Angiogenesis

pre-existing vessels, endothelial cells

Angiogenesis is the physiological process through which new blood vessels are formed from ________. This is distinct from vasculogenesis, which is the de novo formation of ________ from mesoderm cell precursors. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing. However, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one, leading to the use of angiogenesis inhibitors. * The essential role of angiogenesis in tumor growth was first proposed in 1971 by Dr. Judah Folkman*

they are recruited for new vessel formation (from pre-existing vessels)

2. Discuss the role of endothelial cells (ECs) in angiogenesis.

1. Degrade basement membrane 2. Develop sprouts from pre-existing vessels 3. Invade extracellular matrix 4. Form tubes 5. Connect, stabilize and recruit pericytes

3. List the steps involved in the process of angiogenesis.

necessary in wound healing; different diseases are brought about by either an excess or insufficient amount of angiogenesis

5. Discuss the role of angiogenesis in normal physiology and disease pathology.

monoclonal antibodies, small molecule tyrosine kinase inhibitors (TKIs), inhibitors of mTOR (mammalian target of rapamycin)

7. List the currently approved angiogenesis modulators (general)

(KNOW?)

Angiogenesis A highly regulated cascade 1. Angiogenic factor production 2. Release of angiogenic factors 3. EC receptor binding 4. Intracellular signaling 5. EC activation 6. Matrix degradation 7. EC proliferation 8. Directional Migration 9. Matrix remodeling 10. Tube formation 11. Loop formation 12. EC differentiation 13. Vascular stabilization

local invasion, lymph node, metastasis

Angiogenesis facilitates cancer progression • Organ confined primary tumor • _____________; no positive nodes • Regional ________ involvement • ________ to distant organs For prostate cancer -- 5-year survival Stage T1 Organ confined; incidental ~100% Stage T2 Confined, but felt by palpation >90% Stage T3 Locally invasive; LN or SV >50-60% Stage T4 Distant mets. at dx. ~30%

angiostatin, thrombospondin (..TIMPs important too)

Inhibitors of Angiogenesis:

COME BACK TO - slide 16

Ischemia causes angiogenesis?

Hif1-a, VEGF, Ang-2 (Hypoxia inducing factor (Hif1-a - transcription factor), tumors utilize hypoxia to..)

List the factors involved-1

VEGF, FGF

List the factors involved-2

Ang-2

List the factors involved-3

PDGF, Ang-1

List the factors involved-4

protein growth factors, angiogenic, angiogenesis

Tumor Site Endothelial cells in the capillary release ________; tumor cells release ________ proteins and suppress levels of ________ inhibitors

endothelium, disorginization, pericytes

Typical structure of tumor vasculature Hallmark of pathogenic angiogenesis is continued growth of ________; another hallmark is ________ and poor recruitment of ________. • Note coiling, irregularity, size heterogeneity

angiogenesis

VEGF and related receptors have kinase activity, stimulate ___________, lymphangiogenesis, cell proliferation

diabetic retinopathy, excess

What disease of the eye is related to angiogenesis? Is it bc of an excess or insufficient amount?

left (Normal vasculature (on right) is very orderly, unbranched, nearly parallel vessels compared with tumor vasculature (on left))

Which side is the tumor vasculature (rather than normal)?

angiogenesis, vasculogenesis

________: recruitment of endothelial cells from existing vessels ________: activation of endothelial cell precursors

pericytes

__________ - precursor cells that attach to the different areas that.. they enhance the communications b/w diff endothelial cells bc they connect them and stabilize the membrane

highly regulated

Angiogenesis requires a cascade of _________ events

Bind Integrin-Alpha,beta to inhibit endothelial cell proliferation, migration, tube formation and neovascularization

Arresten MOA and Target

angiogenesis inhibitor; binds VEGF (prevents its interaction with VEGF receptors (VEGFR-1 and VEGFR-2), thereby inhibiting endothelial cell proliferation and angiogenesis.)

Bevacizumab (Avastin®) MOA/ Target

Bind Integrin-Alpha,beta to inhibit endothelial cell proliferation, migration, and tube formation

Canstatin MOA and Target

monoclonal antibodies, small molecule tyrosine kinase inhibitors (TKIs), inhibitors of mTOR (mammalian target of rapamycin)

Clinically approved angiogenesis inhibitors • In the U.S., there are currently thirteen approved anti-cancer therapies with recognized antiangiogenic properties in oncology. • These agents, which interrupt critical cell signaling pathways involved in tumor angiogenesis and growth, comprise three primary categories:- 1) ________, directed against specific proangiogenic growth factors and/or their receptors. 2) ________ of multiple proangiogenic growth factor receptors. 3) ________. • In addition, at least two other approved angiogenic agents may indirectly inhibit angiogenesis through mechanisms that are not completely understood.

endostatin; arresten, canstatin, tumstatin, and restin

Drugs That Inhibit Angiogenesis Directly ________ inhibits the migration of endothelial cells through disruption of cell-matrix adhesions, cell-cell adhesions, and cytoskeletal reorganization. • Other collagen derived antiangiogenic factors include ________.

