Tumor growth requires angiogenesis to develop new blood vessels. This process is regulated by a balance of pro-angiogenic and anti-angiogenic factors. Tumors disrupt this balance by inducing hypoxia and secreting factors like VEGF, which activate the "angiogenic switch" and promote new vessel growth. This allows tumors to recruit blood vessels to supply nutrients and remove waste. Anti-angiogenic therapies aim to block this process by targeting VEGF and its receptors. Drugs like bevacizumab and sorafenib inhibit angiogenesis to limit tumor growth and progression.

1. Tumor Angiogenesis andanti-
angiogenictherapy

2. • Angiogenesis is an important event in various physiological settings such
as embryonic development, female reproductive system and wound
repair.
• Angiogenesis is also central to the etiology of various pathological
processes such as solid tumors, diseases of the eye, and chronic
inflammatory disorders such as rheumatoid arthritis, psoriasis and
periodontitis.

3. • During embryonic development, blood vessel formation occurs via two
distinct mechanisms :
1. Vasculogenesis : birth of new endothelial cells and their assembly
into tubes
2. Angiogenesis : sprouting of new vessels from existing ones

4. • Like normal tissues, tumor requires nutrients and oxygen for survival, as
well as an ability to evacuate metabolic wastes and carbon dioxide.
• The tumor-associated neovasculature, generated by the process of
angiogenesis addresses these needs.
• Angiogenesis is considered as one of the important hallmarks of cancer.

6. The angiogenic switch
• The regulation of angiogenesis is dependent upon the dynamic
balance of angiogenic inducers and inhibitors.
• Increasing the activity of the inducers or decreasing the activity of
the inhibitors tips the balance of the “angiogenic switch” to the “on”
position, and vice versa.

7. Angiogenic inducers Angiogenic inhibitors
• Vascular endothelial growth
factor (VEGF) – endothelial-cell-
specific
• Fibroblast growth factor (FGF)
(acidic and basic)
• Hepatocyte-derived growth
factor (HGF)
• Epidermal growth factor (EGF)
• Angiostatin
• Endostatin
• Prolactin
• Protein 53 (p53)
• Thrombospondin 1,2

9. VEGF
• VEGF family is comprised of five members:
- VEGFA
- VEGFB
- VEGFC
- VEGFD
- Placental growth factor (PGF)
• The VEGF ligands can bind to three tyrosine kinase receptors:
- VEGFR1/FLT1
- VEGFR2/ KDR
- VEGFR3/ FLT4

10. • The angiogenic switch is regulated in two ways during
tumorogenesis:
1) As the tumor grows, it creates conditions of hypoxia
and this induces the hypoxia-inducible factor-1α (HIF-
1α).
- One target of HIF-1α is VEGF. It induces expression of
VEGF and its receptor.
- VEGF is responsible for initiating growth of capillaries by
stimulating endothelial cells.

13. 2) Oncogenic proteins and loss of tumor suppressors
contribute to the modification of angiogenic switch.
- direct roles in angiogenesis are now recognized.
- approx. 30 oncoproteins have been shown to tip the
balance towards angiogenesis.
- Tumor suppressor proteins normally upregulate
angiogenic inhibitors, but when these are mutated, anti-
angiogenic activity decreases.

14. Tumor cells recruit new blood vessels by several
different mechanisms:
• They produce diffusible angiogenic factors that directly
activate endothelial cells, stimulating them to sprout and
grow toward the developing tumor.

15. • The tumor cells elaborate cytokines, which attract and
activate macrophages, mast cells and neutrophils, which in
turn elaborate angiogenic factors.
• The tumor cells are also able to block the production 0f
angiogenic inhibitors or become refractory to the
inhibitors.

16. • In the adults, as part of physiologic processes such as
wound healing and female reproductive cycling,
angiogenesis is turned on, but only transiently.
• In contrast, during tumor progression, the angiogenic
switch is almost always activated and remains on, helping
the expanding neoplastic growths.
• Tumor : a wound that never heals.

17. Role of inflammatory cells in angiogenesis
• Currently, tumors are viewed as “organs” composed of
multiple highly interactive cells.
• Thus, the tumor is composed of primary cancer cells
and surrounding stromal cells (modified):
- mesenchymal derived cells (fibroblasts, smooth muscle
cells)
- inflammatory cells
- vascular cells (endothelial cells and pericytes)

18. • The inflammatory cells seen in the tumor
microenvironment include:
- tumor-associated macrophages (TAM)
- mast cells
- eosinophils
- neutrophils
- dendritic cells
• Inflammatory cells produce and release pro-angiogenic
factors.
• Angiogenesis requires growth factors (VEGF, FGF, TGF),
chemokines (IL-6,IL-8), and matrix metalloproteinases
(MMP-9, MMP-13), which are produced by inflammatory
cells.

19. The angiogenic cascade
• The target vessels for angiogenic factors are the post-
capillary venules and small terminal venules.
1) Initiation of angiogenic response
• One of the first step in the angiogenic response involves
disruption of focal contacts between adjacent endothelial
cells, pericytes and smooth muscle cells.

