Download Chapter 6 Neoplasia

Invasion and Metastasis
Dr Wirsma Arif Harahap
Surgical Oncologist
Malignant versus Benign Tumors
• Benign tumors
generally do not
spread by
invasion or
metastasis
• Malignant
tumors are
capable of
spreading by
invasion and
metastasis
OBJECTIVE
1. Biology of tumor growth
2. Tumor angiogenesis
3. Tumor progression and heterogeneity
4. Cancer Cells and Microeviroment
5. Tumor spread
OBJECTIVE
1. Biology of tumor growth
2. Tumor angiogenesis
3. Tumor progression and heterogeneity
4. Cancer Cells and Microeviroment
5. Tumor spread
1. Biology of tumor growth
The natural history of malignant tumors
can be divided into four phase:
A.
B.
C.
D.
Transformation
Growth of transformation cells
Local invasion
Distant metastases
Tumor growth
(a) Rate of growth
Benign: slowly years to decades
Malignant: rapidly moths to years
(b) Pattern of growth
① Expansile
a. Well-demarcated and encapsulated
b. Gradually
c. Surgically enucleated easely.
d. The particular growth pattern of
benign tumors
Expansile Growth pattern
② Invasive
a. Progressive infiltration, invasion, and
destruction of the surrounding tissue
b. Ill-defined and non-encapsuled
c. The particular
malignant tumors
growth
pattern
d. Be surgically enucleated difficultly
of
Invasive growth pattern
③ Exospheric
a. Tumors growth projecting on the
surface, booty cavities, or the lumen
b. Commonly polyp, mushroom, and
finger-like
c. Growth pattern of both benign and
malignant tumors
Exospheric growth pattern
OBJECTIVE
1. Biology of tumor growth
2. Tumor angiogenesis
3. Tumor progression and heterogeneity
4. Cancer Cells and Microeviroment
5. Tumor spread
(2) Tumor angiogenesis
Angiogenesis is necessary for biologic
correlate of malignancy.
Development cancer > 1mm  hypoxia
cell  cancer release hif ( hipoxia
inducing factor )  endothel release
VEGF ( vascular endothelial growth fc)
VEGF  angiogenesis
Tumor Angiogenesis
15
Tumor Angiogenesis
16
Angiogenesis is required for tumors to
grow beyond a few millimeters in
diameter
In 1971, Judah Folkman, signal
molecules for new blood vessel
formation
► Tumor angiogenesis
►

The processes of cancer cells stimulate the
development of a blood supply
Tumor Angiogenesis
18
OBJECTIVE
1. Biology of tumor growth
2. Tumor angiogenesis
3. Tumor progression and heterogeneity
4. Cancer Cells and Microeviroment
5. Tumor spread
(3) Tumor progression and heterogeneity
Despite most malignant tumors are
monoclonal in origin, by the time they
become
clinically
evident,
their
constituent
cells
are
extremely
heterogeneous resulting from multiple
mutations
that
accumulate
independently in different cells.
OBJECTIVE
1. Biology of tumor growth
2. Tumor angiogenesis
3. Tumor progression and heterogeneity
4. Cancer Cells and Microeviroment
5. Tumor spread
4. Cancer Cells and Microeviroment