combretastatin A4

Drugs That Inhibit Angiogenesis Directly • Another drug, ________ (Microtubules), causes growing endothelial cells to commit suicide (apoptosis).

endothelial progenitors, pericytes (PCs), smooth muscle cells (SMCs)

During vasculogenesis, __________ give rise to a primitive vascular labyrinth of arteries and veins; during susequent angiogenesis, the network expands, __________ and ____________ cover nascent endothelial channels, and a stereotypically organized vascular network emerges

angiogenesis inhibitor (direct); binds integrin-a2B1 to inhibit endothelial cell migration (IDK SEE SLIDES double check real answer)

Endostatin MOA/ Target

matrix metalloproteinases, degrade, PDGF-BB

Endothelial cells contain receptors for angiogenic growth factor binding and allow for the activation of angiogenesis Once activated, endothelial cells release _________ that ______ the basement membrane and allow for the release of _______ and other angiogenic growth factors —> allow for endothelial cell proliferation and the directional migration of sprouts branching off from pre-existing vessels and pericyte recruitment

endothelial cell inhibitor; binds EGFR (epidermal growth factor receptor)

Gefitinib (Iressa) MOA/ Target

angiogenesis inhibitor; binds HIF-1a

HIF inhibitors such as phenethyl isothiocyanate (PEITC) MOA/ Target

bFGF (Basic fibroblast growth factor), VEGF (Vascular endothelial growth factor) (also EGF - epidermal growth factor)

Naturally Occurring Activators of Angiogenesis (proteins):

cancer (activation of oncogenes/ loss of tumor suppressors), vascular malformations, obesity, psoriasis/ warts/ allergic dermatitis

Organ Specific Diseases caused by excessive Angiogenesis 1. Numerous Organs: 2. Blood Vessels: 3. Adipose Tissue: 4. Skin:

persistent hyperplastic vitreous syndrome, primary pulmonary HTN, inflammatory bowel & periodontal disease, endometriosis/ uterine bleeding/ ovarian cysts/ ovarian hyperstimulation, arthritis/ synovitis/ osteomyelitis/ osteophyte formation

Organ Specific Diseases caused by excessive Angiogenesis 5. Eye: 6. Lung: 7. Intestines: 8. Reproductive system: 9. Bone, joints:

alzheimers, atherosclerosis, gastric or oral ulcerations/ crohn's disease, hair loss

Organ Specific Diseases caused by insufficient Angiogenesis 1. Nervous System: 2. Blood Vessels: 3. GI: 4. Skin:

pre-eclampsia, neonatal respiratory distress, nephropathy, osteoporosis (impaired bone fracture healing)

Organ Specific Diseases caused by insufficient Angiogenesis 5. Reproductive System: 6. Lung: 7. Kidney: 8. Bone:

nitric oxide synthase (NOS)

Other putative targets.......? • Results reveal a strong positive correlation between the expression of ___________ and tumor angiogenesis and tumor progression. Endothelium-derived nitric oxide (EDNO) synthesis and action: Crucial role in angiogenesis

Hypoxia-inducible factors (HIFs)

Role of Hypoxia inducible factor (HIF-1a) • Small tumors are not always avascular masses stimulating vessel growth...some "co-opt" existing vessels, then stimulate angiogenesis through hypoxia. • ____________ are transcription factors that respond to changes in available oxygen in the cellular environment. • HIF inhibitors such as phenethyl isothiocyanate (PEITC) are under investigation for anti-cancer effects.

angiogenesis inhibitor; bind tyrosine kinase (Seven TKIs with antiangiogenic activity are currently approved as anticancer therapies:- • axitinib (Inlyta), cabozantinib (Cometriq), pazopanib (Votrient), regorafenib (Stivarga), sorafenib (Nexavar), sunitinib (Sutent), and vandetanib (Caprelsa).)

TKIs MOA/ Target

mTOR inhibitors

ends in "rolimus"

TKI

ends in "tinib" think

MOA/ Target angiogenesis inhibitor; binds mTOR

mTOR inhibitors

VEGF upregulation, TSP1 downregulation; angiogenic properties in neuroblastoma; VEGF upregulation; VEGF, bFGF, IL-8 upregulation; VEGF upregulation

tumors know they need angiogenesis to grow.. tumors exploit oncogenes to get it and cause factors to be released and angiogenic switch to occur Some examples of Pro-angiogenic oncogenes are 1. KRAS, HRAS 2. n-MYC 3. ERBB2 4. EGFR 5. BCL2 List what causes each to become pro-angiogenic

cytokines and chemokines, chemokine receptor antagonists (CCR5.. - mariviroc) (actually wait double check yuja here..)

• Nitric oxide modulates basal vascular tone, and exerts a dilator effect on vascular smooth muscle, inhibition of monocyte adhesion. • Inflammatory ___________ decrease NO levels, increase ROS levels, and activate endothelial growth and angiogenesis Therefore we get _____________ to combat this angle

hemangioma, benign

• _____________ in a newborn infant may cover as much as 80% of the body surface. • These are usually ___________ lesions and spontaneously regress within the first 2-3 years of life. • May be treated with negative modulators of angiogenesis