Website References

• https://www.youtube.com/watch?
v=bdWRZd19swg very good
video
• https://www.youtube.com/watch?
v=Ep_nCSEDeAE Same as
above

2
 Metastasis
• The spread of tumor from the site of origin to a remote site
leading to development of secondary implants
(metastases; mets) discontinuous with the primary tumor.
• Metastases (Mets ):
– are tumor implants discontinuous with the primary
tumor.
• In general:
– the more aggressive, the more rapidly growing, and the
larger the primary neoplasm—
– the greater the likelihood that it will metastasize or
already has metastasized.

3
 Routes of Metastasis

1. Lymphatic spread to lymph nodes

2. Hematogenous spread (via veins)
3. Seeding of body cavities.
• What makes MT capable of metastasizing:
• The invasiveness of cancer cells permits
them to penetrate into
• blood vessels, lymphatics, and body
cavities, providing the opportunity for
spread.
4
 Lymphatic Spread

• MC type of metastasis
• It is the most common pathway for the initial
dissemination of carcinomas**(prefer lymph nodes),
less for sarcoma – blood!!!
• Exceptions:
– Follicular carcinoma (thyroid), Renal cell
carcinoma, Hepatocellular carcinoma.
• Regional lymphnodes:
– first line of defense against the cancer spread.
– serve as effective barriers to further dissemination
of the tumor, at least for a while.
– Eventually lymphatics empty into blood vessels
and spread is hematogenous.
• Involved LN are enlarged , nontender and hard in
consistency
5
 Metastasis-cervical
lymphnode

Lymphnode metastasis 6
 7
Metastatic adenocarcinoma in a lymphnode
 Hematogenous Spread
• Usual mechanism of dissemination of sarcomas
(blood).
• Sarcomas predominate but Carcinomas ‘are not shy’
either**
• Arteries are rarely invaded
• Veins* are the route of hematogenous spread
– The liver and lungs and bones are most frequently
involved secondarily in hematogenous
dissemination
– Cells entering the portal vein metastasize to the
liver
– Cells entering the vena cava metastasize to the
lungs. 8
 Blood vessel

Tumor emboli

Malignant tumor

9
 Blood vessel

Tumor embolus

10
Metastasis to lung

11
Metastasis - Hematogenous Spread

12
Liver studded with metastatic cancer.
Bone Metastases

13
 Seeding of body cavities

• Malignant cells exfoliate and implant and

invade tissue in a body cavity.
• Sites of seeding:
– Peritoneal cavity (MC site, ovarian, GI
and pancreatic cancers)
– Pleural cavity (primary /metastatic
lung cancers)
– Subarachnoid space (glioblastoma
multiforme)
14
Seeding in peritoneal cavity

Metastasis Rectal
Carcinoma
15
Seeding in peritoneal cavity

16
 Bone Metastasis
• Vertebral column:
– MC metastatic site in bone.
– Due to Batson paravertebral venous plexus
• It has connections with vena cava and the
vertebral bodies.
• Bone metastasis: two types:
1. Osteoblastic metastasis
2. Osteolytic metastasis (activate osteoclast)

(Batson venous plexus, also known as Batson veins, are a network of veins with no valves that connect
deep pelvic veins draining the bladder, prostate, and rectum to the internal vertebral venous plexus 1. These
veins are important because they are believed to provide a route for spread of pelvic cancer metastases or
infections to the spine) 17
 Osteoblastic metastasis – straight to bone

• Radiodensities are seen

on X rays
• Increased serum alkaline
phosphatase: indicate
reactive bone formation
(this happens when
osteocyte eats up bones
– leading to increase of
alkaline phosphatase)
– Ex: prostate cancer
MC type
Osteoblastic metastasis
18
 Osteolytic Metastasis

• Produce lucencies in bone on X ray.

• Example: Carcinoma breast, carcinoma
lung.
• Pathogenesis:
– Tumors produce factors that activate
osteoclasts
• PG E2, Osteoclast activating factor (IL-
1). (inflammation eats up bones**)
• Potential outcome:
– Pathological fractures
– Hypercalcemia
19
Osteolytic metastasis 20
 Metastatic sites for common cancers –
TCM has answers****
Cancer Site
Stomach adenocarcinoma Virchow’s left
supraclavicular node
Breast cancer Lung , bone
Colorectal cancer Liver
Renal adenocarcinoma Lung
Lung Adrenal / liver
Melanoma Liver/lung
Prostate Bone
Testicular tumor Paraaortic lymph nodes ((also
known as lumbar) are a group of lymph nodes that 21
lie in front of the lumbar vertebrae near the aorta.
Mechanism
of
Metastasis

22
 Mechanism of Metastasis

• Invasion and metastasis are

hallmark of malignant tumors.
• Metastasis involves a number of
steps.
1. Invasion of the extra cellular
matrix
2. Vascular dissemination and
homing of tumor cells.