20. 2) Endothelial cell migration, proliferation and tube
formation
• These ‘activated’ endothelial cells produce matrix
metalloproteinases, that degrade the extra-cellular
matrix and enable them to migrate away from the
parent vessel.
• The endothelial cells begin to divide and soon organize
into hollow tubes that evolve gradually into a mature
network of blood vessels with the help of an adhesion
factor such as integrin α or β.

22. 3) Maturation of neovasculature
• Newly formed blood vessels need to stabilize or
mature. Angiotensin -1, -2 and their receptor Tie-2 can
stabilize these newly formed vessels and govern
vascular growth.
• Anastamosis of developing buds occurs with other
growing buds or pre-existing vessels to form intact
capillary loops that facilitates transport of blood.

24. Characteristics of tumor blood vessels
• Precocious capillary sprouting
• Convoluted and excessive vessel branching
• Distorted and enlarged vessels
• Erratic blood flow
• Microhemorrhaging : leaking of plasma into the tissue
parenchyma
• Abnormal levels of endothelial cell proliferation and
apoptosis

26. • Cancer cells grow preferentially around the blood vessels.
• Those tumor cells that are located more than 0.2 mm
away from the blood vessels are found to be non-growing,
while other even farther away are seen to be dying.
• 0.2 mm represents the distance that oxygen can effectively
diffuse through living tissues.

27. • Angiogenesis is a necessity for tumor expansion beyond
400 μm of tumor size.
• The induction of vascular growth is only possible by
building a proangiogenic environment through the
collective effort of tumor cells and resident inflammatory
cells.

28. • What are the therapeutic implications ???

29. Anti-angiogenic therapy
• It is designed to prevent the formation of new blood
vessels.
• Rather than targeting the tumor cells directly, the aim of
anti-angiogenic therapy is to interfere the responsiveness
of endothelial cells to pro-angiogenic signals.
• Overall, these drugs are cytostatic rather than cytotoxic,
and therefore may need long-term continuous
administration.

30. I. Anti – VEGF monoclonal antibodies
II. Small molecule tyrosine kinase inhibitors
III. mTOR inhibitors

32. Anti – VEGF monoclonal antibodies
Drug Cellular targets Indications
Bevacizumab
(Avastin)
VEGF Metastatic CRC
Metastatic NSCLC
Recurrent GBM
Metastatic RCC
Metastatic ovarian carcinoma
Advanced cervical carcinoma
Ziv-aflibercept VEGFA, VEGFB,
PGF1, PGF2
Metastatic CRC (after prior
oxaliplatin-containing regimen)

33. Bevacizumab, a humanised monoclonal antibody,
precisely targets VEGF
Bevacizumab
VEGF receptor
VEGF

34. Bevacizumab exerts multiple effects that contribute to increased
treatment efficacy
Regression
of existing tumour vasculature
Inhibition
of new vessel growth
Anti-permeability
of surviving vasculature

35. Small-molecule TKI
Drug Cellular targets Indications
Sorafenib VEGFR2, VEGFR3, PDGFR, FLT3,
c-Kit
Advanced RCC
Unresectable HCC
RAI-refractory DTC
Sunitinib VEGFR1, VEGFR2, VEGFR3,
PDGFR, c-Kit, RET
Imatinib-resistant 0r
-intolerant GIST
Advanced RCC
Advanced pNET
Pazopanib VEFGR1, VEGFR2, VEGFR3,
PDGFR, ltk, Lck, c-Fms
Advanced RCC
Advanced soft tissue sarcoma
Vandetanib RET, VEGFR, EGFR, BRK, TIE2 Advanced MTC

36. Cont…
Axitinib VEGFR1, VEGFR2, VEGFR3 Advanced RCC (after failure
of prior therapy)
Cabozatinib MET, VEGFR2, RET, KIT,
AXL, FLT3
Progressive, metastatic MTC
Regorafenib RET, VEGFR1, VEGFR2,
VEGFR3, TIE3, KIT, PDGFR
Previously treated metastatic
CRC
GIST
Lenvatinib VEGFR1, VEGFR2, VEGFR3 Metastatic radioactive iodine-
refractory differentiated
thyroid cancer
Advanced RCC

37. mTOR inhibitor
Drug Cellular targets Indications
Temsirolimus mTOR Advanced RCC
Everolimus mTOR Second-line advanced RCC (after
VEGFR TKI failure)
SEGA associated with TSC
Advanced HR+, HER2- breast cancer
Angiomyolipoma associated with TSC

38. Anti-VEGFR2 Monoclonal Antibody
Drugs Cellular targets Indications
Ramucirumab VEGFR2 Advanced gastric and GE
junction adenocarcinoma
Metastatic NSCLC

39. Examples of drugs that possess anti-angiogenic activity or inhibit
angiogenesis as a secondary function
Cetuximab
Panitumumab
Trastuzumab
Gefitinib
Erlotinib
Thalidomide
Lenalidomide
Bortezomib
Celecoxib
Zoledronic acid

40. Vascular targeting
• It is a therapeutic approach designed to destroy the existing
neovasculature in order to starve the tumor of oxygen and
nutrients and lead to tumor regression.
• Combretastatin and its recently developed derivatives are under
clinical trials.
• Combretastatin compounds bind tubulin and disrupt the
cytoskeleton
• Their effects have been explained by the hypothesis that
immature endothelium may have a more intrinsic need for a
tubulin cytoskeleton to maintain its shape.

41. THANK YOU