Angiogenesis, Invasion and Metastasis

dr.Mardiah Suci Hardianti,PhD, SpPD-KHOM

Division of Hematology-Medical Oncology,

Department of Internal Medicine
Faculty of Medicine Universitas Gadjah Mada/ Sardjito Hospital
Yogyakarta
ANGIOGENESIS
1. Normal 2. Pathological
is the formation of process process
new capillary
vasculature out of
pre-existing blood
vessels under the Menstrual cycle and Embryogene
regulation of pregnancy sis

growth factor and

inhibitors
Wound
healing

Felmeden et al, 2003

Angiogenic switch
Antiangiogenic
• Thrombospodin
• Angiostatin
• Endostatin
Proangiogenic • Interferon α, β
• Angopoietin 2
• VEGF
• Platelet factor 4
• Interleukin 8
• Lain-lain
• Acidic and basic FGF
• Epidermal growth factor
• Hepatocyte growth factor
• Placenta growth factor
• Transforming Growth factor
Microvessels Density
• basic fibroblast growth factor
[bFGF]
• Stromal-derived factor 1α
[SDF1α]
• Lain-lain

(Poon et al, 2001)

Angiogenic cascade

(Viallard & Larrive, 2017)

The role of angiogenesis in cancer development

Poon et al, 2001.J Clin Oncol 19:1207-1225

(Viallard & Larrive, 2017)
VEGF Signaling Pathway
Metastasis facts
1. Metastases are responsible
for more than 90% of all
cancer-related deaths.
2. Gene dysregulation, tumor
microenvironment, and host
cells drive the metastatic
spread of tumor cells.
Lung mets
3. Morbidity and mortality Bone mets
arising from metastatic
disease can result from direct
organ damage by the growing
lesions, paraneoplastic
syndromes, or from the
complications of tx. Brain mets Liver mets
Patterns of Metastatic Spread of Solid Tumors

• Lung cancer metastasis→ within

months after initial diagnosis
• Prostate cancer and some
subtypes of breast cancer can
produce distant relapse up to
decades
• Lung and breast cancers
metastasize to different organs
(with a different propensity)
• Colon cancer → liver, lung
• Prostate cancer typically (but not
exclusively) metastasizes to bone

(Obenauf and Massagué, 2015)

 Fundamentals of
Tissue Invasion And Metastasis

• Leucocyte rolling
Genetic program • Epithelial to
in a wrong time and place Mesenchymal
Transition (EMT)

cellular motility and chemotaxis,

Interaction ECM, Integrin,cadherin, CAM, CSA,
between cancer
cell &metastatic selectin, Metastatic & metast
factors supressor genes, Proteinase,
chemokines
 Metastasis Cascade

1.Invasion and Migration

2. Intravasation

3. Circulation

4. Extravasation

5. Colonization, Proliferation
& Angiogenesis

(Diepenbruck and Christofori, 2016)

 Metastasis Cascade (1):
Invasion and Migration: EMT Concept
• Epithelial-mesenchymal transformation
(EMT) first described by E.D. Hay in 1995
EMT-inducing transcription factors (EMT-TFs),
including Snail 1, Snail 2 (Slug), ZEB1, and
Twist, play a central role in regulating
molecular changes during EMT

• During EMT, tumor cells acquire

mesenchymal phenotype, detach from the
tumor mass, and migrate by mesenchymal
mechanism.

• Hypoxia, a significant aspect in cancer

progression, triggers EMT and participates
in the EMT regulatory network

(Krakhmal et al., 2015; Jie et al., 2017)

 Metastasis Cascade:

Intravasation – Circulation – Extravasation:

Cascades with Microenvironmental interaction

transendothelial migration (TEM), MAM (Lambert et al., 2017)

The tissue tropism patterns
of metastasis

(Jin & Li et al. 2017)