Cancer cells cannot growth by itself
It is need support by microenviroment
(stromal).
Lack of supporting  cancer cells will
die.
Microenvironment
-Fibroblasts/Myofibroblasts
Tumor Cells
-Endothelial Cells
-Epithelial
-Myoepithelial Cells
-Mesenchymal
-Leukocytes
-Hematopoietic
-Extracellular Matrix
-Usually Bulk of Tumor
Bi-directional Interactions
between Cancer cells and
enviroment
Microenvironment can contribute positive or
negative signals to tumor cells: signals
may be mediated by bioactive products
or cell-cell contact
Tumor cells modify the microenvironment to
produce
bioactive products such as growth factors, chemokines,
matrix-degrading enzymes that enhance the proliferation,
survival, invasion, and metastasis of tumor cells.
Crosstalk Between Tumor Cells and
Microenvironment
Mueller and Fusenig, 2004
OBJECTIVE
1. Biology of tumor growth
2. Tumor angiogenesis
3. Tumor progression and heterogeneity
4. Cancer Cells and Microeviroment
5. Tumor spread
5. Tumor spread
The spread is a
malignant tumors
(1) Local invasion
(2) Metastasis
cheracteristic
of
1. Local Invasion
Cancers cells invade, penetrate local tissue fissure
progressively.
The steps and mechanism of invasion :
i. Cancerous cells attaching basement
membrane.
ii. Local proteolysis
iii. Locomotion
The three steps of invasion
1
2
Matrix attachment
Matrix degradation
3
Locomotion
Liotta, LA. Tumor invasion and metastasis-role of the extracellular matrix.
Cancer Res 46: (1986)
How do cells move through
tissues?

Acquire invasive ability


Acquire motile ability



Ability to degrade extracellular matrix
(ECM)
Lose cell-cell junctions (EMT-like switch)
Acquire motile capability
Directed migration to hospitable sites


Chemotaxis
Communication between tumor and host
cells
How do cells move through tissues?
Cont..