23
 Invasion of extra cellular matrix

1. Detachment of tumor
cells from each other
– In MT E-
cadherin
((intercellular
adhesion agent) is
not produced.

24
25
 E-Catherin & Metastasis

• E-cadherin function is lost in almost all

epithelial cancers
– either by mutational inactivation of E-
cadherin genes
– by activation of β-catenin genes (growth
signals)
– by inappropriate expression of the SNAIL
and TWIST transcription factors, which
suppress E-cadherin expression

26
 Invasion of the ECM

2. Degradation of
extra cellular
matrix:
Cell release
type IV
collagenase
that dissolves
the BM

27
 Degradation of the BM and interstitial
connective tissue

• tumor cells may either secrete proteolytic enzymes

themselves
• or induce stromal cells (e.g., fibroblasts and
inflammatory cells) to secrete proteases.
– multiple different families of proteases, such as
– matrix metalloproteinases (MMPs) -matrix
metalloproteinases or matrixins, are metalloproteinases that are calcium-
dependent zinc-containing endopeptidases enzymes are capable of degrading
all kinds of extracellular matrix proteins

– cathepsin D
– urokinase plasminogen activator

28
 MMPs & Metastasis

regulate tumor invasion

– by remodeling insoluble components of
the basement membrane and interstitial
matrix
– by releasing ECM-sequestered growth
factors
• cleavage products of collagen and
proteoglycans
– chemotactic, angiogenic, and growth-
promoting effects
29
 MMPs & Metastasis

• MMP-9 is a gelatinase (type IV

collagenase)
– cleaves type IV collagen
(epithelial and vascular
basement membrane)
– stimulates release of VEGF from
ECM-sequestered pools

30
 Invasion of extra cellular matrix

3. Attachment to matrix
component:
• Cell receptors
attach to laminin
(glycoprotein in
BM)

• This whole thing via capillaries

into basement membrane**
they hook up to collagen, with
receptors for adhesion.

31
 Attachment to ECM

• changes in attachment of tumor cells to ECM

proteins

cleavage of the basement membrane

proteins-collagen IV and laminin-by
MMP-2 or MMP-9 generates novel sites
that bind to receptors on tumor cells
and stimulate migration.
Broken into MMP2, MMP9 – chemotactic tumor cells*** look
slide migration*
32
 Invasion of ECM

4. Migration of tumor
cells.
• Cell receptors
attach to
fibronectin in ECM
• Cells produce
cytokines
(stimulate
locomotion) and
protease (dissolves
connective tissue)

33
 Migration

• Two types of migration

– Degradation of BM & ECM
– Ameboid migration (cells squeezes
through ECM – no cutting); poor response
to MMP inhibitors in clinical trials
• Migration is a complex, multistep process
– receptors and signaling proteins
– potentiated and directed by tumor cell-
derived cytokines (autocrine motility
factors)
34
 Migration

• cleavage products of matrix components

(e.g., collagen, laminin) and some growth
factors (e.g., insulin-like growth factors I and
II)
• chemotactic for tumor cells.
• stromal cells also produce paracrine
effectors (hepatocyte growth factor/ scatter
factor {HGF/SCF}) of cell motility
– bind to receptors on tumor cells.
Very much highjaking cells*
35
 Homing of Metastasis***

• many tumors metastasize to the organ that is first

capillary bed - after entering the circulation
• many cases of tumor does follow above path
– adhesion molecules of tumor cells, complimentary
ligands on the endothelium of the target organ
– chemokines & their receptors (chemotaxis)
• Breast CA - chemokine receptors (CXCR4 &
CCR7); target organ ligands of endothelium***
(chemokines CXCL12 & CCL21)

36
 Molecular Basis of Metastasis

• Two theories
– metastatic subclones with distinct
combinations of mutations required for
metstasis
– develop a predilection for metastatic
spread early, during primary
carcinogenesis
– probably both theories works in tumor
metastasis

37
38
 Molecular Basis of Metastasis
“Metastasis Oncogene”

• SNAIL and TWIST (transcription factors)

– promote a process called epithelial-to-
mesenchymal transition (EMT)
• EMT (documented mainly in breast cancers)
– down-regulate certain epithelial markers
(e.g., E-cadherin)
– up-regulate certain mesenchymal markers
(e.g., vimentin and smooth muscle actin)
• promigratory phenotype - essential for
metastasis 39
 Summary
Vascular Dissemination and Homing of Tumor

• Tumor cells form emboli by aggregating

and attaching to platelets and leucocytes.
• The site where tumor cells lodge and
produce secondary growth is influenced by
several factors:
1. Vascular and lymphatic drainage
2. Interaction of tumor cells with organ
specific receptors
3. Microenvironment of the organ or site.

40
For self study

41
Comparison
between
Benign
and
Malignant
Tumors
42
 Characteristics Benign Malignant

Differentiation Well differentiated; Some lack of

structure typical of differentiation with
tissue of origin anaplasia; structure often
atypical
Rate of growth Progressive and slow Erratic and may be slow
to rapid; mitotic figures
may be numerous and
abnormal

Local Invasion Expansile mass; well Locally invasive, infiltrate

demarcated; do not the surrounding normal
invade or infiltrate tissue
surrounding tissue

Metastasis Absent Frequently present 43

Leiomyoma v Leiomyosarcoma

44
Malignant tumor- liver carcinoma
Large & infiltrative

45
Carcinoma lung: local infiltration

46
Cross-section of a female breast infiltrated by
cancer.

Retracted nipple
Fat

Carcinoma
Dissected
Axillary 47
lymphnode
Teratoma or Dermoid cyst

48
Metastases
to the liver

49
Metastases to
the lung

50
 Aorta

Periaortic LN

51