lung cancer.
Seeding and Reseeding
 Histological markers of cellularproliferation were
unchanged suggesting that this augmented growth
was not simply a consequence of accelerated
progression through the cell cycle.
 Some of the genes that mediated metastasis have
dual function.
Impact of the Cell of Origin
Certain cell lineages may express molecules that bias the
metastatic efficiency to different target organs.
The developmental history of a cell may also predispose it to
activate expression of specific metastasis-promoting mechanisms
upon malignant transformation.
such as Slug in melanoma remains to be established. One
possibility is that lineage-specific signaling and transcription-factor
circuitries may alter the cellular response to the same oncogenic
alterations.
Corollary a
1. Until the primary tumor is diagnosed and surgically
removed, the primary mass have already undergone
dissemination.
2. As technologies advance and more pathways are
implicated in metatatic progression, it becomes
increasingly feasible to focus on molecular mediators that
withstand rigorous tehst for clinical relevance.
Thank You