Cell motility activation



Proteases production


31
By signal molecules
From cancer cells or surrounding cells
To remove cancer cell movement barriers
Plasminogen activator (plasminogen →
plasmin) (fig. 3-9)
Invasion and Metastasis
32
Matrix degradation by proteinases
Metalloproteinases (MMPs)
Serine proteinases (plasmin, uPA)
Cysteine proteinase (Cathepsin B,L)
Aspartyl proteinases (Cathepsin D)
Threonine proteinases
(not extracellular)
(2) Metastasis
Definition: metastasis connotes the
development of secondary implants
discontinuous with the primary tumor,
possibly in remote tissue.
Distant Metastasis
Cancer Cells Follow
The blood stream
Growth in another
Organ
35
Invasion and Metastasis
Invasion-Metastasis Cascade Adapted from Fidler, Nat. Rev. Cancer
3: 453-458, 2003
Figure 14.4 The Biology of Cancer (© Garland Science 2007) p. 591
Fig. 2.2b and c
Weinberg
p. 27
Colon Carcinoma Metastatic
to Liver
Breast Carcinoma Metastatic to
Brain
Organ-specific factors play a role in determining
where cancer cells will metastasize
Seed and soil hypothesis
► Only a few sites provide an optimal
environment for the growth for a particular
type of cancer cell
► The ability of cancer cells to grow in
different locations is affected by interactions
between cancer cells and molecules present
in the specific organs
►
① Lymphatic metastasis
a. This is the most common pathway for
initial dissemination of carcinoma.
b. Tumor cells gain access to an afferent
lymphatic channel and carried to the regional
lymph nodes.
In lymph nodes, initially tumor cell are
confined to the subcapsular sinus; with the
time, the architecture of the nodes may be
entirely destroyed and replaced by tumor.
c. Through the efferent lymphatic channels
tumor may still be carried to distanced lymph
rode, and enter the bloodstream by the way of
the thoracic duct finally.
d. Destruction of the capsule or infiltration to
neighboring lymph nodes eventually causes
these nodes to become firm, enlarged and
matted together.
Metastasis via Lymphatics
Lymphatic Drainage of the Breast
Metastasis via Lymphatics
Identification of “Sentinel” Lymph Node with Dye
Metastasis via Lymphatics
H&E Staining: Breast Ca in Lymph Node
Metastasis via Lymphatics
Keratin Staining: Breast Ca in Lymph Node
② Hematogenous metastasis
a. This pathway is typical of sarcoma
but is also used by carcinoma
b. Process: tumor cells →small blood
vessels→ tumor emboli→ distant
parts→ adheres to the endothelium of
the vessel→ invasive the wall of the
vessel→ proliferate in the adjacent
tissue→ establish a new metastatic
tumor.
c. follow the direction of blood flow. Tumors
entering the superior or inferior vena cava
will be carried to the lungs tumors entering
the portal system will metastasize to the liver.
d. Some cancers have preferential sites for
metastases lung cancer offal metastasize to
the brain, bones, and adrenal glands.
Prostate cancer frequently metastasize to the
bones.
e. Morphologic features of metastasis tumors
multiple, circle, scatter
③ Implantation metastasis
a. Tumor cells seed the surface of body
cavities
b. Most often involved is the peritoneal
cavity
c.
But also may affect pleural,
pericardial, subarachnoid, and joint space.
Mechanisms of invasion and metastasis
① Invasion of the extracellular metastasis
a. Loosening up of tumor cells from each other:
E-adhering expression is reduced
b. Attachment to matrix components: cancer
cells have many more receptors of lamina
and fibronectin.
c. Degradation of extra cellular matrix:
Tumor cells can secrete proteolytic enzymes or
induce host cells to elaborate proteases.
② Vascular dissemination and homing of
tumor cells
a.
Tumor cells may also express adhesion
molecules whose ligands are expressed
preferentially on the endothelial cells of target
organ.
b.
Some target organs may liberate
chmoattractonts that tend to recruit tumor
cells to the site. e. g. insulin-like growth
factor Ⅰ, Ⅱ.
c. In some cases, the target tissue may be not
an permissive environment. i. g. inhibitors of
proteases could prevent the establishment of
mend of a tumor cottony.
③ Molecular genetics of metastases
At present, no single “metastasis gene” has
been found, just son conciliates
a.
High expression of nm23 gene often
accompanied with low metastatic potential.
b. KAI-I gene, located on 11pn-2, expressed
in normal prostate but not in metastasis
prostate cancer.
c.
KISS gene, also located on human
chromosome Ⅱ, analogous manner in
human malignant melanoma.
(Quoted from
Robbins《 Pathology
Basis of disease》)
Primary Tumors and Preferred Sites of Metastatic Spread
Figure 14.42 The Biology of Cancer (© Garland Science 2007)
p. 635
Presence of Micrometastases and Clinical Prognosis: Colon Cancer
Figure 14.50b The Biology of Cancer (© Garland Science 2007)
p. 645
Factors Hindering Metastatic Spread
1.
Metastasis-Suppressor Genes:
e.g. - TIMP: Tissue Inhibitor of Metalloproteinases
- CAD1 gene: for E-cadherin
2. Host Responses



Activated Macrophages
Natural Killer Cells
Cytotoxic Lymphocytes
3. Hydrodynamic Effects in Host circulation
4. Failure to Recognize and Arrest at Secondary
Site
StopMets
Specific genes promote or suppress the
ability of cancer cells to metastasize
►
►
Matrix metalloproteinases (MMPs) inhibitors
can inhibit cancer cells metastasis
Metastasis promoting genes

►
cancer cells


56
MMPs
Enhancement of metastasis promoting genes
Diminishing of metastasis suppressor genes
Routes of tumor spread
• Hematogenous (bloodstream)
sarcomas, carcinomas, leukemias
• Lymphatic (lymph nodes)
carcinomas
• Direct extension (surface implantation, ascites)
ovarian, other carcinomas
Organ site preference for metastasis
Lung and liver: common sites of metastasis
Colon adenocarinoma
Breast adenocarcinoma
Prostate adenocarcinoma
Lung: SCLC
Melanoma - cutaneous
Thyroid adenocarcinoma
Kidney clear cell carcinoma
Testis carcinoma
Bladder carcinoma
Neuroblastoma
Liver
Bone, brain, adrenal
Bone
Bone, brain, liver
Brain, liver, colon
Bone
Bone, liver, thyroid
Liver
Brain
Liver, adrenal